CN101622240A - Fused substituted aminopyrrolidine derivative - Google Patents
Fused substituted aminopyrrolidine derivative Download PDFInfo
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- CN101622240A CN101622240A CN200780052025A CN200780052025A CN101622240A CN 101622240 A CN101622240 A CN 101622240A CN 200780052025 A CN200780052025 A CN 200780052025A CN 200780052025 A CN200780052025 A CN 200780052025A CN 101622240 A CN101622240 A CN 101622240A
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Abstract
A quinolone synthetic antibacterial agent having excellent properties as a medicine is provided, which has strong antibacterial activity not only to Gram-negative bacteria but also to Gram-positive cocci that have low sensitivity to quinolone antibacterial agents, and which exhibits high safety and excellent pharmacokinetics. A compound represented by the formula (I) or a salt thereof, or a hydrate thereof. Specifically, a quinolone derivative of the formula (I) wherein substituents R6 and R7 taken together with the carbon atoms to which they are bonded form a cyclic structure which may contain an oxygen atom as a ring constituent atom, the cyclic structure forming a 5-4, 5-5, or 5-6 fused bicyclic pyrrolidinyl substituent, the substituent being bonded to a quinolone mother skeleton Q containing a pyridobenzoxazine structure.
Description
Background of invention
Invention field
The present invention relates to be used as the carbostyril compound of medicine, veterinary drug, fish medicine (fishery medicines) or antibiotic antiseptic.
Description of related art
Since having found norfloxicin, the quinolones synthetic antibacterial drug has the anti-microbial activity of improvement and being developed as all effective chemotherapeutic of nearly all systemic infection of pharmacokinetic properties in (comprising those with pyrido-benzoxazine skeleton), and they a lot all have been used for clinical (referring to TOHKEMY 61-282382 or TOHKEMY 63-45261 and ClinicalMicrobiology and Infection at present, the 11st volume, the 4th phase, the 256th page (2005)).
Yet, in recent years, the quantity of the low bacterial species of quinolones synthetic antibacterial drug susceptibility is clinically the trend of continuous rising.For example, to being not that quantity with chemical sproof bacterial species of the medicine of quinolones synthetic antibacterial drug continues to rise, described bacterium is so-called multidrug resistance bacterium, gram-positive cocci for example comprises the streptococcus aureus low to β-Nei Xiananleikangshengsu susceptibility (Staphylococcus aureus) (methicillin-resistant staphylococcus aureus: MRSA) and streptococcus pneumoniae (penicillin resistance streptococcus pneumoniae (Streptococcuspneumonia): PRSP); And to low (the drug resistance of vancomycin faecalis: VRE) and to the low faecalis of quinolones synthetic antibacterial drug susceptibility of aminoglycoside antimicrobial drug susceptibility.The known infectation of bacteria very serious usually (fatal) that causes by this class resistance gram-positive microorganism and be difficult to treatment.Therefore, clinically especially need be to gram-positive cocci more efficient drug (referring to Drugs, the 66th volume, the 6th phase, the 751st page (2005)).
On the other hand, the anti-microbial activity of the quinolones synthetic antimicrobial compound of producing in recent years is than previous those much higher (referring to TOHKEMY 2-231475 or TOHKEMY 3-95176).Yet the carbostyril compound that many these classes have a high anti-microbial activity causes unobservable side effect in formerly the quinolones synthetic antibacterial drug based on its physiological action and pharmacological action meeting.
The side effect example of quinolones synthetic antibacterial drug comprises the side effect of frequent report, and (slight central nervous system disorder for example rocks, has a headache and has a sleepless night for the convulsions that is caused during for example with NSAID (non-steroidal anti-inflammatory drug) (NSAID) coupling, central action (centralaction); And serious side effects, for example mortality convulsive attack) and phototoxicity (photosensitivity); And disclosed in recent years side effect, for example liver toxicity (serious hepatitis autoallergic), the cardiac toxic (fatal arrhythmia that electrocardiographic abnormality causes, being viewed as QT or QTc prolongs), tardy property drug rash (fash) and glucose level be unusually (referring to Hiroyuki Kobayashi (writing), Clinical Application of NewQuinolone Agents, Iyaku (Medicine and Drug) Journal Co., Ltd.; Drugs, the 62nd volume, the 1st phase, the 13rd page (2002); Toxicology Letters, the 127th volume, the 269th page (2002); Clinical Infectious Diseases, the 41st volume, the 1269th page (2005)); With International Journal of Antimicrobial Agents, the 23rd volume, the 5th phase, the 421st page (2004)).
In recent years, in these side effects, the clinical episodes of cardiac toxic is a problem especially.For some commercially available quinolones synthetic antibacterial drug (for example grepafloxacin, Sparfloxacin, Moxifloxacin, Gatifloxacin and gemifloxacin), reported that tangible QT or QTc prolong, and have also reported some serious problems (fatal arrhythmia that electrocardiographic abnormality causes).Follow the outbreak (trovafloxacin: of the serious hepatitis autoallergic of liver transplantation referring to Clinical InfectiousDiseases, the 41st volume, the 1269th page (2005)) and comprise the unusual (Gatifloxacin: of glucose level of mortality hypoglycemia referring to International Journal of AntimicrobialAgents, the 23rd volume, the 5th phase, the 421st page (2004)) etc. serious side effects also be clinical problem.In addition, in clinical trial, also reported the tardy property drug rash (fash) that repeats to give due to the quinolones (Gatifloxacin: referring to Clinical Infectious Diseases, the 41st volume, the 1269th page (2005)).In these cases, give some quinolones synthetic antibacterial drug and be restricted, non-development zones and use are as some quinolones synthetic antibacterial drug of human medicine.That is to say, observed some quinolones synthetic antibacterial drug and had very strong anti-microbial activity, but consider side effect and not too be suitable as medicine.
Therefore, need safer quinolones synthetic antibacterial drug as the human medicine, it should only have very low side effect, for example think common adverse effect with the NSAID (non-steroidal anti-inflammatory drug) coupling time convulsions, central action and the phototoxicity (photosensitivity) that are caused; And the cardiac toxic, liver toxicity, tardy property drug rash (fash) and the glucose level that become a clinical difficult problem in recent years are unusual.Therefore, need exploitation at the conceptive compound that is different from the compound that routinizes (it has high anti-microbial activity but causes side effect and can not be used as medicine).That is to say to have the strong and safe carbostyril compound of anti-microbial activity (referring to The Japanese Journal for History ofPharmacy, the 38th volume, the 2nd phase, the 161st page (2003)) simultaneously.
Know, the anti-microbial activity of quinolones synthetic antibacterial drug, pharmacokinetic properties and security are subjected to the influence of substituent structure on each position of quinolone skeleton, especially be subjected to 7-position (corresponding to the 10-position of pyrido-benzoxazine skeleton) and go up the influence of substituent structure (for example referring to Clinical Microbiology and Infection, the 11st volume, the 4th phase, the 256th page (2005)).
The peculiar feature of The compounds of this invention be they to have with following formula 1 on the 7-position of quinolone precursor skeleton be the substituting group of representative:
[formula 1]
R wherein
1, R
2, R
3, R
4, R
5, R
6And R
7Such as claim 1 definition.That is to say that the 7-bit substituent of The compounds of this invention has by pyrrolidine ring and ring texture and condenses the condensed-bicyclic amine structure that forms, this ring texture is by R
6And R
7The carbon atom that is connected with them combines and constitutes, and this condensed-bicyclic amine structure also has amino on bridgehead position.For the Carbostyril derivative that the 7-bit substituent with a kind of like this structure replaces, following compound is known.
For example, the TOHKEMY 64-56673 pyridone carboxylic acid derivatives that to have disclosed with following general formula 2 be representative:
[formula 2]
Wherein on behalf of low alkyl group, junior alkyl halides, low-grade alkenyl, cycloalkyl, R maybe can have substituent phenyl; X represents nitrogen-atoms or C-A, and wherein A represents hydrogen atom or halogen atom; Y represents hydrogen atom or halogen atom; The Z representative is the group of representative with following formula 3:
[formula 3]
R wherein
1The acyl group of representing hydrogen atom, elementary alkoxy carbonyl or can being replaced by halogen atom; R
2, R
3, R
4And R
5In two directly in conjunction with or by lower alkyl chains be combined into ring, and R
2, R
3, R
4And R
5Two of middle residues are represented hydrogen atom separately; N represents 0 or 1, and condition is R
2And R
3It when being bonded to each other chemical bond.The definition of substituting group etc. and be not suitable for The compounds of this invention in the compound that with formula 2 is representative is although they have used same symbol.Yet, the not concrete open and The compounds of this invention (R in its Chinese style 3 among the TOHKEMY 64-56673
4And R
5Be combined together to form 4-7 unit ring and n=0) consistent carbostyril compound.
The pyridone formic acid class antimicrobial drug that to disclose with following general formula 4 among the EP-A-343524 be representative:
[formula 4]
R wherein
1Be hydrogen, hydroxyl, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, oxo, halogen or amino, it can be chosen wantonly by C
1-C
4Alkyl and/or C
1-C
4Alkyloyl replaces; R
2Be azido-, hydroxyl, C
1-C
4Alkoxyl group, C
1-C
4Alkoxy carbonyl, C
1-C
4Alkyloyl or amino, it can be chosen wantonly by C
1-C
4Alkyl and/or C
1-C
4Alkyloyl replaces; A is for being the quinolone structure of representative with following formula 5:
[formula 5]
R
3Be hydrogen or carboxyl-protecting group; R
4Be C
1-C
4Alkyl, C
2-C
5Thiazolinyl, C
3-C
5Cycloalkyl, phenyl-monofluoride base or difluorophenyl or five yuan or hexa-member heterocycle, it can be chosen wantonly by halogen and/or C
1-C
4Alkyl replaces; R
5Be hydrogen, amino, hydroxyl or C
1-C
4Alkoxyl group; R
6Be halogen; X is CH-(C
1-C
4Alkyl), C=CH
2, N-H or N-(C
1-C
4Alkyl); Z is CQ or N; Q is hydrogen, C
1-C
4Alkoxyl group, halogen, C
1-C
4Alkyl or cyano group; M is 0 or 1 integer; Respectively the do for oneself integer of 1-3 of n and p.Yet as the relevant particular compound of The compounds of this invention, only disclosing among the EP-A-343524 with following formula 6 is the quinolonecarboxylic acid derivative of representative, that is to say, m is 0 in this derivative, and p is 1, and substituent R
2Be amino on the Wyovin bridgehead position:
[formula 6]
In addition, among the EP-A-343524 and be not disclosed in the compound that has halogenated cyclopropyl on the 1-position, this compound is the representative instance of The compounds of this invention just.Disclosed in EP-A-343524 is in the compound of representative with formula 6, and the structure of 7-bit substituent is (1R
*, 5S
*)-configuration.This compound is so-called cis-racemic modification, and does not put down in writing the anti-microbial activity of optically active isomer among the EP-A-343524.In addition, do not put down in writing the security of disclosed compound among the EP-A-343524.According to validity and security, preferred stereochemistry simplification compound is as the human medicine.In addition, the compound that with formula 6 is representative has fluorine atom on the 8-position of quinolone skeleton, thereby supposition can cause the phototoxicity (photosensitivity) (for example referring to Journal ofAntimicrobial Chemotherapy, the 33rd volume, the 683rd page (1994)) of high probability.That is to say, do not think with formula 6 to be that the compound of representative must be enough to as human medicine safely and effectively.European Journal of Medicinal Chemistry, the 26th volume has only disclosed the content consistent with EP-A-343524 in the 889th page (1991).
Disclose the pyridone formic acid class antimicrobial drug that is replaced by bicyclic amino group among the WO 95/21163, it is representative with following general formula 7:
[formula 7]
R wherein
1And R
2Identical or different and represent hydrogen atom, low alkyl group or amino protecting group separately; R
3And R
4Identical or different and represent hydrogen atom, halogen atom, cyano group, hydroxyl, oxo, lower alkoxy or low alkyl group separately; N represents 0 or 1 integer; R
5Represent low alkyl group, low-grade alkenyl, low-grade cycloalkyl, phenyl or heterocyclic radical (they can further be replaced); G represents C-E, and wherein E represents hydrogen atom or and R
5Form together with-S-SE (CH
3)-for the crosslinked group of representative; T represents C-Z or nitrogen-atoms, and wherein Z represents hydrogen atom, halogen atom, cyano group, lower alkoxy, halogenated lower alkoxy, low alkyl group or junior alkyl halides or and R
5Form together with-O-CH
2-CH (CH
3)-for the crosslinked group of representative; X represents hydrogen atom, halogen atom, hydroxyl, low alkyl group or amino, and it can be protected; D represents C-Y, and wherein Y represents hydrogen atom or halogen atom.Yet with regard to The compounds of this invention, for the bicyclic amino group in the Carbostyril derivative 7-bit substituent, only specifically disclosing with following formula 8 is the substituting group of representative, that is to say R in formula 7
3And R
4Respectively do for oneself hydrogen atom and n is 0:
[formula 8]
In addition, not concrete open fused substituted aminopyrrolidine derivative (Wyovin) as feature of the present invention that is to say substituent R on the Wyovin in the compound that with formula 7 is representative among the WO 95/21163
3And R
4In one or two have substituting group except that hydrogen atom.
Disclosing with following general formula 9 among the WO 96/23782 is the N of representative
1The pyridone carboxylic acid derivatives that-(halogenated cyclopropyl) replaces:
[formula 9]
X wherein
1Represent halogen atom or hydrogen atom; X
2Represent halogen atom; R
1Represent hydrogen atom, hydroxyl, thiol group, halogenated methyl, amino, alkyl or alkoxyl group; R
2Represent following formula 10 substituting groups:
[formula 10]
R wherein
3And R
4Represent hydrogen atom or alkyl separately, n represents 1 or 2 integer; A represents following formula 11 groups:
[formula 11]
X wherein
3Represent hydrogen atom, halogen atom, cyano group, amino, alkyl, halogenated methyl, alkoxyl group or halogenated methoxy; R represents hydrogen atom, phenyl, acetoxy-methyl, valeryl oxygen ylmethyl, ethoxy carbonyl, choline base, dimethyl aminoethyl, 5-indanyl, phthalidyl (phthalidinyl), 5-alkyl-2-oxo-1,3-Dioxol-4-yl methyl, 3-acetoxyl group-2-oxo butyl, alkyl, alkoxy methyl or phenyl.Be the definition of substituting group etc. in the compound of representative with formula 9 and be not suitable for The compounds of this invention, although they have used same symbol.Yet with regard to The compounds of this invention, for the bicyclic amino group in the Carbostyril derivative 7-bit substituent, only specifically disclosing with following formula 12 is the substituting group of representative, that is to say that n is 2 in formula 10:
[formula 12]
In addition, among the WO 96/23782 and be not disclosed in substituent 1-amino-3-azabicyclo [3.2.0] heptane derivative that has on the dicyclo except that hydrogen atom, this derivative is one of feature of The compounds of this invention.
Quinolone-carboxylic acid derivatives or naphthyridines ketone-carboxylic acid derivatives that to disclose with following general formula 13 among the TOHKEMY 8-225567 be representative:
[formula 13]
T-Q
Wherein Q represents the quinolone structure of following formula 14:
[formula 14]
X wherein
1Represent halogen or nitro; X
2Represent hydrogen, halogen, amino, hydroxyl, methoxyl group etc.; A and D represent N or C-R separately
7(R wherein
7=H, F, OCH
3Deng); R
1Represent C
1-C
4Alkyl, C
3-C
6Cycloalkyl etc.; R
2Representation hydroxy, methoxyl group, benzyloxy etc.; R
9Represent hydrogen or C
1-C
3Alkyl; R
11Represent hydrogen, methyl or CH
2F; And T represents following formula 15:
[formula 15]
Wherein B represents amino, hydroxyl etc.; R
6Represent hydrogen or methyl.Be the definition of substituting group etc. in the compound of representative with formula 13 and be not suitable for The compounds of this invention, although they have used same symbol.Yet only disclosing with following formula 16 among the TOHKEMY 8-225567 is the compound of representative, and this compound is that B is amino derivative.
[formula 16]
In addition, do not disclose the particular compound that the present invention is correlated with among the TOHKEMY 8-225567.
Summary of the invention
Therefore, the purpose of this invention is to provide quinolones synthetic antibacterial drug and the medicine that is used for the treatment of infection, these medicines all have very strong broad spectrum antibiotic activity to gram-positive microorganism (comprising low those of quinolone susceptibility) and Gram-negative bacteria, and have high security.
The present inventor studies the compound that has 3-amino-pyrroles alkyl on the 7-position of carbostyril compound or its corresponding position (for example 10-position of pyrido-benzoxazine compound).The present inventor has been found that, have with following formula 17 is the substituent Carbostyril derivative of fused substituted aminopyrrolidine base of representative, gram-positive microorganism (especially to the resistance gram-positive cocci, for example multidrug resistance (comprising anti-quinolone) streptococcus pneumoniae) and Gram-negative bacteria are had very strong broad spectrum antibiotic activity:
[formula 17]
Wherein the 3-position of 3-amino-pyrroles alkyl is combined together to form the 4-7 unit ring texture that can contain two keys and can contain Sauerstoffatom or sulphur atom with the carbon atom that substituting group on the 4-position is connected with them, and this ring texture forms with pyrrolidine ring and condenses ring-type (dicyclo) structure.Various clinical preceding evaluations show, these carbostyril compounds not only have so high anti-microbial activity, and only cause the conventional known side effect (for example cause and faint from fear and phototoxicity (photosensitivity)) of the Comprecin of low probability and the side effect of reporting clinically in recent years (for example cardiac toxic (QT prolongation), glucose level is unusual and tardy property drug rash).Also very clear, these carbostyril compounds show good oral absorption and to the perviousness of organ.According to the disclosed content of above-mentioned patent document, these results are very unexpected.
Finally, it is that the carbostyril compound of representative and corresponding salt thereof and hydrate all are the quinolones synthetic antibacterial drugs that has good medicinal property such as very high anti-microbial activity and security and show good pharmacokinetic properties that the present inventor has been found that with described formula (I) subsequently.These discoveries have caused of the present invention finishing.
Specifically, the invention provides with following formula (I) is compound, its salt or the hydrate of representative:
[formula 18]
R wherein
1Represent hydrogen atom, have the alkyl of 1-6 carbon atom, have the cycloalkyl of 3-6 carbon atom, perhaps derived from the substituted carbonyl of amino acid, dipeptides or tripeptides; Described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, cyano group, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;
R
2Represent hydrogen atom, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;
R
3And R
4Represent hydrogen atom independently of one another or have the alkyl of 1-6 carbon atom, and described alkyl can have one or more following substituting groups that are selected from: halogen atom and have the alkoxyl group of 1-6 carbon atom;
R
5Represent hydrogen atom, halogen atom, alkyl with 1-6 carbon atom, alkoxyl group with 1-6 carbon atom, thiazolinyl with 2-6 carbon atom, alkynyl with 2-6 carbon atom, have 3-6 carbon atom and can have substituent cycloalkyl, have 6-10 carbon atom and can have substituent aryl and maybe can have substituent heteroaryl, described alkyl, thiazolinyl and alkynyl can be straight or brancheds, alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, alkylthio and alkoxyl group with 1-6 carbon atom with 1-6 carbon atom, and thiazolinyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom;
R
6And R
7The carbon atom that is connected with them is combined together to form 4-7 unit ring texture, this ring texture representative forms the part-structure that condenses ring-type (dicyclo) structure with pyrrolidine ring, this 4-7 unit ring texture can contain two keys and also can contain Sauerstoffatom or the sulphur atom composed atom as ring
R
5Can be methylene radical, its can with R
6Be combined together to form 3 yuan and condense the ring-type structure division, and the ring of Xing Chenging can be positioned at the other parts that condense ring-type (dicyclo) structure as mentioned above, and described 4-7 unit ring texture can have one or more following substituting groups that are selected from: have 1-6 carbon atom and can have substituent alkyl, have 1-6 carbon atom and can have substituent alkoxyl group, have 2-6 carbon atom and can have substituent thiazolinyl, have 2-6 carbon atom and can have substituent alkynyl, have 3-6 carbon atom and can have substituent cycloalkyl, can have substituent outer methylene radical (exomethylene group), can have substituent spirane base, have 6-10 carbon atom and can have substituent aryl, can have substituent heteroaryl, have 1-6 carbon atom and can have substituent Alkoximino, halogen atom, hydroxyl, cyano group and oxyimino; Perhaps have 2-5 carbon atom polymethylene chain can in conjunction with and form spiro system; With
The Q representative is the part-structure of representative with following formula (II):
[formula 19]
R wherein
8Representative have 1-6 carbon atom alkyl, have 2-6 carbon atom thiazolinyl, have alkyl that the halogen of 1-6 carbon atom replaces, have 3-6 carbon atom also can have substituent cycloalkyl, can have substituent halogen replacement phenyl, can have substituent halogen replacement heteroaryl, have the alkoxyl group of 1-6 carbon atom or have the alkylamino of 1-6 carbon atom;
R
9Represent hydrogen atom or have the alkylthio of 1-6 carbon atom, perhaps R
9And R
8The atom that links to each other with them is combined together to form ring texture, and described ring texture can contain the composed atom of sulphur atom as ring, and the halogen-substituted alkyl that can have the alkyl that contains 1-6 carbon atom or contain 1-6 carbon atom is as substituting group;
R
10Represent hydrogen atom, phenyl, acetoxy-methyl, valeryl oxygen ylmethyl, ethoxy carbonyl, choline base, dimethyl aminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo butyl, have 1-6 carbon atom alkyl, have the alkoxy methyl of 2-7 carbon atom or by the alkylidene group with 1-6 carbon atom and phenyl and the phenylalkyl that forms;
R
11Represent hydrogen atom, amino, hydroxyl, thiol group, halogenated methyl or have the alkyl of 1-6 carbon atom, and should amino can have one or two and be selected from following substituting group: formyl radical, have the alkyl of 1-6 carbon atom and have the acyl group of 2-5 carbon atom;
X
1Represent halogen atom or hydrogen atom;
A
1Represent nitrogen-atoms or be the part-structure of representative with following formula (III):
[formula 20]
X wherein
2The methyl or the halogenated methoxy that represent hydrogen atom, have the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, cyano group, halogen atom, halogen replace, perhaps X
2And R
8Be combined together to form ring texture with their precursor skeleton connection portion, described ring texture can contain Sauerstoffatom, nitrogen-atoms or the sulphur atom composed atom as ring, and can be had 1-6 carbon atom and can have substituent alkyl replacement; With
A
2And A
3Represent nitrogen-atoms or carbon atom separately, and A
1, A
2, A
3, R
8And A
2With A
3The carbon atom that is connected is combined together to form following part-structure:
＞C＝C(-A
1＝)-N(-R
8)-
Or following part-structure:
＞N-C(-A
1＝)＝C(-R
8)-。
The present invention provides also that to comprise with formula (I) be compound, its salt or the hydrate of the representative medicine as activeconstituents.
The present invention also provides the method for treatment disease, and this method comprises to giving formula (I) and is the compound of representative, its salt or hydrate.It is compound, its salt or the hydrate purposes in producing medicine of representative that the present invention more provides with formula (I).
The present invention can provide the synthetic antibacterial drug of the quinolones with good medicinal property, these medicines not only all have very strong anti-microbial activity to Gram-negative bacteria but also to gram-positive cocci (its susceptibility to Comprecin is low), and show very high security and good pharmacokinetic properties.
The accompanying drawing summary
Fig. 1 shows (3S)-3-(3-hydroxyl-1-propyl group)-5-oxo of obtaining in the reference example 24-1-[(1R)-1-phenylethyl] the ORTEP figure of the X-ray crystallography structure of tetramethyleneimine-3-t-butyl formate.
Fig. 2 shows (3S)-3-(3-hydroxyl-1-propyl group)-5-oxo of obtaining in the reference example 24-1-[(1R)-1-phenylethyl] absolute configuration of tetramethyleneimine-3-t-butyl formate.
Description of Preferred Embodiments
R
1Represent hydrogen atom, have the alkyl of 1-6 carbon atom, have the cycloalkyl of 3-6 carbon atom, perhaps derived from the substituted carbonyl of amino acid, dipeptides or tripeptides.Alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, cyano group, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom.
R
2Represent hydrogen atom, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom.Alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom.Cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom.
Work as R
1Or R
2During for alkyl, alkyl can be a straight or branched, and is preferably methyl, ethyl, propyl group or sec.-propyl, more preferably methyl or ethyl, also methyl more preferably.
Work as R
1Or R
2When having hydroxyl, amino or cyano group as substituent alkyl, alkyl can be the straight or branched alkyl with 1-6 carbon atom, and preferably is substituted base replaces on the terminal carbon of alkyl.Alkyl with hydroxyl is suitably the alkyl with 3 carbon atoms at the most and is preferably 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.Having amino alkyl is suitably the alkyl with 3 carbon atoms at the most and is preferably 2-amino-ethyl, 2-aminopropyl or 3-aminopropyl.Alkyl with cyano group is suitably the alkyl with 2-4 carbon atom and is preferably the 2-cyano ethyl or 2-cyano group-2, the 2-dimethyl ethyl.
Work as R
1Or R
2When having halogen atom as substituent alkyl, this alkyl can be the straight or branched alkyl with 1-6 carbon atom, and halogen atom is preferably fluorine atom.Alkyl can be that a fluorine replaces to perfluor and replaces.The suitable example of halogen-substituted alkyl comprises a methyl fluoride, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
Work as R
1Or R
2When having alkylthio or alkoxyl group as substituent alkyl, this alkyl can be a straight or branched, and the moieties in alkylthio or the alkoxyl group also can be a straight or branched.Alkyl with alkylthio is preferably alkylthio methyl, alkylthio ethyl or alkylthio propyl group, and this alkylthio preferably has 1-3 carbon atom.More preferably example with alkyl of alkylthio comprises methylthiomethyl, ethylmercapto group methyl and methylmercaptoethyl.Alkyl with alkoxyl group is preferably alkoxy methyl, alkoxyethyl or alkoxyl group propyl group, and this alkoxyl group preferably has 1-3 carbon atom.More preferably example with alkyl of alkoxyl group comprises methoxymethyl, ethoxyl methyl and methoxy ethyl.
Work as R
1Or R
2During for cycloalkyl, this cycloalkyl is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl.Cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom.Specifically, substituting group is preferably methyl, ethyl, amino, hydroxyl, fluorine atom or chlorine atom.
R
1And R
2Preferably combination be R wherein
1Be selected from hydrogen atom, alkyl, cycloalkyl and derived from the substituted carbonyl of amino acid, dipeptides or tripeptides; And R
2Be hydrogen.R
1And R
2More preferably combination be R wherein
1Be selected from hydrogen atom, alkyl and cycloalkyl, and R
2Be hydrogen.Alkyl is preferably methyl or ethyl, especially preferable methyl.Cycloalkyl is preferably cyclopropyl or cyclobutyl, especially preferred cyclopropyl.Also preferred combination is R wherein
1And R
2All be hydrogen atom, perhaps R wherein
1And R
2In one for hydrogen atom another is methyl, ethyl, fluoro ethyl or cyclopropyl.
R
1Be substituted carbonyl and R derived from amino acid, dipeptides or tripeptides
2For the Carbostyril derivative of hydrogen atom can be used as prodrug.Amino acid, dipeptides or the tripeptides that is used to provide this class prodrug is at carboxyl and R
1And R
2Form those that form the unhindered amina compound after peptide bond also cuts in vivo between institute's bonded amino.Be used to provide the example of the substituted carbonyl of this class prodrug to comprise substituted carbonyl derived from amino acid (for example glycine, L-Ala and aspartic acid); The dipeptides (for example glycine-glycine, glycine-L-Ala and Ala-Ala) that forms by glycine, L-Ala or l-asparagine; The tripeptides (for example glycine-glycine-L-Ala and glycine-Ala-Ala) that forms by glycine, L-Ala or l-asparagine.
R
3And R
4The independent alkyl of representing hydrogen atom or having 1-6 carbon atom.Alkyl can have one or more substituting groups that are selected from halogen atom and have the alkoxyl group of 1-6 carbon atom.
Work as R
3And R
4When being alkyl independently, this alkyl can be a straight or branched, and is preferably methyl, ethyl, propyl group or sec.-propyl, more preferably methyl or ethyl, also more preferably methyl.
Work as R
3And R
4When being alkyl independently, substituting group can be the group that is selected from halogen atom and has the alkoxyl group of 1-6 carbon atom.Halogen atom is preferably fluorine atom.Alkyl can be that a fluorine replaces to perfluor and replaces.The suitable example of halogen-substituted alkyl comprises a methyl fluoride, difluoromethyl and trifluoromethyl.Preferred embodiment with alkoxyl group of 1-6 carbon atom comprises methoxymethyl, ethoxyl methyl and methoxy ethyl.Work as R
3And R
4When being substituted alkyl independently, this group especially is preferably methyl fluoride.
R
3And R
4Preferably combination be R
3And R
4In one for hydrogen atom another is methyl or methyl fluoride.R
3And R
4More preferably combination be R
3And R
4It all is hydrogen atom.
R
5Represent hydrogen atom, halogen atom, have the alkyl of 1-6 carbon atom, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl (it can have substituting group), aryl (it can have substituting group) or heteroaryl (it can have substituting group) with 6-10 carbon atom with 3-6 carbon atom with 2-6 carbon atom with 2-6 carbon atom with 1-6 carbon atom.
Work as R
5During for alkyl, alkenyl or alkynyl, this group can be a straight or branched.Alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom.Thiazolinyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom.
Work as R
5During for halogen atom, halogen atom is preferably fluorine atom or chlorine atom, especially is preferably fluorine atom.
Work as R
5When having the alkyl of 1-6 carbon atom, this alkyl is preferably methyl, ethyl, propyl group or sec.-propyl.This alkyl is methyl or ethyl more preferably, especially is preferably methyl.
Alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom.
When hydroxyl or amino were substituting group on alkyl, this substituting group was preferably on the alkyl terminal carbon.Alkyl with hydroxyl is preferably hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.Have amino alkyl and be preferably amino methyl, 2-amino-ethyl, 2-aminopropyl or 3-aminopropyl.Have hydroxyl or amino alkyl is preferably methyl or ethyl, more preferably hydroxymethyl, have the amino methyl of hydroxyl or the amino on methyl.
When alkyl had halogen atom as substituting group, alkyl can be the straight or branched alkyl with 1-6 carbon atom, and more preferably methyl or ethyl, especially preferable methyl.Halogen atom is preferably fluorine atom.Alkyl can be that a fluorine replaces to perfluor and replaces.The example of halogen-substituted alkyl comprises a methyl fluoride, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.Especially a preferred methyl fluoride, difluoromethyl or trifluoromethyl.
When alkyl had alkylthio or alkoxyl group as substituting group, alkyl can be a straight or branched, and the moieties in alkylthio or the alkoxyl group also can be straight or branched.Alkyl with alkylthio is preferably alkylthio methyl or alkylthio ethyl, and this alkylthio preferably has 1-2 carbon atom.More preferably example with alkyl of alkylthio comprises methylthiomethyl, ethylmercapto group methyl and methylmercaptoethyl.Alkyl with alkoxyl group is preferably alkoxy methyl or alkoxyethyl, and this alkoxyl group preferably has 1-2 carbon atom.More preferably example with alkyl of alkoxyl group comprises methoxymethyl, ethoxyl methyl and methoxy ethyl.Therein, also more preferably methylthio group and methoxymethyl.
Work as R
5When having the alkoxyl group of 1-6 carbon atom, this alkoxyl group is preferably the alkoxyl group with 1-3 carbon atom, especially methoxy or ethoxy.
Work as R
5When having the thiazolinyl of 2-6 carbon atom, this thiazolinyl preferably contains two keys and position of double bond is not specifically limited.Thiazolinyl is preferably vinyl, propenyl or butenyl, especially preference such as vinyl.
Thiazolinyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom.
Halogen atom is preferably fluorine atom.When thiazolinyl had halogen atom as substituting group, this thiazolinyl was preferably the thiazolinyl with 2-3 carbon atom, more preferably had the vinyl of fluorine atom, and is especially preferably fluoride-based.
When thiazolinyl had alkoxyl group as substituting group, this thiazolinyl preferably had 2 or 3 carbon atoms.Example with thiazolinyl of alkoxyl group comprises alkoxy vinyl and alkoxypropan thiazolinyl, especially methoxy-ethylene base and vinyl ethyl ether base.Especially preferred methoxy-ethylene base.
Work as R
5When having the alkynyl of 2-6 carbon atom, this alkynyl preferably contains a triple bond and this triple bond can be in any position.Alkynyl is preferably ethynyl, proyl or butynyl, especially preferred ethynyl.
Work as R
5During for cycloalkyl (it can have substituting group) with 3-6 carbon atom, this cycloalkyl is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl.
Cycloalkyl can have one or more following substituting groups that are selected from: alkyl, phenyl, halogen atom, amino and hydroxyl with 1-6 carbon atom.Specifically, substituting group is preferably methyl, ethyl, phenyl, fluorine atom or chlorine atom, more preferably methyl or fluorine atom.
Work as R
5During for aryl (it can have substituting group) or for heteroaryl (it can have substituting group) with 6-10 carbon atom; this heteroaryl is 5 yuan of rings or 6 yuan of rings and can contains the heteroatoms that 1-4 is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom arbitrarily, and aryl or heteroaryl can have one or more following substituting groups that are selected from: halogen atom, amino, hydroxyl, cyano group, nitro, carboxyl, formamyl, have 1-6 carbon atom alkyl, have 1-6 carbon atom alkoxyl group, have the alkoxy carbonyl of 2-6 carbon atom and have the acyl group of 2-5 carbon atom.Alkyl, alkoxyl group, alkoxy carbonyl or acyl group can have one or more following substituting groups that are selected from: halogen atom, hydroxyl and have the alkoxyl group of 1-6 carbon atom.
Substituting group on aryl or the heteroaryl is preferably halogen atom, amino, hydroxyl, cyano group, carboxyl, have the alkyl of 1-6 carbon atom, have the alkoxyl group of 1-6 carbon atom or have the alkoxy carbonyl of 2-6 carbon atom.
Halogen atom as preferred substituents is preferably fluorine atom or chlorine atom, more preferably fluorine atom.
Can be to have the straight or branched alkyl of 1-6 carbon atom and be for example methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl, preferable methyl or ethyl as the alkyl of preferred substituents.Substituting group on the alkyl is preferably halogen atom, more preferably fluorine atom.The example of halogen-substituted alkyl comprises methyl fluoride and trifluoromethyl.
Alkoxyl group as preferred substituents is preferably the alkoxyl group with 1-3 carbon atom, especially methoxy or ethoxy, especially preferably methoxyl group.Substituting group on the alkoxyl group is preferably halogen atom, more preferably fluorine atom.The example of halogen substituted alkoxy comprises trifluoromethoxy.
Be preferably as the alkoxy carbonyl of preferred substituents and have the alkoxy carbonyl of 3 carbon atoms at the most.The preferred embodiment of alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.Substituting group on the alkoxy carbonyl is preferably halogen atom, more preferably fluorine atom.The example of the alkoxy carbonyl that halogen replaces comprises the trifluoromethoxy carbonyl.
R
6And R
7The carbon atom that is connected with them is combined together to form 4-7 unit ring texture, and ring texture has been represented with pyrrolidine ring and formed the part-structure that condenses ring-type (dicyclo) structure.The 4-7 unit ring texture that forms in this manner partly can contain Sauerstoffatom or the sulphur atom composed atom as ring.These condense cyclic amine is representative with the following formula:
[formula 21]
R wherein
1, R
2, R
3, R
4And R
5Such as claim 1 definition; D
1, D
2, D
3, D
4And D
5Represent carbon atom (it can have substituting group), Sauerstoffatom or sulphur atom separately, condition is to work as D
1, D
2, D
3, D
4And D
5In 2 or more a plurality of respectively doing for oneself when Sauerstoffatom or sulphur atom, adjacent two is not Sauerstoffatom or sulphur atom simultaneously in them, and sulphur atom can be oxidized sulphur atom, for example S=O or S (=O)
2Substituting group (describing hereinafter) on the Y representative ring; N represents the integer of 0-3.
R
6And R
7When combining, the carbon atom that is connected with them forms 4-7 unit ring texture.The preferred embodiment that condenses cyclic amine is listed below:
[formula 22]
R
6And R
7The 4-7 unit ring texture that constitutes of combining the carbon atom that is connected with them can contain becomes two keys on the ring of forming structure.When ring texture contains two keys as the composition structure, R
6Partly (the nuclear substituted carbon atom of tetramethyleneimine) and R
5Can be combined together to form two key part-structures, itself and R
7Forming together with the following formula is the 5-7 unit ring texture of representative:
[formula 23]
Yet, two key part-structures and R
7Be preferably formed 5 yuan or 6 yuan of ring texturees.The preferred embodiment of Wyovin is listed below:
[formula 24]
4-7 unit ring texture can have and is selected from following substituting group: the alkyl (it can have substituting group) with 1-6 carbon atom, alkoxyl group (it can have substituting group) with 1-6 carbon atom, thiazolinyl (it can have substituting group) with 2-6 carbon atom, alkynyl (it can have substituting group) with 2-6 carbon atom, cycloalkyl (it can have substituting group) with 3-6 carbon atom, Heterocyclylalkyl (it can have substituting group) with 3-6 carbon atom, outer methylene radical (it can have substituting group), spirane base (it can have substituting group), aryl (it can have substituting group) with 6-10 carbon atom, heteroaryl (it can have substituting group), halogen atom, hydroxyl, cyano group, oxyimino and Alkoximino (it can have substituting group) with 1-6 carbon atom.
Alkyl (it can have substituting group) with 1-6 carbon atom can be a straight or branched.The specific examples of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, methyl fluoride, trifluoromethyl, 2-fluoro ethyl, 2,2, the tertiary butyl, hydroxymethyl, 2-hydroxyethyl, 2-cyano ethyl, methoxymethyl and 2-methoxy ethyl that 2-trifluoroethyl, fluorine replace.Alkyl is preferably methyl, ethyl, sec.-propyl, methyl fluoride, 2-cyano ethyl or methoxymethyl.
Alkoxyl group (it can have substituting group) with 1-6 carbon atom can be from abovementioned alkyl deutero-alkoxyl group, and is preferably the alkoxyl group with 1-3 carbon atom, specifically, and methoxy or ethoxy.
The position that thiazolinyl (it can have substituting group) with 2-6 carbon atom preferably contains two keys and this pair key is not limit.Thiazolinyl is preferably vinyl, propenyl or butenyl.Substituting group on the thiazolinyl is preferably halogen atom or alkoxyl group, and this halogen atom is preferably fluorine atom.The example of substituted alkenyl comprises fluoride-based and the methoxy-ethylene base.
Alkynyl (it can have substituting group) with 2-6 carbon atom preferably contains a triple bond and this triple bond can be at an arbitrary position.Alkynyl is preferably ethynyl, proyl or butynyl.Preferred alkynyl does not have substituting group except that hydrogen atom.
Cycloalkyl (it can have substituting group) with 3-6 carbon atom is preferably cyclopropyl or cyclobutyl.Cycloalkyl can be selected from following substituting group and replace by one or more: alkyl, halogen atom, amino and hydroxyl with 1-6 carbon atom.Specifically, substituting group is preferably methyl, ethyl, fluorine atom or chlorine atom.
Heterocyclylalkyl (it can have substituting group) with 3-6 carbon atom is preferably trimethylene oxide-3-base, thia trimethylene oxide-3-base (thioxetan-3-yl), tetrahydrofuran base, THP trtrahydropyranyl or 2,2-dimethyl-1,3-dioxane-4-base.
Outer methylene radical (it can have substituting group) does not preferably have substituent outer methylene radical except that hydrogen atom.Substituting group except that hydrogen atom is preferably amino, fluorine atom, chlorine atom, methylthio group or methoxyl group.
Spirane base (it can have substituting group) is preferably Spirocyclopropyl or volution butyl.The spirane base is made up of the alicyclic ring component and is formed the volution ring system.Spiro cycloalkyl group can be selected from following substituting group and replace by one or more: alkyl, halogen atom, amino and hydroxyl with 1-6 carbon atom.Specifically, substituting group is preferably methyl, ethyl, fluorine atom or chlorine atom.
When the substituting group on the 4-7 unit ring texture was aryl (it can have substituting group) with 6-10 carbon atom or heteroaryl (it can have substituting group), this heteroaryl was 5 yuan of rings or 6 yuan of rings and can contains the individual heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom arbitrarily of 1-4.Aryl or heteroaryl can have one or more following substituting groups that are selected from: halogen atom, amino, hydroxyl, cyano group, nitro, carboxyl, formamyl, have 1-6 carbon atom alkyl, have 1-6 carbon atom alkoxyl group, have the alkoxy carbonyl of 2-6 carbon atom and have the acyl group (alkyl-carbonyl that promptly has 2-5 carbon atom) of 2-5 carbon atom.Alkyl, alkoxyl group, alkoxy carbonyl or acyl group can have one or more following substituting groups that are selected from: halogen atom, hydroxyl and have the alkoxyl group of 1-6 carbon atom.Substituting group on aryl or the heteroaryl is preferably halogen atom, amino, hydroxyl, cyano group, carboxyl, have the alkyl of 1-6 carbon atom, have the alkoxyl group of 1-6 carbon atom or have the alkoxy carbonyl of 2-6 carbon atom.Particularly preferred substituting group comprises fluorine atom, chlorine atom, methyl, methyl fluoride, methoxyl group, oxyethyl group, methoxycarbonyl and ethoxy carbonyl on aryl or the heteroaryl.
When substituting group was halogen atom, this halogen atom was preferably fluorine atom or chlorine atom, especially preferred fluorine atom.
Preferred embodiment with Alkoximino (it can have substituting group) of 1-6 carbon atom comprises methoxyimino and ethoxy imino.
Above-mentioned substituent preferred embodiment comprises methyl, ethyl, methyl fluoride, 2-fluoro ethyl, methoxymethyl, cyano ethyl, methoxyl group, cyclopropyl, Spirocyclopropyl, phenyl, oxazolyl, fluorine atom, hydroxyl, oxyimino and methoxyimino.Wherein, special preferable methyl, methyl fluoride, methoxymethyl, methoxyl group, fluorine atom, cyano ethyl and methoxyimino.
In conjunction with and the polymethylene chain that forms spiro system preferably has 2-3 carbon atom, more preferably have 2 carbon atoms.
R
5Can be methylene radical, itself and R
6Be combined together to form 3 yuan and condense ring texture, and this ring texture is passed through R
6And R
7Be combined into three ring ring systems and constitute the condensed-bicyclic structure.In addition, derived from R
5And R
6The 3rd ring system can be positioned at derived from R
6And R
7Another part of condensed-bicyclic ring system.In other words, the condensed-bicyclic substituting group of 7-position can be by becoming three ring ring systems in conjunction with the cyclopropane ring on the arbitrary part of dicyclo ring structure.
The Q representative is the part-structure of representative with the following formula:
[formula 25]
A wherein
2And A
3Represent nitrogen-atoms or carbon atom separately, and A
1, A
2, A
3, R
8And A
2With A
3The carbon atom that is connected is represented following part-structure together:
＞C＝C(-A
1＝)-N(-R
8)-
Or following part-structure:
＞N-C(-A
1＝)＝C(-R
8)-
Wherein "＞" is meant the key (down together) that exists two to connect nitrogen-atoms or carbon atom.
It is the annelated heterocycles pastern separation structure of representative that Q preferably represents with the following formula:
[formula 26]
Or be the annelated heterocycles pastern separation structure of representative with the following formula:
[formula 27]
R wherein
8Representative have 1-6 carbon atom alkyl, have 2-6 carbon atom thiazolinyl, have the halogen replacement of 1-6 carbon atom alkyl, have 3-6 carbon atom cycloalkyl (it can have substituting group), can have substituent halogen replacement phenyl, can have substituent halogen replacement heteroaryl, have the alkoxyl group of 1-6 carbon atom or have the alkylamino of 1-6 carbon atom.
Work as R
8When having the alkyl of 1-6 carbon atom, this alkyl can be a straight or branched.The specific examples of alkyl comprises methyl, ethyl, sec.-propyl, sec-butyl and the tertiary butyl.Wherein, the preferred ethyl and the tertiary butyl.
Work as R
8When having the thiazolinyl of 2-6 carbon atom, this thiazolinyl can be a straight or branched.The preferred embodiment of thiazolinyl comprises vinyl and pseudoallyl.
Work as R
8During the alkyl that replaces for the halogen with 1-6 carbon atom, this moieties can be a straight or branched.The specific examples of moieties comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl.Wherein, the preferred ethyl and the tertiary butyl.Halogen atom substituting group on the alkyl is preferably fluorine atom or chlorine atom, more preferably fluorine atom.The example of the alkyl that halogen replaces comprises methyl fluoride, trifluoromethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2,2,2-trifluoroethyl, 1,1-dimethyl-2-fluoro ethyl, 1-methyl isophthalic acid-(methyl fluoride)-2-fluoro ethyl and 1,1-(difluoromethyl)-2-fluoro ethyl.Wherein, preferred 2-fluoro ethyl and 1,1-dimethyl-2-fluoro ethyl.
Work as R
8During for cycloalkyl (it can have substituting group) with 3-6 carbon atom, the example of this cycloalkyl comprises cyclopropyl, cyclobutyl and cyclopentyl.Wherein preferred cyclopropyl.Substituting group on the cycloalkyl is preferably halogen atom, methyl or phenyl, more preferably halogen atom.Halogen atom is preferably fluorine atom or chlorine atom, especially preferred fluorine atom.Substituent quantity can be 1 or 2, but is preferably 1.Specifically, can have substituent cycloalkyl and be preferably a fluorine cyclopropyl, more preferably 1,2-is suitable-2-fluorine cyclopropyl, especially preferred (1R, 2S)-2-fluorine cyclopropyl.
Work as R
8For can have the phenyl that substituent halogen replaces the time, this halogen atom is preferably fluorine atom or chlorine atom, more preferably fluorine atom.The substituent quantity of halogen atom is preferably 1 or 2.Substituting group on the phenyl that halogen replaces is preferably amino, hydroxyl or methyl.The example that can have the phenyl of substituent halogen replacement comprises 2-fluorophenyl, 4-fluorophenyl, 2,4-fluorophenyl and 5-amino-2,4 difluorobenzene base.Wherein, preferred 2,4 difluorobenzene base and 5-amino-2,4 difluorobenzene base.
Work as R
8For can have the heteroaryl that substituent halogen replaces the time, this heteroaryl can be to contain one or more heteroatomic 5 yuan or 6 yuan of aromatic heterocyclic radicals that are selected from nitrogen-atoms, sulphur atom and Sauerstoffatom.This heteroaryl is preferably 5 yuan or 6 yuan of nitrogenous aromatic heterocyclic radicals that contain 1 or 2 nitrogen-atoms.The specific examples of heteroaryl comprises pyridyl, pyrimidyl, pyridazinyl, imidazolyl, thiazolyl He oxazolyl.Wherein preferred pyridyl.Halogen atom is preferably fluorine atom or chlorine atom, more preferably fluorine atom.The quantity of halogen atom is preferably 1 or 2.Substituent preferred embodiment on the halogen substituted heteroaryl comprises amino, hydroxyl and methyl.This heteroaryl that can have substituent halogen replacement is preferably 6-amino-3,5-difluoro pyridine-2-base.
Work as R
8When having the alkoxyl group of 1-6 carbon atom, this alkoxyl group is preferably methoxyl group.
Work as R
8When having the alkylamino of 1-6 carbon atom, this alkylamino is preferably methylamino.
Above-mentioned R
8Being preferably cyclopropyl or 1,2-is suitable-2-fluorine cyclopropyl, more preferably (1R, 2S)-2-fluorine cyclopropyl.
R
9Represent hydrogen atom or have the alkylthio of 1-6 carbon atom.R
9With above-mentioned R
8Can (comprise R with the precursor skeleton part
9Carbon atom that is connected and A
2Be combined together to form ring texture down together).The ring of Xing Chenging can contain the composed atom of sulphur atom as ring in this manner, and the halogen-substituted alkyl that can have the alkyl that contains 1-6 carbon atom or contain 1-6 carbon atom is as substituting group.The ring of Xing Chenging can be 4 yuan to 6 yuan rings thus, and can be saturated, fractional saturation or undersaturated.The fused rings structure of Xing Chenging can be representative with the following structural in this manner:
[formula 28]
R
10Represent hydrogen atom, phenyl, acetoxy-methyl, valeryl oxygen ylmethyl, ethoxy carbonyl, choline base, dimethyl aminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo butyl, have 1-6 carbon atom alkyl, have the alkoxy methyl of 2-7 carbon atom or the phenylalkyl that forms by alkylidene group with 1-6 carbon atom and phenyl.
R
10Be preferably hydrogen atom.
R
11Represent hydrogen atom, amino, hydroxyl, thiol group, halogenated methyl or have the alkyl of 1-6 carbon atom.Amino can have one or two and be selected from following substituting group: formyl radical, have the alkyl of 1-6 carbon atom and have the acyl group of 2-5 carbon atom.
Work as R
11When having the alkyl of 1-6 carbon atom, this alkyl can be straight or branched and be preferably methyl, ethyl, propyl group or sec.-propyl, especially preferable methyl.
Work as R
11During for halogenated methyl, this halogen atom is preferably fluorine atom, and the quantity of halogen atom can be 1 to 3.
Work as R
11During for amino, hydroxyl or thiol group, this group can be protected by protecting group commonly used.
The example of this class protecting group comprises: (replacement) alkoxy carbonyl, tert-butoxycarbonyl and 2,2 for example, 2-trichlorine ethoxy carbonyl; (replacement) aromatic alkoxy carbonyl, for example benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl with to the nitro benzyloxycarbonyl; (replacement) acyl group, for example ethanoyl, methoxyl group ethanoyl, trifluoroacetyl group, chloracetyl, valeryl, formyl radical and benzoyl; (replacement) alkyl or (replacement) aralkyl, for example the tertiary butyl, benzyl, to nitrobenzyl, to methoxy-benzyl and trityl group; (replacement) ether, for example methoxymethyl, tert.-butoxy methyl, THP trtrahydropyranyl and 2,2,2-trichlorine ethoxyl methyl; The silyl that (alkyl-and/or aralkyl-) replaces, for example trimethyl silyl, sec.-propyl dimetylsilyl and t-butyldiphenylsilyl.Especially preferably has the substituent compound protected by this class protecting group as producing intermediate.
In above-mentioned example, R
11Be preferably hydrogen atom, amino, hydroxyl or methyl, especially preferred hydrogen atom or amino.
X
1Represent halogen atom or hydrogen atom.Halogen atom is preferably fluorine atom or chlorine atom, more preferably fluorine atom.X
1Be preferably fluorine atom or hydrogen atom.
A
1Represent nitrogen-atoms or be the part-structure of representative with following formula (III):
[formula 29]
X wherein
2Represent hydrogen atom, have the alkyl of 1-6 carbon atom, alkoxyl group, cyano group, halogen atom, halogenated methyl or halogenated methoxy, X with 1-6 carbon atom
2And R
8The precursor skeleton part that can be connected with them (comprises X
2Carbon atom that is connected and A
2) being combined together to form ring texture, the ring that forms according to this mode can contain Sauerstoffatom, nitrogen-atoms or the sulphur atom composed atom as ring, and this ring can be had 1-6 carbon atom and also can have substituent alkyl and replace.
Work as A
1For being the part-structure and the X of representative with formula (III)
2When having the alkyl of 1-6 carbon atom, this alkyl can be a straight or branched, and is preferably methyl, ethyl, propyl group or sec.-propyl, more preferably methyl or ethyl, also more preferably methyl.
Work as X
2When having the alkoxyl group of 1-6 carbon atom, this alkoxyl group can be from abovementioned alkyl deutero-alkoxyl group.Alkoxyl group is preferably the alkoxyl group with 1-3 carbon atom, especially preferred methoxyl group.
Work as X
2During for halogen atom, halogen atom is preferably fluorine atom or chlorine atom.As above-mentioned R
11During for hydrogen atom, X
2Be preferably the chlorine atom; Work as R
11During for amino, hydroxyl or methyl, X
2Be preferably fluorine atom.
Work as X
2During for halogenated methyl, halogen atom is preferably fluorine atom.The preferred embodiment of halogenated methyl comprises methyl fluoride, difluoromethyl and trifluoromethyl.
Work as X
2During for halogenated methoxy, halogen atom is preferably fluorine atom, and is identical with above-mentioned situation.The specific examples of halogenated methoxy comprises fluoro methoxyl group, difluoro-methoxy and trifluoromethoxy.More preferably difluoro-methoxy wherein.
Work as A
1Be when being the part-structure of representative with formula (III), X
2And R
8Can form ring texture, comprise quinolone skeleton part [X
2The carbon atom that is connected, R
8The A that is connected
2(A wherein
2Be nitrogen-atoms or carbon atom), and carbon atom and A
2The framework ring carbon atom that is connected].The ring of Xing Chenging is preferably 5 yuan to 7 yuan rings and can is saturated or undersaturated thus.This ring texture can contain Sauerstoffatom, nitrogen-atoms or sulphur atom, and can be had the alkyl or the X of 1-6 carbon atom
2The middle halogenated methyl of describing replaces.The fused rings structure that forms according to this mode can be representative with the following structural:
[formula 30]
Work as A
1For being the part-structure and the substituent X of representative with formula (III)
2When not forming ring texture, X
2Be preferably methyl, ethyl, methoxyl group, difluoro-methoxy, cyano group or chlorine atom, especially preferable methyl, methoxyl group, difluoro-methoxy or cyano group.When A when being the part-structure of representative with the following formula, preferred especially such substituting group:
[formula 31]
In addition, when Q for being the part-structure 1-[(1R of representative with the following formula, 2S)-2-fluorine cyclopropyl]-1, during 4-dihydro-4-Oxoquinoline-3-formic acid skeleton, more preferred such substituting group:
[formula 32]
Work as A
1For being the part-structure and the substituent X of representative with formula (III)
2When forming ring texture, be preferably formed 2,3-dihydro-3-methyl (or methyl fluoride)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid skeleton.Especially preferably with following formula (Y
0Compound be methyl) be the 3-of representative (S)-picoline and benzoxazine skeleton:
[formula 33]
The feature of The compounds of this invention is that to have with the following formula on the 7-position (or its corresponding position) at the quinolone skeleton be the substituting group of representative structure:
[formula 34]
Specifically, the substituting group of The compounds of this invention has amino on the corresponding position of pyrrolidyl 3-position, and substituent R
7(it is replaced by amino on carbon atom) and substituent R
6(it is on the corresponding position of pyrrolidyl 4-position) and form 4-7 unit ring texture with the carbon atom that they connected.That is to say, the substituting group of The compounds of this invention is the fused substituted aminopyrrolidine structure, as follows, wherein ring texture with pyrrolidine ring form with the following formula be representative condense ring-type (dicyclo) structure, wherein condense ring texture and replaced by amino at bridgehead position:
[formula 35]
In addition, it is the ring texture of representative that the substituting group of The compounds of this invention has with the following formula, wherein by substituent R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings, and R
5And R
6Be combined together to form two key part-structures,
As follows:
[formula 36]
Bicyclic amino group contains unsymmetrical carbon and has stereoisomerism (rotational isomerism) phenomenon).Now this steric isomerism will be described.In addition, for the bridgehead position that amino replaced, following two classes are arranged:
[formula 37]
Here, the preferred wherein amino following structure that is beta configuration:
[formula 38]
In addition, work as substituent R
5And R
6When not being combined together to form two key, for R
5The unsymmetrical carbon that is replaced has following 4 classes:
[formula 39]
Usually, structure 1 than structure 2 more preferably, and structure 3 is than structure 4 more preferably; Yet preferably what kind of structure depends on substituent R
5Structure.Usually, work as substituent R
6And R
7Form 4 yuan of whens ring, structure 1 than structure 3 more preferably and is worked as substituent R
6And R
7When forming 6 yuan of rings, structure 3 than structure 1 more preferably; Yet preferably what kind of structure depends on substituent R
6And R
7The size of formed ring.The present invention includes all the above-mentioned types.
Preferred precursor skeleton is listed below, and for example has above-mentioned substituent quinolonecarboxylic acid (or pyrido-benzoxazine formic acid) basic framework on 7-position (or its corresponding position):
[formula 40]
Substituent preferred embodiment on 7-position (or its corresponding position) is listed below:
(1) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(2) (1S, 5S, 6R)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(3) (1S, 5S, 6S)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(4) (1S, 5S)-1-amino-6,6-two fluoro-3-azabicyclo [3.2.0] heptane-3-bases;
(5) (1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;
(6) (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;
(7) (1S, 5R, 6R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;
(8) (1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;
(9) spiral shell [(1S, 5S)-1-amino-3-azabicyclo [3.2.0] heptane-6,1 '-cyclopropane]-the 3-base;
(10) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-base;
(11) (1S, 5S)-1-amino-3-azabicyclo [3.3.0] octane-3-base;
(12) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(13) (1R, 5R)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(14) (1S, 5R, 6S)-1-amino-6-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(15) (1S, 5R)-1-amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-bases;
(16) (1S, 5R, 7S)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(17) (1S, 5R, 7R)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(18) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;
(19) (1S, 5R)-1-amino-7-methyl-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;
(20) (1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;
(21) (1S)-1-amino-6-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;
(22) (1R, 5R)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;
(23) (1R, 5S)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;
(24) (1R, 5R)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;
(25) (1R, 5S)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;
(26) 6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-base;
(27) (1S, 5R)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;
(28) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;
(29) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-7-alkene-3-base;
(30) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-8-alkene-3-base;
(31) (1S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene-3-base;
(32) (1R, 6S)-1-amino-5-oxa--8-azabicyclo [4.3.0] nonane-8-base;
(33) (1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-base; With
(34) (1S, 6S)-1-amino-3-oxa--8-azabicyclo [4.3.0] nonane-8-base.
[formula 41]
Substituent also preferred example on 7-position (or its corresponding position) is listed below:
[formula 42]
Therefore, preferred The compounds of this invention is the compound (above precursor skeleton of giving an example and above substituent combination of giving an example) that has the above quinolone carboxylic acid skeleton of giving an example that is replaced by above 7-bit substituent of giving an example separately.In following formula, be preferably beta configuration by the configuration of the amino 3-position (or its corresponding position) that replaces on the pyrrolidine ring.The absolute configuration of 3-position (or its corresponding position) can be 3S or 3R, decides on the type of 4-bit substituent.The compounds of this invention is preferably simplification compound on the stereochemistry.
The preferred embodiment of The compounds of this invention (form that can be salt or hydrate) is listed below:
(1) 7-[(1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(2) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(3) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(4) 10-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(5) 7-[(1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(6) 7-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(7) 10-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(8) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(9) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(10) 10-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(11) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(12) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(13) 10-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(14) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(15) 10-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(16) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(17) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(18) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(19) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(20) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(21) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(22) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(23) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(24) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(25) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(26) 7-[(1S)-1-amino-5-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(27) 10-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(28) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(29) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(30) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(31) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(32) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(33) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(34) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(35) 10-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(36) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
(37) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(38) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(39) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(40) 10-[(1S, 6S)-1-amino-8-azepine-3-oxa--dicyclo [4.3.0] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid.
Below, the substituting group on the quinolone skeleton 7-position (or its corresponding position) relevant with The compounds of this invention will be described.Specifically, substituting group has amino on the corresponding position of pyrrolidyl 3-position, and the substituent R on the amino carbon atom that is replaced
7With substituent R
6The carbon atom that (on the corresponding position of the 4-position of pyrrolidyl) is connected with them is combined together to form 4-7 unit ring texture.More particularly, substituting group is a fused substituted aminopyrrolidine derivative, wherein ring texture with pyrrolidine ring form with the following formula be representative condense ring-type (dicyclo) structure, wherein condense ring texture and on bridgehead position, replaced by amino:
[formula 43]
In addition, substituting group is the fused substituted aminopyrrolidine base substituting group that has with the following formula ring texture that is representative, wherein by substituent R
6And R
7The ring texture that the carbon atom that is connected with them is combined together to form is 5 yuan of rings or 6 yuan of rings, and R
5And R
6Be combined together to form two key part-structures:
[formula 44]
Preferred The compounds of this invention (it also can be the form of its salt or hydrate) is exemplified below:
[1] be the compound of representative with formula (I), wherein it is to be the compound of representative with the following formula:
[formula 45]
Or be the compound of representative with the following formula:
[formula 46]
[2] be the compound of representative with formula (I), wherein it is to be the compound of representative with the following formula:
[formula 47]
[3] compound is being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) is the structure of representative:
[formula 48]
Or be the structure of representative with the following formula:
[formula 49]
[4] compound is being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) is the structure of representative:
[formula 50]
[5] compound, wherein in formula (I), R
1And R
2The hydrogen atom of respectively doing for oneself.
[6] compound, wherein in formula (I), R
1And R
2In one be hydrogen atom, another is to be selected from following substituting group: methyl, ethyl, sec.-propyl, fluoro ethyl, cyano ethyl, cyclopropyl and cyclobutyl.
[7] compound, wherein in formula (I), R
3And R
4The hydrogen atom of respectively doing for oneself.
[8] compound, wherein in formula (I), R
5Be hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, sec.-propyl, cyclopropyl, methyl fluoride, fluoro ethyl, trifluoromethyl, methoxymethyl, vinyl, ethynyl, methoxyl group, Ben Ji Huo oxazole-2-base.
[9] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 4 yuan of rings, and it can be replaced by one or more substituting groups.
[10] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, it can be replaced by one or more substituting groups.
[11] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is to contain two keys as 5 yuan of rings or 6 yuan of rings of forming structure, and it can be replaced by one or more substituting groups.
[12] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is to contain Sauerstoffatom as 5 yuan of composed atom rings or 6 yuan of rings, and it can be replaced by one or more substituting groups.
[13] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the cis-condensed-bicyclic structure of representative:
[formula 51]
[14] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the trans-condensed-bicyclic structure of representative:
[formula 52]
[15] compound is wherein in formula (I), by R
6And R
7The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, R
5And R
6Be combined together to form two key part-structures, the gained ring texture is representative with the following formula:
[formula 53]
[16] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, X
1Be hydrogen atom or fluorine atom.
[17] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, X
1Be fluorine atom.
[18] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, A
1Be nitrogen-atoms.
[19] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, A
1For being the part-structure of representative with formula (III).
[20] compound, wherein in formula (III), X
2Be methyl, ethyl, methoxyl group, difluoro-methoxy, cyano group or chlorine atom.
[21] compound, wherein in formula (III), X
2Be methyl or methoxy.
[22] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8Be 1,2-is suitable-the 2-halogenated cyclopropyl.
[23] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8Single 1 for stereochemistry, 2-is suitable-the 2-halogenated cyclopropyl.
[24] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
81,2-is suitable-the 2-halogenated cyclopropyl be (1R, 2S)-the 2-halogenated cyclopropyl.
[25] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8(1R, 2S)-the 2-halogenated cyclopropyl be (1R, 2S)-2-fluorine cyclopropyl.
[26] compound is being in the compound of representative with formula (I) wherein, and Q is for being the compound of representative with the following formula:
[formula 54]
Y wherein
0Be methyl or methyl fluoride.
[27] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
9Be hydrogen atom.
[28] compound is being in the compound of representative with formula (I) wherein, and Q is to be the compound of representative with following formula (IV):
[formula 55]
Y wherein
0Be methyl or methyl fluoride.
[29] compound, wherein in formula (IV), Y
0Be methyl.
[30] compound is among the part-structure Q of representative with formula (II) in formula (I) wherein, R
10Be hydrogen atom.
[31] compound is that the compound of representative is a stereochemistry simplification compound with formula (I) wherein.
Will describe hereinafter and in the quinolone precursor skeleton, introduce the synthetic of the required pyrrolidine compound of substituting group.Fused substituted aminopyrrolidine derivative synthetic has some feasible methods.Some case summaries of the representative synthetic method that the present inventor implements following (see for details " embodiment " partial reference embodiment described in).Yet the synthetic method of fused substituted aminopyrrolidine derivative of the present invention is not limited thereto.
It is 1 of representative that the present inventor utilizes with following flow process, the 3-Dipolar Cycloaddition, α with β-electron-withdrawing group-replacement, β-unsaturated cyclic or open chain compound and azomethine ylide (azomethine ylide) are as response element (reactive element), through the suitable reactions step, synthesize important synthesis intermediates, and synthesized fused substituted aminopyrrolidine derivative:
[formula 56]
In this flow process, EWG is an electron-withdrawing group; PG is an amino protecting group; R
31, R
41, R
51, R
61And R
71Respectively do for oneself hydrogen atom or be applicable to the substituting group of intermediate; R
3, R
4, R
5, R
6, R
7, Y and n as above define.
The α of used β-electron-withdrawing group-replacement in this reaction, β-unsaturated compound can be ring-type or non-annularity.Can be by ring compound one-step synthesis bicyclic pyrrole alkane derivatives.Can carry out suitable cyclization or ring-closure reaction by making suitable synthetic intermediate, open chain compound is converted into the bicyclic pyrrole alkane derivatives, and described reaction for example forms reaction or carbon-oxygen (or sulphur) key formation reaction by the C-C of carbanion nucleophilic reaction; Ether (or thioether) ring by intramolecularly three letter (Mitsunobu) reactions forms reaction; Being called lactone or lactan forms the one-tenth cyclic esterization of reaction or becomes cyclic amideization; Intramolecular condensation ring-closure reaction, for example aldol condensation (aldol condensation), diekmann condensation (Dieckmann condensation), acyloin condensation (acyloin condensation), Wittig (Wittig) condensation or reformatsky reaction (Reformatsky reaction); Closed loop replacement(metathesis)reaction (RCM); Di Ersi-A Deer (Diels-Alder) reaction; Deoxidation coupling cyclization, for example MacMurray reaction (McMurryreaction); The free radical cyclization; Use the coupling ring-closure reaction of metal complex; Or cyclization reaction.
In addition, can pass through one or several steps, β-electron withdrawing group that above-mentioned reaction is used is because of-the α that replaces, the amino that the electron-withdrawing group in β-unsaturated compound (EWG) is converted into amino or is protected by the appropriate protection base.This class examples of groups comprises ester group, cyano group, acyl group, formamyl, carboxyl and nitro.Be converted into carboxyl (carboxylic acid) by hydrolysis afterwards, can passing through Curtius (Curtius) rearrangement reaction, ester group or cyano group are being converted into sulfonamide derivatives.After being converted into formamyl, can pass through Huffman (Hofmann) rearrangement reaction, cyano group or carboxyl are converted into sulfonamide derivatives.After being converted into oxyimino, can pass through Beckman (Beckmann) rearrangement reaction etc., acyl group is converted into sulfonamide derivatives.By reduction reaction nitro is converted into sulfonamide derivatives.
On the other hand, by the trifluoroacetic acid of catalytic amount or the silver fluoride of catalytic amount are joined in reagent N-benzyl-N-(methoxymethyl) trimethyl silyl methylamine, can be created in the azomethine ylide that is used as response element in this reaction, for example [referring to Journal of Organic Chemistry, the 52nd volume, the 2nd phase, the 235th page (1987)].In the above-mentioned reaction formula, the suitable amino protecting group of PG representative in the azomethine ylide.Be used for producing the mentioned reagent of azomethine ylide, protecting group is a phenmethyl, but preferred examples is optically active 1-styroyl.This amino protecting group (PG) and the amino protecting group that produces by the conversion electron-withdrawing group in one step of back can be identical or different; Protecting group can be selected from amino protecting group commonly used aptly, as long as they do not influence reaction, does not for example suppress per step reactions steps, and at easy deprotection of later stage.
Next, the synthetic of optical rotatory substance will be described.Can synthesize optical rotatory substance by the optical resolution of for example appropriate intermediate.The specific examples of optical resolution comprises that the HPLC that uses chiral column splits and be used for the diastereoisomeric salt preferential crystallization of appropriate intermediate; And with chirality element and appropriate intermediate in conjunction with and intermediate is converted into diastereomer, separates diastereomer with appropriate separation technology such as silica gel chromatographys then and remove the chirality element and diastereomer is converted into the method for optical rotatory substance.Also can make up module (chiral building block) and synthesize optical rotatory substance as raw material from chirality.Specifically, optically-active ring adducts can obtain by following reaction: by 1 of enantiomorph selection, and the 3-Dipolar Cycloaddition, (for example asymmetric functional group is 1-for example to use the dipolarophile reagent with asymmetric element
Base, (2 ' S)-camphane-10,2-sultam base or (S)-4-benzyl-2-oxazolidine ketone group); 1 of enantiomorph selection, the 3-Dipolar Cycloaddition is used the azomethine ylide (for example (the 1R)-1-styroyl in the molecule) with asymmetric element; Or diastereomer select 1, the 3-Dipolar Cycloaddition is used asymmetric dipolarophile reagent and asymmetric azomethine ylide [referring to Journal of the Chemical Society PerkinTransactions 1, the 1076 page (2002)].In addition, can be by asymmetric 1, the 3-Dipolar Cycloaddition as catalyzer, obtains optically-active ring adducts [referring to Angewandte Chemie International Edition, the 44th rolls up the 6272nd page (2005)] with asymmetric metal complex or salt.
The present inventor adopts the α of β-electron-withdrawing group-replacement, 1 of β-unsaturated compound, the 3-Dipolar Cycloaddition is carried out the synthetic of fused substituted aminopyrrolidine derivative as committed step and with azomethine ylide as response element, described synthesizing will adopt the synthetic of 1-amino-3-azabicyclo [3.3.0] Octane derivatives to specifically describe as an example:
[formula 57]
In above flow process, Boc represents tert-butoxycarbonyl, and Cbz represents benzyloxycarbonyl, and condition is that these substituting groups can be identical or different amino protecting groups commonly used; And R
12Representative has the alkyl of 1-6 carbon atom.
Step 2 is the steps that the benzyl on 3-azabicyclo [3.3.0] the octane ring 3-position are converted into protecting group.Carry out this step and be carboxylic acid derivative (if benzyl does not transform, then the formation of amino acid derivative, separation and purifying can be very difficult) for the ease of producing after extraction, separation and the ester hydrolysis of purifying 1-position.The protecting group that the protecting group difference of the 1-bit amino that 3-position protecting group is produced after being preferably and can transforming with 1-position carboxylic acid usually in deprotection steps is come, but also can be identical with the protecting group of 1-bit amino.3-position protecting group is preferably benzyloxycarbonyl or tert-butoxycarbonyl, especially preferred benzyloxycarbonyl.Usually can carry out the benzyloxycarbonyl reaction,, use for example chloroformic acid benzyl ester in the methylene dichloride of solvent promptly by the direct conversion of Feng's Braun (von Braun) reaction; Or after catalytic hydrogenolytic cleavage, in the presence of alkali, by making the chloroformic acid benzyl ester reaction in the suitable solvent with catalyzer (for example palladium-carbon).
Step 3 is hydrolysing steps of the ester on 3-azabicyclo [3.3.0] the octane ring 1-position.Ester is the alkyl ester with 1-6 carbon atom, preferred methyl esters, ethyl ester or the tert-butyl ester.By adopting usual way, use the alkali or the acid that do not influence 3-position protecting group, reaction is hydrolyzed.In the hydrolysis of methyl esters or ethyl ester; with ester and alkaline solution (for example ethanol of the ethanol of the ethanol of sodium hydroxide or the aqueous solution, potassium hydroxide or the aqueous solution or hydrated barta or the aqueous solution) reaction; come acidifying, separation and purification again with the appropriate acid that does not influence 3-position protecting group then.The hydrolysis tert-butyl ester in suitable solvent, wherein ester can dissolve under acidic conditions or in the presence of an acidic catalyst.Preferred acid comprises hydrochloric acid, formic acid, acetate, trifluoroacetic acid and tosic acid.
Step 5 is the amino protected steps on 1-amino-3-azabicyclo [3.3.0] octane ring 1-position; Yet this protection can not carried out subsequent step yet.The protecting group of 1-bit amino can be the amino protecting group of using always, but is preferably in deprotection steps the protecting group that can make a distinction with 3-position protecting group.The specific examples of protecting group comprises tert-butoxycarbonyl, ethanoyl and trifluoroacetyl group.The present inventor has selected tert-butoxycarbonyl.
By rearrangement reaction, use suitable solvent, can a step carry out step 4 and step 5.For example can pass through Curtius (Curtius) rearrangement reaction, with the two phenoxy group phosphoryl azides (DPPA) that are dissolved in the trimethyl carbinol, preparation 1-(tert-butoxycarbonyl) amino-3-azabicyclo [3.3.0] Octane derivatives.
Step 6 is optical resolution steps of 1-amino-3-azabicyclo [3.3.0] Octane derivatives.Can split by HPLC, carry out this step with suitable chiral column.Result as this optical resolution, have been found that, derived from the anti-microbial activity of the quinolonecarboxylic acid derivative of the gained enantiomorph of the 1-amino with positive optical-3-azabicyclo [3.3.0] Octane derivatives, than more superior (referring to " embodiment " part) derived from the quinolonecarboxylic acid derivative of gained enantiomorph with negative rotation photosensitiveness.The present inventor has selected the protecting group of tert-butoxycarbonyl as the 1-bit amino; Yet, even not protected or can carry out optical resolution when being protected when the 1-bit amino by protecting group except that tert-butoxycarbonyl yet.For example; when the 1-bit amino not protected or when being protected by protecting groups such as the benzyl or the tertiary butyls (in this case; protected amino is alkaline); also can carry out suitable opticity acid is converted into the method for diastereoisomeric salt and preferential crystallization diastereoisomeric salt, except carrying out the HPLC optical resolution with suitable chiral column.In this case, can be converted into free alkali by diastereoisomeric salt, and obtain opticity 1-amino-3-azabicyclo [3.3.0] Octane derivatives preferential crystallization.In addition; when the 1-bit amino is not protected, can use following method: in conjunction with the chirality element, so that derivative is converted into diastereomer; separate diastereomer with suitable isolation technique such as silica gel chromatographys then, and remove the chirality element and diastereomer is converted into optical rotatory substance.
The present inventor has described concrete method for optical resolution in this step; Yet, when suitable synthetic intermediate can be by optical resolution, can select this intermediate aptly and carry out optical resolution as described above.
Step 7 is deprotection steps of 1-amino-3-azabicyclo [3.3.0] Octane derivatives 3-position.Deprotection reaction can carry out not changing under any condition of other functional group and configuration.Therefore; since the 1-position protecting group of The compounds of this invention is a benzyloxycarbonyl; so under deprotection condition commonly used, carry out deprotection reaction; for example; using catalyzer for example under the condition of palladium-carbon, perhaps use ammonium formiate, in proton polar solvent, carry out deprotection reaction by the catalytic hydrogenolysis.When 3-azabicyclo [3.3.0] Octane derivatives has carbon-to-carbon unsaturated bond at intramolecularly, also must keep carbon-to-carbon unsaturated bond when carrying out deprotection.Therefore; since the 3-position protecting group of The compounds of this invention is a benzyloxycarbonyl; so (for example Hydrogen bromide-acetate, trifluoroacetic acid or trifluoromethanesulfonic acid-trifluoroacetic acid) carries out also keeping 3-azabicyclo [3.3.0] octane nuclear carbon-carbon unsaturated link(age) in the deprotection under strong acid condition, promptly by use sodium-liquid ammonia (Birch reductive condition) or by using for example hydrated barta.
In addition, can come synthetic fused substituted aminopyrrolidine derivative with the chirality pyrrolidin derivatives as raw material as The compounds of this invention.In synthetic, use following synthetic intermediate, used for example so-called chirality to make up module.The chirality pyrrolidin derivatives that can be used as intermediate is not limited to following compounds.
[formula 58]
[Journal of Medicinal Chemistry, the 30th volume, the 10th phase, the 1171st page (1987); WO 94/14794; Tetrahedron, the 61st volume, the 23rd phase, the 5465th page (2005); Tetrahedron Asymmetry, the 15th volume, the 20th phase, the 3249th page (2004)]
In the step of suitable quantity, these chirality pyrrolidin derivatives can be converted into bicyclic pyrrole alkane derivatives as The compounds of this invention.For example, the chirality pyrrolidin derivatives can be converted into fused substituted aminopyrrolidine derivative, promptly 3-position and the 4-position by suitable substituents being introduced pyrrolidine ring carried out suitable homologation or functional group then and transformed, and carries out cyclisation (closed loop) reaction.Comprise that as cyclisation (closed loop) the reaction example of the suitable synthetic intermediate of described conversion reaction important step C-C by the carbanion nucleophilic reaction forms reaction or carbon-oxygen (or sulphur) key forms reaction; Ether (or thioether) ring by intramolecularly three letter (Mitsunobu) reactions forms reaction; Being called lactone or lactan forms the one-tenth cyclic esterization of reaction or becomes cyclic amideization; Intramolecular condensation ring-closure reaction, for example aldol condensation, diekmann condensation, acyloin condensation, Wittig (Wittig) condensation or reformatsky reaction; Deoxidation coupling cyclization, for example McMurry reaction; Closed loop replacement(metathesis)reaction (RCM); Di Ersi-A Deer (Diels-Alder) reaction; The free radical cyclization; Use the coupling ring-closure reaction of metal complex; React with cyclization.
The present inventor adopts the chirality pyrrolidin derivatives to carry out the synthetic of fused substituted aminopyrrolidine derivative as important intermediate, described synthetic will the employing (1S, 5R)-specifically describe as an example synthesizing of 1-amino-3-azabicyclo [3.3.0] Octane derivatives.The present inventor has selected the protecting group of tert-butoxycarbonyl as 1-position amine moiety; Yet the protecting group of 1-bit amino can be such protecting group: it is not a tert-butoxycarbonyl, and does not influence (for example not suppressing) each reactions steps and deprotection easily, and this protecting group can be identical with the protecting group of 3-position.Under following situation, 1-position protecting group is (1R)-1-phenylethyl:
[formula 59]
In above flow process, Boc represents tert-butoxycarbonyl.
Step 8 is allylation steps of the 3-position (alpha-position of ester) of pyrrolidine ring.Common employing allyl halide for example allyl bromide 98 in the presence of alkali, carry out step 8 as allylation reagent.The example of alkali comprises salt of wormwood, cesium carbonate, sodium hydride, sodium Metal 99.5, sodium ethylate, potassium tert.-butoxide, lithium diisopropylamine (LDA) and two (trimethyl silyl) Lithamide.The example of reaction solvent comprises tetrahydrofuran (THF), acetone, N, dinethylformamide, toluene and mixed solvent thereof.After reaction was finished, the diastereomer of allylation compound can carry out separation and purification by methods such as silica gel chromatographys.The present inventor has used the ester of the tert-butyl ester as pyrrolidine ring 3-position; Yet, also can use other ester derivative.When using a large amount of tert-butyl ester, carry out above diastereomer lock out operation easily.
Step 9 is that allyl group partly is converted into primary alconol () step specifically, the 1-hydroxypropyl, i.e. hydroboration-oxidizing reaction by allyl group part terminal olefin.Usually in anhydrous tetrahydro furan, use following all ingredients, carry out hydroboration: borane complex (for example borane-tetrahydrofuran complex and borane-dimethyl sulphide complex compound), an alkyl borane (for example hexyl borine), Dialkylborane (for example assorted dicyclo [3.3.1] nonane (9-BBN) of 9-boron, dicyclohexyl borine and two (1, the 2-dimethyl propyl) borine), chloroborane-dimethyl sulphide complex compound, two chloroboranes-dimethyl sulphide complex compound, adjacent benzene dioxy borine etc.Usually use aqueous hydrogen peroxide solution, at the aqueous solution of sodium hydroxide etc. or contain under the alkaline condition of aqueous ethanolic solution, carry out the oxidizing reaction of the organoborane compounds that hydroboration produced.
The synthetic such compound of the present inventor: wherein in 2 steps shown in step 8 and the step 9, the 1-hydroxypropyl is introduced the 3-position of pyrrolidine ring; Yet, also can synthesize this product by another synthetic method.For example; product can followingly synthesize: protect with the hydroxylic moiety of appropriate protection base (for example t-butyldimethylsilyl) with commercially available 3-iodine propyl alcohol; in the presence of suitable alkali (for example described alkali of step 8), carry out 3-and replace hydroxypropylation, deprotection under conditions suitable subsequently again.In addition,, can carry out 3-after a hydroxyl of ammediol is protected with the appropriate protection base and replace the hydroxypropylation reaction, then another hydroxyl is converted into halogen atom or known leavings group 1.In this case, the example of leavings group comprises methane sulfonyl oxygen base, trifluoromethane sulfonyl group oxygen base, benzenesulfonyl oxygen base and p-toluenesulfonyl oxygen base.
Step 10 is bromination step of hydroxyl.It is unaccommodated carrying out bromination reaction under the typical strong acid condition of Hydrogen bromide-vitriol oil, Sodium Bromide-sulfuric acid etc., because the tert-butyl ester is arranged in the molecule.Bromination reaction is suitable reaction, use the methylene dichloride or the tetrahydrofuran (THF) of triphenylphosphine-tetrabromomethane, the N of dibrominated triphenylphosphine is used in reaction, dinethylformamides etc. are [referring to Journal ofAmerican Chemical Society, the 125th volume, the 43rd phase, the 13625th page (2003)].In addition, in this bromination reaction, N, Tetrabutyl amonium bromide in the dinethylformamide or Vilsmeier reagent [((chlorine methylene radical) dimethyl chlorination imonium] can be used as reagent.After hydroxylic moiety was converted into suitable leavings group, with being dissolved in N, the bromide reagent in dinethylformamide or the dimethyl sulfoxide (DMSO) (for example Sodium Bromide, lithiumbromide or Calcium Bromide) can carry out bromination reaction.In this case, the example of leavings group comprises methane sulfonyl oxygen base, trifluoromethane sulfonyl group oxygen base, benzenesulfonyl oxygen base and p-toluenesulfonyl oxygen base.
The present inventor has synthesized such compound: wherein the 1-bromopropyl is introduced the 3-position of pyrrolidine ring, as the compound that is used for next step.Next step is spendable, be not the compound that the examples for compounds of this product comprises the 1-iodo compound and wherein introduces leavings group, described leavings group is methane sulfonyl oxygen base, trifluoromethane sulfonyl group oxygen base, benzenesulfonyl oxygen base or p-toluenesulfonyl oxygen base for example.
Step 11 is (acid amides: the alpha-position of pyrrolidone) go up the step that produces carbanion in step 10 a synthetic bromine compounds pyrrolidine ring 4-position, use suitable alkali, cause the reaction that forms carbon-to-carbon double bond by internal nucleophilic substitution (intramolecular ring-closing reaction).The representative instance of alkali comprises salt of wormwood, cesium carbonate, sodium hydride, sodium Metal 99.5, sodium ethylate, potassium tert.-butoxide, lithium diisopropylamine (LDA), two (trimethyl silyl) Lithamide, two (trimethyl silyl) potassium amides and two (trimethyl silyl) sodium amide.The example of reaction solvent comprises tetrahydrofuran (THF), acetone, N, dinethylformamide, toluene and mixed solvent thereof.The formed pentamethylene ring of intramolecular ring-closing reaction can form cis-fused rings (cis-3-azabicyclo [3.3.0] octane ring) with the pyrrolidine ring part usually.This synthetic method can be used for synthetic fused substituted aminopyrrolidine derivative, 3-azabicyclo [4.3.0] nonane derivatives for example, but can produce the cis of fused substituted aminopyrrolidine derivative and the mixture of trans-isomer(ide).In this case, can separate necessary isomer by suitable separation and purification operation (for example silica gel chromatography).
Step 12 is by hydrolysis or deprotection and the tert-butyl ester is converted into the step of carboxylic acid.The present inventor has selected the tert-butyl ester as ester; Yet ester is suitably the alkyl ester with 1-6 carbon atom, preferred methyl esters, ethyl ester or the tert-butyl ester.The tert-butyl ester is hydrolysis or deprotection in suitable solvent, wherein ester acidic conditions or in the presence of acid catalyst solubilized.Preferred acid comprises hydrochloric acid, formic acid, acetate, trifluoroacetic acid and tosic acid.In the hydrolysis of methyl esters or ethyl ester; ester and basic solution (for example ethanol of the ethanol of the ethanol of sodium hydroxide or the aqueous solution, potassium hydroxide or the aqueous solution or hydrated barta or the aqueous solution) reaction; come acidifying, separation and purification again with the appropriate acid that does not influence 3-position protecting group then.
Step 13 is the steps that the carboxylic acid of 3-azabicyclo [3.3.0] octane ring 1-position are converted into amine.Usually by rearrangement reaction, carry out this step from carboxylic acid to amine.For example; when rearrangement reaction is Curtius (Curtius) rearrangement reaction; at suitable solvent for example in the toluene; with reagent for example sodiumazide, trimethyl silyl nitrine or two phenoxy group phosphoryl azides (DPPA); carboxylic acid is converted into acid azide; with reaction soln heating, forming isocyanic ester again, is amine by the hydrolysis with hydrochloric acid etc. with isocyanate conversion again.
Step 14 is protection steps of the amino of 1-amino-3-azabicyclo [3.3.0] octane ring 1-position; Yet subsequent step can carry out under the condition of not having this protection.The protecting group of 1-bit amino can be the amino protecting group of using always, can distinguish the protecting group that comes with 3-position protecting group but be preferably in deprotection steps.The specific examples of protecting group comprises tert-butoxycarbonyl, ethanoyl and trifluoroacetyl group.The present inventor has selected tert-butoxycarbonyl.
Use the trinitride reagent in the suitable solvent, by rearrangement reaction, can a step completing steps 13 and a step 14.For example,, use the t-butanol solution of two phenoxy group phosphoryl azides (DPPA), preparation 1-(tert-butoxycarbonyl) amino-3-azabicyclo [3.3.0] Octane derivatives by Curtius (Curtius) rearrangement reaction.
Step 15 is reduction steps of the carboxyl of pyrrolidone (being called acid amides).Use metal hydride for example lithium aluminum hydride or two (2-methoxy ethoxy) sodium aluminum hydride or borohydride compound for example diboron hexahydride or borane-tetrahydrofuran complex can carry out steps 15 as reductive agent.With toluene or tetrahydrofuran (THF) is that the ether solvents of representative is usually as solvent.Reaction is carried out under-78 ℃ to 100 ℃ temperature usually.
Step 16 is deprotection steps of pyrrolidine ring 1-position.Deprotection reaction can carry out under the condition that does not change other functional group and configuration.Therefore; since the 1-position protecting group of The compounds of this invention is (1R)-1-phenylethyl; so under deprotection condition commonly used, carry out deprotection reaction; for example; using catalyzer for example under the condition of palladium-carbon, perhaps use ammonium formiate, in proton polar solvent, carry out deprotection reaction by the catalytic hydrogenolysis.When intramolecularly has carbon-to-carbon unsaturated bond as substituting group, also must keep carbon-to-carbon unsaturated bond when carrying out deprotection.Therefore, since the 1-position protecting group of The compounds of this invention is (1R)-1-phenylethyl, thus also keep carbon-to-carbon unsaturated bond in the molecule deprotection time, promptly by using for example sodium-liquid ammonia (Birch reductive condition).By Feng's Braun (von Braun) reaction, use usually at the solvent chloroformic acid benzyl ester in the methylene dichloride for example, 1-position (1R)-1-phenylethyl is converted into after the benzyloxycarbonyl, group can pass through the aforesaid method deprotection.
In addition, formerly synthetic corresponding heterogeneous ring compound (important synthesis intermediates) afterwards can be by common synthetic method etc., and formation is as the pyrrolidine ring of the fused substituted aminopyrrolidine derivative of The compounds of this invention, referring to following flow process:
[formula 60]
R wherein
13For ester group, formamyl, nitro or the cyano group (it can be converted into amino) with 2-7 carbon atom maybe can have substituent amino; PG is an amino protecting group; R
14And R
15Be the known suitable substituent that combines, optional then experience suitable reactions and form pyrrolidine ring; R
3, R
4, R
5, R
6, R
7, Y and n as above define.
Substituent R
13Be preferably and have 2-7 carbon atom and can have substituent ester group or amino, especially preferably form all stable group in each reactions steps of reaction at following cited pyrrolidine ring.
At this, substituent R will be described
14And R
15And pyrrolidine ring formation method, wherein R
14And R
15Combine optional then experience suitable reactions.
Work as substituent R
14And R
15Methylol (CH respectively does for oneself
2OH) time, can be by being converted into alkylation again behind halogen atom or the suitable leavings group with the direct alkylation of primary amine or with hydroxylic moiety, and form pyrrolidine ring.The preferred embodiment of halogen atom comprises chlorine, bromine and iodine.The example of leavings group comprises methane sulfonyl oxygen base, trifluoromethane sulfonyl group oxygen base, benzenesulfonyl oxygen base and p-toluenesulfonyl oxygen base.
Work as substituent R
14And R
15When respectively doing for oneself carboxyl, ester group or acyl halide; can or pass through by direct synthetic diimide derivative to synthesize diimide derivative by suitable condensation reaction institute synthetic acid anhydrides; with the imide reduction, synthetic intermediate is converted into pyrrolidin derivatives then.Ester group preferably has 2-7 carbon atom.Use metal hydride for example lithium aluminum hydride or two (2-methoxy ethoxy) sodium aluminum hydride or borohydride compound for example diboron hexahydride or borane-tetrahydrofuran complex reduce imide as the imide reductive agent.The ether solvents that with the tetrahydrofuran (THF) is representative is usually as solvent.Reaction is carried out under-78 ℃ to 100 ℃ temperature usually.
Work as substituent R
14And R
15In one be amino methyl (CH
2NH
2), and another comes synthesizing amide derivative (lactam derivatives) by suitable condensation reaction when being carboxyl or ester group, then with reduction of amide, synthetic intermediate is converted into pyrrolidin derivatives.Ester group preferably has 2-7 carbon atom.Usually in alcoholic solvent, exist or not heating and synthesizing amide derivative (lactam derivatives) under the existence condition in appropriate base.Use metal hydride for example lithium aluminum hydride or two (2-methoxy ethoxy) sodium aluminum hydride or borohydride compound for example diboron hexahydride or borane-tetrahydrofuran complex as imide reductive agent, reducing amide.The ether solvents that with the tetrahydrofuran (THF) is representative is usually as solvent.Reaction is carried out under-78 ℃ to 100 ℃ temperature usually.The substituent R that is used for the precursor of synthetic intermediate amide derivatives (lactam derivatives)
14And R
15In one can be nitro methyl (CH
2NO
2), azido methyl (CH
2N
3) or cyano group (CN) (in this case, another substituting group is carboxyl or ester group).By in reduction step, substituting group being converted into amino methyl (CH
2NH
2), carry out condensation reaction then, can with precursor conversion amide derivatives (lactam derivatives).Use the catalytic hydrogen reduction; Metal hydride is lithium borohydride, lithium aluminum hydride or two (2-methoxy ethoxy) sodium aluminum hydride for example; Or borohydride compound for example diboron hexahydride or borane-tetrahydrofuran complex, carry out reduction step.In addition, work as substituent R
14And R
15In one be methylol (CH
2OH) or halogenated methyl, and another is when being carboxyl or ester group, can be with the synthetic lactone derivatives is converted into lactam derivatives by suitable condensation reaction.
Work as substituent R
14And R
15In one be amino methyl (CH
2NH
2), and another comes the synthesis of cyclic imine derivative by using suitable condensation reaction when being formyl radical, makes imines reduction (specifically, the reductive amination reaction) then, and synthetic intermediate is converted into pyrrolidin derivatives.Can be by making imines experience catalytic hydrogen reduction and suitable condensation reaction, synthesizing amide derivative (lactam derivatives) makes reduction of amide then, and synthetic intermediate is converted into pyrrolidin derivatives.
Work as substituent R
14And R
15In one be methyl, and another be N-halo amino methyl (for example-CH
2NCl-) time, can form pyrrolidine ring (Hofmann-Loeffler-Freitag tetramethyleneimine building-up reactions) by free radical reaction.
Some representative pyrrolidine ring formation methods are example with the following flow process of synthetic 3-benzyl-1-(tert-butoxycarbonyl)-3-azabicyclo [3.3.0] Octane derivatives, and this derivative is the synthetic intermediate that is used for representative compounds 1-amino of the present invention-3-azabicyclo [3.3.0] Octane derivatives:
[formula 61]
According to the above description of finding novel synthesis, those skilled in the art can make amendment to the reaction that is used for synthetic fused substituted aminopyrrolidine derivative in the above step of giving an example, and above description should not be considered as restriction.
In order to produce the included compound of the present invention, be the quinolonecarboxylic acid precursor skeleton compound and 1-(tert-butoxycarbonyl) amino-3-azabicyclo [3.3.0] the octane reaction of representative promptly by introducing 7-position (10-position) substituting group of 1-(tert-butoxycarbonyl) amino-3-azabicyclo [3.3.0] Octane derivatives (it is the fused substituted aminopyrrolidine derivative that obtains as described above), can making with the following formula as quinolonecarboxylic acid precursor skeleton (pyrido-benzoxazine formic acid precursor skeleton):
[formula 62]
R wherein
8, R
9, R
11, X
1And A
1As above definition; R
101Represent hydrogen atom, have the alkyl or the boron substituting group (it can form Boron chelate complexes) of 1-6 carbon atom; Represent leavings group with X.
Preferred embodiment with alkyl of 1-6 carbon atom comprises methyl, ethyl, sec.-propyl and the tertiary butyl.The boron substituting group can be dihalo boryl or two acyloxy boryls.The dihalo boryl is preferably difluoro boryl (BF
2).Two acyloxy boryls are preferably diacetyl oxygen base boryl [B (OAc)
2].Can obtain these boron substituting groups according to currently known methods.
The preparation of this compounds that the present invention is included will be that example is described with the compound of following embodiment 11:
[formula 63]
Can be by quinolonecarboxylic acid precursor skeleton compound be dissolved in the suitable solvent, and this compound and (-)-1-(tert-butoxycarbonyl) amino-3-azabicyclo [3.3.0] octane (its be used for introducing in the presence of alkali and as the compound of 7-bit substituent) are reacted, can obtain target compound.Be used for introducing and can protect by protected base as the amino of the compound of 7-bit substituent.Except that tert-butoxycarbonyl (Boc yl), the example of protecting group also comprises benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, ethanoyl, methoxyl group ethanoyl, trifluoroacetyl group, valeryl, formyl radical, benzoyl, the tertiary butyl, benzyl, trimethyl silyl and sec.-propyl dimetylsilyl.The example of operable alkali comprises carbonate, supercarbonate or the hydroxide salt of basic metal or alkaline-earth metal; Trialkylamine, for example triethylamine and N, N-diisopropylethylamine; And nitrogen-containing heterocycle compound, for example pyridine, 1,8-diazabicyclo undecylene and N-methyl piperidine.Preferred trialkylamine, N-methyl piperidine and triethylamine.Solvent for use is not specifically limited, needs only its not inhibited reaction.Solvent is preferably N, dinethylformamide, dimethyl sulfoxide (DMSO), tetramethylene sulfone, acetonitrile, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF) or N-Methyl pyrrolidone, especially preferred dimethyl sulfoxide (DMSO), tetramethylene sulfone, acetonitrile or N,N-DIMETHYLACETAMIDE.
When quinolonecarboxylic acid precursor skeleton compound is the boron chelate compound, can pass through hydrolytic rupture boron substituting group part, make the amino protecting group deprotection then, and obtain target compound.The boron substituting group can hydrolysis under condition commonly used.For example, can be by in the presence of aqueous alcohol solvent (for example methyl alcohol or ethanol) and alkali reaction and hydrolysis boron substituting group.Alkali is preferably triethylamine.Reaction is preferably being carried out in ice-cooled temperature range between to 90 ℃.Deprotection carries out under by the condition that is suitable for used protecting group with for example concentrated hydrochloric acid treating water hydrolysis products.After reaction was finished, reaction soln was used suitable acid (for example hydrochloric acid) neutralization then with for example sodium hydroxide solution alkalization; The crystal of subsequent filtration collecting precipitation or use chloroform extraction; With the gained compound suitable by the recrystallization operation, for example use that suitable solvent comes purifying, to obtain target compound.
In the presence of suitable solvent and catalyzer, optional and part coexistence down, and in the presence of alkali, the reaction of the quinolone framework compound by fused substituted aminopyrrolidine derivative and following formula, can prepare carbostyril compound of the present invention, especially on the 8-position, have those of methyl:
[formula 64]
This reaction can be carried out under the situation of part not having.
The substituent R of quinolone framework compound
101Be hydrogen atom or alkyl with 1-6 carbon atom.The example of preferred alkyl is methyl, ethyl, sec.-propyl and the tertiary butyl.For leavings group X
1, commonly used those in this area also preferably are applicable to this reaction.The preferred embodiment of this class leavings group is for example bromine atoms or an iodine atom of halogen atom; Substituted sulphonyl oxygen base, for example trifluoromethane sulfonyl group oxygen base.For catalyzer, commonly used those in this area also preferably are applicable to this reaction.Preferred Pd catalyzer, Cu catalyzer or Ni catalyzer, more preferably Pd catalyzer or the Cu catalyzer of using.Catalyzer is applicable to the reaction mixture that is following form: three (dibenzalacetones) close two palladiums (0), acid chloride (II), four (triphenylphosphines) and close nickel (0), acetylacetonate nickel (II), cuprous iodide (I) or cuprous bromide (I) etc.React used part for the present invention, this area unidentate ligand or bitooth ligand commonly used is preferred for this reaction.The example of these parts is 1, two (diphenylphosphino) ferrocene, 4 of 1-, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene or BINAP.For alkali, commonly used those in this area preferably are applicable to this reaction.Preferred alkaline-earth metal or alkali-metal carbonate (for example cesium carbonate, salt of wormwood or yellow soda ash) and alkali alcoholate for example sodium methylate, sodium ethylate or the potassium tert.-butoxide of using.
This reacts referring to following reaction process:
[formula 65]
In suitable solvent, in the presence of catalyzer, optional and part coexists down, and in the presence of alkali, by with quinolonecarboxylic acid framework compound and the reaction of fused substituted aminopyrrolidine compound, obtains carbostyril compound of the present invention.The amino that condenses the substituted azole hydride compounds that is used to introduce the 7-bit substituent can have protecting group.The example of this class protecting group is an alkoxy carbonyl, for example tert-butoxycarbonyl; Aromatic alkoxy carbonyl, for example benzyloxycarbonyl or to methoxyl group benzyloxy base carbonyl; Acyl group or alkyl-carbonyl, for example ethanoyl, methoxyl group ethanoyl, trifluoroacetyl group, valeryl or formyl radical; Aromatic alkyl carbonyl, for example benzoyl or p-nitrophenyl formyl radical; Alkyl, for example tertiary butyl; Aralkyl, for example benzyl, to methoxy-benzyl or to nitrobenzyl; Replace silyl, for example trimethyl silyl or sec.-propyl dimetylsilyl.The example that is used for the alkali of this reaction is carbonate, supercarbonate, phosphoric acid salt, hydrate or the alkoxide of alkali metal atom or alkaline earth metal atom; Trialkylamine, for example triethylamine or N, N-diisopropylethylamine; Nitrogen-containing heterocycle compound, for example pyridine, 1,8-diazabicyclo undecylene or N-methyl piperidine.For solvent, any solvent of inhibited reaction all preferably is not applicable to this reaction.The example of solvent is an acid amides, N for example, dinethylformamide, N,N-dimethylacetamide or N-N-methyl-2-2-pyrrolidone N-; Aryl hydrocarbon, for example toluene or dimethylbenzene; Ether, tetrahydrofuran (THF), 1 for example, 4-diox or 1,2-glycol dimethyl ether; And acetonitrile.Preferred solvent is N, dinethylformamide, dimethylbenzene, 1,4-diox or 1,2-glycol dimethyl ether.
Reaction should be carried out with the form of homogeneous phase and heterogeneous reaction.Reaction is also preferably carried out in the catalysis phase reaction.Be reflected in 10 minutes to 7 days and finish.Reaction can carried out in 0 ℃ to 300 ℃ temperature range, preferably between 30 ℃ to the temperature of the boiling temperature of solvent for use.Before adding other compound of reaction, catalyst compound and ligand compound can be mixed to form catalyst complex, perhaps all reactive components can mix once.The catalyst consumption scope be catalytic amount to equimolar amount, the preferred catalytic amount.
Have at the quinolone framework compound under the situation of ester moiety,,, obtain carboxylic compound by the ester group cracking according to means known in the art.According to the currently known methods of corresponding protecting group, the cracking by fused substituted aminopyrrolidine is partly gone up amino part protecting group obtains carbostyril compound.After the protecting group cracking, isolate carbostyril compound according to means known in the art (for example recrystallization from suitable solvent etc.).
The production intermediate that can be used as The compounds of this invention (I) with the following two formulas compound that is representative respectively:
[formula 66]
In following formula, R
11The R that representative has defined
1(hydrogen atom has the alkyl of 1-6 carbon atom, has the cycloalkyl of 3-6 carbon atom or derived from the substituted carbonyl of amino acid, dipeptides or tripeptides; Described alkyl can have and is selected from following substituting group: hydroxyl, amino, cyano group, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom) or amino protecting group;
R
21The R that representative has defined
2(hydrogen atom, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom; Alkyl can have and is selected from following substituting group: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom) or amino protecting group; With
R
3, R
4, R
5, R
6And R
7As defining.
At this, R will be described
11Or R
21The amino protecting group of representative.The limiting protecting base is not commonly used as long as it is this area.The example of protecting group comprises alkoxy carbonyl, tert-butoxycarbonyl and 2,2 for example, 2-trichlorine ethoxy carbonyl; Aromatic alkoxy carbonyl, for example benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl with to the nitro benzyloxycarbonyl; Acyl group, for example ethanoyl, methoxyl group ethanoyl, trifluoroacetyl group, chloracetyl, valeryl, formyl radical and benzoyl; Alkyl or aralkyl, for example the tertiary butyl, benzyl, to nitrobenzyl, to methoxy-benzyl and trityl group; Ether, for example methoxymethyl, tert.-butoxy methyl, THP trtrahydropyranyl and 2,2,2-trichlorine ethoxyl methyl; The silyl that (alkyl-and/or aralkyl-) replaces, for example trimethyl silyl, sec.-propyl dimetylsilyl, t-butyldimethylsilyl, tribenzyl silyl and t-butyldiphenylsilyl; And allyl group.
[formula 67]
In following formula, R
16Represent amino protecting group; R
11, R
21, R
3, R
4, R
5, R
6And R
7As defining.
Do not limit R
16The protecting group of representative, commonly used as long as it is this area.The example of protecting group comprises alkoxy carbonyl, tert-butoxycarbonyl and 2,2 for example, 2-trichlorine ethoxy carbonyl; Aromatic alkoxy carbonyl, for example benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl with to the nitro benzyloxycarbonyl; Acyl group, for example ethanoyl, methoxyl group ethanoyl, trifluoroacetyl group, chloracetyl, valeryl, formyl radical and benzoyl; Alkyl or aralkyl, for example the tertiary butyl, benzyl, to nitrobenzyl, to methoxy-benzyl and trityl group; Ether, for example methoxymethyl, tert.-butoxy methyl, THP trtrahydropyranyl and 2,2,2-trichlorine ethoxyl methyl; The silyl that (alkyl-and/or aralkyl-) replaces, for example trimethyl silyl, sec.-propyl dimetylsilyl, t-butyldimethylsilyl, tribenzyl silyl and t-butyldiphenylsilyl; And allyl group.
Work as R
11, R
21And R
16In two or more when being protecting group, can select any protecting group according to the general knowledge of this area, protecting group can be removed by selectivity.
According to the experimental example of describing later, know, 7-position at quinolonecarboxylic acid precursor skeleton (or its corresponding position) is had anti-microbial activity by the compound that obtains as mentioned above (compound with embodiment X is representative) that condensed-bicyclic amino-pyrrolidine derivatives of the present invention replaces, specifically, at stronger than this area levofloxacin commonly used or Ciprofloxacin of the anti-microbial activity of streptococcus aureus and gram-positive microorganism (for example streptococcus pneumoniae).Verified in this case, in the 7-bit substituent, be asymmetric carbon, and had more high reactivity and show more superior characteristic, pharmacokinetic properties and security by the quinolonecarboxylic acid that the 7-bit substituent from an enantiomorph replaces by the amino site that replaces.By the result of the mensuration of the synthetic and anti-microbial activity of chirality pond (chiral pool) method, confirmed that it is the configuration of representative that the 7-bit amino has with the following formula as the X-ray crystallography of high reactivity 7-bit substituent or every kind of enantiomorph:
[formula 68]
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7With Q as defining.
The compounds of this invention can be a free form.Perhaps, the salt that can form acid salt or form with carboxyl.The example of acid salt comprises inorganic acid salt, for example hydrochloride, vitriol, nitride (nitride), hydrobromate, hydriodate and phosphoric acid salt; And organic acid salt, for example sulfonate (for example mesylate, benzene sulfonate, tosilate) and carboxylate salt (for example acetate, Citrate trianion, maleate, fumarate, lactic acid salt).The example of the salt that forms with carboxyl comprises an alkali metal salt, for example lithium salts, sodium salt and sylvite; Alkaline earth salt, for example magnesium salts and calcium salt; Ammonium salt, triethylamine salt, N-methylglucosamine salt and three-(methylol) aminomethane salt.Be the acid salt of the The compounds of this invention of free form and compound or can be hydrate forms with salt that carboxyl forms.
Compound of the present invention (I) has strong anti-microbial activity, therefore can be used as people's medication, animal-use drug and fish medication, agrochemicals or food antiseptics.As people's medication, the used dosage of The compounds of this invention is adult 50mg to 1g every day, more preferably 100mg to 500mg.Animal is with dosage different and different because of administration purpose, the animal size for the treatment of, pathogenic agent kind that animal infected and disease severity; Daily dosage portion is generally animal per kg body weight 1mg to 200mg, more preferably 5mg to 100mg.Daily dosage portion gives once every day, or gives with 2-4 fractionated dose.In case of necessity, daily dosage portion can exceed above dosage.
Compound of the present invention (I) all has activity to the broad-spectrum micro-organisms that causes various infection, and can treat, prevents or alleviate the disease that is caused by these pathogenic agent.The compounds of this invention comprises Staphylococcus (Staphylococcus) to the example of its effective bacterium or bacterium sample microorganism, streptococcus pyogenes (Streptococcus pyogenes), Hemolytic streptococcus, faecalis, streptococcus pneumoniae, Peptostreptococcus (Peptostreptococcus), gonococcus, intestinal bacteria (Escherichiacoli), Citrobacter (Citrobacter), Shigellae (Shigella), Klebsiella pneumonia (Klebsiella pneumoniae), enterobacter (Enterobacter), serratia (Serratia), proteus (Proteus), Pseudomonas aeruginosa (Pseudomonasaeruginosa), Haemophilus influenzae (Haemophilus infiuenzae), acinetobacter (Acinetobacter), campylobacter (Campylobacter) and chlamydia trachomatis (Chlamydiatrachomatis).
The example of disease that these pathogenic agent cause comprises folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis, paronychia, subcutaneous abscess, spiradenitis, acne conglobata, infectious sebaceous cyst, perirectal abscess, mazoitis, shallow table secondary infection is traumatic infection for example, burn infection or surgical wound infection, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, dispersivity bronchiolitis (diffuse panbronchiolitis), the infection of chronic respiratory disease secondary, pneumonia, pyelonephritis, urocystitis, prostatitis, epididymitis, gonococcal urethritis, non gonococcal urethritis, cholecystitis, cholangitis, shigellosis, enteritis, adnexitis, intrauterine infection, bartholinitis, blepharitis, sty, dacryocystitis, meibomitis, keratohelcosis, otitis media, sinusitis paranasal sinusitis, periodontitis, pericoronitis, ganathitis disease, peritonitis, endocarditis, sepsis, meningitis and skin infections.
The compounds of this invention (I) comprises tubercule bacillus (mycobacterium tuberculosis (Mycobacterium tuberculosis) to the example of its effective mycobacterium, Mycobacterium bovis (M.bobis) and mycobacterium africanum (M.africanum)) and atypical mycobacterium (mycobacterium kansasii (M.cansasii), Mycobacterium marinum (M.marinum), scrofula mycobacterium (M.scrofulaceum), mycobacterium avium (M.avium), Mycobacterium intracellulare (M.intracellulare), mycobacterium littorale (M.xenopi), mycobacterium fortutitum (M.fortuitum) and Mycobacterium chelonei (M.chelonae)).The caused mycobacterial infections of these pathogenic agent broadly is divided into tuberculosis, atypical mycobacterial infections and leprosy.Except lung, m tuberculosis infection is also observed in following position: thoracic cavity, trachea and bronchus, lymphoglandula, whole body disperse distribution, osteoarthrosis, meninx and brain, digestion organs (intestines and liver), skin, mammary gland, eye, middle ear and throat, urethra, genital orgnas,male and female sex organ.Atypical mycobacterial infections (non tuberculous Mycobacterium infection) mainly influences lung, also can occur in following infection: regional nodes's inflammation, skin soft-tissue infection, osteoarthritis or whole body dispersivity infect.
The compounds of this invention is also effective to causing animal infected various microorganism, for example Escherichia (Escherichia), salmonella (Salmonella), pasteurella (Pasteurella), hemophilus (Haemophilus), bordetella bacillus (Bordetella), Staphylococcus (Staphylococcus) and Mycoplasma (Mycoplasma).The specific examples of Animal diseases comprises ornithosis, for example colibacillosis, white dysentery, bird paratyphoid, bird cholera, infectious rhinitis, staphylococcosis and mycoplasma infection; Swine disease, for example colibacillosis, salmonellosis, pasteurellosis, hemophilus infection, atrophic rhinitis, exudative epidermitis and mycoplasma infection; Cattle disease, for example colibacillosis, salmonellosis, hueppe's disease, mycoplasma infection, infectivity pleuropneumonia and mazoitis; Dog disease, for example colisepsis, Salmonella infection, hueppe's disease, pyometra and urocystitis; And cat disease, for example wet pleurisy, urocystitis, chronic rhinitis, hemophilus infection, kitten diarrhoea and mycoplasma infection.
According to the preparation method of medication and the various common dosage forms of preparation, can select to contain the antibacterials of The compounds of this invention (I) aptly.Contain The compounds of this invention and comprise tablet, pulvis, granule, capsule, solution, syrup, elixir and oiliness or aqueous suspension as the example of the antibacterials formulation of main ingredient.Injection preparation can contain additive, for example stablizer, sanitas or solution auxiliary, and can prepare by solid preparation before use, this solid preparation be by for example in container, deposit the solution that contains additive, this solution of freeze-drying makes then.A dosage can be deposited in the container, perhaps a plurality of dosage can be deposited in a container.The example of external preparation comprises solution, suspensoid, emulsion, ointment, gelifying agent, ointment, lotion and sprays.Solid preparation can contain pharmaceutically acceptable additive and active compound.The example of additive comprises weighting agent, tackiness agent, disintegrating agent, solution promotor (solution promoter), wetting agent and lubricant.Liquid preparation can be solution, suspensoid, emulsion etc., and can contain additive, for example suspension agent or emulsifying agent.
Below, preparation embodiment will be described.
Preparation embodiment 1[capsule]:
The compound 100.0mg of embodiment 11
W-Gum 23.0mg
Calcium carboxymethylcellulose 22.5mg
Walocel MT 20.000PV 3.0mg
Magnesium Stearate 1.5mg
Amount to 150.0mg
Preparation embodiment 2[pharmaceutical solutions]:
The compound 1-10g of embodiment 11
Acetate or sodium hydroxide 0.5-2g
Ethyl p-hydroxybenzoate 0.1g
Pure water 87.9-98.4g
Amount to 100g
Preparation embodiment 3[treats and feed blended pulvis]
The compound 1-10g of embodiment 17
W-Gum 89.5-98.5g
Light anhydrous silicic acid 0.5g
Amount to 100g
Embodiment
To specifically describe the present invention with reference example below; Yet the present invention is not limited to embodiment, and these embodiment should not be considered as restricted embodiment going up in all senses.
[reference example 1]
(S)-3-(t-butyldimethylsilyl oxygen base)-2 Methylpropionic acid methyl esters
[formula 69]
With imidazoles (13.3g, 196mmol) and tert-butyldimethylsilyl chloride (14.2g, 94.1mmol) (11.0g, in dimethyl formamide 93.1mmol) (100ml) solution, mixture at room temperature stirred 4 hours to join (S)-3-hydroxy-2-methyl methyl propionate.Water is joined in the reaction mixture, then use hexane extraction 2 times.Extraction liquid is again through dried over mgso.After the filtration, solvent evaporated under reduced pressure obtains 24g (quantitatively) title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：3.76-3.72(1H，m)，3.64(3H，s)，3.63-3.59(1H，m)，2.65-2.57(1H，m)，1.10(3H，d，J＝6.84Hz)，0.84(9H，s)，0.01(3H，s)，0.00(3H，s)。
[reference example 2]
(E)-(R)-5-(t-butyldimethylsilyl oxygen base)-4-methylpent-2-olefin(e) acid methyl esters
[formula 70]
At-78 ℃, with the diisobutyl aluminium hydride (hexane solution of 1M, (20g in methylene dichloride 86.1mmol) (400ml) solution, stirs mixture 2 hours under same temperature 86ml) to join (S)-3-(t-butyldimethylsilyl oxygen base)-2 Methylpropionic acid methyl esters.Saturated potassium sodium tartrate solution is joined in the reaction mixture, then it is heated to room temperature while stirring.Separate organic layer, water layer ethyl acetate extraction then.Merge organic layer, through dried over mgso and filtration, again with solvent removed under reduced pressure.Resistates is dissolved in the methylene dichloride (200ml).
Add down inferior phosphono (phosphonylidene) methyl acetate of triphenyl (32g 94.7mmol), at room temperature stirs mixture and to spend the night ice-cooled.Filtering reacting solution is then with solvent removed under reduced pressure.Hexane is joined in the gained resistates, remove by filter insolubles.Filtrate is through concentrating under reduced pressure, and the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain 25g (quantitatively) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：6.94(1H，dd，J＝7.10，15.90Hz)，5.84(1H，dd，J＝1.20，15.90Hz)，3.73(3H，s)，3.57-3.49(2H，m)，2.53-2.46(1H，m)，1.05(3H，d，J＝6.80Hz)，0.89(9H，s)，0.04(6H，s)。
[reference example 3]
The 1-benzyl-4-[(R)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-3-
Methyl-formiate
[formula 71]
With N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (16.6ml, 65.0mmol) join (E)-(R)-5-(t-butyldimethylsilyl oxygen base)-4-methylpent-2-olefin(e) acid methyl esters (14g, 54.2mmol) methylene dichloride (100ml) solution in, add the trace trifluoroacetic acid then.Mixture was stirred 30 minutes, add saturated sodium bicarbonate aqueous solution then.Separate organic layer and through dried over mgso.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain the title compound of 14.6g (69%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 4]
4-[(R)-and 2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-1, the 3-diformazan
Acid 1-benzyl ester 3-methyl esters
[formula 72]
With benzyloxycarbonyl chlorine (10.2ml, 71.5mmol) join 1-benzyl-4-[(R)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-3-methyl-formiate (14.0g, 35.8mmol) methylene dichloride (200ml) solution in, mixture was stirred 1 hour.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture.Separate organic layer, through dried over mgso and filtration.Then, solvent evaporated under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain the title compound of 13.9g (89%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 5]
4-[(R)-and 2-hydroxyl-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters
[formula 73]
Under ice-cooled, (4ml) joins 4-[(R with hydrogen fluoride-pyridine)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl]-tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters (6.0g, 7.1mmol) pyridine (20ml) solution in, mixture was at room temperature stirred 13 hours.Reaction mixture is poured in the frozen water, also used 1N hydrochloric acid and salt water washing with ethyl acetate extraction then.Through dried over mgso and after filtering, solvent evaporated under reduced pressure obtains the title compound of 4.1g (93%) non-enantiomer mixture, is colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 6]
4-[(R)-2-iodo-1-(methyl) ethyl]-tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters
[formula 74]
Under ice-cooled, with triethylamine (2.7ml, 19.1mmol) and methylsulfonyl chloride (1.2ml, 15.3mmol) join 4-[(R)-2-hydroxyl-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters (4.1g, 12.8mmol) methylene dichloride (100ml) solution in, then mixture was at room temperature stirred 30 minutes.After joining methyl alcohol in the reaction mixture, the mixture of gained mixture with ethyl acetate and 10% citric acid solution mixed.Organic layer is with the salt water washing and through dried over mgso.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in acetone (100ml).(4.1g 27.4mmol), refluxes mixture heating up 20 hours to add sodium iodide.Reaction mixture is then with solvent removed under reduced pressure.The gained resistates mixes with the mixture of ethyl acetate and water.Organic layer, filters, with solvent removed under reduced pressure through dried over mgso then with saturated sodium thiosulfate solution and salt water washing.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 7: 3), obtain the title compound of 5.0g (84%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.33(5H，m)，5.13(2H，s)，3.83-3.71(4H，m)，3.58-3.51(1H，m)，3.27-3.23(1H，m)，3.18-3.09(2H，m)，2.92-2.83(1H，m)，2.64-2.55(1H，m)，1.81-1.75(1H，m)，1.53-1.48(1H，m)，1.06-1.01(3H，m)。
[reference example 7]
(S)-and 6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester 1-methyl esters
[formula 75]
Under argon atmospher, at-78 ℃, with toluene solution (28ml 14.0mmol) is added drop-wise to 4-[(R)-2-iodo-1-(methyl) ethyl of 0.5M hexamethyl two silicon nitrine potassium] tetramethyleneimine-1, (5.0g is in anhydrous tetrahydro furan 11.5mmol) (100ml) solution for 3-dioctyl phthalate 1-benzyl ester 3-methyl esters.After being added dropwise to complete, mixture was stirred 30 minutes under same temperature.Add ammonium chloride solution, with mixture heating up to room temperature.Behind ethyl acetate extraction, through dried over mgso, and filter, solvent removed under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 7: 3), obtain the title compound of 3.2g (91%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.32(5H，m)，5.17-5.14(2H，m)，3.94(0.5H，dd，J＝10.86，18.92Hz)，3.76-3.69(5H，m)，3.46(0.5H，d，J＝11.72Hz)，3.36(0.5H，dd，J＝6.10，11.47Hz)，3.25(0.5H，dd，J＝8.06，11.96Hz)，3.06(0.5H，t，J＝8.30Hz)，2.73-2.65(1.5H，m)，2.13-2.09(1.5H，m)，1.11(1.5H，d，J＝6.10Hz)，0.94(1.5H，brs)。
[reference example 8]
(S)-and 6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester
[formula 76]
Under ice-cooled, 1N sodium hydroxide solution (21ml) is added drop-wise to (S)-6-methyl-3-azabicyclo [3.2.0] heptane-1, (3.2g in the mixing solutions of tetrahydrofuran (THF) 10.4mmol) (60ml) and methyl alcohol (20ml), stirs mixture 30 minutes 3-dioctyl phthalate 3-benzyl ester 1-methyl esters.Reaction soln is used ethyl acetate extraction then with the neutralization of 1N hydrochloric acid.Extract is through dried over mgso and filtration.Solvent evaporated under reduced pressure obtains the title compound of 3.0g (quantitatively) non-enantiomer mixture, is colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 9]
(S)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate (revolves
Photoisomer A, optically active isomer B)
[formula 77]
At room temperature, with triethylamine (2.9ml, 20.7mmol) and two phenoxy group phosphoryl azide (3.4ml, 15.6mmol) join (S)-6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester (3.0g, 10.4mmol) toluene (60ml) solution in, add the trimethyl carbinol (60ml) then.Mixture heats and stirred 15 hours at 100 ℃.Reaction mixture is then with solvent removed under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 8: 2), obtain the title compound (3.1g) of non-enantiomer mixture, be colorless oil.Diastereomer Chiralpak AD (2cm, hexane: Virahol=92.5: 7.5, flow velocity: 30ml/min) separate, obtain the colorless oil (optically active isomer A) of 1.48g (40%) first flow point and the colorless oil (optically active isomer B) of 1.38g (37%) second flow point.
Optically active isomer A:
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5H，m)，5.14(2H，s)，4.81-4.76(1H，m)，3.84(1H，d，J＝10.70Hz)，3.61-3.53(3H，brm)，2.43-2.31(2H，m)，1.92-1.86(1H，m)，1.75-1.68(1H，m)，1.43(9H，s)，1.14(3H，d，J＝6.80Hz)。
Optically active isomer B:
1H-NMR(400MHz，CDCl
3)δ：7.37-7.30(5H，m)，5.16(2H，s)，4.87-4.73(1H，brm)，3.88-3.79(1H，m)，3.72(1H，d，J＝11.00Hz)，3.43-3.28(2H，brm)，2.89-2.77(1H，brm)，2.67-2.58(1H，m)，2.32(1H，t，J＝11.70Hz)，1.76-1.68(1H，m)，1.44(9H，s)，0.95-0.92(3H，m)。
According to the NMR between the lower isomer of the higher isomer of polarity and polarity relatively, optically active isomer A is accredited as (1R, 5S, 6S)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate, optically active isomer B is accredited as (1S, 5R, 6S)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.
[reference example 10]
(1R, 5S, 6S)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane
[formula 78]
Will (1R, 5S, 6S)-(1.4g 3.9mmol) is dissolved in the mixed solvent of methyl alcohol (20ml) and tetrahydrofuran (THF) (10ml) 1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.Add a small amount of 10% palladium-carbon (50% is wet), mixture was stirred 3 hours under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains 0.89g (quantitatively) title compound through concentrating under reduced pressure, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.80(1H，brs)，3.09(1H，d，J＝11.20Hz)，3.02(2H，dd，J＝5.40，11.20Hz)，2.82(2H，d，J＝11.20Hz)，2.27-2.22(2H，m)，1.77-1.69(2H，m)，1.44(9H，s)，1.17(3H，d，J＝6.60Hz)。
[reference example 11]
(1S, 5R, 6S)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane
[formula 79]
Will (1S, 5R, 6S)-(1.4g 3.8mmol) is dissolved in the mixed solvent of methyl alcohol (20ml) and tetrahydrofuran (THF) (10ml) 1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.Add a small amount of 10% palladium-carbon (50% is wet), mixture was stirred 3 hours under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains 0.85g (quantitatively) title compound through concentrating under reduced pressure, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.88(1H，brs)，3.06(1H，d，J＝12.00Hz)，2.96-2.89(2H，m)，2.71-2.61(3H，m)，2.39-2.33(1H，m)，1.58(1H，dd，J＝7.40，12.80Hz)，1.45(9H，s)，0.94(3H，d，J＝6.80Hz)。
[embodiment 1]
7-{ (1R, 5S, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptan-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 80]
Will (1R, 5S, 6S)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane (870mg, 3.84mmol) with 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(1.25g 3.46mmol) is dissolved in the dimethyl sulfoxide (DMSO) (15ml) inner complex.Add triethylamine (0.64ml), mixture was stirred 12 hours at 40 ℃.After ice-cooled reaction soln, add entry, filter collecting precipitation, wash with water and drying.Precipitation is dissolved in the ethanol (140ml).Add entry (30ml) and triethylamine (0.64ml), mixture heating up was refluxed 5 hours.Reaction mixture is with ethyl acetate dilution and with 10% citric acid solution, water and salt water washing.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.(25ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 1 hour.Then, reaction soln washs with chloroform, with the 10mol/L sodium hydroxide solution water layer is adjusted to pH12.0 down ice-cooled, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform-methanol (9: 1) extraction 8 times then.Organic layer filters, with solvent removed under reduced pressure then through anhydrous sodium sulfate drying.The gained resistates is dissolved in the ethanol, removes by filter insolubles.After the solvent evaporated under reduced pressure, the Powdered thing of gained obtains 562mg (35%) title compound through drying under reduced pressure, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.49(1H，brs)，7.70(1H，d，J＝13.70Hz)，5.03-4.85(1H，m)，4.09-4.03(1H，m)，3.90(1H，d，J＝10.50Hz)，3.67(3H，s)，3.48(1H，d，J＝10.50Hz)，3.03(1H，d，J＝10.50Hz)，2.44(1H，dd，J＝12.00，8.80Hz)，2.15(1H，t，J＝5.10Hz)，1.92-1.84(1H，m)，1.69-1.62(1H，m)，1.61-1.49(1H，m)，1.14(3H，d，J＝7.10Hz)。
C
21H
23F
2N
3O
40.7H
2The analytical calculation value of O0.2EtOH: C, 58.25; H, 5.85; F, 8.61; N, 9.52.Measured value: C, 58.22; H, 5.84; F, 8.47; N, 9.37.
MS(ESI)m/z：420(M+H)
+。
[embodiment 2]
7-{ (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptan-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 81]
Will (1S, 5R, 6S)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane (820mg, 3.62mmol) with 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(1.18g 3.26mmol) is dissolved in the dimethyl sulfoxide (DMSO) (15ml) inner complex.Add triethylamine (0.61ml), mixture was stirred 12 hours at 40 ℃.After ice-cooled reaction soln, add entry, filter collecting precipitation, wash with water and drying.Precipitation is dissolved in the ethanol (120ml).Add entry (30ml) and triethylamine (0.61ml), mixture heating up was refluxed 5 hours.Reaction mixture is with ethyl acetate dilution and with 10% citric acid solution, water and salt water washing.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.(25ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 1 hour.Then, reaction soln washs with chloroform.With the 10mol/L sodium hydroxide solution water layer is adjusted to pH12.0 down ice-cooled, is adjusted to pH7.4 with hydrochloric acid then, then with chloroform-methanol (9: 1) extraction 6 times.Organic layer is through anhydrous sodium sulfate drying, with solvent removed under reduced pressure.The gained resistates is dissolved in the ethanol, removes by filter insolubles.After the solvent evaporated under reduced pressure, the Powdered thing of gained obtains 1.1g (72%) title compound through drying under reduced pressure, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.46(1H，d，J＝2.20Hz)，7.72(1H，d，J＝13.70Hz)，5.10-4.90(1H，m)，4.07-4.02(1H，m)，3.75(1H，d，J＝11.20Hz)，3.64(3H，s)，3.64-3.59(1H，m)，3.49-3.47(1H，m)，3.09(1H，d，J＝10.00Hz)，2.68-2.60(1H，m)，2.51(1H，t，J＝7.30Hz)，2.20(1H，t，10.5Hz)，1.85(1H，dd，J＝8.50，12.70Hz)，1.63-1.42(2H，m)，0.96(3H，d，J＝7.30Hz)。
C
21H
23F
2N
3O
40.7H
2The analytical calculation value of O: C, 58.38; H, 5.69; F, 8.79; N, 9.73.Measured value: C, 58.24; H, 5.69; F, 8.59; N, 9.52.
MS(ESI)m/z：420(M+H)
+。
[embodiment 3]
10-{ (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptan-3-yl }-9-fluoro-2,3-two
Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid
[formula 82]
Will (1S, 5R, 6S)-(546.3mg 2.41mmol) is dissolved in the dimethyl sulfoxide (DMSO) (12ml) 1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane.Add 9,10-two fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid-BF
2Inner complex (794.1mg, 2.41mmol) and triethylamine (1221mg 12.07mmol), stirs mixture 5 days.Then, 90% aqueous ethanol (135ml) and triethylamine (15ml) are joined in the reaction mixture, it was stirred 4.5 hours at 80 ℃.Solvent evaporated under reduced pressure also adds 10% citric acid solution, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the short silica gel column chromatography processing (3% methyl alcohol/chloroform) of gained resistates.The gained crude product is dissolved in concentrated hydrochloric acid and uses washed with dichloromethane.At 0 ℃, with aqueous sodium hydroxide solution water layer is adjusted to pH12, be adjusted to pH7.4 with hydrochloric acid then, use chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained solid obtains title compound (695mg) with washing with alcohol and through drying under reduced pressure, is light yellow solid.
mp：122-124℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.31(1H，s)，7.46(1H，d，J＝13.67Hz)，4.55(1H，d，J＝6.84Hz)，4.46(1H，d，J＝11.47Hz)，4.30(1H，d，J＝11.47Hz)，3.71(1H，d，J＝10.74Hz)，3.45(1H，d，J＝9.77Hz)，3.27(1H，t，J＝8.79Hz)，3.09(1H，d，J＝9.77Hz)，2.58-2.56(1H，m)，2.37(1H，t，J＝7.81Hz)，2.12(1H，t，J＝11.47Hz)，1.78(1H，dd，J＝12.33，8.42Hz)，1.48(3H，d，J＝6.59Hz)，0.94(3H，d，J＝7.08Hz)。
C
20H
22FN
3O
4H
2The analytical calculation value of O: C, 59.25; H, 5.97; N, 10.36; F, 4.69.Measured value: C, 59.41; H, 5.65; N, 10.36; F, 4.97.
MS(EI)m/z：388(M+H)
+。
IR(ATR)v：2956，2929，2866，1716，1612，1579，1523，1450，1385，1335，1298，1255cm
-1。
[reference example 12]
(R)-3-(t-butyldimethylsilyl oxygen base)-2 Methylpropionic acid methyl esters
[formula 83]
With imidazoles (6.44g, 42.8mmol) and tert-butyldimethylsilyl chloride (6.05g, 88.8mmol) (5.0g in dimethyl formamide 42.33mmol) (50ml) solution, at room temperature stirred mixture 1.5 hours to join (R)-3-hydroxy-2-methyl methyl propionate.Water is joined in the reaction mixture, use hexane extraction then 2 times.Extract is again through dried over mgso.After the filtration, solvent evaporated under reduced pressure obtains 9.3g (95%) title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：3.76-3.72(1H，m)，3.64(3H，s)，3.63-3.59(1H，m)，2.65-2.57(1H，m)，1.10(3H，d，J＝6.84Hz)，0.84(9H，s)，0.01(3H，s)，0.00(3H，s)。
[reference example 13]
(E)-(S)-5-(t-butyldimethylsilyl oxygen base)-4-methylpent-2-olefin(e) acid methyl esters
[formula 84]
At-78 ℃, with the diisobutyl aluminium hydride (hexane solution of 1M, 17.2ml) (4.0g in methylene dichloride 17.2mmol) (100ml) solution, stirs mixture 4 hours under same temperature to join (R)-3-(t-butyldimethylsilyl oxygen base)-2 Methylpropionic acid methyl esters.Saturated potassium sodium tartrate solution is joined reaction mixture, with its stirring and be heated to room temperature.Separate organic layer, water layer ethyl acetate extraction then.Merge organic layer, through dried over mgso and filtration.Then, solvent evaporated under reduced pressure obtains aldehyde (3.5g), is colorless oil.Gained aldehyde is dissolved in the methylene dichloride (50ml).Ice-cooled down, (7.08g 20.75mmol), at room temperature stirs mixture and to spend the night to add the inferior phosphine acyl acetic acid methyl esters of triphenyl.After the solvent evaporated under reduced pressure, the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain 3.8g (85%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：6.94(1H，dd，J＝7.10，15.90Hz)，5.84(1H，dd，J＝1.20，15.90Hz)，3.73(3H，s)，3.57-3.49(2H，m)，2.53-2.46(1H，m)，1.05(3H，d，J＝6.80Hz)，0.89(9H，s)，0.04(6H，s)。
[reference example 14]
The 1-benzyl-4-[(S)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-3-
Methyl-formiate
[formula 85]
With N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (2.97ml, 11.6mmol) join (E)-(S)-5-(t-butyldimethylsilyl oxygen base)-4-methylpent-2-olefin(e) acid methyl esters (2.5g, 9.67mmol) methylene dichloride (20ml) solution in, add the trifluoroacetic acid of trace then.Mixture was stirred 30 minutes, add saturated sodium bicarbonate aqueous solution then.Separate organic layer and through dried over mgso.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain the title compound of 3.0g (78%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 15]
4-[(S)-and 2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-1, the 3-diformazan
Acid 1-benzyl ester 3-methyl esters
[formula 86]
With benzyloxycarbonyl chlorine (3.25ml, 22.8mmol) join 1-benzyl-4-[(S)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-3-methyl-formiate (2.97g, 7.58mmol) methylene dichloride (20ml) solution in, mixture was stirred 1 hour.Saturated sodium bicarbonate aqueous solution is joined in the reaction mixture.Separate organic layer, through dried over mgso and filtration.Then, solvent evaporated under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1), obtain the title compound of 3.1g (96%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
[reference example 16]
4-[(S)-and 2-hydroxyl-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters
[formula 87]
Under ice-cooled, (2ml) joins 4-[(S with hydrogen fluoride-pyridine)-2-(t-butyldimethylsilyl oxygen base)-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters (6.0g, 7.1mmol) pyridine (20ml) solution in, mixture was at room temperature stirred 13 hours.Add the 2ml hydrogen fluoride-pyridine again, mixture was stirred 23 hours.Reaction mixture is poured in the frozen water, also used 1N hydrochloric acid and salt water washing with ethyl acetate extraction then.Through dried over mgso and after filtering, solvent evaporated under reduced pressure obtains the title compound of 4.5g (quantitatively) non-enantiomer mixture, is colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.31(5H，m)，5.13(2H，brs)，3.87-3.75(2H，brm)，3.72(3H，s)，3.52-3.47(3H，m)，3.27-3.11(1H，m)，2.98-2.90(1H，m)，2.69-2.58(1H，m)，1.82-1.66(2H，m)，0.95(3H，d，J＝19.80Hz)。
[reference example 17]
4-[(S)-and 2-iodo-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters
[formula 88]
Under ice-cooled, with triethylamine (3.4ml, 24mmol) and methylsulfonyl chloride (1.5ml, 19.2mmol) join 4-[(S)-2-hydroxyl-1-(methyl) ethyl] tetramethyleneimine-1,3-dioctyl phthalate 1-benzyl ester 3-methyl esters (5.1g, in methylene dichloride 16mmol) (50ml) solution, then mixture was at room temperature stirred 30 minutes.After joining methyl alcohol in the reaction mixture, the mixture of gained mixture with ethyl acetate and 10% citric acid solution mixed.Organic layer is with the salt water washing and through dried over mgso.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in acetone (100ml).(4.8g 32mmol), refluxes mixture heating up 20 hours to add sodium iodide.Reaction mixture is then with solvent removed under reduced pressure.The gained resistates mixes with the mixture of ethyl acetate and water.Organic layer, filters, with solvent removed under reduced pressure through dried over mgso then with saturated sodium thiosulfate solution and salt water washing.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 7: 3), obtain the title compound of 6.5g (94%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.35(5H，m)，5.13(2H，s)，3.83-3.71(4H，m)，3.58-3.51(1H，m)，3.27-3.23(1H，m)，3.18-3.09(2H，m)，2.92-2.83(1H，m)，2.64-2.55(1H，m)，1.59-1.48(2H，m)，1.02(3H，d，J＝6.60Hz)。
[reference example 18]
(R)-and 6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester 1-methyl esters
[formula 89]
Under argon atmospher, at-78 ℃, with toluene solution (33ml 16.5mmol) is added drop-wise to 4-[(S)-2-iodo-1-(methyl) ethyl of 0.5M hexamethyl two silicon nitrine potassium] tetramethyleneimine-1, (6.4g is in anhydrous tetrahydro furan 14.8mmol) (100ml) solution for 3-dioctyl phthalate 1-benzyl ester 3-methyl esters.After being added dropwise to complete, mixture was stirred 30 minutes under same temperature.Add ammonium chloride solution, with mixture heating up to room temperature.Behind ethyl acetate extraction, through dried over mgso and filtration, with solvent removed under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 7: 3), obtain the title compound of 3.5g (78%) non-enantiomer mixture, be colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.29(5H，m)，5.18(2H，brs)，3.97-3.89(1H，m)，3.77-3.69(4H，m)，3.46(1H，d，J＝11.70Hz)，3.25(1H，dd，J＝12.10，7.90Hz)，3.08-3.03(1H，m)，2.60-2.75(2H，m)，1.51-1.57(1H，m)，0.94(3H，brs)。
[reference example 19]
(R)-and 6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester
[formula 90]
Under ice-cooled, 1N sodium hydroxide solution (23ml) is added drop-wise to (R)-6-methyl-3-azabicyclo [3.2.0] heptane-1, (3.5g in the mixing solutions of tetrahydrofuran (THF) 11.5mmol) (60ml) and methyl alcohol (20ml), stirs mixture 30 minutes 3-dioctyl phthalate 3-benzyl ester 1-methyl esters.Reaction soln is used ethyl acetate extraction then with the neutralization of 1N hydrochloric acid.Extract is through dried over mgso and filtration.Solvent evaporated under reduced pressure obtains the title compound of 3.4g (quantitatively) non-enantiomer mixture, is colorless oil.Diastereomer need not to separate and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.30(5H，m)，5.19(2H，brs)，4.00-3.91(1H，m)，3.81-3.70(1H，m)，3.50(1H，d，J＝11.70Hz)，3.27(1H，dd，J＝11.70，7.80Hz)，3.11(1H，t，J＝7.70Hz)，2.80-2.66(2H，m)，0.95(3H，s)。
[reference example 20]
(R)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate
(optically active isomer C, optically active isomer D)
[formula 91]
At room temperature, with triethylamine (3.2ml, 22.8mmol) and two phenoxy group phosphoryl azide (3.7ml, 17.1mmol) join (R)-6-methyl-3-azabicyclo [3.2.0] heptane-1,3-dioctyl phthalate 3-benzyl ester (3.3g, 11.4mmol) toluene (70ml) solution in, add the trimethyl carbinol (70ml) then.Mixture was 100 ℃ of heated and stirred 15 hours.Reaction mixture is then with solvent removed under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 0 → 8: 2), obtain the title compound of 3.5g non-enantiomer mixture, be colorless oil.Diastereomer separates (2cm by Chiralpak AD, hexane: Virahol=92.5: 7.5, flow velocity: 30ml/min), obtain the colorless oil (optically active isomer C) of 1.72g (42%) first flow point and the colorless oil (optically active isomer D) of 1.68g (41%) second flow point.
Optically active isomer C:
1H-NMR(400MHz，CDCl
3)δ：7.37-7.30(5H，m)，5.16(2H，s)，4.87-4.73(1H，brm)，3.88-3.79(1H，m)，3.72(1H，d，J＝11.00Hz)，3.43-3.28(2H，bm)，2.89-2.77(1H，brm)，2.67-2.58(1H，m)，2.32(1H，t，J＝11.70Hz)，1.76-1.68(1H，m)，1.44(9H，s)，0.95-0.92(3H，m)。
Optically active isomer D:
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5H，m)，5.14(2H，s)，4.81-4.76(1H，m)，3.84(1H，d，J＝10.70Hz)，3.61-3.53(3H，brm)，2.43-2.31(2H，m)，1.92-1.86(1H，m)，1.75-1.68(1H，m)，1.43(9H，s)，1.14(3H，d，J＝6.80Hz)。
According to the NOE test-results, optically active isomer C is accredited as (1R, 5S, 6R)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate, and optically active isomer D is accredited as (1S, 5R, 6R)-1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.
[reference example 21]
(1R, 5S, 6R)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane
[formula 92]
Will (1R, 5S, 6R)-(180mg 0.59mmol) is dissolved in the methyl alcohol (5ml) 1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.Add a small amount of 10% palladium-carbon (50% is wet), mixture was stirred 1 hour under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains 114mg (85%) title compound through concentrating under reduced pressure, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.88(1H，brs)，3.06(1H，d，J＝12.00Hz)，2.96-2.89(2H，m)，2.71-2.61(3H，m)，2.39-2.33(1H，m)，1.58(1H，dd，J＝12.80，7.40Hz)，1.45(9H，s)，0.94(3H，d，J＝6.80Hz)。
[reference example 22]
(1S, 5R, 6R)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane
[formula 93]
Will (1S, 5R, 6R)-(1.1g 3.1mmol) is dissolved in the mixed solvent of methyl alcohol (20ml) and tetrahydrofuran (THF) (10ml) 1-tert-butoxycarbonyl amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-benzyl formate.Add a small amount of 10% palladium-carbon (50% is wet), mixture was stirred 3 hours under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains 0.70g (quantitatively) title compound through concentrating under reduced pressure, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.80(1H，brs)，3.09(1H，d，J＝11.20Hz)，3.02(2H，dd，J＝11.20，5.40Hz)，2.82(2H，d，J＝11.20Hz)，2.27-2.22(2H，m)，1.77-1.69(2H，m)，1.44(9H，s)，1.17(3H，d，J＝6.60Hz)。
[embodiment 4]
7-{ (1R, 5S, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptan-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 94]
Will (1R, 5S, 6R)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane (114mg, 0.50mmol) with 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(155mg 0.43mmol) is dissolved in the dimethyl sulfoxide (DMSO) (2ml) inner complex.Add triethylamine (0.084ml), mixture was stirred 12 hours at 40 ℃.After ice-cooled reaction soln, add entry, filter collecting precipitation, wash with water and drying.Precipitation is dissolved in the ethanol (20ml).Add entry (5ml) and triethylamine (0.084ml), mixture heating up was refluxed 3 hours.Reaction mixture is dissolved in the ethyl acetate also with 10% citric acid solution, water and salt water washing.Organic layer filters, solvent evaporated under reduced pressure then through anhydrous sodium sulfate drying again.(5ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 1 hour.Then, reaction soln washs with chloroform.Under ice-cooled, water layer is adjusted to pH12.0 with the 10mol/L sodium hydroxide solution, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform-methanol (9: 1) extraction 8 times again.Organic layer filters, solvent evaporated under reduced pressure then through anhydrous sodium sulfate drying again.The gained resistates is dissolved in the ethanol and removes by filter insolubles.After the solvent evaporated under reduced pressure, the Powdered thing of gained obtains 70mg (39%) title compound through drying under reduced pressure, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.50(1H，s)，7.70(1H，d，J＝13.67Hz)，5.02-4.84(1H，m)，4.07-4.03(1H，m)，3.74(1H，d，J＝10.25Hz)，3.62(3H，s)，3.60-3.56(2H，m)，2.94(1H，d，J＝10.25Hz)，2.63-2.55(1H，m)，2.51-2.47(1H，m)，2.24-2.18(1H，m)，1.85(1H，dd，J＝12.57，7.93Hz)，1.69-1.48(2H，m)，0.87(3H，d，J＝6.84Hz)。
C
21H
23F
2N
3O
40.4H
2The analytical calculation value of O0.3EtOH: C, 58.90; H, 5.86; F, 8.63; N, 9.54.Measured value: C, 58.84; H, 5.78; F, 8.66; N, 9.51.
MS(ESI)m/z：420(M+H)
+。
[embodiment 5]
7-{ (1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptan-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 95]
Will (1S, 5R, 6R)-1-(tert-butoxycarbonyl amino)-6-methyl-3-azabicyclo [3.2.0] heptane (705mg, 3.12mmol) with 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(1.07g 2.96mmol) is dissolved in the dimethyl sulfoxide (DMSO) (12ml) inner complex.Add triethylamine (0.52ml), mixture stirred 12 hours at 40 ℃.After ice-cooled reaction soln, add entry, filter collecting precipitation, wash with water and drying.Precipitation is dissolved in the ethanol (120ml).Add entry (30ml) and triethylamine (0.52ml), mixture heating up was refluxed 3 hours.Reaction mixture is dissolved in the ethyl acetate also with 10% citric acid solution, water and salt water washing.Organic layer filters, solvent evaporated under reduced pressure then through anhydrous sodium sulfate drying again.(25ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 1 hour.Then, reaction soln washs with chloroform.Under ice-cooled, water layer is adjusted to pH12.0 with the 10mol/L sodium hydroxide solution, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform-methanol (9: 1) extraction 8 times again.Organic layer filters, solvent evaporated under reduced pressure then through anhydrous sodium sulfate drying again.The gained resistates is dissolved in the ethanol and removes by filter insolubles.After the solvent evaporated under reduced pressure, the Powdered thing of gained obtains 740mg (57%) title compound through drying under reduced pressure, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，d，J＝1.71Hz)，7.70(1H，d，J＝13.67Hz)，5.07-4.88(1H，m)，4.08-4.03(1H，m)，3.73-3.63(2H，m)，3.67(3H，s)，3.55-3.51(1H，m)，3.18(1H，d，J＝10.50Hz)，2.40(1H，dd，J＝12.21，8.79Hz)，2.13(1H，t，J＝5.13Hz)，1.95-1.89(1H，m)，1.16(3H，d，J＝7.08Hz)，1.66-1.57(2H，m)，1.56-1.44(1H，m)。
C
21H
23F
2N
3O
4HCl1.3H
2The analytical calculation value of O0.6EtOH: C, 52.60; H, 6.00; Cl, 6.99; F, 7.50; N, 8.29.Measured value: C, 52.35; H, 5.74; Cl, 6.84; F, 7.54; N, 8.01.
MS(ESI)；m/z：420(M+H)
+。
[reference example 23]
(3R)-3-allyl group-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (polarity
Lower isomer)
(3S)-3-allyl group-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (polarity
Higher isomer)
[formula 96]
With 5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (30g, 104mmol) and allyl bromide 98 (62.71g 518mmoL) is dissolved in the dimethyl formamide (300ml), with the former atmosphere of argon replaces.Under ice-cooled, (55% oil dispersion, 11.3g 259mmol), at room temperature stirred mixture 5 hours to add sodium hydride.Add 10% tartaric acid solution, use ethyl acetate extraction then.Organic layer is with the salt water washing and through dried over mgso.After the filtration, with solvent removed under reduced pressure.Then, resistates is by silica gel chromatography separation and purification (hexane: ethyl acetate=100: 0 → 80: 20 → 65: 35), obtain the colorless oil (isomer that polarity is lower) of 15.8g (46%) first flow point and the colorless oil (isomer that polarity is higher) of 15.1g (44%) second flow point.Crystallization when the higher isomer of gained polarity at room temperature leaves standstill.
According to the X-ray crystallography structure of reference example 24 described products, after the isomer that polarity is higher is converted into product, measured the absolute configuration of every kind of isomer 3-position.
The isomer that polarity is lower:
1H-NMR(400MHz，CDCl
3)δ：7.37-7.26(5H，m)，5.52-5.42(2H，m)，4.95(1H，dd，J＝10.30，1.00Hz)，4.78(1H，dd，J＝17.10，1.20Hz)，3.60(1H，d，J＝10.30Hz)，2.86(1H，d，J＝17.10Hz)，2.80(1H，d，J＝10.30Hz)，2.35(1H，d，J＝17.10Hz)，2.27(1H，dd，J＝13.70，6.80Hz)，2.16(1H，dd，J＝13.70，7.80Hz)，1.52(3H，d，J＝7.30Hz)，1.44(9H，s)。
The isomer that polarity is higher:
1H-NMR(400MHz，CDCl
3)δ：7.35-7.24(5H，m)，5.72-5.62(1H，m)，5.49(1H，q，J＝7.20Hz)，5.15(1H，s)，5.13-5.10(1H，m)，3.28(1H，d，J＝10.30Hz)，3.16(1H，d，J＝10.30Hz)，2.88(1H，d，J＝17.10Hz)，2.48-2.35(3H，m)，1.51(3H，d，J＝7.10Hz)，1.35(9H，s)。
[reference example 24]
(3S)-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester (derived from the higher isomer of polarity)
[formula 97]
With (3S)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] (51.5g 0.156mol) is dissolved in the tetrahydrofuran (THF) (780ml) tetramethyleneimine-3-t-butyl formate (isomer that polarity is higher).Then, under nitrogen gas stream, be to stir while cool off during 0 ℃ cryosel is bathed at internal temperature, with the tetrahydrofuran solution of addition funnel dropping 0.5M 9-BBN (345ml, 0.173mol).After being added dropwise to complete, mixture was stirred 30 minutes under same temperature, at room temperature stirred again 1.5 hours.Mixture cooling in cryosel is bathed once more, when internal temperature is 2 ℃, with addition funnel drip 0.5M 9-BBN tetrahydrofuran solution (156ml, 78mmol).After being added dropwise to complete, mixture was stirred 30 minutes under same temperature, at room temperature stirred again 1.5 hours.Mixture cooling in cryosel is bathed once more, when internal temperature is 2 ℃, with addition funnel drip 0.5M 9-BBN tetrahydrofuran solution (120ml, 60mmol).After being added dropwise to complete, mixture was stirred 30 minutes under same temperature, at room temperature stirred again 1.5 hours.Mixture cooling in cryosel is bathed once more, when internal temperature was 0 ℃, (internal temperature: 2 ℃ or lower) dripped 780ml 1N sodium hydroxide solution in 15 minutes.Mixture was stirred 10 minutes, was 4 ℃ or when lower at internal temperature then, dripped 78ml 30% superoxol in 30 minutes.After 30 minutes, add the 1.6L ether in vigorous stirring under the same temperature.Add after the 1.6L saturated sodium bicarbonate solution, separate each layer, the water layer extracted with diethyl ether.The organic layer that merges washs successively with salt solution, 10% citric acid solution, 10% hypo solution, salt solution, again through anhydrous sodium sulfate drying.After the filtration, concentrated filtrate, and with the gained resistates by quick silica gel column chromatography and with methyl alcohol-chloroform (1: 50, mixed solvent wash-out v/v).Merge the flow point contain the target material, concentrate and, obtain 40.61g (74.9%) title compound, be colorless oil through drying under reduced pressure.In addition, the division header compound can be used for the X-ray crystallography analysis by from the ether recrystallization and purifying obtains needle-like crystal.As a result, the absolute configuration of the 3-position of this product is (3S)-configuration after measured.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.24(5H，m)，5.48(1H，q，J＝7.3Hz)，3.62(2H，t，J＝6.2Hz)，3.34(1H，d，J＝10.3Hz)，3.14(1H，d，J＝10.3Hz)，2.95(1H，d，J＝17.1Hz)，2.33(1H，d，J＝16.8Hz)，1.88-1.67(3H，m)，1.51(3H，d，J＝7.1Hz)，1.54-1.47(1H，m)，1.33(9H，s)。
[table 1]
The X-ray crystallography condition:
Crystallographic dimension
0.36Mm *
0.18Mm *
0.08Mm
Radiation CuK α
Tube current
50KV
Tube voltage
80MA
Diffractometer
AFC7R
Temperature
25 ℃
Formula
C20H29NO4
Formula weight
347.45
Crystallographic system
Quadrature
Spacer
P2 1 2 1 2
The Z value
4
Unit cell parameters
α＝90.0000°β＝90.0000°γ＝90.0000°
d
Calculated value 1.11G/cm
3
The reflection number that records
1828(unique)
μ
6.19cm -1
Phase determination
Direct method(software; SIR92)
Phase place refine complete matrix method of least squares
R1
5.3％＝∑||Fo|-|Fc||/∑|Fo|forI＞
2.0σdata
R?
7.0％＝∑(Fo
2-Fc
2)/∑Fo
2
Rw?
14.0％＝[∑w(Fo
2-Fc
2)
2/∑w(Fo
2)
2]
1/2
Under the condition determination shown in the last table, collect data, measure start-phase by direct method then, and by complete matrix method of least squares refine phase place.For refine, anisotropic temperature factor is used for non-hydrogen atom and determines the position of hydrogen atom by calculating the match coordinate.Analytical results is that the relative configuration of this compound is seen the ORTEP figure of Fig. 1.According to asymmetric carbon a, measure the absolute configuration of asymmetric carbon b with known absolute configuration.The results are shown in Figure 2.
[reference example 25]
(3S)-and 5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 98]
At-74 ℃, to (3S)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] (3.29g feeds ozone in methyl alcohol 10.0mmol) (100ml) solution to tetramethyleneimine-3-t-butyl formate.When reaction soln becomes blue, stop to feed ozone, under same temperature, in solution, feed nitrogen again.Under same temperature, add sodium borohydride (568mg), mixture was stirred 1.5 hours, be heated to-40 ℃ simultaneously.Reaction soln is poured in 10% citric acid solution (50ml), fully stirred the mixture then.Boil off methanol content, (200ml 100ml) extracts water layer with ethyl acetate then.Organic layer is with salt water washing (50ml * 2), then through anhydrous sodium sulfate drying.After the filtration, filtrate is through concentrating under reduced pressure pulp thing.Hexane is joined in the gained resistates, and stir the gained soup compound.Solid collected by filtration and drying obtain the 1.70g title compound, are white solid.Concentrated filtrate joins hexane in the gained resistates, stirs the gained soup compound.Solid collected by filtration obtains the 0.66g title compound, is white solid.Repeat same operation, obtain 0.35g title compound (ultimate production: 2.7l g, 82%, white solid).
1H-NMR(400MHz，CDCl
3)δ：9.71(1H，s)，7.35-7.24(5H，m)，5.50(1H，q，J＝7.3Hz)，3.41(1H，d，J＝10.5Hz)，3.20(1H，d，J＝10.5Hz)，2.98(1H，d，J＝17.1Hz)，2.92(1H，d，J＝17.8Hz)，2.87(1H，d，J＝17.8Hz)，2.37(1H，d，J＝17.1Hz)，1.51(3H，d，J＝7.3Hz)，1.31(9H，s)。
MS(ESI)m/z：332(M+H)
+。
[reference example 26]
(3S)-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 99]
At-40 ℃, sodium borohydride (465mg) being joined (3S)-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl] (2.71g is in methanol solution 8.19mmol) for tetramethyleneimine-3-t-butyl formate.After being heated to room temperature, 10% citric acid solution being joined in the reaction soln, and stir the mixture.Reaction soln is poured in the mixture of ethyl acetate (50ml) and 10% citric acid solution (10ml), used ethyl acetate (100ml) extraction then.Water layer merges organic layer then and uses salt solution (50ml * 2) washing with ethyl acetate (100ml) extraction.The gained organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1 → 0: 1 → ethyl acetate-methyl alcohol=10: 1), obtain 2.20g (81%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.24(5H，m)，5.48(1H，q，J＝7.1Hz)，3.73-3.64(2H，m)，3.38(1H，d，J＝10.2Hz)，3.23(1H，d，J＝10.2Hz)，2.97(1H，d，J＝17.0Hz)，2.41(1H，d，J＝17.0Hz)，2.05(1H，dt，J＝14.0，6.8Hz)，1.91(1H，dt，J＝14.0，6.6Hz)，1.51(3H，d，J＝7.1Hz)，1.32(9H，s)。
MS(ESI)m/z：334(M+H)
+。
[reference example 27]
(3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-the 5-oxo-1-[(1R)-1-phenyl second
Base] tetramethyleneimine-3-t-butyl formate
[formula 100]
With triethylamine (3.0ml 21.8mmol) joins (3S)-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl] (2.42g in methylene dichloride 7.25mmol) (70ml) solution, is cooled to 0 ℃ with mixture to tetramethyleneimine-3-t-butyl formate.(2.50ml 10.9mmol), stirs mixture 1.5 hours under same temperature to drip trifluoromethanesulfonic acid (t-butyldimethylsilyl) ester.Add after ice cube and the stirring, reaction soln is poured in ethyl acetate (50ml) and saturated sodium bicarbonate (50ml) mixture, use ethyl acetate (200ml, 100ml) extraction then.Merge organic layer and use salt solution (50ml) washing.Through anhydrous sodium sulfate drying and after filtering, solvent is through concentrating under reduced pressure.The gained resistates is by silica gel chromatography purifying (hexane: ethyl acetate=4: 1 → 2: 1), obtain 2.84g (88%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.22(5H，m)，5.45(1H，q，J＝7.1Hz)，3.62-3.57(2H，m)，3.38(1H，d，J＝10.3Hz)，3.26(1H，d，J＝10.3Hz)，2.93(1H，d，J＝17.0Hz)，2.42(1H，d，J＝17.0Hz)，1.98(1H，dt，J＝13.7，6.8Hz)，1.88(1H，dt，J＝13.7，6.7Hz)，1.50(3H，d，J＝7.1Hz)，1.31(9H，s)。
[reference example 28]
(3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-4-fluoro-5-oxo-1-[(1R)-1-benzene
The base ethyl] tetramethyleneimine-3-t-butyl formate
[formula 101]
Under nitrogen atmosphere, at-73 ℃, in 10 minutes, the tetrahydrofuran solution (4.10ml) of 1.8M lithium diisopropylamine is added drop-wise to (3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-5-oxo-1-[(1R)-1-phenylethyl] in the tetrahydrofuran solution of tetramethyleneimine-3-t-butyl formate.After stirring 15 minutes under the same temperature, in 15 minutes, drip N-fluorobenzene sulfimide (2.63g, tetrahydrofuran (THF) 8.33mmol) (18ml) solution.After stirring 30 minutes under the same temperature, add saturated ammonium chloride solution (20ml), with mixture heating up to 0 ℃.Reaction soln is poured in the mixture of ethyl acetate (100ml) and 1mol/ml hydrochloric acid (50ml), used ethyl acetate (200ml) extraction then.Organic layer is used saturated sodium bicarbonate solution (50ml) and salt solution (50ml * 2) washing successively, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.Methylene dichloride is joined in the gained resistates preparation soup compound, solids removed by filtration.Concentrated filtrate removes by filter the gained solid.Further concentrated filtrate obtains the rough title compound of 3.44g, is light yellow oil.The gained crude product need not to be further purified and just can be used for next reaction.
[reference example 29]
(3S)-4-fluoro-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester
[formula 102]
Under nitrogen atmosphere, at 0 ℃, with acetate (0.66ml, 11.54mmol) and the tetrahydrofuran solution of 1M tetrabutyl ammonium fluoride (8.3ml 8.3mmol) joins rough (3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl successively]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl] in the tetrahydrofuran solution of tetramethyleneimine-3-t-butyl formate (3.44g).After at room temperature stirring 20 hours, reaction soln is poured in ethyl acetate (100ml) and saturated sodium bicarbonate solution (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml * 2) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=1: 1), obtain 2.06g (91%, two step) title compound, be clear crystal.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.26(5H，m)，5.48(1H，q，J＝7.1Hz)，5.21(1H，d，J＝51.7Hz)，3.78-3.69(2H，m)，3.38(1H，dd，J＝1.1，10.5Hz)，3.30(1H，d，J＝10.5Hz)，2.10(1H，m)，2.01(1H，m)，1.56(3H，d，J＝7.1Hz)，1.32(9H，s)。
[reference example 30]
(3S)-3-(2-bromotrifluoromethane)-4-fluoro-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester
[formula 103]
Under nitrogen atmosphere, at 0 ℃, with carbon tetrabromide (1.88g, 5.68mmol) and triphenyl phosphine (1.49g, 5.68mmol) join (3S)-4-fluoro-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl successively] (1.66g is in methylene dichloride 4.74mmol) (20ml) solution for tetramethyleneimine-3-t-butyl formate.After being heated to room temperature, reaction soln was stirred 1 hour and being concentrated into about 5ml.Resistates is by silica gel column chromatography purifying (methylene dichloride → hexane: ethyl acetate=2: 1), obtain 2.17g (91%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.25(5H，m)，5.48(1H，q，J＝7.1Hz)，5.22(1H，d，J＝51.5Hz)，3.39(1H，ddd，J＝5.5，10.7，11.0Hz)，3.30-3.23(3H，m)，2.42(1H，dddd，J＝1.2，5.5，11.0，14.2Hz)，2.32(1H，dddd，J＝2.4，5.5，10.7，14.2Hz)，1.57(3H，d，J＝7.1Hz)，1.33(9H，s)。
[reference example 31]
(1S, 5R)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane-1-first
Tert-butyl acrylate
[formula 104]
Under nitrogen atmosphere, at-72 ℃, in 10 minutes, the tetrahydrofuran solution (5.02ml) of 1.0M hexamethyl two silicon nitrine lithiums is added drop-wise to (3S)-3-(2-bromotrifluoromethane)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl] (2.04g is in tetrahydrofuran (THF) 4.92mmol) (40ml) solution for tetramethyleneimine-3-t-butyl formate.Mixture was stirred 15 minutes under same temperature, stirred 30 minutes at 0 ℃ then.Reactant is poured in the mixture of ethyl acetate (100ml) and 10% citric acid solution (20ml) then with 10% citric acid solution (2ml) quencher.After ethyl acetate (150ml) extraction, organic layer is with salt water washing (20ml * 2), through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1), obtain 1.41g (86%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.26(5H，m)，5.57(1H，q，J＝7.3Hz)，3.53(1H，d，J＝10.7Hz)，3.09(1H，dd，J＝4.9，10.7Hz)，2.76-2.51(3H，m)，1.57(3H，d，J＝7.3Hz)，1.45(9H，s)，1.42(1H，m)。
MS(ESI)m/z：334(M+H)
+。
[reference example 32]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-nitrogen
Assorted dicyclo [3.2.0] heptane
[formula 105]
Trifluoroacetic acid (10ml) is joined (1S, 5R)-1-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-(1.06g is in methylene dichloride 3.18mmol) (10ml) solution for 3-azabicyclo [3.2.0] heptane-1-t-butyl formate.Mixture was stirred 4 hours, and solvent is through concentrating under reduced pressure then.(40ml) joins in the resistates with toluene, and trifluoroacetic acid is removed in evaporation.Resistates obtains rough formic acid through drying under reduced pressure, is light yellow solid.
Triethylamine (0.89ml) and two phenoxy group phosphoryl azides (0.75ml) are joined in the toluene (10ml) and the trimethyl carbinol (10ml) solution of the rough formic acid of above acquisition successively.Mixture was at room temperature stirred 20 minutes, stirred 1 hour, stirred 1 hour at 90 ℃ again at 40 ℃.Reaction soln is through concentrating under reduced pressure, and the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1 → 3: 2), obtain 811mg (73%) title compound, be white amorphous thing.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.27(5H，m)，5.59(1H，q，J＝7.3Hz)，5.36(1H，br)，3.68(1H，br)，2.96(1H，brd，J＝10.0Hz)，2.66-2.45(2H，m)，2.39(1H，br)，1.72(1H，dt，J＝12.9，9.0Hz)，1.56(3H，d，J＝7.3Hz)，1.40(9H，s)。
MS(ESI)m/z：349(M+H)
+。
[reference example 33]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-[(1R)-the 1-phenylethyl]-the 3-azabicyclo
[3.2.0] heptane
[formula 106]
At 0 ℃, in 5 minutes, the tetrahydrofuran solution (6.0ml) of 1.16M borane-tetrahydrofuran complex is added drop-wise to (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-(811mg is in tetrahydrofuran (THF) 2.33mmol) (6.0ml) solution for 3-azabicyclo [3.2.0] heptane.Mixture heating up stirred 5 hours to room temperature, was cooled to-10 ℃ then.Drip ethanol (9.0ml)-water (1.0ml) mixture carefully.Drip triethylamine (3.0ml) afterwards, mixture heating up was refluxed 1 hour.Concentrated reaction solution, sedimentary white solid is removed by diatomite filtration.Concentrated filtrate, the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=9: 1 → 4: 1), obtain 530mg (68%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.18(5H，m)，5.19(1H，br)，3.37(1H，q，J＝6.8Hz)，3.27(1H，dd，J＝1.7，9.0Hz)，3.13(1H，brd，J＝8.3Hz)，2.49-2.38(2H，m)，2.23(1H，m)，2.13-2.08(2H，m)，2.00(1H，m)，1.39(9H，brs)，1.36(3H，d，J＝6.8Hz)。
[reference example 34]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.2.0] heptane
[formula 107]
(50% is wet with 10% palladium carbon catalyst, 50mg) join (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane (530mg, 1.58mmol) ethanolic soln in, the gained mixture stirred 5 hours at 50 ℃ under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains the rough amine of 321mg through concentrating under reduced pressure, is white solid.
1H-NMR(400MHz，CD
3OD)δ：3.07-3.00(2H，m)，2.87-2.80(2H，m)，2.35(1H，m)，2.03-1.95(2H，m)，1.67(1H，dt，J＝12.0，9.0Hz)，1.34(9H，s)，1.00(1H，dd，J＝2.1，6.2Hz)。
[embodiment 6]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.2.0] heptan-3-yl]-6-fluoro-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 108]
With 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (577mg, 1.60mmol) and triethylamine (0.699ml, 5.02mmol) join successively (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.2.0] heptane (crude product; In dimethyl sulfoxide (DMSO) 321mg) (5.0ml) solution.Mixture is while stirring 40 ℃ of heating 24 hours.Add triethylamine (0.35ml), gained mixture restir 17 hours under same temperature.Then, add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (58mg) and triethylamine (0.125ml).In addition, after 6 hours and 24 hours, add 6 respectively, 7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (480mg, 240mg) and triethylamine (0.389ml, 0.195ml).The last adding after the reagent, mixture was stirred 5.5 hours.Then, with ethanol: the mixture of water=4: 1 (30ml) and triethylamine (4.5ml) joins in the reaction soln, and mixture heating up was refluxed 2 hours.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (150ml) and uses 10% citric acid solution (30ml), water (30ml * 2) and salt solution (30ml) to wash successively.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Gained resistates (890mg) is dissolved in the concentrated hydrochloric acid (4.0ml), and gained solution at room temperature stirred 10 minutes.Reaction soln washs with the dilution of 6M hydrochloric acid and with chloroform (5ml * 15).Water layer is adjusted to pH13.2 with saturated sodium hydroxide solution down ice-cooled, is adjusted to pH 7.4 with hydrochloric acid then, then with chloroform (80ml * 3) extraction.Organic layer is through anhydrous sodium sulfate drying, and removes by filter siccative.Then, filtrate decompression is concentrated.Resistates is thorough drying under vacuum, is dissolved in chloroform again: in the mixed solvent of methyl alcohol=10: 1, filter by membrane filter.Filtrate obtains the tawny solid through concentrating under reduced pressure.The gained solid is light yellow needle-like crystal by from ethanol-ammoniacal liquor recrystallization and purifying obtains 193mg (33%) title compound.
Mp:235 ℃ (decomposition).
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，d，J＝1.2Hz)，7.73(1H，d，J＝13.4Hz)，4.96(1H，m)，4.13(1H，m)，4.07(1H，m)，3.72(3H，s)，3.60(1H，brd，J＝10.4Hz)，3.52(1H，m)，3.42(1H，brd，J＝10.4Hz)，2.51(1H，m)，2.32(1H，m)，1.99-1.92(2H，m)，1.70-1.52(2H，m)。
C
20H
20F
3N
3O
4The analytical calculation value: C, 56.74; H, 4.76; F, 13.46; N, 9.92.Measured value: C, 56.68; H, 4.71; F, 13.15; N, 9.86.
HRMS (FAB); M/z C
20H
21F
3N
3O
4(M+H)
+Calculated value: 424.1484.Measured value: 424.1475.
IR(ATR)v：2938，2842，1720，1616，1544，1511，1450，1436，1365，1324，1276，1222，1180，1159，1135，1052，1010，931cm
-1。
[reference example 35]
(3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-4-methyl-5-oxo-1-[(1R)-1-
Phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 109]
Under nitrogen atmosphere, at-72 ℃, in 5 minutes, the tetrahydrofuran solution (3.10ml) of 1.8M lithium diisopropylamine is added drop-wise to (3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-the 5-oxo-1-[(1R)-the 1-phenylethyl] (2.24g is in tetrahydrofuran (THF) 5.00mmol) (20ml) solution for tetramethyleneimine-3-t-butyl formate.After stirring 10 minutes under the same temperature, and the adding methyl-iodide (0.34ml, 5.50mmol).Mixture was stirred 15 minutes under same temperature, then at 10 minutes internal heating to-10 ℃.Add 10% aqueous citric acid solution (5ml) then.Reaction soln is poured in ethyl acetate (100ml) and 10% citric acid solution (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml * 2) washing, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Gained Vandyke brown resistates need not to be further purified and just can be used for next reaction.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.23(5H，m)，5.46(0.5H，q，J＝7.1Hz)，5.45(0.5H，q，J＝7.1Hz)，3.73-3.54(2H，m)，3.37(0.5H，d，J＝10.5Hz)，3.36-3.31(1H，m)，3.28(0.5H，d，J＝10.2Hz)，2.75(0.5H，q，J＝7.3Hz)，2.40(0.5H，q，J＝7.3Hz)，2.03(0.5H，m)，1.92(0.5H，ddd，J＝5.4，7.2，13.8Hz)，1.83(0.5H，m)，1.71(0.5H，m)，1.51(1.5H，d，J＝7.1Hz)，1.50(1.5H，d，J＝7.1Hz)，1.35(4.5H，s)，1.34(4.5H，s)，1.21(1.5H，d，J＝7.3Hz)，1.12(1.5H，d，J＝7.3Hz)，0.88(2×4.5H，s)，0.03(2×1.5H，s)，0.02(1.5H，s)，0.01(1.5H，s)。
[reference example 36]
(3S)-3-(2-hydroxyethyl)-4-methyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle
Butyl ester
[formula 110]
With above-mentioned rough (3S)-3-[2-(t-butyldimethylsilyl oxygen base) ethyl]-4-methyl-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate is dissolved in the tetrahydrofuran (THF) (10ml).Then, under nitrogen atmosphere, add successively acetate (0.572ml, 10.0mmol) and the tetrahydrofuran solution of 1M tetrabutyl ammonium fluoride (10.0ml, 10.0mmol).After at room temperature stirring 12 hours, reaction soln is poured in ethyl acetate (100ml) and salt solution (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=1: 1 → 1: 2), obtain the title compound of 1.56g (90%, two step) non-enantiomer mixture, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.25(5H，m)，5.46(0.5H，q，J＝7.1Hz)，5.45(0.5H，q，J＝7.1Hz)，3.73-3.62(2H，m)，3.35(0.5H，d，J＝10.5Hz)，3.33(0.5H，d，J＝10.5Hz)，3.26(0.5H，d，J＝10.5Hz)，3.25(0.5H，d，J＝10.5Hz)，2.78(0.5H，q，J＝7.3Hz)，2.42(0.5H，q，J＝7.3Hz)，2.13(0.5H，dt，J＝14.2，6.6Hz)，2.00(0.5H，dt，J＝14.2，6.8Hz)，1.84(0.5H，dt，J＝14.2，6.4Hz)，1.71(0.5H，dt，J＝14.2，6.4Hz)，1.52(1.5H，d，J＝7.1Hz)，1.50(1.5H，d，J＝7.1Hz)，1.37(4.5H，s)，1.35(4.5H，s)，1.22(1.5H，d，J＝7.3Hz)，1.14(1.5H，d，J＝7.3Hz)。
[reference example 37]
(3S)-3-(2-bromotrifluoromethane)-4-methyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle
Butyl ester
[formula 111]
Under nitrogen atmosphere, at 0 ℃, with carbon tetrabromide (1.64g, 4.95mmol) and triphenyl phosphine (1.30g, 4.95mmol) join (3S)-3-(2-hydroxyethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl successively] (1.56g is in methylene dichloride 4.50mmol) (20ml) solution for tetramethyleneimine-3-t-butyl formate.After being heated to room temperature, reaction soln stirred 10 minutes and was concentrated into about 5ml.Resistates is by silica gel column chromatography purifying (methylene dichloride → hexane: ethyl acetate=4: 1 → 2: 1 → 1.5: 1), obtain the title compound of 1.30g (70%) non-enantiomer mixture, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.26(5H，m)，5.47(0.5H，q，J＝7.1Hz)，5.46(0.5H，q，J＝7.1Hz)，3.35-3.19(3H，m)，3.14(0.5H，d，J＝10.5Hz)，3.13(0.5H，d，J＝10.5Hz)，2.80(0.5H，q，J＝7.4Hz)，2.48-2.39(1H，m)，2.30(0.5H，ddd，J＝6.2，10.4，13.9Hz)，2.19-2.02(1H，m)，1.54(1.5H，d，J＝7.1Hz)，1.52(1.5H，d，J＝7.1Hz)，1.37(4.5H，s)，1.36(4.5H，s)，1.22(1.5H，d，J＝7.4Hz)，1.14(1.5H，d，J＝7.4Hz)。
MS(ESI)m/z：410(M+H)
+。
[reference example 38]
(1S, 5S)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane-1-
T-butyl formate
[formula 112]
Under nitrogen atmosphere, at-72 ℃, in 7 minutes, tetrahydrofuran solution (3.8ml with 1.0M hexamethyl two silicon nitrine lithiums, 3.80mmol) be added drop-wise to (3S)-3-(2-bromotrifluoromethane)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl] (1.30g is in tetrahydrofuran (THF) 3.17mmol) (20ml) solution for tetramethyleneimine-3-t-butyl formate.Mixture was stirred 30 minutes under same temperature.Be heated to-10 ℃ and stir 1.5 hours after, (4.0ml, 4.0mmol), mixture stirred 20 hours at 0 ℃ to add the tetrahydrofuran solution of 1.0M hexamethyl two silicon nitrine lithiums in 2 minutes.Under same temperature, add 10% citric acid solution (20ml).Reaction soln is poured in ethyl acetate (100ml) and 10% citric acid solution (10ml) mixture.After ethyl acetate (150ml) extraction, organic layer is with salt solution (30ml) washing, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1), obtain 0.845g (81%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.26(5H，m)，5.56(1H，q，J＝7.1Hz)，3.42(1H，d，J＝10.2Hz)，3.13(1H，d，J＝10.2Hz)，2.65(1H，ddd，J＝4.7，10.3，11.9Hz)，2.25(1H，ddd，J＝4.7，9.5，11.9Hz)，2.09(1H，m)，1.86(1H，dt，J＝11.9，9.5Hz)，1.57(3H，d，J＝7.1Hz)，0.71(9H，s)，1.25(3H，s)。
MS(ESI)m/z：330(M+H)
+。
[reference example 39]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-
Azabicyclo [3.2.0] heptane
[formula 113]
Trifluoroacetic acid (5ml) is joined (1S, 5S)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-(0.845g is in methylene dichloride 2.56mmol) (10ml) solution for 3-azabicyclo [3.2.0] heptane-1-t-butyl formate.Mixture was stirred 15 hours, and reaction soln is through concentrating under reduced pressure then.(3 * 40ml) join in the resistates, and trifluoroacetic acid is removed in evaporation with toluene.Resistates obtains rough formic acid through drying under reduced pressure, is white solid.
Triethylamine (0.786ml) and two phenoxy group phosphoryl azides (0.608ml) are joined in the toluene (10ml) and the trimethyl carbinol (10ml) solution of the rough formic acid of above acquisition successively.Mixture was at room temperature stirred 1 hour, stirred 10 hours at 80 ℃ again.Reaction soln is through concentrating under reduced pressure, and the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=7: 3 → 3: 2), obtain 548mg (62%, two step) title compound, be colourless thickness oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.23(5H，m)，5.55(1H，q，J＝7.1Hz)，4.81(1H，br)，3.60(1H，br)，3.02(1H，d，J＝11.3Hz)，2.30-2.10(3H，m)，2.02(1H，m)，1.56(3H，d，J＝7.1Hz)，1.38(9H，s)，1.27(3H，s)。
MS(ESI)m/z：345(M+H)
+。
[reference example 40]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-3-[(1R)-the 1-phenylethyl]-the 3-azepine is two
Ring [3.2.0] heptane
[formula 114]
At 0 ℃, in 5 minutes, tetrahydrofuran solution (3.6ml with 1.09M borane/tetrahydrofuran complex, 3.98mmol) be added drop-wise to (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-(548mg is in tetrahydrofuran (THF) 1.59mmol) (10ml) solution for 3-azabicyclo [3.2.0] heptane.After being heated to room temperature and stirring 3 hours, and the tetrahydrofuran solution of adding 1.09M borane/tetrahydrofuran complex under same temperature (3.6ml, 3.98mmol).Mixture was at room temperature stirred 15 hours, be cooled to 0 ℃ then.Drip ethanol (9.0ml)-water (1.0ml) mixture carefully.Drip triethylamine (3.0ml) afterwards, mixture heating up was refluxed 1 hour.Concentrated reaction solution, sedimentary white solid is removed by diatomite filtration.Concentrated filtrate, the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 1 → 5: 1), obtain 184mg (35%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.17(5H，m)，4.58(1H，br)，3.28(1H，q，J＝6.6Hz)，2.95(1H，d，J＝8.5Hz)，2.91(1H，brd，J＝9.0Hz)，2.14-2.05(4H，m)，1.68(1H，m)，1.38(9H，brs)，1.34(3H，d，J＝6.6Hz)，1.14(3H，s)。
[reference example 41]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-3-azabicyclo [3.2.0] heptane
[formula 115]
(50% is wet with 10% palladium carbon catalyst, 200mg) join (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane (184mg, 0.057mmol) ethanolic soln in, mixture stirred 5 hours at 40 ℃ under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains rough amine through concentrating under reduced pressure, is white solid.
1H-NMR(400MHz，CDCl
3)δ：4.69(1H，br)，3.27(1H，d，J＝11.5Hz)，2.92(1H，br)，2.82(1H，d，J＝11.2Hz)，2.62(1H，brd，J＝11.2Hz)，2.13(1H，brm)，1.98(1H，ddd，J＝5.6，9.8，12.7Hz)，1.71(1H，m)，1.59(1H，m)，1.44(9H，s)，1.16(3H，s)。
[embodiment 7]
7-[(1R, 5S)-1-amino-5-methyl-3-azabicyclo [3.2.0] heptan-3-yl]-6-fluoro-1-[(1R, 2S)-2-
The fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 116]
With 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (231mg, 0.668mmol) and triethylamine (0.279ml, 2.01mmol) join successively above-mentioned rough (1S, 5S)-dimethyl sulfoxide (DMSO) (2.0ml) solution of 1-(tert-butoxycarbonyl amino)-5-methyl-3-azabicyclo [3.2.0] heptane in.Mixture heats and stirred 5 hours at 40 ℃.Then, with ethanol: water=4: 1 (7.5ml) and triethylamine (1.0ml) mixture join in the reaction soln, and mixture heating up was refluxed 1.5 hours.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (100ml), and uses 10% citric acid solution (20ml), water (20ml * 2) and salt solution (20ml) washing successively.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates obtains light yellow solid by anti-phase preparation HPLC purifying (0.1% formic acid solution-acetonitrile system).The gained light yellow solid is dissolved in the concentrated hydrochloric acid (1.0ml), and solution at room temperature stirred 10 minutes then.Reaction soln washs with 6M hydrochloric acid (8ml) dilution and with chloroform (5ml).Water layer is adjusted to pH 12.4 with saturated sodium hydroxide solution down ice-cooled, is adjusted to pH 7.3 with hydrochloric acid then, and chloroform (50ml * 3) extraction is used in then water (10ml) dilution again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is thorough drying in a vacuum, is dissolved in chloroform then: in the mixed solvent of methyl alcohol=10: 1, filter by membrane filter.Filtrate obtains 60mg (26%) title compound through concentrating under reduced pressure, is light yellow solid.
mp：123-125℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.46(1H，d，J＝1.7Hz)，7.70(1H，d，J＝13.7Hz)，4.97(1H，m)，4.05(1H，m)，3.74(1H，d，J＝11.5Hz)，3.68(3H，s)，3.65(1H，m)，3.20(1H，brd，J＝9.8Hz)，3.11(1H，brd，J＝10.3Hz)，2.11(1H，m)，1.95(1H，m)，1.83(1H，m)，1.72-1.46(3H，m)，1.14(3H，s)。
C
21H
23F
2N
3O
4H
2The analytical calculation value of O0.25EtOH: C, 57.52; H, 5.95; F, 8.46; N, 9.36.Measured value: C, 57.80; H, 5.77; F, 8.41; N, 9.40.
HRMS (FAB); C
21H
24F
2N
3O
4(M+H)
+The m/z calculated value: 420.1735.Measured value: 420.1739.
IR(ATR)v：2931，2842，1727，1616，1540，1508，1436，1346，1315，1270，1226，1187，1133，1097，1051cm
-1。
[reference example 42]
(4R)-4-allyl group-4-methylol-1-[(1R)-the 1-phenylethyl] pyrrolidin-2-one
[formula 117]
(4.96g 0.228mol) is suspended in the tetrahydrofuran (THF) (500ml) with lithium borohydride.In 10 minutes, with dropping funnel with (3R)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] (50.0g, tetrahydrofuran (THF) 0.152mol) (100ml)-ethanol (17.7ml) solution joins in this suspension tetramethyleneimine-3-t-butyl formate.Mixture heating up to 40 ℃ stirred 12 hours, and reflux is 20 hours then.After being cooled to 0 ℃, add saturated ammonium chloride solution (100ml) carefully.After decompression steams the tetrahydrofuran (THF) component, reaction soln is poured in ethyl acetate (100ml) and saturated ammonium chloride solution (100ml) mixture, used ethyl acetate (1000ml, 750ml) extraction then.Merge organic layer and use salt solution (200ml) washing.Through anhydrous sodium sulfate drying and after filtering, filtrate decompression is concentrated.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=1: 4), obtain 29.9g (76%) title compound, be colourless thickness oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.25(5H，m)，5.59-5.47(2H，m)，4.97(1H，m)，4.90(1H，m)，3.50(2H，d，J＝5.1Hz)，3.23(1H，d，J＝10.1Hz)，2.71(1H，d，J＝10.1Hz)，2.37(1H，d，J＝16.8Hz)，2.26(1H，d，J＝16.8Hz)，2.08(2H，d，J＝7.3Hz)，1.84(1H，m)，1.51(3H，d，J＝7.1Hz)。
MS(ESI)m/z：260(M+H)
+。
[reference example 43]
(4R)-4-allyl group-4-benzyloxymethyl-1-[(1R)-the 1-phenylethyl] pyrrolidin-2-one
[formula 118]
Under nitrogen atmosphere, at 0 ℃, with bromotoluene (17.1ml, 0.144mol) and sodium hydride (55% is dissolved in whiteruss, 6.27g, 0.144mol) join (4R)-4-allyl group-4-methylol-1-[(1R)-1-phenylethyl successively] (31.1g is in tetrahydrofuran (THF) 0.120mol) (300ml)-dimethyl formamide (75ml) solution for pyrrolidin-2-one.Mixture was stirred 30 minutes under same temperature.Add methyl alcohol (5ml) and stirring carefully, up to stopping aerogenesis.Then, reactant saturated ammonium chloride solution (50ml) quencher.Reaction soln is poured in the mixture of ethyl acetate (1000ml) and water (150ml), used ethyl acetate (1500ml) extraction then.Organic layer is water (200ml) and salt solution (200ml * 2) washing successively, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=3: 1 → 2: 1 → 1: 1), obtain 41.3g (99%) title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.23(10H，m)，5.52-5.42(2H，m)，4.93(1H，m)，4.84(1H，m)，4.51(1H，d，J＝12.2Hz)，4.47(1H，d，J＝12.2Hz)，3.27(2H，s)，3.21(1H，d，J＝10.0Hz)，2.69(1H，d，J＝10.0Hz)，2.37(1H，d，J＝16.9Hz)，2.26(1H，d，J＝16.9Hz)，2.11(1H，m)，2.05(1H，m)，1.46(3H，d，J＝7.3Hz)。
[reference example 44]
(4R)-and 4-benzyloxymethyl-4-(2-hydroxyethyl)-1-[(1R)-1-phenylethyl] pyrrolidin-2-one
[formula 119]
At-70 ℃, to (4R)-4-allyl group-4-benzyloxymethyl-1-[(1R)-1-phenylethyl] (4.00g feeds ozone and stirred 15 minutes under same temperature pyrrolidin-2-one in methylene dichloride 11.45mmol) (100ml) solution.When reaction soln becomes mazarine, stop to feed ozone, in reaction soln, feed nitrogen then, become colorless up to solution.Under same temperature, add sodium borohydride (434mg, 11.45mmol) and methyl alcohol (40ml), with mixture at 3 hours internal heating to room temperature.Add sodium borohydride (325mg, 8.58mmol), with mixture restir 24 hours at room temperature.Add saturated ammonium chloride solution, mixture was stirred 10 minutes.Then, reaction soln is poured in ethyl acetate (200ml) and water (200ml) mixture, used ethyl acetate (500ml) extraction then.Organic layer is with salt solution (200ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=1: 2 → 1: 9 → 0: 1), obtain 3.22g (79%) title compound, be colourless thickness oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.23(10H，m)，5.46(1H，q，J＝7.1Hz)，4.55(1H，d，J＝11.8Hz)，4.48(1H，d，J＝11.8Hz)，3.54-3.45(2H，brm)，3.36(2H，s)，3.24(1H，d，J＝10.2Hz)，2.72(1H，d，J＝10.2Hz)，2.38(1H，d，J＝17.0Hz)，2.28(1H，d，J＝17.0Hz)，2.15(1H，br)，1.69-1.58(2H，m)，1.44(3H，d，J＝7.1Hz)。
[reference example 45]
(4S)-and 4-benzyloxymethyl-4-(2-bromotrifluoromethane)-1-[(1R)-1-phenylethyl] pyrrolidin-2-one
[formula 120]
Under nitrogen atmosphere, with carbon tetrabromide (3.17g, 9.56mmol) and triphenyl phosphine (2.51g, 9.56mmol) join (4R)-4-benzyloxymethyl-4-(2-hydroxyethyl)-1-[(1R)-1-phenylethyl successively] pyrrolidin-2-one (3.22g, 9.10mmol) methylene dichloride (20ml) solution in, and mixture stirred 15 minutes.Reaction soln is through concentrating under reduced pressure, and the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1 → 1: 2), obtain 3.18g (84%) title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.25(10H，m)，5.46(1H，q，J＝7.1Hz)，4.52(1H，d，J＝12.2Hz)，4.46(1H，d，J＝12.2Hz)，3.28(2H，s)，3.25(1H，d，J＝10.1Hz)，3.17-3.04(2H，m)，2.67(1H，d，J＝10.1Hz)，2.37(1H，d，J＝17.1Hz)，2.26(1H，d，J＝17.1Hz)，2.05(1H，ddd，J＝5.9，10.4，14.0Hz)，1.96(1H，ddd，J＝6.1，10.6，14.0Hz)，1.44(3H，d，J＝7.1Hz)。
[reference example 46]
(1S, 5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0]
Heptane-1-methyl-formiate
[formula 121]
Under nitrogen atmosphere, at 0 ℃, tetrahydrofuran solution (14.5ml with 1.0M hexamethyl two silicon nitrine lithiums, 14.5mmol) join (4S)-4-benzyloxymethyl-4-(2-bromotrifluoromethane)-1-[(1R)-1-phenylethyl] pyrrolidin-2-one (2.75g, 6.60mmol) and methyl-chloroformate (0.54ml is in tetrahydrofuran (THF) 6.93mmol) (20ml) solution.Mixture was stirred 12 hours, be heated to room temperature simultaneously gradually.Reaction soln is cooled to 0 ℃.Add saturated ammonium chloride solution (5ml), mixture was stirred 10 minutes.Then, reaction soln is poured in ethyl acetate (100ml) and water (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml) washing, again through anhydrous sodium sulfate drying.Remove by filter siccative, then filtrate decompression is concentrated.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=3: 1 → 2: 1 → 1: 1), obtain 2.12g (82%) title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.24(10H，m)，5.59(1H，q，J＝7.1Hz)，4.47(1H，d，J＝12.0Hz)，4.43(1H，d，J＝12.0Hz)，3.63(3H，s)，3.53(1H，d，J＝9.3Hz)，3.49(1H，d，J＝9.3Hz)，3.37(1H，d，J＝10.0Hz)，2.78(1H，ddd，J＝9.3，9.5，12.2Hz)，2.73(1H，d，J＝10.0Hz)，2.22(1H，ddd，J＝3.4，9.3，12.2Hz)，1.91(1H，ddd，J＝3.4，10.5，12.2Hz)，1.63(1H，ddd，J＝9.5，10.5，12.2Hz)，1.58(3H，d，J＝7.1Hz)。
MS(ESI)m/z：394(M+H)
+。
[reference example 47]
(1S, 5R)-5-methylol-2-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane
-1-methyl-formiate
[formula 122]
(50% is wet with 10% palladium carbon catalyst, 200mg) join (1S, 5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane-1-methyl-formiate (1.82g, 4.62mmol) ethanol (20ml)-tetrahydrofuran (THF) (20ml) solution in, mixture is under nitrogen atmosphere, stirred 2.5 hours at 40 ℃.Remove by filter after the catalyzer, concentrated filtrate obtains title compound, is clear crystal.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.27(5H，m)，5.60(1H，q，J＝7.1Hz)，3.79(1H，dd，J＝4.2，11.8Hz)，3.78(3H，s)，3.58(1H，dd，J＝7.1，11.8Hz)，3.56(1H，d，J＝10.0Hz)，2.73-2.65(2H，m)，2.57(1H，dd，J＝4.2，7.1Hz)，2.30(1H，m)，1.83(1H，m)，1.62(1H，m)，1.59(3H，d，J＝7.1Hz)。
MS(ESI)m/z：304(M+H)
+。
[reference example 48]
(1S, 5R)-5-methyl fluoride-2-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane
-1-methyl-formiate
[formula 123]
Under nitrogen atmosphere, at room temperature, with two (2-methoxy ethyl) amino sulfur trifluoride (1.98ml, 10.7mmol) join (1S, 5R)-5-methylol-2-oxo-3-[(1R)-the 1-phenylethyl]-(1.30g is in dichloromethane solution 4.30mmol) for 3-azabicyclo [3.2.0] heptane-1-methyl-formiate.Mixture heating up to 50 ℃ also stirred 12 hours.Then, add saturated sodium bicarbonate solution (10ml), mixture was stirred 10 minutes.Reaction soln is poured in ethyl acetate (50ml) and water (30ml) mixture, used ethyl acetate (200ml) extraction then.After the filtration, filtrate decompression is concentrated.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=3: 1 → 2: 1 → 1.5: 1), obtain 1.26g (96%) title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.40-7.29(5H，m)，5.63(1H，q，J＝7.2Hz)，4.51(1H，dd，J＝9.8，47.1Hz)，4.47(1H，dd，J＝9.8，47.0Hz)，3.76(3H，s)，3.41(1H，d，J＝10.0Hz)，2.78(1H，m)，2.76(1H，d，J＝10.0Hz)，2.27(1H，ddd，J＝3.6，9.3，12.5Hz)，1.93(1H，ddd，J＝3.6，10.5，12.4Hz)，1.68(1H，m)，1.62(3H，d，J＝7.2Hz)。
MS(ESI)m/z：306(M+H)
+。
[reference example 49]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl fluoride-2-oxo-3-[(1R)-1-phenyl second
Base]-3-azabicyclo [3.2.0] heptane
[formula 124]
The 1M sodium hydroxide solution is joined (1S, 5R)-5-methyl fluoride-2-oxo-3-[(1R)-the 1-phenylethyl]-(1.26g is in tetrahydrofuran (THF) 4.13mmol) (10ml)-methyl alcohol (5.0ml) solution for 3-azabicyclo [3.2.0] heptane-1-methyl-formiate.Mixture was stirred 12 hours.Reaction soln is adjusted to pH2 or lower with 6M hydrochloric acid, and filtration under diminished pressure is removed tetrahydrofuran (THF) and methyl alcohol component.Resistates is poured in ethyl acetate and the 1M hydrochloric acid mixture, used ethyl acetate extraction then.Organic layer washs with saturated nacl aqueous solution, again through anhydrous sodium sulfate drying.After removing by filter siccative, filtrate obtains the rough formic acid of 1.17g (97%) through concentrating under reduced pressure, is white solid.
Under nitrogen atmosphere, with rough formic acid (1.02g, 3.51mmol) be dissolved in toluene (20ml), the trimethyl carbinol (20ml) and triethylamine (0.98ml, in mixture 7.03mmol), add again two phenoxy group phosphoryl azides (0.833ml, 3.87mmol).Mixture stirred 1 hour at 40 ℃, stirred 12 hours at 80 ℃ then.Reaction soln is poured in ethyl acetate (50ml) and saturated sodium bicarbonate solution (30ml) mixture, used ethyl acetate (150ml) extraction then.Organic layer is with salt solution (30ml) washing, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=3: 1 → 2: 1 → 1: 1), obtain 746mg (59%) title compound, be clear crystal.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.29(5H，m)，5.60(1H，q，J＝7.1Hz)，4.95(1H，br)，4.61(1H，dd，J＝9.6，47.3Hz)，4.47(1H，dd，J＝9.6，47.3Hz)，2.15(1H，d，J＝9.5Hz)，2.70(1H，d，J＝9.5Hz)，2.36(1H，m)，2.17-2.08(2H，m)，1.60(3H，d，J＝7.1Hz)，1.42(9H，s)。
MS(ESI)m/z：363(M+H)
+。
[reference example 50]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl fluoride-3-[(1R)-the 1-phenylethyl]-the 3-azepine
Dicyclo [3.2.0] heptane
[formula 125]
Under nitrogen atmosphere, at-15 ℃, in 10 minutes, with 65%Red-Al
TMToluene solution (1.76ml, 5.85mmol) be added drop-wise to (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl fluoride-2-oxo-3-[(1R)-the 1-phenylethyl]-(707mg is in toluene solution 1.95mmol) for 3-azabicyclo [3.2.0] heptane.Mixture heating up to room temperature, was stirred 1.5 hours, and is cooled to 0 ℃.Add 25% Seignette salt tetrahydrate solution (10ml) carefully, keep the reaction soln internal temperature simultaneously at 10 ℃ or lower.Reaction soln is poured in ethyl acetate (10ml) and salt solution (10ml) mixture, used ethyl acetate (150ml) extraction then.Organic layer is with salt solution (30ml) washing, again through anhydrous sodium sulfate drying.Remove by filter siccative, then filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=9: 1 → 5: 1 → 2: 1), obtain 567mg (83%) title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.18(5H，m)，4.89(1H，br)，4.63(1H，dd，J＝9.8，47.9Hz)，4.53(1H，J＝9.8，47.6Hz)，3.33(1H，q，J＝6.4Hz)，2.95(2H，d，J＝8.8Hz)，2.40(1H，d，J＝8.8Hz)，2.18-2.14(3H，m)，1.93-1.87(2H，m)，1.37(9H，s)，1.36(3H，d，J＝6.4Hz)。
MS(ESI)m/z：349(M+H)
+。
[embodiment 8]
7-[(1S, 5S)-1-amino-5-methyl fluoride-3-dicyclo [3.2.0] heptan-3-yl]-6-fluoro-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 126]
With 10% palladium carbon catalyst (M, about 50% is wet, 50mg) join (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl fluoride-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane (567mg, 1.63mmol) ethanol (10ml) solution in, mixture was stirred 2.5 hours at 50 ℃ under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains rough amine (364mg) through concentrating under reduced pressure, is clear crystal.
Rough amine is dissolved in the dimethyl sulfoxide (DMSO) (4.0ml), add successively triethylamine (0.62ml, 4.45mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (642mg, 1.78mmol).Mixture was 40 ℃ of heated and stirred 24 hours.Then, with ethanol: water=3: 1 (20.0ml) and triethylamine (3.0ml) mixture join in the reaction soln, and mixture heating up was refluxed 1.5 hours.Reaction soln is poured in ethyl acetate (20ml) and 10% citric acid solution (10ml) mixture, used ethyl acetate (50ml * 3) extraction then.Merge organic layer and use salt solution (50ml) washing.Then, organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates obtains light yellow solid by anti-phase preparation HPLC purifying (0.1% formic acid solution-acetonitrile system).The gained light yellow solid is dissolved in the concentrated hydrochloric acid (1.5ml), and gained solution at room temperature stirred 10 minutes.Reaction soln washs with 6M hydrochloric acid (20ml) dilution and with chloroform (7ml).Water layer is adjusted to pH12.4 with saturated sodium hydroxide solution down ice-cooled, is adjusted to pH7.3 with hydrochloric acid then, uses chloroform (50ml * 2) extraction again.Water layer is adjusted to pH7.4 once more, uses chloroform (50ml * 2) extraction again.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, filtrate decompression is concentrated.Resistates is thorough drying in a vacuum, is dissolved in chloroform then.Solution filters by membrane filter, and filtrate decompression is concentrated.The gained resistates is dissolved in the ethanol, uses the hexane reprecipitation then.The gained solid filtering collects and is dry, obtains 219mg (31%) title compound, is light yellow solid.
mp：186-188℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，4.34(1H，d，J＝7.9Hz)，4.96(1H，m)，4.70(1H，dd，J＝10.0，47.4Hz)，4.64(1H，dd，J＝10.0，47.1Hz)，4.02(1H，m)，3.67-3.61(5H，m)，3.33(1H，brd，J＝10.5Hz)，3.22(1H，brd，J＝9.8Hz)，2.11(1H，m)，2.00-1.88(2H，m)，1.73(1H，m)，1.60(1H，m)，1.47(1H，m)。
C
21H
22F
3N
3O
40.25H
2The analytical calculation value of O0.25EtOH: C, 56.95; H, 5.33; F, 12.57; N, 9.27.Measured value: C, 56.94; H, 5.11; F, 12.74; N, 9.23.
HRMS (FAB); C
21H
23F
3N
3O
4(M+H)
+The m/z calculated value: 438.16406.Measured value: 438.16743.
IR(ATR)v：3386，2935，1716，1616，1540，1508，1442，1436，1351，1319，1274，1228，1184，1122，1051cm
-1。
[reference example 51]
(4R)-4-allyl group-4-methoxymethyl-1-[(1R)-the 1-phenylethyl] pyrrolidin-2-one
[formula 127]
Under nitrogen atmosphere, at 0 ℃, with methyl-iodide (1.87ml, 30.1mmol) and sodium hydride (55% is dissolved in whiteruss, 1.31g, 30.1mol) join (4R)-4-allyl group-4-methylol-1-[(1R)-1-phenylethyl successively] (7.09g is in tetrahydrofuran (THF) 27.3mmol) (80ml)-dimethyl formamide (20ml) solution for pyrrolidin-2-one.Mixture heating up is to room temperature and stirred 1 hour.Add methyl alcohol (2ml) and stirring carefully up to stopping aerogenesis.Then, reactant saturated ammonium chloride solution (10ml) quencher.Reaction soln is poured in ethyl acetate (100ml) and water (100ml) mixture, used ethyl acetate (800ml) extraction then.Organic layer is water (200ml) and salt solution (200ml * 2) washing successively, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=4: 1 → 2: 1 → 1: 1), obtain 7.42g (99%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.24(5H，m)，5.54-5.43(2H，m)，4.94(1H，m)，4.84(1H，m)，3.33(3H，s)，3.20(2H，s)，3.19(1H，d，J＝10.0Hz)，2.69(1H，d，J＝10.0Hz)，2.36(1H，d，J＝17.1Hz)，2.24(1H，d，J＝17.1Hz)，2.05-2.03(2H，m)，1.50(3H，d，J＝7.3Hz)。
[reference example 52]
(4R)-4-(2-hydroxyethyl)-4-methoxymethyl-1-[(1R)-the 1-phenylethyl] pyrrolidin-2-one
[formula 128]
At-70 ℃, to (4R)-4-allyl group-4-methoxymethyl-1-[(1R)-1-phenylethyl] (3.28g feeds ozone in methyl alcohol 12.0mmol) (20ml)-methylene dichloride (20ml) solution to pyrrolidin-2-one, and stirs 30 minutes under same temperature.When reaction soln becomes mazarine, stop to feed ozone, in reaction soln, feed nitrogen then, become colorless up to solution.Under same temperature, add sodium borohydride (454mg, 12.0mmol), with mixture at 2 hours internal heating to room temperature.After the heating, (227mg 6.0mmol), stirs mixture 24 hours to add sodium borohydride.Then, (113mg 3.0mmol), stirs mixture 0.5 hour to add sodium borohydride once more.Add saturated ammonium chloride solution (10ml), mixture was stirred 10 minutes.Then, reaction soln is poured in ethyl acetate (50ml) and water (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (ethyl acetate: methyl alcohol=10: 0 → 10: 1), obtain 2.85g (86%) title compound, be colourless thickness oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.25(5H，m)，5.49(1H，q，J＝7.1Hz)，3.55-3.44(2H，m)，3.37(3H，s)，3.30(1H，d，J＝9.5Hz)，3.28(1H，d，J＝9.5Hz)，3.22(1H，d，J＝10.0Hz)，2.72(1H，d，J＝10.0Hz)，2.38(1H，d，J＝16.8Hz)，2.26(1H，d，J＝16.8Hz)，1.64(2H，t，J＝6.0Hz)，1.50(3H，d，J＝7.1Hz)。
[reference example 53]
(4S)-4-(2-bromotrifluoromethane)-4-methoxymethyl-1-[(1R)-the 1-phenylethyl] pyrrolidin-2-one
[formula 129]
Under nitrogen atmosphere, at 0 ℃, with carbon tetrabromide (3.58g, 10.8mmol) and triphenyl phosphine (2.83g, 10.8mmol) join (4R)-4-(2-hydroxyethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl successively] pyrrolidin-2-one (2.85g, 10.3mmol) methylene dichloride (30ml) solution in, mixture was stirred 10 minutes.Mixture heating up is to room temperature and stirred 24 hours, and reaction soln is through concentrating under reduced pressure then.Resistates is by silica gel column chromatography purifying (methylene dichloride → hexane: ethyl acetate=2: 1 → 1: 1 → 1: 2), obtain 2.07g (59%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.25(5H，m)，5.49(1H，q，J＝7.3Hz)，3.32(3H，s)，3.24(1H，d，J＝10.3Hz)，3.23(2H，s)，3.20-3.07(2H，m)，2.67(1H，d，J＝10.3Hz)，2.38(1H，d，J＝16.8Hz)，2.25(1H，d，J＝16.8Hz)，2.03-1.90(2H，m)，1.50(3H，d，J＝7.3Hz)。
[reference example 54]
(1S, 5R)-5-methoxymethyl-2-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0]
Heptane-1-methyl-formiate
[formula 130]
Under nitrogen atmosphere, at-70 ℃, tetrahydrofuran solution (13.4ml with 1.0M hexamethyl two silicon nitrine lithiums, 13.4mmol) join (4S)-4-(2-bromotrifluoromethane)-4-methoxymethyl-1-[(1R)-1-phenylethyl] pyrrolidin-2-one (2.07g, 6.08mmol) and methyl-chloroformate (0.493ml is in tetrahydrofuran (THF) 6.38mmol) (20ml) solution.Mixture was stirred 14 hours, be heated to room temperature simultaneously gradually.Reaction soln is cooled to 0 ℃.Add 10% citric acid solution (20ml), mixture was stirred 10 minutes.Then, reaction soln is poured in ethyl acetate (100ml) and water (50ml) mixture, used ethyl acetate (200ml) extraction then.Organic layer is with salt solution (50ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1 → 2: 1), obtain 1.53g (79%) title compound, be light brown oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.26(5H，m)，5.60(1H，q，J＝7.1)，3.72(3H，s)，3.43(1H，d，J＝9.5Hz)，3.40(1H，d，J＝9.5Hz)，3.36(1H，d，J＝9.8Hz)，3.28(3H，s)，2.75(1H，dt，J＝12.2，10.5Hz)，2.72(1H，d，J＝9.5Hz)，2.21(1H，ddd，J＝3.4，9.3，12.2Hz)，1.86(1H，ddd，J＝3.4，10.5，12.2Hz)，1.62(1H，dt，J＝12.2，9.3Hz)，1.58(3H，d，J＝7.1Hz)。
MS(ESI)m/z：318(M+H)
+。
[reference example 55]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methoxymethyl-2-oxo-3-[(1R)-1-phenyl second
Base]-3-azabicyclo [3.2.0] heptane
[formula 131]
(5.0ml) joins (1S with the 1M sodium hydroxide solution, 5R)-5-methoxymethyl-2-oxo-3-[(1R)-the 1-phenylethyl]-(1.53g is in tetrahydrofuran (THF) 4.82mmol) (10ml)-methyl alcohol (5.0ml) solution for 3-azabicyclo [3.2.0] heptane-1-methyl-formiate.Mixture was stirred 9 hours.Reaction soln is adjusted to pH 2 or lower with 6M hydrochloric acid, and filtration under diminished pressure is removed tetrahydrofuran (THF) and methyl alcohol component.Resistates is poured in ethyl acetate (30ml) and 1M hydrochloric acid (30ml) mixture, used ethyl acetate (150ml) extraction then.Organic layer is with saturated nacl aqueous solution (30ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate obtains rough formic acid again through concentrating under reduced pressure, is light yellow oil.
Under nitrogen atmosphere, with rough formic acid be dissolved in the trimethyl carbinol (30ml) and triethylamine (1.34ml, 9.64mmol) in the mixture, add two phenoxy group phosphoryl azides (1.14ml, 5.30mmol).Mixture stirred 2 hours at 40 ℃, stirred 20 hours at 80 ℃ then.Reaction soln is through concentrating under reduced pressure, and the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1), obtain 595mg (33%, two step) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.23(5H，m)，2.25(1H，q，J＝7.1H)，4.87(1H，brs)，3.55(1H，d，J＝9.2Hz)，3.42(1H，brd，J＝9.2Hz)，3.35(1H，d，J＝9.6Hz)，3.33(3H，s)，2.71(1H，d，J＝9.6Hz)，2.33(1H，m)，2.12-2.00(2H，m)，1.60(3H，d，J＝7.1Hz)，1.43(9H，s)。
[reference example 56]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methoxymethyl-3-[(1R)-the 1-phenylethyl]-3-
Azabicyclo [3.2.0] heptane
[formula 132]
Under nitrogen atmosphere, at 0 ℃, in 2 minutes, with 65%Red-Al
TMToluene solution (1.43ml, 4.75mmol) be added drop-wise to (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methoxymethyl-2-oxo-3-[(1R)-the 1-phenylethyl]-(593mg is in toluene solution 1.58mmol) for 3-azabicyclo [3.2.0] heptane.Mixture heating up to room temperature, was stirred 2 hours and is cooled to 0 ℃.Add 20% Seignette salt tetrahydrate solution (10ml) carefully, keep the reaction soln internal temperature simultaneously at 10 ℃ or lower.Reaction soln is poured in ethyl acetate (10ml) and salt solution (10ml) mixture, used ethyl acetate (100ml) extraction then.Organic layer is with salt solution (20ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=19: 1 → 9: 1), obtain 244mg (43%) title compound, be clear crystal.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.17(5H，m)，5.56(1H，brs)，3.58(1H，d，J＝10.0Hz)，3.43(1H，d，J＝10.0Hz)，3.37(3H，s)，3.28(1H，q，J＝6.5Hz)，3.10(1H，br)，2.86(1H，d，J＝8.7Hz)，2.34(1H，d，J＝8.7Hz)，2.23-2.01(3H，brm)，1.84(2H，brt，J＝8.1Hz)，1.35(9H，brs)，1.34(3H，d，J＝6.5Hz)。
MS(ESI)m/z：361(M+H)
+。
[embodiment 9]
7-[(1S, 5S)-1-amino-5-methoxymethyl-3-azabicyclo [3.2.0] heptan-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 133]
(50% is wet with 10% palladium carbon catalyst, 50mg) join (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methoxymethyl-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.2.0] heptane (242mg, 0.67mmol) ethanol (20ml) solution in, mixture stirred 7 hours at 50 ℃ under nitrogen atmosphere.Remove by filter after the catalyzer, filtrate obtains rough amine (164mg) through concentrating under reduced pressure, is colourless thickness oily matter.
Rough amine (164mg) is dissolved in the dimethyl sulfoxide (DMSO) (2.0ml), add successively triethylamine (0.178ml, 1.28mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid-BF
2Inner complex (254mg, 0.704mmol).Mixture was 40 ℃ of heated and stirred 23 hours.Then, with ethanol: water=5: 1 (6.0ml) and triethylamine (1.0ml) mixture join in the reaction soln, and mixture heating up was refluxed 2 hours.Reduction vaporization is poured resistates in ethyl acetate (20ml) and 10% citric acid solution (10ml) mixture into after removing ethanol and triethylamine component in the reaction soln, uses ethyl acetate (80ml) extraction then.Organic layer is with salt solution (20ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates obtains light yellow amorphous thing by anti-phase preparation HPLC purifying (0.1% formic acid solution-acetonitrile system).The light yellow amorphous thing of gained is dissolved in the concentrated hydrochloric acid (2.0ml), and solution at room temperature stirred 10 minutes.Reaction soln washs with 6M hydrochloric acid (15ml) dilution and with chloroform (10ml).Water layer is adjusted to pH12 with saturated sodium hydroxide solution down ice-cooled, is adjusted to pH 7.4 with hydrochloric acid then, uses chloroform (50ml * 2,30ml) extraction again.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, filtrate decompression is concentrated.Resistates is thorough drying in a vacuum, is dissolved in chloroform then.Solution filters by membrane filter, and filtrate decompression is concentrated.The gained resistates filters and collects crystal and dry from the hexane crystallization, obtains 184mg (61%) title compound, is light yellow solid.
mp：86-88℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，d，J＝1.5Hz)，7.69(1H，d，J＝13.4Hz)，4.95(1H，m)，4.02(1H，m)，3.70-3.58(7H，m)，3.39(3H，s)，3.23(1H，d，J＝10.5Hz)，3.19(1H，d，J＝10.3Hz)，2.09(1H，m)，1.99-1.87(2H，m)，1.74(1H，m)，1.61(1H，m)，1.48(1H，m)。
C
22H
25F
2N
3O
50.25H
2The analytical calculation value of O0.25EtOH: C, 58.06; H, 5.85; F, 8.16; N, 9.03.Measured value: C, 57.92; H, 5.86; F, 8.16; N, 9.09.
HRMS (FAB); C
22H
26F
2N
3O
5(M+H)
+The m/z calculated value: 450.18405.Measured value: 450.18358.
IR(ATR)v：2931，2827，1724，1616，1546，1504，1434，1392，1348，1313，1274，1228，1184，1101，1051cm
-1。
[reference example 57]
(3R)-3-[1-(methylol) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine
[formula 134]
With lithium borohydride (1.174g, 53.90mmol) join 1-[(3R)-5-oxo-1-[(1S)-1-phenylethyl] tetramethyleneimine-3-yl] the cyclopropane-carboxylic acid ethyl ester is [referring to Journal of MedicinalChemistry, the 46th volume, the 6th phase, the 1005th page (2003)] (2.03g is in tetrahydrofuran (THF) 6.74mmol) (20ml) solution.Mixture is heated in 70 ℃ of oil baths and stirred 30 hours.After being cooled to room temperature, reaction soln is poured in ice-cooled 10% citric acid solution (80ml), used ethyl acetate (200ml) extraction then.Organic layer water (80ml) and salt solution (80ml) washing through anhydrous sodium sulfate drying, are filtered, then with solvent removed under reduced pressure.The gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 2 → 1: 1 → 2: 1 → 1: 0 → chloroform: methyl alcohol=9: 1), obtain 1.30g (74%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.26-7.35(5H，m)，5.48(1H，q，J＝6.9Hz)，3.45(2H，s)，3.04-3.12(1H，m)，2.37-2.50(2H，m)，2.19(1H，dd，J＝16.0，8.9Hz)，1.51(2H，d，J＝7.1Hz)，0.43(4H，s)。
MS(ESI)m/z：260(M+H)
+。
[reference example 58]
(3R)-3-[1-(tert-butyl diphenyl siloxy-methyl) ring third-1-yl]-the 5-oxo-1-[(1S)-1-
Phenylethyl] tetramethyleneimine
[formula 135]
With t-butyldiphenylsilyl chlorine (2.83ml, 10.88mmol) join (3R)-3-[1-(methylol) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine (2.35g, 9.06mmol) and imidazoles (925mg, 13.59mmol) N, in dinethylformamide (30ml) solution, mixture was at room temperature stirred 20 hours.Reaction soln dilutes with ethyl acetate (150ml), and water (50ml * 2) and salt solution (50ml * 2) washing are through anhydrous sodium sulfate drying and filtration.Solvent evaporated under reduced pressure.The gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 19 → 1: 9 → 1: 4 → 1: 1), obtain 3.88g (86%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.56-7.59(4H，m)，7.26-7.46(11H，m)，5.48(1H，q，J＝7.0Hz)，3.46(1H，d，J＝10.7Hz)，3.39(1H，d，J＝10.7Hz)，3.10(2H，td，J＝18.4，9.6Hz)，2.51(1H，m)，2.32(1H，dd，J＝16.5，8.9Hz)，2.14(1H，dd，J＝16.5，10.4Hz)，1.46(3H，d，J＝7.1Hz)，1.01(9H，s)，0.33-0.39(4H，m)。
MS(ESI)m/z：498(M+H)
+。
[reference example 59]
(3R)-3-[1-(tert-butyl diphenyl siloxy-methyl) ring third-1-yl]-the 5-oxo-1-[(1S)-1-
Phenylethyl] tetramethyleneimine-4-base ethyl formate
[formula 136]
At 0 ℃, in 2 minutes, with Vinyl chloroformate (0.059ml, 0.617mmol) and the tetrahydrofuran solution (1.0M of hexamethyl two silicon nitrine lithiums, 0.57ml, 0.570mmol) be added drop-wise to (3R)-3-[1-(tert-butyl diphenyl siloxy-methyl) ring third-1-yl successively]-the 5-oxo-1-[(1S)-the 1-phenylethyl] (258mg is in tetrahydrofuran (THF) 0.518mmol) (2ml) solution for tetramethyleneimine.Mixture stirred 30 minutes at 0 ℃, at room temperature stirred again 30 minutes, and then the tetrahydrofuran solution of adding hexamethyl two silicon nitrine lithiums (1.0M, 0.57ml, 0.570mmol).Mixture was at room temperature stirred 2.5 hours, carry out ice-cooled then.Reactant is with 10% citric acid solution (20ml) quencher.The gained mixture extracts with ethyl acetate (50ml).Organic layer water (20ml) and salt solution (20ml) washing are again through anhydrous sodium sulfate drying.After the filtration, with solvent removed under reduced pressure.Then, the gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 9 → 1: 4 → 1: 2), obtain 227mg (77%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.54-7.64(4H，m)，7.26-7.45(11H，m)，5.46(1H，q，J＝6.9Hz)，4.23(1H，ddd，J＝14.3，7.1，1.8Hz)，3.29-3.52(4H，m)，3.12(1H，t，J＝9.0Hz)，2.65(1H，dd，J＝18.6，8.5Hz)，1.48(2H，d，J＝7.1Hz)，1.29(3H，t，J＝7.1Hz)，1.02(9H，s)，0.33(4H，m)。
MS(ESI)m/z：570(M+H)
+。
[reference example 60]
(3R)-3-[1-(methylol) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine-4-base
Ethyl formate
[formula 137]
At 0 ℃, in 5 minutes, hydrogen fluoride-pyridine complex compound (10ml) is added drop-wise to (3R)-3-[1-(tert-butyl diphenyl siloxy-methyl) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine-(2.81g is in pyridine 4.93mmol) (20ml) solution for 4-base ethyl formate.Mixture was at room temperature stirred 2.5 hours, pour into then in the frozen water (150ml), use ethyl acetate (300ml) extraction again.The gained organic layer is with 10% citric acid solution (100ml), water (100ml) and salt solution (100ml) washing, again through anhydrous sodium sulfate drying.After the solvent evaporated under reduced pressure, the gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 2 → 1: 1 → 2: 1), obtain 1.378g (84%) title compound, be light yellow gluey solid.
1H-NMR(400MHz，CDCl
3)δ：7.26-7.36(5H，m)，5.46(1H，q，J＝7.1Hz)，4.25(2H，q，J＝7.2Hz)，3.49(2H，dd，J＝23.2，10.5Hz)，3.36(1H，d，J＝11.7Hz)，3.09(2H，dt，J＝20.8，8.9Hz)，2.67(1H，q，J＝8.5Hz)，1.54(3H，d，J＝7.1Hz)，1.31(3H，t，J＝7.1Hz)，0.35-0.50(4H，m)。
MS(ESI)m/z：332(M+H)
+。
[reference example 61]
(3R)-3-[1-(iodomethyl) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine-4-base
Ethyl formate
[formula 138]
At room temperature, with imidazoles (708mg, 10.40mmol), triphenyl phosphine (2.727g, 10.40mmol) and iodine (2.111g, 8.32mmol) join (3R)-3-[1-(methylol) ring third-1-yl successively]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine-(1.378g is in methylene dichloride 4.16mmol) (50ml) solution for 4-base ethyl formate.Mixture was at room temperature stirred 15 hours.Solvent evaporated under reduced pressure.Then, resistates is dissolved in the washing of ethyl acetate (200ml) and water (50ml * 2) and salt solution (50ml).Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.The gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 9 → 1: 4 → 1: 2), obtain 1.606g (88%) title compound, be light yellow gluey solid.
1H-NMR(400MHz，CDCl
3)δ：7.26-7.39(5H，m)，5.47(1H，q，J＝7.2Hz)，4.28(2H，q，J＝7.2Hz)，3.19-3.23(2H，m)，3.03-3.12(3H，m)，2.94(1H，m)，1.54(3H，d，J＝7.1Hz)，1.33(3H，t，J＝7.1Hz)，0.80-0.87(2H，m)，0.63(2H，m)。
MS(ESI)m/z：442(M+H)
+。
[reference example 62]
(1S, 5S)-the 2-oxo-3-[(1S)-the 1-phenylethyl]-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane
-1-base ethyl formate
[formula 139]
Ice-cooled down at salt, in 5 minutes, toluene solution (0.5M with hexamethyl two silicon nitrine potassium, 8.94ml, 4.47mmol) be added drop-wise to (3R)-3-[1-(iodomethyl) ring third-1-yl]-the 5-oxo-1-[(1S)-the 1-phenylethyl] tetramethyleneimine-(1.517g is in toluene 3.44mmol) (30ml) solution for 4-base ethyl formate.Mixture was stirred under same temperature 1 hour 20 minutes, at room temperature stirred then 5.5 hours.Reaction soln carries out ice-cooled, and reactant is used ethyl acetate (200ml) extraction then with 10% citric acid solution (20ml) quencher.Organic layer water (50ml * 2) and salt solution (50ml) washing.Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.The gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 9 → 1: 4 → 1: 2), obtain 717mg (67%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.27-7.38(5H，m)，5.61(1H，q，J＝7.1Hz)，4.14-4.28(2H，m)，3.02-3.07(3H，m)，2.91(1H，dt，J＝9.8，3.8Hz)，2.29(1H，d，J＝12.2Hz)，1.61(3H，d，J＝7.1Hz)，1.28(3H，t，J＝7.2Hz)，0.62(2H，m)，0.44(2H，m)。
MS(ESI)m/z：314(M+H)
+。
[reference example 63]
(1R, 5S)-3-[(1S)-the 1-phenylethyl]-6-spirocyclopropane-2-sulfo--3-azabicyclo [3.2.0] heptan
Alkane-1-base ethyl formate
[formula 140]
With Lawesson's reagent (Lawesson ' s reagent) (1.146g, 2.83mmol) join (1S, 5S)-the 2-oxo-3-[(1S)-the 1-phenylethyl]-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-(592mg is in toluene 1.89mmol) (20ml) solution for 1-base ethyl formate.Mixture heating and stirring 6.5 hours under nitrogen atmosphere, in 90 ℃ of oil baths.After the solvent evaporated under reduced pressure, resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 19 → 1: 9 → 1: 4), obtain 0.57g (92%) title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.30-7.36(5H，m)，6.40(1H，q，J＝7.1Hz)，4.11-4.32(2H，m)，3.33(1H，dd，J＝12.0，6.8Hz)，3.22(2H，t，J＝11.7Hz)，3.09(1H，d，J＝6.3Hz)，2.37(1H，d，J＝12.2Hz)，1.68(3H，d，J＝7.1Hz)，1.28(3H，t，J＝7.2Hz)，0.58(1H，m)，0.42(2H，m)。
MS(ESI)m/z：330(M+H)
+。
[reference example 64]
(1S, 5S)-3-[(1S)-the 1-phenylethyl]-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-1-Ji Jia
Acetoacetic ester
[formula 141]
Raney nickel (4ml) is joined (1R, 5S)-3-[(1S)-the 1-phenylethyl]-6-spirocyclopropane-2-sulfo--3-azabicyclo [3.2.0] heptane-(0.57g is in ethanol 1.73mmol) (40ml) solution for 1-base ethyl formate.Mixture stirred 30 minutes under nitrogen atmosphere, room temperature.Behind diatomite filtration, filtrate decompression is concentrated.Resistates is dissolved in ethyl acetate, filters by short silicagel column then.Filtrate obtains 503mg (97%) title compound through reduction vaporization, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.22-7.44(5H，m)，4.20(2H，q，J＝7.0Hz)，3.30(1H，m)，3.24(1H，d，J＝8.8Hz)，2.72(1H，d，J＝5.1Hz)，2.59(1H，d，J＝11.5Hz)，2.52(1H，d，J＝9.8Hz)，2.45(1H，d，J＝8.8Hz)，2.26(1H，d，J＝11.5Hz)，1.95(1H，dd，J＝9.3，5.6Hz)，1.39(3H，d，J＝6.3Hz)，1.29(3H，t，J＝7.1Hz)，0.51(1H，m)，0.31-0.40(3H，m)。
MS(ESI)；m/z：300(M+H)
+。
[reference example 65]
(1S, 5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-1-base formic acid second
Ester
[formula 142]
With chloroformic acid benzyl ester (0.72ml, 5.04mmol) join (1S, 5S)-3-[(1S)-the 1-phenylethyl]-(503mg is in methylene dichloride 1.68mmol) (10ml) solution for 6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-1-base ethyl formate.Mixture stirred 16 hours under nitrogen atmosphere, room temperature.After the solvent evaporated under reduced pressure, resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 9 → 1: 4 → 1: 2), obtain 505mg (91%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.27-7.40(5H，m)，5.18(2H，m)，4.21(2H，q，J＝7.2Hz)，3.92(1H，dd，J＝36.6，12.0Hz)，3.64(2H，dd，J＝23.3，11.6Hz)，3.27(1H，m)，3.02(1H，d，J＝6.1Hz)，2.73(1H，m)，2.02(1H，t，J＝10.4Hz)，1.29(3H，t，J＝7.1Hz)，0.47-0.58(3H，m)，0.32(1H，m)。
MS(ESI)；m/z：330(M+H)
+。
[reference example 66]
(1S, 5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-spirocyclopropane-3-azabicyclo
[3.2.0] heptane
[formula 143]
At room temperature, with 1N sodium hydroxide solution (4.60ml, 4.60mmol) join (1S, 5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-(500mg is in ethanol/tetrahydrofuran (THF) 1.52mmol) (4.6ml/2.3ml) solution for 1-base ethyl formate.Mixture was stirred 1 hour under same temperature.Solvent evaporated under reduced pressure, resistates 1N hcl acidifying is used ethyl acetate (100ml) extraction then.Organic layer is through anhydrous sodium sulfate drying and filtration.Solvent evaporated under reduced pressure obtains that rough (1S 5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-1-base formic acid (501mg), is the water white transparency colloidal solid.
At room temperature, with two phenoxy group phosphoryl azide (0.393ml, 1.82mmol) join the rough (1S of gained, 5S)-(0.381ml is in toluene 2.73mmol) (7.5ml) solution for 3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-1-base formic acid (501mg) and triethylamine.Mixture stirred 5 minutes under nitrogen atmosphere, room temperature, stirred 40 minutes in 90 ℃ of oil baths then.Then, (15ml) joins in the reaction soln with the trimethyl carbinol, and mixture heats in 120 ℃ of oil baths and stirred 6 hours.Behind the reduction vaporization reaction solvent, the gained resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=1: 9 → 1: 4 → 1: 2), obtain 347mg (two steps, 61%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.28-7.39(5H，m)，5.16(2H，m)，4.90(1H，m)，3.95(1H，t，J＝11.6Hz)，3.41-3.58(3H，m)，2.80(1H，m)，2.34(1H，t，J＝10.3Hz)，2.20(1H，d，J＝12.0Hz)，1.45(9H，s)，0.46-0.56(3H，m)，0.28(1H，m)。
MS(ESI)m/z：317(M-tBu+H)
+。
[embodiment 10]
7-[(1S, 5R)-1-amino-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane-3-
Base]-1-[(1R, 2S)-2-fluorine cyclopropyl]-6-fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-first
Acid
[formula 144]
(about 50% is wet with 10% palladium carbon catalyst, 103mg) join (1S, 5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane (342mg, 0.918mmol) methyl alcohol (30ml) solution in, mixture stirred 1.5 hours under nitrogen atmosphere, room temperature.Remove by filter catalyzer, solvent evaporated under reduced pressure then obtains that rough (1S 5R)-1-(tert-butoxycarbonyl amino)-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane (230mg), is the water white transparency colloidal solid.
Under nitrogen atmosphere, at room temperature, with the rough (1S of gained, 5R)-1-(tert-butoxycarbonyl amino)-6-spirocyclopropane-3-azabicyclo [3.2.0] heptane (230mg), 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (331mg, 0.918mmol), triethylamine (0.384ml, 2.76mmol) and the mixture of dimethyl sulfoxide (DMSO) (3ml) stirred 17 hours.Then, ethanol (20ml), water (5ml) and triethylamine (2.5ml) are joined in the reaction soln gained mixture reflux 3 hours in 110 ℃ of oil baths.After the solvent evaporated under reduced pressure, (50ml) joins in the resistates with 10% citric acid solution, uses ethyl acetate (200ml) extraction again.Organic layer water (50ml * 2) and salt solution (50ml) washing and through anhydrous sodium sulfate drying, solvent evaporated under reduced pressure then.The gained resistates is dissolved in concentrated hydrochloric acid (20ml).The gained acidic solution is moved in the separating funnel, use chloroform (20ml * 8) washing then.Water layer is adjusted to pH12.0 with the 10mol/L sodium hydroxide solution down ice-cooled, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform again: the mixed extractant solvent of methyl alcohol=9: 1 (200ml * 2).Merge organic layer and through anhydrous sodium sulfate drying and filtration, solvent evaporated under reduced pressure then.The gained resistates obtains 125mg (32%) title compound by from the ethyl alcohol recrystallization purifying and through drying under reduced pressure, is the baby pink powder.
Mp:182-203 ℃ (decomposition).
[α]
D 23.5＝-14.4°(c＝0.104，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，d，J＝1.2Hz)，7.71(1H，d，J＝13.9Hz)，4.98(1H，dm，J＝47.4Hz)，4.03-4.08(1H，m)，3.70-3.73(1H，m)，3.70(3H，s)，3.61(1H，d，J＝10.7Hz)，3.37(1H，m)，3.23(1H，d，J＝10.0Hz)，2.42(1H，d，J＝5.9Hz)，2.29(1H，d，J＝12.2Hz)，2.16(1H，d，J＝12.5Hz)，1.44-1.66(2H，m)，0.48-0.57(3H，m)，0.29-0.33(1H，m)。
C
22H
23F
2N
3O
40.75H
2The analytical calculation value of O0.25HCl: C, 58.19; H, 5.49; N, 9.25; F, 8.37; Cl, 1.95.Measured value: C, 57.93; H, 5.41; N, 9.15; F, 8.43; Cl, 2.44.
MS(FAB)m/z：432(M+H)
+。
HRMS (FAB) C
22H
23F
2N
3O
4The calculated value of+H: 432.1735.Measured value: 432.1714.
IR(ATR)v：2871，2763，2721，2575，2517，1720，1612，1568，1535，1493，1456，1365，1350，1321，1267，1205，1157cm
-1。
[reference example 67]
(1R
*
, 5R
*
)-3-benzyl-3-azabicyclo [3.3.0] octane-1-base methyl-formiate
[formula 145]
At room temperature, the trifluoroacetic acid of catalytic amount is joined 1-cyclopentenes-1-methyl-formiate (2.52g, 20.0mmol) and N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (5.00g, 21.1mmol) methylene dichloride (40ml) solution in, mixture at room temperature heats and stirred 15.5 hours.Reaction soln washs with methylene dichloride (100ml) dilution and with saturated sodium bicarbonate solution (80ml).Water layer after the washing is used methylene dichloride (50ml) extraction again.Merge organic layer, again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=95: 5 → 90: 10 → 80: 20), obtain 4.28g (83%) title compound, be water white transparency oily thing.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.21(5H，m)，3.67(3H，s)，3.58(1H，d，J＝13.2Hz)，3.52(1H，d，J＝13.2Hz)，2.92(1H，d，J＝9.3Hz)，2.88(1H，m)，2.67(1H，t，J＝8.2Hz)，2.44(1H，d，J＝9.3Hz)，2.31(1H，dd，J＝8.8，4.4Hz)，2.06-1.60(5H，m)，1.54-1.47(1H，m)。
MS?(ESI)；m/z：260(M+H)
+。
[reference example 68]
(1R
*
, 5R
*
)-3-benzyloxycarbonyl-3-azabicyclo [3.3.0] octane-1-base methyl-formiate
[formula 146]
At room temperature, (3.53ml 24.6mmol) joins (1R with chloroformic acid benzyl ester
*, 5R
*)-3-benzyl-3-azabicyclo [3.3.0] octane-(4.27g, in methylene dichloride 16.46mmol) (50ml) solution, mixture stirred 23 hours in 40 ℃ of oil baths 1-base methyl-formiate.After the solvent evaporated under reduced pressure, resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=90: 10 → 80: 20 → 67: 33), obtain 2.24g (45%) title compound, be water white transparency oily thing.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.28(5H，m)，5.12(2H，s)，3.97(1H，d，J＝11.7Hz)，3.71-3.64(4H，m)，3.45-3.28(2H，m)，2.94-2.87(1H，m)，2.23-2.15(1H，m)，2.03-1.94(1H，m)，1.85-1.71(3H，m)，1.52(1H，m)。
MS(ESI)m/z：304(M+H)
+。
[reference example 69]
(1R
*
, 5R
*
)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] suffering
Alkane
[formula 147]
At room temperature, (22.0ml 22.0mmol) joins (1R with the 1N sodium hydroxide solution
*, 5R
*)-3-benzyloxycarbonyl-3-azabicyclo [3.3.0] octane-(2.21g in methyl alcohol 7.29mmol) (22ml)-tetrahydrofuran (THF) (44ml) solution, at room temperature stirred mixture 2 hours 1-base methyl-formiate.Behind the concentrating under reduced pressure solvent, resistates 3N hcl acidifying is used ethyl acetate (200ml) extraction again.The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure obtains rough formic acid.The rough formic acid of gained need not to be further purified and just can be used for next reaction.
Ice-cooled down, (2.03ml, (2.02ml is in toluene 14.5mmol) (40ml) solution 9.42mmol) to join the rough formic acid of above acquisition and triethylamine with two phenoxy group phosphoryl azides.Mixture at room temperature heats and stirred 30 minutes, then in 90 ℃ of oil baths the heating and stirred 3.5 hours.Reaction soln is with ethyl acetate (200ml) dilution and use saturated sodium bicarbonate solution (80ml), water (80ml) and salt solution (80ml) washing successively.The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure obtains rough isocyanic ester.The rough isocyanic ester of gained is dissolved in 1, in the 4-diox (20ml), adds 6N hydrochloric acid (20ml).Then, mixture heats in 50 ℃ of oil baths and stirred 0.5 hour.Reaction soln water and alcohol dilution, concentrating under reduced pressure is then with ethanol component distillation (2 times).Resistates is dissolved in the methylene dichloride (40ml), at room temperature add successively triethylamine (5.05ml, 36.3mmol) and tert-Butyl dicarbonate (3.17g, 14.5mmol).Reaction soln at room temperature stirred 5 hours, used ethyl acetate (200ml) dilution and water (80ml) and salt solution (80ml) washing then.The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=90: 10 → 80: 20 → 67: 33), obtain 1.32g (3.66mmol, 51%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.27(5H，m)，5.12(2H，s)，4.75(1H，brs)，3.74-3.59(3H，m)，3.31-3.23(1H，m)，2.74-2.48(1H，m)，2.04-1.88(3H，m)，1.80-1.71(2H，m)，1.43(10H，m)。
MS(ESI)m/z：305(M-tBu+H)
+。
[reference example 70]
(+)-(1R
*
, 5S
*
)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0]
Octane and (-)-(1R
*
, 5S
*
)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo
[3.3.0] octane
[formula 148]
Racemic modification (the 1R that more than obtains
*, 5S
*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (1.32g, 3.66mmol) carry out optical resolution (CHIRALCEL OJ by the optically-active post, 20mm diameter * 250mm, hexane: Virahol=90: 10, flow velocity=20ml/min, each 50mg that splits), obtain (+)-(1R
*, 5S
*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (586mg, 1.626mmol, retention time=5.5min, [α]
D 25.1=+19.3 ° (c=0.145, chloroform)) and (-)-(1R
*, 5S
*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (590mg, 1.637mmol, retention time=6.9min, [α]
D 25.1=-20.0 ° (c=0.155, chloroform).
[embodiment 11]
7-{ (1R
*
, 5S
*
)-1-amino-3-azabicyclo [3.3.0] octane-3-yl }-6-fluoro-1-[(1R, 2S)-2-
The fluorine cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid [the 7-bit substituent derived from
(+)-optically active isomer]
[formula 149]
(about 50% is wet, 115mg) joins (+)-(1R with 10% palladium carbon catalyst
*, 5S
*(575mg, in methyl alcohol 1.595mmol) (20ml) solution, the gained mixture stirred 2 hours under nitrogen atmosphere, room temperature)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane.Remove by filter catalyzer, solvent evaporated under reduced pressure obtains rough 1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (388mg) then, is the water white transparency colloidal solid.
With rough 1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (388mg), 6 of above acquisition, 7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (576mg, 1.595mmol) and triethylamine (0.667ml 4.79mmol) is dissolved in the dimethyl sulfoxide (DMSO) (4ml), and gained solution heats in 35-40 ℃ of oil bath and stirred 16 hours.With ethanol: the mixing solutions of water=4: 1 (50ml) and triethylamine (5ml) joins in the reaction soln, mixture reflux 3 hours in 90 ℃ of oil baths.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (200ml) also with 10% citric acid solution (80ml), water (50ml * 2) and salt solution (50ml) washing.Organic layer is through anhydrous sodium sulfate drying and filtration, solvent evaporated under reduced pressure then.Under ice-cooled, the gained resistates is dissolved in the concentrated hydrochloric acid (10ml).After at room temperature stirring 20 minutes, reaction soln washs with chloroform (30ml * 3).Water layer is adjusted to pH 12.0 with the 10mol/L sodium hydroxide solution down ice-cooled, is adjusted to pH 7.4 with hydrochloric acid then.Then, solvent evaporated under reduced pressure.Resistates is suspended in methyl alcohol and filters.Then, filtrate is suspended in chloroform through concentrating under reduced pressure (2 times): in the mixed solvent of methyl alcohol=9: 1, filter then.Mother liquor is removed sodium-chlor through concentrating under reduced pressure.The gained resistates is by PTLC purifying (preparation type TLC; Lower floor's solvent chloroform: methyl alcohol: water=7: 3: 1), by from ethanol-ammoniacal liquor recrystallization and purifying obtains 111mg (17%) title compound, be buff powder again.
mp：169-172℃。
[α]
D 25.1＝+103.5°(c＝0.228，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，7.68(1H，d，J＝13.9Hz)，5.05-4.80(1H，m)，4.04(1H，m)，3.77(1H，t，J＝9.0Hz)，3.63(3H，s)，3.52(2H，s)，3.35(1H，dd，J＝9.8，4.9Hz)，2.30(1H，m)，2.04(1H，m)，1.89-1.47(7H，m)。
C
21H
23F
2N
3O
40.25EtOH0.75H
2The analytical calculation value of O: C, 58.10; H, 5.90; F, 8.55; N, 9.45.Measured value: C, 57.87; H, 5.51; F, 8.60; N, 9.11.
MS(EI)；m/z：419(M
+)。
IR(ATR)v：2952，2873，2831，2177，1712，1614，1577，1535，1498，1460，1389，1360，1323，1271，1205cm
-1。
[embodiment 12]
7-[(1R
*
, 5S
*
)-1-amino-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid [the 7-bit substituent derived from (-)-
Optically active isomer]
[formula 150]
(about 50% is wet, 114mg) joins (-)-(1R with 10% palladium carbon catalyst
*, 5S
*(569mg, in methyl alcohol 1.579mmol) (30ml) solution, the gained mixture stirred 2 hours under nitrogen atmosphere, room temperature)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane.Remove by filter catalyzer, solvent evaporated under reduced pressure obtains rough 1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (373mg) then, is the water white transparency colloidal solid.
With rough 1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane (373mg), 6 of above acquisition, 7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (570mg, 1.579mmol) and triethylamine (0.660ml 4.74mmol) is dissolved in the dimethyl sulfoxide (DMSO) (4ml), and gained solution heats in 35-40 ℃ of oil bath and stirred 16 hours.With ethanol: the mixed solvent of water=4: 1 (50ml) and triethylamine (5ml) joins in the reaction soln, mixture reflux 3 hours in 90 ℃ of oil baths.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (200ml) also with 10% citric acid solution (80ml), water (50ml * 2) and salt solution (50ml) washing.Organic layer is through anhydrous sodium sulfate drying and filtration, solvent evaporated under reduced pressure then.Under ice-cooled, the gained resistates is dissolved in the concentrated hydrochloric acid (10ml).After at room temperature stirring 20 minutes, reaction soln washs with chloroform (30ml * 3).Water layer is adjusted to pH 12.0 with the 10mol/L sodium hydroxide solution down ice-cooled, is adjusted to pH 7.4 with hydrochloric acid then.Then, solvent evaporated under reduced pressure.Resistates is suspended in methyl alcohol: ammoniacal liquor=20: 1 and filtration.Then, filtrate is suspended in chloroform through concentrating under reduced pressure (2 times): in the mixed solvent of methyl alcohol=9: 1 and filter.Mother liquor is removed sodium-chlor through concentrating under reduced pressure.Water=7: 3: 1) and crystallization in alcohol-ether the gained resistates is by PTLC purifying (lower floor's solvent chloroform: methyl alcohol:, obtain 32mg (5%) title compound, be the tawny powder.
mp：171-174℃。
[α]
D 25.1＝+52.1°(c＝0.073，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，7.65(1H，d，J＝13.9Hz)，5.02-4.82(1H，m)，4.00(1H，m)，3.86-3.80(1H，m)，3.62-3.55(4H，m)，3.36-3.31(1H，m)，3.15-3.10(1H，m)，2.24(1H，m)，2.05-1.30(8H，m)。
C
21H
23F
2N
3O
4.0.5EtOH1.25H
2The analytical calculation value of O: C, 56.83; H, 6.18; F, 8.17; N, 9.04.Measured value: C, 56.41; H, 5.68; F, 8.76; N, 8.64.
MS(EI)；m/z：419(M
+)。
IR(ATR)v：2948，2871，2576，2162，1712，1616，1566，1495，1456，1390，1363，1319，1269cm
-1。
[reference example 71]
(3S)-3-[3-(t-butyldimethylsilyl oxygen base)-1-propyl group]-the 5-oxo-1-[(1R)-the 1-phenyl
Ethyl] tetramethyleneimine-3-t-butyl formate
[formula 151]
With (3S)-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (46g) and imidazoles (11.9g) be dissolved in the dimethyl formamide (600ml).Add tert-butyldimethylsilyl chloride (23.2g) afterwards down ice-cooled, mixture was at room temperature stirred 59.5 hours.Reaction soln is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer is used saturated sodium bicarbonate aqueous solution and salt water washing successively, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=9: 1 → 8: 2 → 2: 1), obtain the 29.7g title compound, be light yellow oil through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.22(5H，m)，5.48(1H，q，J＝7.11Hz)，3.58(2H，t，J＝6.13Hz)，3.34(1H，d，J＝10.05Hz)，3.12(1H，d，J＝10.05Hz)，2.94(1H，d，J＝16.91Hz)，2.31(1H，d，J＝17.16Hz)，1.86-1.74(1H，m)，1.72-1.62(1H，m)，1.51(3H，d，J＝7.11Hz)，1.49-1.24(2H，m)，1.33(9H，s)，0.88(9H，s)，0.03(6H，s)。
[reference example 72]
(3S)-3-[3-(t-butyldimethylsilyl oxygen base)-1-propyl group]-4-fluoro-5-oxo
-1-[(1R)-and the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 152]
With (3S)-3-[3-(t-butyldimethylsilyl oxygen base)-1-propyl group]-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (30g) is dissolved in the tetrahydrofuran (THF) (280ml), with the former atmosphere of argon replaces.Then, drip hexamethyl two silicon nitrine lithiums (tetrahydrofuran solution of 1.0M) (78.0ml) at-15 ℃, mixture stirred 30 minutes at-5 ℃.Be cooled to once more after-15 ℃, drip tetrahydrofuran (THF) (220ml) solution of N-fluorobenzene sulfimide (26.6g), mixture was at room temperature stirred 17 hours.Reaction soln is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=9: 1 → 8: 2), obtain the 8.15g title compound, be light yellow solid through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.23(5H，m)，5.53-5.44(1H，m)，5.18(1H，d，J＝51.72Hz)，3.64-3.52(2H，m)，3.32-3.19(2H，m)，1.92-1.65(2H，m)，1.55(3H，d，J＝4.66Hz)，1.33(9H，s)，0.88(9H，s)，0.03(6H，s)。
MS(FAB)m/z：480(M+H)
+。
IR(ATR)v：3421，2977，2935，2877，1698，1454，1369，1309，1249，1153，1058，1035，1006，842cm
-1。
[reference example 73]
(3S)-4-fluoro-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid
The tert-butyl ester
[formula 153]
With (3S)-3-[3-(t-butyldimethylsilyl oxygen base)-1-propyl group]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (8.15g) is dissolved in the tetrahydrofuran (THF) (25.0ml).Add acetate (22.0ml) and tetrabutyl ammonium fluoride (tetrahydrofuran solution of 1.0M) (25.0ml) down ice-cooled, mixture was at room temperature stirred 21.5 hours.Reaction soln is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer is used saturated sodium bicarbonate aqueous solution and salt water washing successively, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=9: 1 → 8: 2 → 1: 1), obtain the 5.77g title compound, be light yellow oil through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.22(5H，m)，5.48(1H，q，J＝7.03Hz)，5.20(1H，d，J＝51.48Hz)，3.69-3.59(2H，m)，3.31-3.21(2H，m)，1.95-1.72(2H，m)，1.68-1.43(2H，m)，1.56(3H，d，J＝7.11Hz)，1.33(9H，s)。
[reference example 74]
(3S)-3-(3-benzenesulfonyl Oxy-1-propyl group)-4-fluoro-5-oxo-1-[(1R)-the 1-phenylethyl] pyrroles
Alkane-3-t-butyl formate
[formula 154]
With (3S)-4-fluoro-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (12.20g) is dissolved in the methylene dichloride (400ml).At ice-cooled benzene sulfonyl chloride (9.06ml), triethylamine (10.7ml) and the 4-Dimethylamino pyridine (2.04g) of adding down, mixture was at room temperature stirred 12.5 hours.Saturated sodium bicarbonate aqueous solution is joined in the reaction soln, mixture was stirred 30 minutes, use dichloromethane extraction again.Organic layer is used 10% citric acid solution and salt water washing successively, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=8: 2 → 1: 1), obtain the 11.7g title compound, be light yellow oil through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.94-7.87(2H，m)，7.71-7.63(1H，m)，7.60-7.53(2H，m)，7.37-7.23(5H，m)，5.46(1H，q，J＝7.11Hz)，5.15(1H，d，J＝51.48Hz)，4.10-3.98(2H，m)，3.26-3.15(2H，m)，1.88-1.50(4H，m)，1.55(3H，s)，1.30(9H，s)。
[reference example 75]
(1S, 5R)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base
T-butyl formate
[formula 155]
With (3S)-3-(3-benzenesulfonyl Oxy-1-propyl group)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (10.9g) is dissolved in the tetrahydrofuran (THF) (350ml), with the former atmosphere of argon replaces.Then, drip hexamethyl two silicon nitrine potassium (toluene solution of 0.5M) (86.5ml) at-15 ℃, mixture stirred 1.5 hours at 0 ℃.After being cooled to-10 ℃, drip saturated aqueous ammonium chloride (100ml), mixture was at room temperature stirred 30 minutes.Reaction soln is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=9: 1 → 7: 1), obtain the 4.36g title compound, be light yellow solid through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.25(5H，m)，5.58-5.49(1H，m)，3.63(1H，d，J＝10.3Hz)，2.91(1H，dd，J＝10.3，3.2Hz)，2.67-2.56(1H，m)，2.50-2.38(1H，m)，2.26-2.09(1H，m)，2.06-1.94(1H，m)，1.74-1.66(1H，m)，1.54(3H，d，J＝7.1Hz)，1.50-1.40(1H，m)，1.34(9H，s)。
[reference example 76]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-nitrogen
Assorted dicyclo [3.3.0] octane
[formula 156]
Will (1S, 5R)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(4.36g 12.5mmol) is dissolved in the methylene dichloride (70ml) 1-base t-butyl formate.Drip trifluoroacetic acid (70ml), mixture was at room temperature stirred 6 hours.After the solvent evaporated under reduced pressure, resistates and methylbenzene azeotropic distillation obtain formic acid (3.70g).
Gained formic acid is dissolved in the toluene.(3.51ml, 25.2mmol) (2.98ml 13.8mmol), refluxes mixture heating up 5 hours with two phenoxy group phosphoryl azides to add triethylamine.Solvent evaporated under reduced pressure.Then, with 1,4-diox (110ml) and 6N hydrochloric acid (110ml) join in the resistates, and the gained mixture stirred 2.5 hours at 60 ℃.Behind water and the ethyl acetate extraction, water layer is with the alkalization of saturated sodium hydroxide solution and with chloroform extraction 2 times.Merge organic layer, through anhydrous sodium sulfate drying and filtration, solvent evaporated under reduced pressure then.(11.05g) joins in the resistates with tert-Butyl dicarbonate, and the gained mixture stirred 6 hours at 75 ℃.Reaction soln is behind concentrating under reduced pressure, and resistates is handled (hexane: ethyl acetate=9: 1 → 1: 1), obtain the 3.69g title compound, be light yellow oil by silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.23(5H，m)，5.50(1H，q，J＝7.1Hz)，5.22(1H，brs)，3.34(2H，s)，2.49-2.37(1H，m)，2.32-2.03(3H，m)，2.02-1.90(1H，m)，1.51(3H，d，J＝7.1Hz)，1.55-1.48(1H，m)，1.35(9H，s)。
[reference example 77]
(1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-[(1R)-the 1-phenylethyl]-the 3-azabicyclo
[3.3.0] octane
[formula 157]
Will (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-(3.69g 10.2mmol) is dissolved in the tetrahydrofuran (THF) (200ml) 3-azabicyclo [3.3.0] octane.(42.4ml 50.9mmol), stirs mixture 2 hours, is heated to room temperature simultaneously gradually at the ice-cooled tetrahydrofuran solution that drips down 1.20M borane-tetrahydrofuran complex.Solvent evaporated under reduced pressure.Down 90% aqueous ethanol (100ml) and triethylamine (100ml) are joined in the resistates ice-cooled, mixture heating up was refluxed 2 hours.After the solvent evaporated under reduced pressure, resistates saturated sodium bicarbonate aqueous solution and dichloromethane extraction.Then, with methylene dichloride the target material is extracted from water.Merge organic layer, use the salt water washing, again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is handled (hexane: ethyl acetate=95: 5 → 90: 10), obtain the 3.33g title compound, be light yellow oil by silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.18(5H，m)，5.38(1H，brs)，3.22(1H，q，J＝6.37Hz)，2.92-2.57(4H，m)，2.12-1.86(4H，m)，1.80-1.67(1H，m)，1.63-1.52(3H，m)，1.42(9H，s)，1.32(3H，d，J＝6.37Hz)。
[reference example 78]
(1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane
[formula 158]
Will (1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-[(1R)-the 1-phenylethyl]-(700mg 2.0mmol) is dissolved in the ethanol (30ml) 3-azabicyclo [3.3.0] octane.Add 10% palladium-carbon (50% is wet) (1.01g), the gained mixture is under nitrogen atmosphere, 50 ℃ of stirrings 15 hours.Remove by filter catalyzer, then filtrate decompression is concentrated.The gained resistates is handled (methylene dichloride: methyl alcohol=98: 2 → 95: 5), obtain the 446mg title compound, be light yellow solid by silica gel column chromatography.
[α]
D 23-15°(c＝0.100，MeOH)。
1H-NMR(400MHz，CDCl
3)δ：5.29(1H，brs)，3.47-3.18(2H，m)，2.93-2.79(2H，m)，2.15-1.71(6H，m)，1.45(9H，s)。
[embodiment 13]
10-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-9-fluoro-2, the 3-dihydro
-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid
[formula 159]
With triethylamine (0.222ml, 1.59mmol) and 9,10-two fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid-BF
2Inner complex (209mg, 0.64mmol) join (1R, 5S)-(129mg is in dimethyl sulfoxide (DMSO) 0.53mmol) (4.0ml) solution for 1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane.The gained mixture stirred 18.5 hours at 40 ℃.(0.111ml 0.80mmol) joins in the reaction soln, and the gained mixture stirred 6.5 hours at 40 ℃ with triethylamine again.Ethanol (6.0ml), water (2.0ml) and triethylamine (2.0ml) are joined in the reaction soln, mixture heating up was refluxed 1.5 hours.After the solvent evaporated under reduced pressure, resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer washes 2 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (methylene dichloride: methyl alcohol=99: 1 → 98: 2), obtain oily matter (261mg) through silica gel column chromatography.Down gained oily matter (261mg) is dissolved in the concentrated hydrochloric acid (2.4ml) ice-cooled, gained solution at room temperature stirred 3 hours.Reaction soln washs 2 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.10% methyl alcohol-chloroform is joined in the resistates.After the filtration, filtrate decompression is concentrated.Resistates is light yellow solid by from ethanol-ammoniacal liquor recrystallization and purifying obtains the 145mg title compound.
Mp:285-293 ℃ (decomposition).
[α]
D 24-40.3°(c＝0.100，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，d，J＝1.23Hz)，7.70(1H，d，J＝13.7Hz)，5.07-4.85(1H，m)，4.10-4.02(1H，m)，3.93-3.78(2H，m)，3.70-3.53(2H，m)，3.66(3H，s)，2.21-2.04(2H，m)，2.01-1.83(2H，m)，1.83-1.46(4H，m)。
MS(FAB)m/z：406(M+H)
+。
C
20H
21F
2N
3O
4The analytical calculation value: C, 59.25; H, 5.22; F, 9.37; N, 10.37.Measured value: C, 59.22; H, 5.16; F, 9.16; N, 10.27.
IR(ATR)v：3365，2931，2861，1706，1619，1521，1461，1442，1415，1396，1278，1230，1141，1130，1093，1047，983，964，900，879，863，800cm
-1。
[embodiment 14]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-8-cyano group-6-fluorine
-1-[(1R, 2S)-2-fluorine ring third-1-yl]-1,4-dihydro-4-Oxoquinoline-3-formic acid
[formula 160]
With triethylamine (0.272ml, 1.95mmol) and 8-cyano group-6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropane]-6,7-two fluoro-1,4-dihydro-4-Oxoquinoline-3-ethyl formate (240mg, 0.71mmol) join (1R, 5R)-(148mg in acetonitrile 0.61mmol) (10ml) solution, at room temperature stirred mixture 3 days 1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane.After the solvent evaporated under reduced pressure, resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=1: 1 → 3: 7), obtain the ethyl ester (231mg) that is replaced by the 7-bit substituent through silica gel column chromatography.Gained ethyl ester (231mg) is dissolved in tetrahydrofuran (THF) (3.0ml) and the ethanol (6.0ml).Add 1N sodium hydroxide solution (0.82ml), mixture was at room temperature stirred 3.5 hours.After the solvent evaporated under reduced pressure, resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.(2.0ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 1 hour.Then, reaction soln washs 2 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.10% methyl alcohol-chloroform is joined in the resistates, remove by filter insolubles.Then, filtrate decompression is concentrated.Resistates is light yellow solid by from ethanol-ammoniacal liquor recrystallization and purifying obtains the 128mg title compound.
Mp:268-280 ℃ (decomposition).
[α]
D 24-1.8°(c＝0.100，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.40(1H，d，J＝1.96Hz)，7.96(1H，d，J＝14.46Hz)，5.29-5.05(1H，m)，4.28-4.00(3H，m)，3.94-3.80(2H，m)，2.23-2.10(2H，m)，2.04-1.56(6H，m)。
MS(FAB)；m/z：433(M+H)
+。
C
21H
19F
3N
4O
3The analytical calculation value: C, 58.33; H, 4.43; F, 13.18; N, 12.96.Measured value: C, 58.24; H, 4.36; F, 13.10; N, 12.84.
IR(ATR)v：3359，3039，2213，1720，1623，1552，1477，1452，1405，1375，1311，1259，1226，1172，1137，1112，1074，1054，991，931，887，806cm
-1。
[embodiment 15]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-
Fluorine ring third-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 161]
With triethylamine (3.30ml, 23.7mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (2.93g, 8.12mmol) join (1R, 5S)-(1.32g is in dimethyl sulfoxide (DMSO) 5.40mmol) (30ml) solution for 1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane.The gained mixture stirred 19 hours at 40 ℃.Again with triethylamine (1.70ml, 12.3mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(1.00g 2.77mmol) joins in the reaction soln inner complex, and the gained mixture stirred 16 hours at 40 ℃.Ethanol (45ml), water (15ml) and triethylamine (15ml) are joined in the reaction soln, mixture heating up was refluxed 1.5 hours.After the solvent evaporated under reduced pressure, the gained resistates is used 10% citric acid solution and ethyl acetate extraction again.Then, organic layer washes 3 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (methylene dichloride: methyl alcohol=99: 1) through silica gel column chromatography.Down gained oily matter (3.30g) is dissolved in the concentrated hydrochloric acid (20ml) ice-cooled, gained solution at room temperature stirred 1 hour.Reaction soln washs 2 times with chloroform, and water layer is adjusted to pH 12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.Chloroform is joined resistates.After the filtration, filtrate decompression is concentrated.Resistates obtains the 769mg title compound by from the ethyl alcohol recrystallization purifying, is light yellow solid.
Mp:191-195 ℃ (decomposition).
[α]
D 24+97°(c＝0.100，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，d，J＝1.23Hz)，7.70(1H，d，J＝13.73Hz)，5.07-4.85(1H，m)，4.10-4.02(1H，m)，3.93-3.78(2H，m)，3.70-3.53(2H，m)，3.66(3H，s)，2.21-2.04(2H，m)，2.01-1.83(2H，m)，1.83-1.46(4H，m)。
MS(FAB)；m/z：438(M+H)
+。
C
21H
22F
3N
3O
40.75H
2The analytical calculation value of O: C, 55.94; H, 5.25; F, 12.64; N, 9.32.Measured value: C, 56.03; H, 5.51; F, 12.79; N, 9.66.
IR(ATR)v：2958，2871，1724，1621，1513，1452，1319，1056，929，804cm
-1。
[embodiment 16]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-1-[(1R, 2S)-2-fluorine ring
Propane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 162]
With triethylamine (0.447ml, 3.21mmol) and 7-fluoro-1-[(1R, 2S)-and 2-fluorine ring third-1-yl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (450mg, 1.61mmol) join (1R, 5S)-(260mg, in dimethyl sulfoxide (DMSO) 1.07mmol) (6.0ml) solution, the gained mixture stirred 18.5 hours at 70-80 ℃ 1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane.(0.224ml 1.61mmol) joins in the reaction soln, and the gained mixture stirred 6 days at 70-80 ℃ with triethylamine once more.(0.447ml, 3.21mmol), the gained mixture stirred 10 days at 70-80 ℃ to add triethylamine once more.Reaction soln is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer washes 2 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (methylene dichloride: methyl alcohol=98: 2), obtain oily matter (369mg) through silica gel column chromatography.Down gained oily matter (369mg) is dissolved in the concentrated hydrochloric acid (3.0ml) ice-cooled, gained solution at room temperature stirred 1 hour.Reaction soln washs 2 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is by the PTLC purifying (chloroform of use lower floor: methyl alcohol: water=7: 3: 1 exhibition layers).Then, the gained flow point obtains resistates through concentrating under reduced pressure, and it solidifies with Virahol, obtains the 21mg title compound, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.50(1H，d，J＝2.94Hz)，8.06(1H，d，J＝8.58Hz)，7.13(1H，d，J＝8.82Hz)，5.13-4.90(1H，m)，4.18-4.10(1H，m)，3.89-3.77(1H，m)，3.45-3.25(3H，m)，2.58(3H，s)，2.20-1.98(3H，m)，1.93-1.82(1H，m)，1.81-1.57(3H，m)，1.37-1.22(1H，m)。
MS(FAB)；m/z：404(M+H)
+。
C
21H
23F
2N
3O
30.5H
2The analytical calculation value of O0.25IPA: C, 61.11; H, 6.13; N, 9.83.Measured value: C, 61.11; H, 5.72; N, 9.74.
IR(ATR)v：2956，2873，2823，1708，1610，1508，1432，1355，1313，1255，1133，929cm
-1。
[embodiment 17]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-
The fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 163]
With triethylamine (0.215ml, 1.54mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid-BF
2Inner complex (530mg, 1.53mmol) join (1R, 5S)-(250mg is in dimethyl sulfoxide (DMSO) 1.02mmol) (5.0ml) solution for 1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane.Mixture was at room temperature stirred 7 days.Again with triethylamine (0.215ml, 1.54mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid-BF
2(530mg 1.53mmol) joins in the reaction soln inner complex, and mixture was at room temperature stirred 7 days.Again with triethylamine (0.215ml, 1.54mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid-BF
2(530mg 1.53mmol) joins in the reaction soln inner complex, and mixture was at room temperature stirred 10 days.Ethanol (6.0ml), water (2.0ml) and triethylamine (2.0ml) are joined reaction soln, and the gained mixture stirred 1 hour at 80 ℃.After the solvent evaporated under reduced pressure, resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer washes 2 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.(methylene dichloride: methyl alcohol=98: 2), the gained flow point is through concentrating under reduced pressure for the processing of resistates process silica gel column chromatography.Then, down resistates is dissolved in the concentrated hydrochloric acid (3.5ml) ice-cooled, gained solution at room temperature stirred 1 hour.Reaction soln washs 5 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is by the PTLC purifying (chloroform of use lower floor: methyl alcohol: water=7: 3: 1 exhibition layers).The gained resistates solidifies with Virahol, obtains the 7.1mg title compound, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.50(1H，s)，7.77(1H，d，J＝13.73Hz)，5.80-4.80(1H，m)，4.22-4.10(1H，m)，3.99-3.85(1H，m)，3.68-3.47(2H，m)，3.43-3.34(1H，m)，2.68(3H，s)，2.21-1.98(3H，m)，1.97-1.56(4H，m)，1.42-1.23(1H，m)。
MS(FAB)；m/z：422(M+H)
+。
C
21H
22F
3N
3O
30.5H
2The analytical calculation value of O0.25IPA: C, 58.65; H, 5.66; F, 12.80; N, 9.43.Measured value: C, 58.63; H, 5.35; F, 12.35; N, 9.22.
IR(ATR)v：2971，2856，1722，1614，1450，1432，1322，1132，1097，987，954，929，887，856，804cm
-1。
[embodiment 18]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-(6-amino-3,5-two for 1-
Fluorine pyridine-2-yl)-1,4-dihydro-8-chloro-6-fluoro-4-Oxoquinoline-3-formic acid
[formula 164]
With N-crassitude (0.246ml, 2.37mmol) and 1-(6-amino-3,5-difluoro pyridine-2-yl)-8-chloro-6,7-two fluoro-1,4-dihydro-4-Oxoquinoline-3-formic acid (306mg, 0.79mmol) join (1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane (193mg, 0.79mmol) acetonitrile (10.0ml) solution in, mixture heating up was refluxed 10 hours.Once more with 1-(6-amino-3,5-difluoro pyridine-2-yl)-8-chloro-6,7-two fluoro-1, (92mg 0.24mmol) joins in the reaction soln 4-dihydro-4-Oxoquinoline-3-formic acid, and gained mixture reheat refluxed 4.5 hours.After the solvent evaporated under reduced pressure, resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer washes 2 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.The gained resistates is handled (methylene dichloride: methyl alcohol=99: 1) by silica gel column chromatography.Down gained oily matter (409mg) is dissolved in the concentrated hydrochloric acid (3.0ml) ice-cooled, gained solution at room temperature stirred 2.5 hours.Reaction soln washs 2 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.Chloroform is joined in the resistates, remove by filter insolubles.Then, filtrate is through reduction vaporization, and the gained resistates obtains the 47mg title compound by from the ethyl alcohol recrystallization purifying, is light yellow solid.
1H-NMR(400MHz，DMSO-d
6)δ：8.79(1H，s)，8.07-7.90(2H，m)，6.75(2H，d，J＝8.58Hz)，3.87-3.65(2H，m)，3.50-3.25(2H，m)，2.09-1.96(2H，m)，1.88-1.53(4H，m)。
MS(FAB)；m/z：512(M+H)
+。
C
22H
18ClF
4N
5O
30.5H
2The analytical calculation value of O: C, 50.73; H, 3.68; Cl, 6.81; F, 14.59; N, 13.45.Measured value: C, 50.75; H, 3.58; Cl, 6.52; F, 14.31; N, 13.09.
IR(ATR)v：3480，3345，3070，2954，2865，1724，1606，1484，1438，1386，1307，1112cm
-1。
[reference example 79]
3-(oxyethane-2-ylmethyl)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester
[formula 165]
With (3S)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (4.9g 14.9mmol) is dissolved in the methylene dichloride, add mCPBA (10.3g, 59.5mmol).Mixture was at room temperature stirred 15 hours, and reflux is 3 hours then.After the solvent evaporated under reduced pressure, the mixture of resistates with ethyl acetate and saturated sodium thiosulfate solution mixed.Organic layer washs with saturated sodium bicarbonate aqueous solution, through dried over mgso and filtration, then with solvent removed under reduced pressure.Resistates obtains 4.33g (84%) colorless oil title compound by silica gel chromatography purifying (hexane/ethyl acetate=4: 1 → 1: 1), is non-enantiomer mixture.Diastereomer need not to separate and purifying just can be used for next step.
[reference example 80]
(1S, 5S)-7-hydroxyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-
The base t-butyl formate
[formula 166]
With 3-(oxyethane-2-ylmethyl)-5-oxo-1-[(1R)-1-phenylethyl] (4.2g 12.16mmol) is dissolved in the tetrahydrofuran (THF) (50ml) tetramethyleneimine-3-t-butyl formate.Under argon atmospher, at-78 ℃, add the tetrahydrofuran solution (18ml, 1.5 equivalents) of 1M hexamethyl two silicon nitrine lithiums, the gained mixture heats gradually.When temperature of reaction reached about room temperature, ethyl acetate extraction was used in reactant ammonium chloride solution quencher then.Extraction liquid is through dried over mgso.After the filtration, with solvent removed under reduced pressure.The gained resistates is by silica gel chromatography purifying (hexane: ethyl acetate=4: 1 → 2: 1 → 1: 1 → 1: 2), obtain the title compound that 1.07g (26%) has individual isomer, be colorless oil.Collect 1.0g (24%) raw material.Obtaining (29%) the 4 yuan of closed compound of ring of 1.20g as by product, is non-enantiomer mixture.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.26(5H，m)，5.48(1H，q，J＝7.08Hz)，4.36-4.30(1H，m)，3.35-3.30(2H，m)，3.12(1H，d，J＝10.25Hz)，2.44-2.38(2H，m)，2.29(1H，dt，J＝13.83，4.94Hz)，2.16-2.09(1H，m)，1.84(1H，dd，J＝13.79，5.25Hz)，1.50(3H，d，J＝7.08Hz)，1.37(9H，s)。
[reference example 81]
(1R, 5R)-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base
T-butyl formate
[formula 167]
Will (1S, 5S)-7-hydroxyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(1.0g 2.89mmol) is dissolved in the methylene dichloride (15ml) 1-base t-butyl formate.Add two (2-methoxy ethyl) amino sulfur trifluorides (BAST) down (0.59ml) ice-cooled, mixture was stirred 1 hour under same temperature.Reaction soln washs with saturated sodium bicarbonate aqueous solution, through dried over mgso and filtration.Then, solvent evaporated under reduced pressure.Resistates is by silica gel chromatography purifying (hexane: ethyl acetate=10: 1 → 4: 1 → 1: 1), obtain 711mg (71%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.25(5H，m)，5.50(1H，q，J＝7.1Hz)，5.24(1H，dt，J＝52.2，3.2Hz)，3.48(1H，d，J＝10.0Hz)，3.26-3.21(2H，m)，2.61-2.37(2H，m)，2.21-2.04(2H，m)，1.48(3H，d，J＝7.1Hz)，1.36(9H，s)。
[reference example 82]
(1R, 5R)-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base
Formic acid
[formula 168]
Will (1R, 5R)-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(705mg 2.03mmol) is dissolved in the methylene dichloride (4ml) 1-base t-butyl formate.At the ice-cooled trifluoroacetic acid (4ml) that adds down, then mixture was at room temperature stirred 1 hour.Reaction soln is through concentrating under reduced pressure.Toluene is joined in the resistates, and the gained mixture obtains 595mg (quantitatively) title compound once more through concentrating under reduced pressure, is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.14(5H，m)，5.48(1H，q，J＝7.08Hz)，5.32-5.19(1H，m)，3.61(1H，d，J＝10.74Hz)，3.43(1H，d，J＝10.01Hz)，3.33(1H，d，J＝10.50Hz)，2.64-2.05(4H，m)，1.49(3H，d，J＝7.08Hz)。
[reference example 83]
(1R, 5S)-1-amino-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] suffering
Alkane
[formula 169]
With toluene (10ml) and triethylamine (565 μ l, 4.05mmol) join (1R, 5R)-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base formic acid (590mg, 2.03mmol) in.Then, add two phenoxy group phosphoryl azides (567 μ l), mixture was at room temperature stirred 30 minutes.Then, reaction soln reflux 1 hour and mix with the mixture of ethyl acetate-saturated sodium bicarbonate aqueous solution.Organic layer is through dried over mgso and filtration.Then, solvent evaporated under reduced pressure.Resistates is dissolved in the diox (10ml).Add 6N hydrochloric acid (10ml), the gained mixture heats and stirred 2 hours at 70 ℃.After the ether washing, water layer is with the alkalization of 10M sodium hydroxide solution, again with toluene extraction 5 times.Extraction liquid is through dried over mgso and filtration, and solvent evaporated under reduced pressure obtains 476mg (90%) title compound then, is colorless oil.Product need not purifying and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.16(5H，m)，5.53(1H，q，J＝7.00Hz)，5.20(1H，dt，J＝52.70，4.40Hz)，3.49(1H，d，J＝10.30Hz)，2.86(1H，d，J＝10.30Hz)，2.66(1H，d，J＝10.00Hz)，2.52-2.19(3H，m)，1.93(1H，ddd，J＝39.50，15.00，4.10Hz)，1.52(2H，brs)，1.47(3H，d，J＝7.10Hz)。
[reference example 84]
(1R, 5S)-1-(tert-butoxycarbonyl amino)-7-fluoro-3-[(1R)-the 1-phenylethyl]-the 3-azabicyclo
[3.3.0] octane
[formula 170]
Will (1R, 5S)-1-amino-7-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-(537mg 2.05mmol) is dissolved in the toluene (20ml) 3-azabicyclo [3.3.0] octane.Under argon atmospher, add Red-Al
TM(2.53ml, 8.12mmol), the gained mixture stirred 1 hour at 80 ℃ (65% toluene solution).The 5M sodium hydroxide solution is joined in the reaction soln, extract with toluene again.Extraction liquid is through dried over mgso and filtration, then with solvent removed under reduced pressure.Resistates is dissolved in the toluene (20ml).(475mg, 2.18mmol), the gained mixture stirred 1 hour at 50 ℃ to add tert-Butyl dicarbonate.After the solvent evaporated under reduced pressure, resistates is by silica gel chromatography purifying (hexane: ethyl acetate=9: 1 → 8: 2 → 7: 3), obtain 450mg (71%) title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.20(5H，m)，5.20(1H，d，J＝54.00Hz)，4.90(1H，brs)，3.22(1H，q，J＝6.50Hz)，2.92(1H，d，J＝7.60Hz)，2.58(1H，d，J＝9.80Hz)，2.48-2.20(4H，m)，1.79(1H，t，J＝16.80Hz)，1.43(9H，s)，1.33(3H，d，J＝6.60Hz)。
[reference example 85]
(1R, 5S)-1-(tert-butoxycarbonyl amino)-7-fluoro-3-dicyclo [3.3.0] octane
[formula 171]
Will (1R, 5S)-1-(tert-butoxycarbonyl amino)-7-fluoro-3-[(1R)-the 1-phenylethyl]-(450mg 1.29mmol) is dissolved in the methyl alcohol (15ml) 3-azabicyclo [3.3.0] octane.Add 10% palladium carbon catalyst (50% is wet) of catalytic amount, the gained mixture is under nitrogen atmosphere, 40 ℃ of stirrings 12 hours.Remove by filter after the catalyzer, filtrate obtains 316mg (quantitatively) title compound through concentrating under reduced pressure, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：5.24(1H，d，J＝53.71Hz)，5.07(1H，s)，3.48-3.42(1H，m)，3.23(2H，dd，J＝14.77，12.33Hz)，2.93-2.87(1H，m)，2.76(1H，brs)，2.44-2.16(3H，m)，1.95-1.86(1H，m)，1.44(9H，s)。
[embodiment 19]
7-{ (1R, 5S)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-yl }-6-
-1-[(R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 172]
Will (1R, 5S)-1-(tert-butoxycarbonyl amino)-7-fluoro-3-azabicyclo [3.3.0] octane (296mg, 1.21mmol) with 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(437mg 1.21mmol) is dissolved in the dimethyl sulfoxide (DMSO) (6ml) inner complex.(203 μ l, 1.45mmol), the gained mixture stirred 1 day at 40 ℃ to add triethylamine.Water is joined in the reaction soln, filter the crystal of collecting precipitation, wash with water and drying, obtain yellow powder, it is dissolved in ethanol (35ml)-water (9ml).Add triethylamine (202 μ l), mixture heating up was refluxed 4 hours.After the solvent evaporated under reduced pressure, the mixture of resistates with ethyl acetate and 10% citric acid solution mixed.Organic layer is through dried over mgso and filtration.Filtrate is through reduction vaporization.Then, (9ml) joins in the resistates with concentrated hydrochloric acid, and mixture was at room temperature stirred 2 hours.Reaction soln dilutes with concentrated hydrochloric acid, moves in the separating funnel, with chloroform washing 3 times again.Then, the hydrochloric acid layer is adjusted to pH12 with the 12M sodium hydroxide solution down ice-cooled.This layer is adjusted to pH7.4 with 1M hydrochloric acid and 0.01M hydrochloric acid again, uses chloroform-methanol (9: 1) extraction again.Then, water layer is adjusted to pH7.4 once more, and carries out extracting operation.Repeat after this operation 5 times, organic layer is through dried over mgso and filter, and filtrate is through reduction vaporization.Ethanol is joined in the resistates solvent evaporated under reduced pressure.Resistates obtains 220mg (42%) title compound through drying under reduced pressure, is light yellow solid.
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，7.66(1H，d，J＝13.70Hz)，5.45-5.31(1H，brm)，5.04-4.86(1H，brm)，4.06-4.01(1H，m)，3.87(1H，t，J＝8.90Hz)，3.73-3.51(6H，m)，2.52-2.25(3H，m)，2.15-1.89(2H，m)，1.64-1.47(2H，m)。
C
21H
22F
3N
3O
41.0H
2The analytical calculation value of O0.4EtOH: C, 55.26; H, 5.62; F, 12.03; N, 8.87.Measured value: C, 55.05; H, 5.35; F, 12.32; N, 8.76.
MS(ESI)m/z：438(M+H)
+。
[reference example 86]
(3S)-3-(2-methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-first
Tert-butyl acrylate
[formula 173]
Tetracol phenixin (550ml), acetonitrile (550ml) and water (550ml) are dissolved in (3S)-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (38.2g, 0.110mol) in, add ruthenium chloride (III) hydrate (456mg successively, 2.20mmol) and high sodium iodide (sodium periodide) (94.1g, 0.440mol).The gained mixture keeps internal temperature at 20-25 ℃ 15 ℃ of stirred in water bath that have constant temperature circulator 2.5 hours simultaneously.Reaction soln cools off in ice bath, and is 10 ℃ or adds 1N hydrochloric acid soln (2.2L) when lower at internal temperature, uses the 2L chloroform extraction again.Water layer extracts with chloroform (1L * 3).Then, merge organic layer, with salt solution (2L * 2) washing, again through anhydrous sodium sulfate drying.After the filtration, solvent is through concentrating under reduced pressure.The gained crude product is dissolved in N, in the dinethylformamide (370ml).At room temperature, add while stirring sodium bicarbonate (37.9g, 0.451mol) and methyl-iodide (70.7g 0.498mol), stirs mixture 3 days.Reaction soln is poured in the frozen water (1.8L), used ethyl acetate (1.8L, 0.5L) extraction then.Merge organic layer, use the salt water washing, then through anhydrous sodium sulfate drying.After the filtration, filtrate is through concentrating under reduced pressure, and resistates is passed through the silica gel column chromatography processing, and (hexane: ethyl acetate=1: 1), the flow point that contains the target material is through concentrating under reduced pressure.The gained solid is dissolved in the ethyl acetate, with the washing of 10% hypo solution, again through anhydrous sodium sulfate drying.After the filtration, filtrate is through concentrating under reduced pressure, and dry gained solid obtains the 35.0g title compound, is the light tan solid.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.25(5H，m)，5.48(1H，q，J＝7.1Hz)，3.68(3H，s)，3.33(1H，d，J＝10.3Hz)，3.13(1H，d，J＝10.3Hz)，2.93(1H，d，J＝16.8Hz)，2.34-2.20(3H，m)，2.13-1.94(2H，m)，1.51(3H，d，J＝7.1Hz)，1.32(9H，s)。
[reference example 87]
(1S, 5R)-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl }
T-butyl formate
[formula 174]
With (3S)-3-(2-methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-1-phenylethyl] (35.0g 93.2mmol) is dissolved in the tetrahydrofuran (THF) (1L) tetramethyleneimine-3-t-butyl formate.Under nitrogen atmosphere, when internal temperature is-69 ℃, in 30 minutes, dropping 2M lithium diisopropylamine/heptane/tetrahydrofuran/ethylbenzene solution (100ml, 200mmol).After under same temperature, stirring 1 hour, reaction soln is poured in the 1N hydrochloric acid soln (2L) in the ice bath, used ethyl acetate (2L, 1L) extraction then.Merge organic layer, use the salt water washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate is filtered the solid of collecting precipitation through concentrating under reduced pressure, obtains the 22.2g title compound, is the light red crystal.Filtrate further concentrates again, obtains the 2.88g title compound, is the light red crystal.Filtrate is through concentrating under reduced pressure, and resistates is handled (hexane: ethyl acetate=1: 1), obtain the 2.09g title compound, be clear crystal by silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.26(5H，m)，5.50(1H，q，J＝7.1Hz)，3.38(1H，d，J＝10.5Hz)，3.23(1H，d，J＝10.5Hz)，2.55-2.35(3H，m)，2.05-1.94(1H，m)，1.53(3H，d，J＝7.1Hz)，1.38(9H，s)。
[reference example 88]
(1S, 5R, 6R)-6-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane
-1-yl } t-butyl formate;
(1S, 5R, 6S)-6-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane
-1-yl } t-butyl formate
[formula 175]
Will (1S, 5R)-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } (1.30g 3.88mmol) is dissolved in the tetrahydrofuran (THF) (40ml) t-butyl formate.At 0 ℃, (185mg 4.92mmol), stirs mixture 1 hour to add sodium borohydride.Saturated ammonium chloride solution is joined in the reaction soln, use ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in methylene dichloride (20ml).Under nitrogen atmosphere, (1.73g 7.82mmol), stirs mixture 2 hours to add [two (2-methoxymethyl) amino] sulfur trifluoride.Reaction soln is poured in the saturated sodium bicarbonate aqueous solution in the ice bath, used ethyl acetate extraction then.Organic layer is with saturated sodium thiosulfate solution and salt water washing, again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates obtains 797mg title (6R)-fluorine isomer (colorless oil) and 170mg title (6S)-fluorine isomer (colorless oil) by silica gel column chromatography processing (30% ethyl acetate/hexane).
(6R)-the fluorine isomer:
1H-NMR(400MHz，CDCl
3)δ：7.36-7.26(5H，m)，5.46(1H，q，J＝7.08Hz)，5.28(1H，d，J＝51.76Hz)，3.48(1H，d，J＝22.71Hz)，3.41(1H，d，J＝10.50Hz)，3.08(1H，d，J＝10.50Hz)，2.57-2.49(1H，m)，2.21-2.12(1H，m)，1.83-1.58(2H，m)，1.50(3H，d，J＝7.08Hz)，1.35(9H，s)。
MS(EI)；m/z：348(M+H)
+。
(6S)-the fluorine isomer:
1H-NMR(400MHz，CDCl
3)δ：7.34-7.26(5H，m)，5.49-5.40(2H，m)，3.51(1H，d，J＝10.24Hz)，3.41(1H，d，J＝29.76Hz)，3.21(1H，d，J＝10.00Hz)，2.46-2.44(1H，m)，2.23-2.20(1H，m)，2.03-1.93(1H，m)，1.88-1.82(1H，m)，1.52(3H，d，J＝6.83Hz)，1.32(9H，s)。
MS(EI)；m/z：348(M+H)
+。
[reference example 89]
(1S, 5S, 6R)-and 3-benzyloxycarbonyl-6-fluoro-3-azabicyclo [3,3,0] octane-1-yl } formic acid uncle fourth
Ester
[formula 176]
With { (1S, 5R, 6R)-6-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } t-butyl formate (420mg, 1.21mmol) be dissolved in the tetrahydrofuran (THF) (20ml), dropping 1M borane-tetrahydrofuran complex under nitrogen atmosphere (3.63ml, 3.63mmol).After 5 hours, add 1M borane-tetrahydrofuran complex (3.63ml, 3.63mmol), after 15 hours, add again 1M borane-tetrahydrofuran complex (3.63ml, 3.63mmol).Stir after 3 hours, add ethanol (18ml), water (2ml) and triethylamine (2ml), the gained mixture stirred 2 hours at 80 ℃.Reaction soln joins saturated ammonium chloride solution in the gained resistates through reduction vaporization, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the methylene dichloride (3ml).(1.03g 6.04mmol), stirs mixture 16 hours to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 367mg title compound by silica gel column chromatography purifying (30% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.26(5H，m)，5.12(2H，s)，4.85(1H，d，J＝52.44Hz)，3.86(1H，d，J＝11.71Hz)，3.77-3.73(1H，m)，3.40-3.35(2H，m)，3.16-3.10(1H，m)，2.46-2.42(1H，m)，2.03-1.82(3H，m)，1.45(9H，s)。
MS(EI)m/z：386(M+Na)
+。
[reference example 90]
(1S, 5S, 6S)-and 3-benzyloxycarbonyl-6-fluoro-3-azabicyclo [3,3,0] octane-1-yl } formic acid uncle fourth
Ester
[formula 177]
With { (1S, 5R, 6S)-6-fluoro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } t-butyl formate (402mg, 1.16mmol) be dissolved in the tetrahydrofuran (THF) (20ml), dropping 1M borane-tetrahydrofuran complex under nitrogen atmosphere (5.79ml, 5.79mmol).After 2 hours, and adding 1M borane-tetrahydrofuran complex (3.47ml, 3.47mmol); After 14 hours, add again 1M borane-tetrahydrofuran complex (3.47ml, 3.47mmol).Stir after 2.5 hours, add ethanol (18ml), water (2ml) and triethylamine (2ml), the gained mixture stirred 2 hours at 80 ℃.Reaction soln joins saturated ammonium chloride solution in the gained resistates through reduction vaporization, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the methylene dichloride (2.8ml).(1.03g, 6.04mmol), the gained mixture stirred 14 hours at 40 ℃ to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 359mg title compound by silica gel column chromatography purifying (25% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.29(5H，m)，5.13(2H，s)，5.06(1H，d，J＝49.84Hz)，3.99(1H，dd，J＝20.12，11.59Hz)，3.79(1H，d，J＝11.95Hz)，3.58-3.55(1H，m)，3.38(1H，dd，J＝46.71，11.34Hz)，3.00(1H，brd，J＝25.37Hz)，2.26-1.94(4H，m)，1.43(9.0H，s)。
MS(EI)m/z：386(M+Na)
+。
[reference example 91]
(1S, 5R, 6R)-and 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl } first
Acid benzyl ester
[formula 178]
Will (1S, 5S, 6R)-and 3-benzyloxycarbonyl-6-fluoro-3-azabicyclo [3,3,0] octane-1-yl } (362mg 1.00mmol) is dissolved in the methylene dichloride (10ml) t-butyl formate.Add trifluoroacetic acid (2.5ml), mixture was stirred 15 hours.Solvent evaporated under reduced pressure.The 1N sodium hydroxide solution is joined in the gained resistates, and the gained mixture washs with chloroform.Chloroform extraction is used in water layer hydrochloric acid soln acidifying again.Extraction liquid is through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the toluene (10ml).(202mg, 1.99mmol) (339mg, 1.20mmol), the gained mixture stirred 2 hours at 100 ℃ with two phenoxy group phosphoryl azides to add triethylamine under nitrogen atmosphere.Reaction soln is through concentrating under reduced pressure.Then, add diox (20ml) and 6N hydrochloric acid (20ml), the gained mixture stirred 3 hours at 40 ℃.Concentrating under reduced pressure and with the ethanol component distillation after, add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.(1087mg 4.98mmol) joins in the gained resistates, and the gained mixture stirred 2 hours at 50 ℃ with tert-Butyl dicarbonate.Reaction soln obtains the 125mg title compound by silica gel column chromatography purifying (20% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.26(5H，m)，5.11(2H，s)，4.95-4.80(2H，m)，3.88-3.63(3H，m)，3.28-3.24(1H，m)，2.83-2.75(1H，m)，2.12-1.98(4H，m)，1.44(9H，s)。
MS(EI)m/z：401(M+Na)
+。
[reference example 92]
(1S, 5R, 6S)-and 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl } first
Acid benzyl ester
[formula 179]
Will (1S, 5S, 6S)-and 3-benzyloxycarbonyl-6-fluoro-3-azabicyclo [3,3,0] octane-1-yl } (354mg 0.97mmol) is dissolved in the methylene dichloride (10ml) t-butyl formate.Add trifluoroacetic acid (3ml), mixture was stirred 21 hours.Solvent evaporated under reduced pressure.The 1N sodium hydroxide solution is joined in the gained resistates, and the gained mixture washs with chloroform.Chloroform extraction is used in water layer hydrochloric acid soln acidifying again.Extraction liquid is through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure is dissolved in the gained resistates in the toluene (8ml) again.Under nitrogen atmosphere, (197mg, 1.95mmol) (359mg 1.27mmol), stirs mixture 1 hour with two phenoxy group phosphoryl azides to add triethylamine.Then, add the trimethyl carbinol (8ml), the gained mixture stirred 19 hours at 100 ℃.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 136mg title compound by silica gel column chromatography purifying (25% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.26(5H，m)，5.13(2H，s)，5.05(1H，d，J＝58.77Hz)，4.68(1H，brs)，3.77(1H，d，J＝10.46Hz)，3.71-3.60(2H，m)，3.57-3.44(1H，m)，3.11-2.86(1H，m)，2.29-2.02(4H，m)，1.43(9H，s)。
MS(EI)；m/z：401(M+Na)
+。
[reference example 93]
(1S, 5R, 6R)-1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane
[formula 180]
Will (1S, 5R, 6R)-and 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl } (120mg 0.32mmol) is dissolved in the methyl alcohol (10ml) benzyl formate.Adding 10% palladium-carbon (M, wet) (50mg), stirs mixture 3 hours under nitrogen atmosphere.Remove by filter catalyzer, then filtrate decompression is concentrated.Add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, filtrate obtains the 77.5mg title compound through concentrating under reduced pressure, is colorless oil.
MS(EI)；m/z：245(M+H)
+。
[reference example 94]
(1S, 5R, 6S)-1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane
[formula 181]
Will (1S, 5R, 6S)-and 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl } (132mg 0.35mmol) is dissolved in the methyl alcohol (10ml) benzyl formate.Adding 10% palladium-carbon (M, wet) (50mg), stirs mixture 3 hours under nitrogen atmosphere.Remove by filter catalyzer, then filtrate decompression is concentrated.Add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, filtrate obtains the 85mg title compound through concentrating under reduced pressure, is colorless oil.
MS(EI)；m/z：245(M+H)
+。
[embodiment 20]
7-{ (1S, 5R, 6R)-1-amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 182]
Will (1S, 5R, 6R)-(77.5mg 0.32mmol) is dissolved in the dimethyl sulfoxide (DMSO) (2ml) 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (120.2mg, 0.33mmol) and triethylamine (96.3mg, 0.95mmol), the gained mixture stirred 18 hours at 40 ℃.Then, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 3 hours at 80 ℃.After the solvent evaporated under reduced pressure, 10% citric acid solution is joined in the resistates, use ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (5% methyl alcohol/chloroform).The gained crude product is dissolved in concentrated hydrochloric acid and washs with chloroform.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.5 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained solid obtains the 96mg title compound with the ether washing and through drying under reduced pressure, is colorless solid.
mp：179-181℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，s)，7.71(1H，d，J＝13.67Hz)，5.10-5.07(1H，m)，5.09(1H，d，J＝52.00Hz)，4.07-4.04(1H，m)，3.88(1H，t，J＝9.64Hz)，3.68-3.63(4H，m)，3.57(1H，dd，J＝16.97，10.62Hz)，3.45(1H，d，J＝11.72Hz)，2.63-2.56(1H，m)，2.10-2.01(4H，m)，1.61-1.51(2H，m)。
C
21H
22F
3N
3O
40.5H
2The analytical calculation value of O: C, 56.50; H, 5.19; N, 9.41; F, 12.77.Measured value: C, 56.28; H, 5.17; N, 9.03; F, 12.47.
MS(EI)；m/z：438(M+H)
+。
IR(ATR)v：3390，2943，2872，1720，1618，1512，1452，1360，1321，1277，1213cm
-1。
[embodiment 21]
7-[(1S, 5R, 6S)-1-amino-6-fluoro-3-azabicyclo [3,3,0] octane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 183]
Will (1S, 5R, 6S)-(85.2mg 0.35mmol) is dissolved in the dimethyl sulfoxide (DMSO) (2ml) 1-tert-butoxycarbonyl amino-6-fluoro-3-azabicyclo [3,3,0] octane.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (132.2mg, 0.37mmol) and triethylamine (105.9mg, 1.05mmol), the gained mixture stirred 15 hours at 40 ℃.Then, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 3 hours at 80 ℃.Solvent evaporated under reduced pressure also joins 10% citric acid solution in the resistates, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (5% methyl alcohol/chloroform).The gained crude product is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.5 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained solid obtains the 101mg title compound with the ether washing and through drying under reduced pressure, is colorless solid.
mp：117-119℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.45(1H，s)，7.70(1H，d，J＝14.15Hz)，5.28(1H，d，J＝53.41Hz)，5.07-4.73(1H，m)，4.05-4.02(1H，m)，3.84-3.64(6H，m)，3.47(1H，d，J＝10.73Hz)，2.59-2.53(1H，m)，2.26-2.06(3H，m)，1.79-1.78(1H，m)，1.58-1.46(2H，m)。
C
21H
22F
3N
3O
4H
2The analytical calculation value of O: C, 55.38; H, 5.31; N, 9.23; F, 12.51.Measured value: C, 55.43; H, 5.46; N, 9.00; F, 12.21.
MS(EI)m/z：438(M+H)
+。
IR(ATR)v：2966，2839，1720，1614，1576，1537，1508，1446，1362，1319，1271，1207cm
-1。
[reference example 95]
(1S, 5S)-6,6-two fluoro-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } first
Tert-butyl acrylate
[formula 184]
Will (1S, 5R)-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } (500mg 1.46mmol) is dissolved in the methylene dichloride (20ml) t-butyl formate.Under nitrogen atmosphere, at 0 ℃, (966.3mg, 4.37mmol), the gained mixture stirred 17 hours at 20 ℃ to add [two (2-methoxymethyl) amino] sulfur trifluoride.Reaction soln is poured in the saturated sodium bicarbonate aqueous solution in the ice bath, used ethyl acetate extraction then.Organic layer is with saturated sodium thiosulfate solution and salt water washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate is through reduction vaporization, and with the gained resistates by short silica gel column chromatography purifying (25% ethyl acetate/hexane).The gained crude product is dissolved in the tetrahydrofuran (THF) (15ml).(4.37ml 4.37mmol), stirs mixture 16 hours to add 1M borane-tetrahydrofuran complex under nitrogen atmosphere.(4.37ml 4.37mmol), stirs mixture 9 hours to add 1M borane-tetrahydrofuran complex.(4.37ml 4.37mmol), stirs mixture 16 hours to add 1M borane-tetrahydrofuran complex once more.Ethanol (45ml), water (5ml) and triethylamine (5ml) are joined in the reaction soln, and the gained mixture stirred 4 hours at 80 ℃.Then, solvent evaporated under reduced pressure and saturated ammonium chloride solution joined in the resistates.The organic layer ethyl acetate extraction, water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, the gained resistates is handled (15% ethyl acetate/hexane) by silica gel column chromatography, obtains the 375.8mg title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.22(5H，m)，3.28(1H，d，J＝9.77Hz)，3.13(1H，q，J＝6.51Hz)，3.01(1H，dd，J＝19.04，7.08Hz)，2.60(1H，d，J＝9.28Hz)，2.39-2.30(3H，m)，2.15-2.09(2H，m)，1.80-1.75(1H，m)，1.41(9H，s)，1.33(3H，d，J＝6.59Hz)。
MS(EI)m/z：352(M+H)
+。
[reference example 96]
(1S, 5S)-3-benzyloxycarbonyl-6,6-two fluoro-3-azabicyclo [3,3,0] octane-1-yls } the formic acid uncle
Butyl ester
[formula 185]
Will (1S, 5S)-6,6-two fluoro-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3,3,0] octane-1-yl } (370.0mg 1.05mmol) is dissolved in the methylene dichloride (3ml) t-butyl formate.(898mg, 5.26mmol), the gained mixture stirred 17 hours at 40 ℃ to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 338mg title compound by silica gel column chromatography purifying (20% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.26(5H，m)，5.13(2H，s)，3.86(2H，d，J＝11.71Hz)，3.54-3.42(2H，m)，3.16-3.07(1H，m)，2.37-2.11(3H，m)，1.88-1.82(1H，m)，1.45(9H，s)。
MS(EI)m/z：404(M+Na)
+。
[reference example 97]
(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3,3,0] octane-3-yls }
Benzyl formate
[formula 186]
Will (1S, 5S)-3-benzyloxycarbonyl-6,6-two fluoro-3-azabicyclo [3,3,0] octane-1-yls } (332.0mg 0.87mmol) is dissolved in the methylene dichloride (10ml) t-butyl formate.Add trifluoroacetic acid (2ml), mixture was stirred 23 hours.Reaction soln is through concentrating under reduced pressure.Add the 1N sodium hydroxide solution, the gained mixture washs with chloroform.Chloroform extraction is used in water layer hydrochloric acid soln acidifying again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the toluene (10ml).(176.2mg, 1.74mmol) (370.4mg, 1.31mmol), the gained mixture stirred 20 hours at 100 ℃ with two phenoxy group phosphoryl azides to add triethylamine under nitrogen atmosphere.Reaction soln is through concentrating under reduced pressure.Then, add diox (10ml) and 6N hydrochloric acid (10ml), the gained mixture stirred 1.5 hours at 40 ℃.Concentrating under reduced pressure and with the ethanol component distillation after, add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.(949.9mg 4.35mmol) joins in the gained resistates, and the gained mixture stirred 16 hours at 50 ℃ with tert-Butyl dicarbonate.Reaction soln obtains the 67.0mg title compound by silica gel column chromatography purifying (25% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.17(5H，m)，5.13(2H，s)，4.80(1H，s)，3.84-3.80(1H，m)，3.71-3.65(3H，m)，3.06-2.96(1H，m)，2.39-2.31(1H，m)，2.16-2.08(3H，m)，1.44(9H，s)。
MS(EI)m/z：397(M+H)
+。
[reference example 98]
(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3,3,0] octanes
[formula 187]
Will [(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3,3,0] octane-3-yls] (65.0mg 0.16mmol) is dissolved in the methyl alcohol (10ml) benzyl formate.(20mg), the gained mixture stirred 1 hour under nitrogen atmosphere to add 10% palladium-carbon (50% is wet).Remove by filter catalyzer, then filtrate decompression is concentrated.Add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, filtrate obtains the 43mg title compound through concentrating under reduced pressure, is colorless solid.
MS(EI)；m/z：263(M+H)
+。
[embodiment 22]
7-[(1S, 5R)-1-amino-6,6-two fluoro-3-azabicyclo [3,3,0] octane-3-yls]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 188]
Will (1S, 5R)-1-tert-butoxycarbonyl amino-6, (43.0mg 0.16mmol) is dissolved in the dimethyl sulfoxide (DMSO) (1.8ml) 6-two fluoro-3-azabicyclo [3,3,0] octanes.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (62.2mg, 0.17mmol) and triethylamine (49.8mg, 0.49mmol), the gained mixture stirred 16 hours at 40 ℃.Then, 90% aqueous ethanol (20ml) and triethylamine (2ml) are joined in the reaction soln, the gained mixture stirred 2.5 hours at 80 ℃.Solvent evaporated under reduced pressure also joins 10% citric acid solution in the resistates, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained crude product is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH 12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained solid is dissolved in ethanol-ammoniacal liquor, and heating is also stirred gained solution.After ammonia steamed, filter the crystal of collecting precipitation and, obtain the 15.2mg title compound, be light yellow solid through drying under reduced pressure.
mp：239-241℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，7.73(1H，d，J＝13.67Hz)，5.07-4.91(1H，m)，4.08-4.05(1H，m)，3.91-3.88(1H，m)，3.79-3.77(1H，m)，3.72-3.70(1H，m)，3.68(3H，s)，3.55(1H，d，J＝10.74Hz)，2.67-2.62(1H，m)，2.36-2.33(2H，m)，2.16-2.12(1H，m)，1.96-1.89(1H，m)，1.64-1.51(2H，m)。
C
21H
21F
4N
3O
40.25H
2The analytical calculation value of O: C, 54.84; H, 4.71; N, 9.14; F, 16.52.Measured value: C, 54.97, H, 4.53; N, 9.09; F, 16.53.
MS(EI)；m/z：456(M+H)
+。
IR(ATR)v：3392，3031，2883，1718，1618，1510，1450，1360，1333，1306，1250cm
-1。
[reference example 99]
(1S, 5R)-5-methyl-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane
-1-base t-butyl formate
[formula 189]
Under argon atmospher, with N, dinethylformamide (2.0ml) join sodium hydride (152mg, 3.48mmol) in.Under ice-cooled, with (1S, 5R)-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base t-butyl formate (1.00g, 2.91mmol) N, dinethylformamide (8.0ml) drips of solution is added in this suspension, and the gained mixture stirred 30 minutes at 0 ℃.(0.217ml 3.49mmol), at room temperature stirred mixture 2.5 hours at the ice-cooled methyl-iodide of dropping down then.Reaction soln carries out ice-cooled, and ethyl acetate extraction is used in reactant water quencher then then.Then, organic layer water and salt water washing are through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=2: 1 → 1: 1), obtain the 0.79g title compound, be light yellow solid through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.41-7.23(5H，m)，5.48(1H，q，J＝6.62Hz)，3.40(1H，d，J＝10.54Hz)，3.13(1H，d，J＝10.54Hz)，2.63-2.40(3H，m)，1.96-1.83(1H，m)，1.54(3H，d，J＝7.11Hz)，1.39(9H，s)，1.22(3H，s)。
[reference example 100]
(1S, 5R)-6,6-second two basic dimercaptos-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-the 3-azepine
Dicyclo [3.3.0] octane-1-base methyl-formiate
[formula 190]
Will (1S, 5R)-5-methyl-4, the 6-dioxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(0.28g 0.78mmol) is dissolved in the toluene (14ml) 1-base t-butyl formate.Add the toluenesulphonic acids monohydrate (155mg, 0.81mmol) and dithioglycol (0.14ml, 1.7mmol), with mixture heating up backflow 9 hours.After the solvent evaporated under reduced pressure, the gained resistates is handled (methylene dichloride: methyl alcohol=98: 2), obtain target 1-position carboxylic acid (289mg), be light yellow solid by silica gel column chromatography.This carboxylic acid (289mg) is dissolved in tetrahydrofuran (THF) (10ml) and the methyl alcohol (3.0ml).At the ice-cooled trimethyl silyl diazomethane (1.7ml) that adds down, mixture was at room temperature stirred 2 hours.After the solvent evaporated under reduced pressure, the gained resistates is handled (hexane: ethyl acetate=3: 2), obtain the 267mg title compound, be light yellow solid by silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.23(5H，m)，5.52(1H，q，J＝6.86Hz)，3.60(3H，s)，3.55(1H，d，J＝10.05Hz)，3.44-3.31(1H，m)，3.28-3.19(1H，m)，3.16(1H，d，J＝10.05Hz)，2.79-2.70(1H，m)，2.54-2.44(1H，m)，2.26-2.15(1H，m)，1.81-1.70(1H，m)，1.59-1.52(2H，m)，1.56(3H，d，J＝7.11Hz)，1.33(3H，s)。
[reference example 101]
(1S, 5R)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-
The base methyl-formiate
[formula 191]
Will (1S, 5R)-6,6-second two basic dimercaptos-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(266mg 0.68mmol) is dissolved in the ethanol (10ml) 1-base methyl-formiate.Drip Raney nickel (2.0ml), mixture heating up was refluxed 5.5 hours.Remove by filter catalyzer, then filtrate decompression is concentrated.The gained resistates is handled (hexane: ethyl acetate=7: 3 → 1: 1), obtain the 133mg title compound, be light yellow solid by silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.24(5H，m)，5.56-5.44(1H，m)，3.64(3H，s)，3.51(1H，d，J＝10.05Hz)，3.02-2.96(1H，m)，2.49-2.26(2H，m)，1.91-1.44(4H，m)，1.52(3H，d，J＝7.35Hz)，1.12(3H，s)。
[reference example 102]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-
Azabicyclo [3.3.0] octane
[formula 192]
Will (1S, 5R)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-(130mg 0.43mmol) is dissolved in the methyl alcohol (5.0ml) 1-base methyl-formiate.At the ice-cooled 1N sodium hydroxide solution (1.5ml) that drips down, mixture was at room temperature stirred 4 hours.Then, drip 1N sodium hydroxide solution (1.5ml), mixture was at room temperature stirred 15 hours.Add sodium hydroxide (93mg) once more, mixture was at room temperature stirred 6 hours.Add sodium hydroxide (90mg) once more, mixture was at room temperature stirred 4 hours, stirred 1 hour at 50 ℃ then.Make reaction soln weak acidization, solvent evaporated under reduced pressure with hydrochloric acid.The gained resistates extracts with methylene dichloride and dilute hydrochloric acid.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is dissolved in the toluene (5.0ml).(0.132ml, 0.95mmol) (0.111ml 0.52mmol), refluxes mixture heating up 3 hours with two phenoxy group phosphoryl azides to add triethylamine.Reaction soln extracts with ethyl acetate and saturated sodium bicarbonate aqueous solution.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.With 1,4-diox (2.0ml) and 6N hydrochloric acid (2.0ml) join in the gained resistates, and the gained mixture stirred 15 hours at 50 ℃.Behind water and the ethyl acetate extraction, water layer is with the alkalization of saturated sodium hydroxide solution and with chloroform extraction 2 times.Merge organic layer, through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.With toluene (3.0ml) and Red-Al
TM(65% toluene solution) (0.50ml) joins in the gained resistates successively, and the gained mixture stirred 2.5 hours at 80 ℃.Down the 3N sodium hydroxide solution is joined in the reaction soln ice-cooled, separate each layer with toluene.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is dissolved in methylene dichloride (10ml) and the methyl alcohol (5.0ml).(560mg 2.57mmol), at room temperature stirred mixture 16 hours to add tert-Butyl dicarbonate.Reaction soln is by silica gel column chromatography purifying (methylene dichloride: methyl alcohol=98: 2), obtain the 77mg title compound, be light yellow solid.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.16(5H，m)，4.79(1H，brs)，3.17-3.00(1H，m)，2.74-2.58(2H，m)，2.53-2.44(1H，m)，2.27-2.13(1H，m)，2.08-1.89(2H，m)，1.74-1.62(2H，m)，1.60-1.24(2H，m)，1.41(9H，s)，1.28(3H，d，J＝6.59Hz)，1.07(3H，s)。
[reference example 103]
(1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-4-oxo-3-azabicyclo [3.3.0] octane
[formula 193]
Will (1S, 5S)-1-(tert-butoxycarbonyl amino)-5-methyl-4-oxo-3-[(1R)-the 1-phenylethyl]-(77mg 0.22mmol) is dissolved in the ethanol (6.0ml) 3-azabicyclo [3.3.0] octane.Add 10% palladium-carbon (50% is wet) (69mg), the gained mixture is under nitrogen atmosphere, 45 ℃ of stirrings 19.5 hours.Remove by filter after the catalyzer, filtrate obtains the 50mg title compound through concentrating under reduced pressure, is light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：4.68(1H，brs)，3.36-3.19(1H，m)，3.00-2.58(4H，m)，2.40-1.89(4H，m)，1.81-1.26(2H，m)，1.44(9H，s)，1.07(3H，s)。
[embodiment 23]
7-[(1R, 5R)-1-amino-3-azepine-5-methyl bicycle [3.3.0] octane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 194]
With triethylamine (0.092ml, 0.66mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropane]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (79.1mg, 0.22mmol) join (1R, 5R)-(50.1mg is in dimethyl sulfoxide (DMSO) 0.21mmol) (2.0ml) solution for 1-(tert-butoxycarbonyl amino)-5-methyl-3-azabicyclo [3.3.0] octane.Mixture stirred 24 hours at 45 ℃.Ethanol (3.0ml), water (1.0ml) and triethylamine (1.0ml) are joined in the reaction soln, mixture heating up was refluxed 2.5 hours.After the solvent evaporated under reduced pressure, the gained resistates is with 10% citric acid solution and ethyl acetate extraction.Then, organic layer washes 2 times and uses the salt water washing with water, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.The gained resistates is handled (methylene dichloride: methyl alcohol=99: 1) by silica gel column chromatography.Down gained oily matter (92.5mg) is dissolved in the concentrated hydrochloric acid (1.0ml) ice-cooled, gained solution at room temperature stirred 0.5 hour.Reaction soln washs 2 times with chloroform, and water layer is adjusted to pH12 with saturated sodium hydroxide solution then.This basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates obtains the 47mg title compound by from the ethyl alcohol recrystallization purifying, is light yellow solid.
Mp:109-113 ℃ (decomposition).
[α]
D 24+78.2°(c＝0.135，0.1N?NaOH)。
1H-NMR(400MHz，0.1N?NaOD)δ：8.45(1H，s)，7.66(1H，d，J＝14.5Hz)，4.79-4.85(1H，m)，4.00-4.10(1H，m)，3.61(3H，s)，3.51-3.75(3H，m)，3.34-3.44(1H，m)，1.94-2.07(1H，m)，1.43-1.93(7H，m)，1.10(3H，s)。
MS(FAB)；m/z：434(M+H)
+。
C
22H
25F
2N
3O
42H
2The analytical calculation value of O: C, 56.28; H, 6.23; F, 8.09; N, 8.95.Measured value: C, 56.57; H, 6.24; F, 8.19; N, 9.01.
IR(ATR)v：2942，2877，1612，1573，1448，1434，1392，1349，1342，1311，1301，1290，1272，821，804cm
-1。
[reference example 104]
(3S)-3-methylol-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 195]
With 5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (4g 13.82mol) is dissolved in N, in the dinethylformamide (40ml), and with paraformaldehyde (0.83g 27.65mmol) is suspended in this solution.(0.60g 13.82mmol), stirs mixture 30 minutes at room temperature to add sodium hydride.Then, at 0 ℃, reaction soln is poured in 10% citric acid solution (150ml).The gained mixture extracts with ethyl acetate (300ml).Organic layer water (100ml * 2) and salt solution (100ml) washing are through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates obtains the 1.03g title compound by silica gel column chromatography purifying (30% ethyl acetate/hexane → 80% ethyl acetate/hexane), is colorless solid.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.28(5H，m)，5.51(1H，q，J＝7.16Hz)，3.77(1H，dd，J＝11.23，5.37Hz)，3.61(1H，dd，J＝11.23，7.81Hz)，3.39(1H，d，J＝10.50Hz)，3.21(1H，d，J＝10.25Hz)，2.78(1H，d，J＝17.09Hz)，2.51(1H，dd，J＝7.81，5.37Hz)，2.40(1H，d，J＝17.33Hz)，1.53(3H，d，J＝7.33Hz)，1.35(9H，s)。
MS(EI)；m/z：320(M+H)
+。
[reference example 105]
(3S)-3-formyl radical-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 196]
With (3S)-3-methylol-5-oxo-1-[(1R)-1-phenylethyl] (4.0g 12.52mmol) is dissolved in the methylene dichloride tetramethyleneimine-3-t-butyl formate.0 ℃ add successively triethylamine (6.34g, 62.62mmol), dimethyl sulfoxide (DMSO) (3.91g, 50.09mmol) and SO
3(3.99g 25.05mmol), stirs mixture 17 hours-pyridine complex.Reaction soln joins water in the resistates through concentrating under reduced pressure, uses ethyl acetate extraction then.Organic layer water and salt water washing are through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates is handled (60% ethyl acetate/hexane) by silica gel column chromatography, obtains the 2.85g title compound, is colorless solid.
1H-NMR(400MHz，CDCl
3)δ：9.62(1H，s)，7.35-7.28(5H，m)，5.47(1H，q，J＝7.00Hz)，3.79(1H，t，J＝9.52Hz)，3.24(1H，d，J＝10.50Hz)，2.93(1H，d，J＝17.33Hz)，2.85(1H，d，J＝17.33Hz)，1.53(3H，d，J＝7.08Hz)，1.38(9H，s)。
MS(EI)；m/z：318(M+H)
+。
[reference example 106]
(3R)-the 5-oxo-1-[(1R)-the 1-phenylethyl]-3-ethenyl pyrrolidone-3-t-butyl formate
[formula 197]
(187.4mg 0.52mmol) is dissolved in the tetrahydrofuran (THF) with first base three phenyl phosphonium bromides.Under nitrogen atmosphere, at-78 ℃, (0.16ml 0.42mmol), stirs mixture 1 hour the hexane solution of dropping 2.62M n-Butyl Lithium.After being heated to 0 ℃, dropping (3S)-3-formyl radical-5-oxo-1-[(1R)-and the 1-phenylethyl] (111mg, tetrahydrofuran solution 0.35mmol) stir mixture 1 hour tetramethyleneimine-3-t-butyl formate.Saturated ammonium chloride solution is joined in the reaction soln, use ethyl acetate extraction then.Organic layer water and salt water washing are through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates is handled (25% ethyl acetate/hexane) by silica gel column chromatography, obtains the 54mg title compound, is yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.26(5H，m)，5.96(1H，dd，J＝17.33，10.74Hz)，5.52-5.45(1H，m)，5.21-5.17(2H，m)，3.45(1H，d，J＝10.25Hz)，3.26(1H，d，J＝10.01Hz)，3.01(1H，d，J＝16.60Hz)，2.54(1H，d，J＝16.60Hz)，1.50(3H，d，J＝7.08Hz)，1.33(9H，s)。
MS(EI)m/z：318(M+H)
+。
[reference example 107]
(3S, 4S)-4-allyl group-5-oxo-1-[(1R)-the 1-phenylethyl]-3-ethenyl pyrrolidone-3-formic acid
The tert-butyl ester
[formula 198]
With (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-ethenyl pyrrolidone-3-t-butyl formate (236.0mg, 0.75mmol) and allyl bromide 98 (271.6mg 2.24mmol) is dissolved in the tetrahydrofuran (THF).Under nitrogen atmosphere, at 0 ℃, the tetrahydrofuran solution of dropping 1M hexamethyl two silicon nitrine lithiums (1.12ml, 1.12mmol).Stir after 1.5 hours, add saturated ammonium chloride solution, use ethyl acetate extraction then.Organic layer water and salt water washing are through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates is handled (10% ethyl acetate/hexane) by silica gel column chromatography, obtains the 135mg title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.26(5H，m)，5.98-5.82(2H，m)，5.47(1H，q，J＝7.00Hz)，5.24-4.97(4H，m)，3.35-3.25(2H，m)，3.03(1H，t，J＝6.82Hz)，2.48-2.41(1H，m)，2.39-2.32(1H，m)，1.54(3H，d，J＝7.08Hz)，1.33(9H，s)。
MS(EI)；m/z：356(M+H)
+。
[reference example 108]
[(1S, 5S)-the 4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] first
Tert-butyl acrylate
[formula 199]
Will (3S, 4S)-4-allyl group-5-oxo-1-[(1R)-the 1-phenylethyl]-(130.0mg 0.37mmol) is dissolved in the benzene (8ml) 3-ethenyl pyrrolidone-3-t-butyl formate.(31.0mg 0.04mmol), at room temperature stirred mixture 2 hours to add s-generation Grubbs catalyzer.Reaction soln is through concentrating under reduced pressure, and the gained resistates is handled (15% ethyl acetate/hexane) by silica gel column chromatography, obtains the 93.2mg title compound, is yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.28(5H，m)，5.94-5.91(1H，m)，5.60-5.59(1H，m)，5.51(1H，q，J＝7.16Hz)，3.34-3.24(3H，m)，2.81-2.79(2H，m)，1.45(3H，d，J＝7.32Hz)，1.38(9H，s)。
MS(EI)m/z：328(M+H)
+。
[reference example 109]
[(1S, 5S)-3-[(1R)-the 1-phenylethyl]-4-sulfo--3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] first
Tert-butyl acrylate
[formula 200]
Will [(1S, 5S)-the 4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] (88.0mg 0.27mmol) is dissolved in the toluene (8ml) t-butyl formate.(81.5mg, 0.20mmol), the gained mixture stirred 4 hours at 80 ℃ to add Lawesson's reagent.Reaction soln is through concentrating under reduced pressure, and the gained resistates is handled (10% ethyl acetate/hexane) by silica gel column chromatography, obtains the 91.6mg title compound, is yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.26(5H，m)，6.41(1H，q，J＝7.08Hz)，5.95-5.94(1H，m)，5.55-5.54(1H，m)，3.74(1H，d，J＝8.30Hz)，3.60(1H，d，J＝11.96Hz)，3.49(1H，d，J＝12.21Hz)，3.15(1H，d，J＝17.09Hz)，3.02-2.98(1H，m)，1.51(3H，d，J＝7.08Hz)，1.36(9H，s)。
MS(EI)m/z：344(M+H)
+。
[reference example 110]
[(1S, 5S)-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] formic acid uncle fourth
Ester
[formula 201]
Will [(1S, 5S)-3-[(1R)-the 1-phenylethyl]-4-sulfo--3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] (88.2mg 0.27mmol) is dissolved in the ethanol t-butyl formate.Add Raney nickel, mixture was stirred 1 hour.Remove by filter catalyzer, then filtrate decompression is concentrated.The gained resistates is handled (10% ethyl acetate/hexane) by silica gel column chromatography, obtains the 55.4mg title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.21(5H，m)，5.74(1H，brs)，5.54(1H，brs)，3.15(1H，q，J＝6.75Hz)，3.04(1H，brs)，2.72-2.70(2H，m)，2.61(1H，t，J＝7.81Hz)，2.53-2.51(2H，m)，2.18(1H，d，J＝16.85Hz)，1.41(9H，s)，1.32(3H，d，J＝6.59Hz)。
MS(EI)m/z：314(M+H)
+。
[reference example 111]
[(1S, 5S)-3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] t-butyl formate
[formula 202]
Will [(1S, 5S)-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] (370mg 1.18mmol) is dissolved in the ethylene dichloride (3ml) t-butyl formate.(1.01g, 5.90mmol), the gained mixture stirred 3 hours at 40 ℃ to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and the gained resistates is handled (10% ethyl acetate/hexane) by silica gel column chromatography, obtains the 385mg title compound, is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.29(5H，m)，5.79(1H，brs)，5.64(1H，brs)，5.12(2H，s)，3.79-3.68(3H，m)，3.21-3.12(2H，m)，2.74(1H，dd，J＝17.44，6.22Hz)，2.19(1H，t，J＝18.54Hz)，1.43(9H，s)。
MS；(EI)m/z：366(M+Na)
+。
[reference example 112]
[(1S, 5R)-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl] the formic acid benzyl
Ester
[formula 203]
Will [(1S, 5S)-3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-7-alkene-1-yl] (380mg 1.11mmol) is dissolved in the methylene dichloride (8ml) t-butyl formate.Add trifluoroacetic acid (1.5ml), mixture was stirred 1 day.Reaction soln adds 1N sodium hydroxide solution (100ml) through concentrating under reduced pressure, and the gained mixture washs with chloroform.Chloroform (200ml * 2) extraction is used in water layer hydrochloric acid soln acidifying again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the toluene (10ml).Under nitrogen atmosphere, (223.3mg, 2.21mmol) (469.5mg, 1.66mmol), the gained mixture stirred 20 hours at 80 ℃ with two phenoxy group phosphoryl azides to add triethylamine.Reaction soln is through concentrating under reduced pressure.Then, add 1,4-diox (10ml) and 6N hydrochloric acid (10ml) stir mixture 3 days.Concentrating under reduced pressure and with the ethanol component distillation after, add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.(1204mg 5.52mmol) joins in the gained resistates, and the gained mixture stirred 16 hours at 50 ℃ with tert-Butyl dicarbonate.Reaction soln obtains the 92.1mg title compound by silica gel column chromatography purifying (20% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.25(5H，m)，5.84(1H，s)，5.78(1H，s)，5.10(2H，s)，4.70(1H，s)，3.87(1H，dd，J＝11.23，8.79Hz)，3.79-3.76(2H，m)，3.24-3.21(1H，m)，2.87-2.72(2H，m)，2.21-2.18(1H，m)，1.43(9H，s)。
MS(EI)；m/z：359(M+H)
+。
[reference example 113]
(1S, 5R)-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-7-alkene
[formula 204]
Will [(1S, 5R)-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl] (85.0mg 0.24mmol) is dissolved in the tetrahydrofuran (THF) (20ml) benzyl formate.Behind-78 ℃ of feeding liquid ammonias (20ml), (17.1mg 0.71mmol), stirs mixture 1 hour to add sodium.Add saturated ammonium chloride solution (6), in ice-water bath, boil off ammonia then.Add the 1N sodium hydroxide solution, use chloroform extraction again 2 times.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, filtrate obtains the 52.9mg title compound through concentrating under reduced pressure, is colorless solid.
MS(EI)m/z：225(M+H)
+。
[embodiment 24]
7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid
[formula 205]
Will (1S, 5R)-(52.9mg 0.24mmol) is dissolved in the dimethyl sulfoxide (DMSO) (2ml) 1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-7-alkene.Add 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (89.4mg, 0.25mmol) and triethylamine (71.6mg, 0.71mmol), the gained mixture stirred 20 hours at 40 ℃.Then, 90% aqueous ethanol (20ml) and triethylamine (2ml) are joined in the reaction soln, the gained mixture stirred 2 hours at 80 ℃.Solvent evaporated under reduced pressure also adds 10% citric acid solution, uses ethyl acetate extraction then.Organic layer water and salt water washing are through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates is by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained crude product is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH 12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH 8 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates obtains the 57.8mg title compound with the alcohol-ether washing and through drying under reduced pressure, is light yellow solid.
mp：206-208℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，s)，7.69(1H，d，J＝13.67Hz)，5.90(1H，brs)，5.69(1H，brs)，4.96(1H，d，J＝60.79Hz)，4.08-4.04(1H，m)，3.77(1H，t，J＝8.91Hz)，3.70(3H，d，J＝10.25Hz)，3.64(1H，s)，3.59-3.57(1H，m)，3.54-3.51(1H，m)，2.91-2.87(1H，m)，2.55-2.53(1H，m)，2.30(1H，d，J＝17.09Hz)，1.63-1.55(2H，m)。
C
21H
21F
2N
3O
40.25H
2The analytical calculation value of O0.5EtOH: C, 59.39; H, 5.55; N, 9.44; F, 8.54.Measured value: C, 59.32; H, 5.44; N, 9.50; F, 8.28.
MS(EI)；m/z：418(M+H)
+。
IR(ATR)v：2929，2848，2758，1726，1614，1577，1537，1504，1435，1392，1352，1315，1269cm
-1。
[reference example 114]
(1R
*
, 5S
*
)-7-benzyl-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone
[formula 206]
Trifluoroacetic acid (0.136ml) is joined N-benzyl-N-(methoxymethyl)-N-trimethyl silyl amine (43.9g, 185mmol) and γ-crotonolactone (12.5g, 176mmol) 1, in 2-methylene dichloride (176ml) solution, the gained mixture stirred 4 hours under nitrogen atmosphere, room temperature.(250ml) joins in the reaction soln with saturated sodium bicarbonate solution, uses chloroform (200ml * 2) extraction again.Organic layer is with salt solution (400ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 84: 16 → 80: 20 → 75: 25 → 66: 34 → 50: 50), obtain the 37.1g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.30-7.26(5H，m)，4.48(1H，t，J＝8.58Hz)，4.08(1H，dd，J＝9.19，3.55Hz)，3.69(1H，d，J＝13.24Hz)，3.54(1H，d，J＝13.24Hz)，3.26(1H，d，J＝9.31Hz)，3.08-2.98(2H，m)，2.80(1H，d，J＝9.56Hz)，2.49-2.38(2H，m)。
MS(ESI)m/z：218(M+H)
+。
[reference example 115]
1-allyl group-7-benzyl-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone
[formula 207]
Ice-cooled down at salt, (2.48ml 29.3mmol) joins (1R with allyl bromide 98 while stirring
*, 5S
*)-7-benzyl-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone (4.25g, in tetrahydrofuran (THF) 19.6mmol) (98ml) solution, under with the cooling of ice-acetone, the tetrahydrofuran solution of dropping 1M hexamethyl two silicon nitrine lithiums (23.5ml, 23.5mmol).Mixture was stirred 2 hours, be heated to room temperature simultaneously gradually.(200ml) joins in the reaction soln with saturated ammonium chloride solution, uses ethyl acetate (100ml * 2) extraction then.Organic layer water (250ml) and salt solution (250ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25 → 66: 34 → 50: 50), obtain the 1.51g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.21(5H，m)，5.80-5.70(1H，m)，5.20-5.14(2H，m)，4.35(1H，t，J＝8.95Hz)，4.03(1H，dd，J＝9.19，3.55Hz)，3.63(1H，d，J＝13.24Hz)，3.51(1H，d，J＝13.24Hz)，3.26(1H，d，J＝9.07Hz)，2.81(1H，d，J＝9.56Hz)，2.73-2.71(1H，m)，2.57(1H，dd，J＝13.73，6.62Hz)，2.49(1H，dd，J＝9.44，6.74Hz)，2.30(1H，dd，J＝13.85，8.21Hz)，2.23(1H，d，J＝9.07Hz)。
MS(ESI)；m/z：258(M+H)
+。
[reference example 116]
7-benzyl-1-(3-hydroxypropyl)-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone
[formula 208]
(11.0g, tetrahydrofuran (THF) 42.7mmol) (142ml) solution cools off with ice-acetone with 1-allyl group-7-benzyl-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone.Under nitrogen atmosphere, (264ml 132mmol), at room temperature stirred mixture 2 hours the tetrahydrofuran solution of assorted dicyclo [3.3.1] nonane of adding 0.5mol/L 9-boron.After the cooling of ice-acetone, under nitrogen atmosphere, add 1mol/L sodium hydroxide solution (142ml) and 30% superoxol, mixture was at room temperature stirred 1 hour.The organic layer of reaction soln extracts through concentrating under reduced pressure and with chloroform (300ml * 1,250ml * 1).Organic layer is with salt solution (600ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.(hexane: ethyl acetate=100: 0 → 66: 34 → 50: 50 → 34: 66 → 20: 80), obtain the resistates that 12.9g contains title compound, it can be directly used in next reaction to the gained resistates by the silica gel column chromatography purifying.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.22(5H，m)，4.41(1H，t，J＝8.82Hz)，4.05(1H，dd，J＝9.19，3.55Hz)，3.81(1H，t，J＝8.95Hz)，3.68-3.63(3H，m)，3.51(1H，d，J＝13.24Hz)，3.29(1H，d，J＝9.31Hz)，2.83(1H，d，J＝9.56Hz)，2.69(1H，s)，2.49(1H，t，J＝7.84Hz)，2.19(1H，t，J＝8.58Hz)，1.93-1.82(3H，m)。
MS(ESI)；m/z：276(M+H)
+。
[reference example 117]
7-benzyl-3-oxa--1-(3-hydroxypropyl)-7-azabicyclo [3.3.0] octane-2-ketone
[formula 209]
Methylene dichloride (113ml) solution is under nitrogen atmosphere, with the cooling of dry ice-methyl alcohol.Add oxalyl chloride (11.2ml, 128mmol) and dimethyl sulfoxide (DMSO) (15.2ml, 214mmol), the stirring 30 minutes under cooling of gained mixture.Adding contains 7-benzyl-1-(3-hydroxypropyl)-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone, and (the gained mixture stirred 1 hour down ice-cooled for 12.9g, the resistates solution of methylene dichloride 42.7mmol) (100ml).(35.8ml, 256mmol), the gained mixture stirred 1 hour under cooling, at room temperature stirred then 1 hour at the ice-cooled triethylamine of adding down.(200ml) joins in the reaction soln with saturated ammonium chloride solution, uses chloroform (150ml * 2) extraction again.Organic layer is with salt solution (450ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.(hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 50: 50), obtain the resistates that 8.91g contains title compound, it can be directly used in next reaction to the gained resistates by the silica gel column chromatography purifying.
1H-NMR(400MHz，CDCl
3)δ：9.77(1H，s)，7.32-7.22(5H，m)，4.42(1H，t，J＝8.95Hz)，4.06(1H，dd，J＝9.31，3.68Hz)，3.62(1H，d，J＝12.99Hz)，3.53(1H，d，J＝13.24Hz)，3.30(1H，d，J＝9.31Hz)，2.84(1.0H，d，J＝9.31Hz)，2.73-2.62(2.0H，m)，2.55-2.51(2.0H，m)，2.04-2.00(2H，m)。
MS(ESI)；m/z：274(M+H)
+。
[reference example 118]
7-benzyl-1-(the 3-butene-1-yl)-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone
[formula 210]
Under nitrogen atmosphere, with tetrahydrofuran (THF) (45.7ml) join the methyl triphenyl phosphonium iodide (6.16g, 15.2mmol) in.Under ice-cooled, (14.0ml 22.0mmol), stirs reaction soln 15 minutes the hexane solution of adding 1.57mol/L butyllithium then.Ice-cooled down, contain 7-benzyl-3-oxa--1-(3-oxopropyl)-7-azabicyclo [3.3.0] octane-2-ketone (5.00g, the resistates solution of tetrahydrofuran (THF) 18.3mmol) (45.7ml) at room temperature stirred mixture 1 hour to wherein dripping.(150ml) joins in the reaction soln with water, uses ethyl acetate (150ml) extraction then.Organic layer salt water washing is again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 1.09g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.22(10.8H，m)，5.83-5.73(1H，m)，5.07-4.96(2.1H，m)，4.40(1H，t，J＝8.95Hz)，4.04(1H，dd，J＝9.19，3.55Hz)，3.63(1H，d，J＝12.99Hz)，3.50(1H，d，J＝13.24Hz)，3.29(1H，d，J＝9.31Hz)，2.83(1H，d，J＝9.56Hz)，2.71-2.69(1H，m)，2.47(1H，dd，J＝9.56，6.62Hz)，2.23-2.02(3H，m)，1.92-1.88(1H，m)，1.69-1.65(1H，m)。
MS(ESI)；m/z：272(M+H)
+。
[reference example 119]
7-benzyloxycarbonyl-1-(the 3-butene-1-yl)-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone
[formula 211]
Under nitrogen atmosphere, with chloroformic acid benzyl ester (1.72ml, 12.0mmol) (3-butene-1-yl)-(1.09g in methylene dichloride 4.02mmol) (13.4ml) solution, at room temperature stirred mixture 5 days 3-oxa--7-azabicyclo [3.3.0] octane-2-ketone to join 7-benzyl-1-.Reaction soln is through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 84: 16 → 80: 20 → 75: 25 → 66: 34 → 50: 50), obtain the 1.13g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.28(5H，m)，5.82-5.72(1H，m)，5.12-5.00(4H，m)，4.42(1H，t，J＝8.33Hz)，4.12(1H，brs)，4.00(1H，d，J＝11.77Hz)，3.83(1H，dd，J＝11.77，8.33Hz)，3.44(2H，d，J＝37.75Hz)，2.95-2.89(1H，m)，2.26-2.17(1H，m)，2.10-2.06，(1H，m)，1.90-1.76(2H，m)。
MS(ESI)；m/z：316(M+H)
+。
[reference example 120]
1-benzyloxycarbonyl-3-(the 3-butene-1-yl)-4-phenyl seleno methyl-3-methyl-formiate
[formula 212]
Under nitrogen atmosphere, with N, dinethylformamide (16.3ml) join two selenizing hexichol (946mg, 3.03mmol) in.Then, with under the cooled with liquid nitrogen, make mixture be decompressed to the vacuum and the freezing degassing (* 3).At room temperature, to wherein add sodium borohydride (229mg, 6.05mmol).The gained mixture at room temperature stirs, and finishes up to aerogenesis, is decompressed to the vacuum and the freezing degassing (* 3) then, the preparation feedback solution A.
Individually, with under the cooled with liquid nitrogen, with 7-benzyl-1-(3-butene-1-yl)-3-oxa--7-azabicyclo [3.3.0] octane-2-ketone (955mg, N 3.03mmol), dinethylformamide (14.0ml) solution decompression is to the vacuum and the freezing degassing (3 times), preparation feedback solution B.
Reaction soln B is joined among the reaction soln A, and the gained mixture stirred 1 hour at 100 ℃.Reaction soln is cooled to room temperature, adds 1N hydrochloric acid (10-20ml) then, use ethyl acetate (100ml * 2) extraction again.Organic layer salt water washing is again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.(chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2 → 97: 3 → 96: 4), obtain the 2.08g title compound, it can be directly used in esterif iotacation step to the gained resistates by the silica gel column chromatography purifying.Trimethyl silyl diazomethane (9.09ml) is joined in methyl alcohol (30.3ml) solution of 2.08g resistates down ice-cooled, mixture was at room temperature stirred 20 minutes.Reaction soln is through concentrating under reduced pressure.Then, resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 485mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.49-7.23(5H，m)，5.73-5.69(1H，m)，5.16-5.09(2H，m)，4.98-4.95(2H，m)，3.98(1H，dd，J＝21.33，11.28Hz)，3.80(1H，ddd，J＝24.08，10.97，7.05Hz)，3.70(3H，s)，3.32-3.21(2H，m)，3.12(1H，dd，J＝12.38，3.06Hz)，2.49(1H，t，J＝12.01Hz)，2.34-2.29(1H，m)，2.10-2.05(1H，m)，1.96-1.92(2H，m)，1.38-1.35(1H，m)。
MS(ESI)；m/z：378(M+H)
+。
[reference example 121]
1-benzyloxycarbonyl-3-(the 3-butene-1-yl)-4-methylene pyrrolidine-3-methyl-formiate
[formula 213]
With the high sodium iodide of 0.5N (sodium periodide) solution (4.99ml, 2.50mmol) (3-butene-1-yl)-(485mg is in tetrahydrofuran (THF) 0.997mmol) (9.97ml) solution for 4-phenyl seleno methyl-3-methyl-formiate to join 1-benzyloxycarbonyl-3-.Mixture was at room temperature stirred 5 hours, stirred 24 hours at 40 ℃-50 ℃ then.(50ml) joins in the reaction soln with water, uses ethyl acetate (50ml * 2) extraction then.Organic layer is through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 285mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.42-7.28(5H，m)，5.79-5.75(1H，m)，5.20-5.15(4H，m)，5.03-4.98(2H，m)，4.21-4.13(3H，m)，3.69(3H，s)，3.41(1H，dd，J＝19.49，11.40Hz)，2.17-2.10(1H，m)，2.04-2.02(2H，m)，1.68-1.64(1H，m)。
MS(ESI)m/z：330(M+H)
+。
[reference example 122]
{ 3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-5-alkene-1-yl } methyl-formiate
[formula 214]
Under nitrogen atmosphere, (29.6mg, (3-butene-1-yl)-(286mg is in methylene dichloride 0.871mmol) (8.71ml) solution for 4-methylene pyrrolidine-3-methyl-formiate 0.871mmol) to join 1-benzyloxycarbonyl-3-with s-generation Grubbs catalyzer.Mixture was at room temperature stirred 19 hours, add methylene dichloride (17.4ml).After 6 hours, reaction soln is through concentrating under reduced pressure 45 ℃ of stirrings.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 87: 13 → 85: 15 → 83: 17 → 80: 20 → 75: 25 → 66: 34), obtain the 187mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5H，m)，5.72(1H，d，J＝13.73Hz)，5.17-5.12(2H，m)，4.20(1H，dd，J＝10.79，2.70Hz)，4.04-3.94(2H，m)，3.68(3H，d，J＝1.47Hz)，3.07(1H，dd，J＝10.79，7.11Hz)，2.95-2.87(1H，m)，2.63-2.48(2H，m)，1.88-1.83(1H，m)。
MS(ESI)m/z：302(M+H)
+。
[reference example 123]
{ 3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-5-alkene-1-yl } formic acid
[formula 215]
Under nitrogen atmosphere, 1N sodium hydroxide solution (1.86ml) is joined { 3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-5-alkene-1-yl } methyl-formiate (187mg, 0.620mmol) methyl alcohol (6.20ml) solution in, mixture was at room temperature stirred 16 hours.Reaction soln is used ether (50ml * 2) washing then through concentrating under reduced pressure.Water layer is used the 1N hcl acidifying down ice-cooled, uses ethyl acetate (100ml * 1,80ml * 1) extraction then.Organic layer water (80ml) and salt solution (80ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains 186mg (quantitatively) title compound through concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.30(5H，m)，5.77(1H，d，J＝17.16Hz)，5.21-5.10(2H，m)，4.25(1H，dd，J＝10.91，5.02Hz)，4.02(2H，t，J＝17.53Hz)，3.09(1H，dd，J＝10.91，7.72Hz)，2.93(1H，brs)，2.60-2.54(2H，m)，1.93-1.83(1H，m)。
MS(ESI)；m/z：288(M+H)
+。
[reference example 124]
Suffering-(optically-active is different for 5-alkene for 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0]
Structure body A, optically active isomer B)
[formula 216]
Under nitrogen atmosphere, with triethylamine (0.181ml, 1.30mmol) and two phenoxy group phosphoryl azides (0.181ml, (186mg is in toluene 0.647mmol) (3.23ml) solution 0.840mmol) to join { 3-benzyloxycarbonyl-3-azabicyclo [3.3.0] suffering-5-alkene-1-yl } formic acid.Mixture was at room temperature stirred 30 minutes, stirred 30 minutes at 100 ℃ then.Reaction soln is through concentrating under reduced pressure, and triethylamine and methylbenzene azeotropic distill (* 3).With 1,4-diox (1.62ml) and 6N hydrochloric acid (1.62ml) join the gained resistates, and the gained mixture stirred 1 hour at 50 ℃.Reaction soln is with water (6.5ml) distillation, and organic layer steams by concentrating under reduced pressure.Resistates washs with ether (20ml * 2).Water layer down with the alkalization of 1N sodium hydroxide solution, is used chloroform (40ml * 1,30ml * 1) extraction ice-cooled again.Organic layer water (40ml) and salt solution (40ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.Methylene dichloride (3.23ml) is joined in the gained resistates, under nitrogen atmosphere, add tert-Butyl dicarbonate (283mg, 1.30mmol).After at room temperature stirring 17 hours, reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 120mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.31(5H，m)，5.74(1H，d，J＝7.48Hz)，5.17-5.11(2H，m)，4.58(1H，s)，4.26(1H，dd，J＝25.37，11.40Hz)，4.02-4.01(2H，m)，3.14(1H，dd，J＝11.28，8.82Hz)，2.80(1H，brs)，2.55-2.52(1H，m)，2.37(1H，brs)，1.94-1.91(1H，m)，1.43(9H，s)。
The racemic modification 3-benzyloxycarbonyl of Huo Deing-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (108mg as described above, 0.301mmol) carry out optical resolution (CHIRALCEL OJ by the optically-active post, 20mm diameter * 250mm, hexane: Virahol=90: 10, flow velocity=20ml/min, each 20mg that splits), obtain 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (optically active isomer A) (50.5mg, 1.41mmol, retention time=8.0min) and enantiomorph 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (optically active isomer B) (55.6mg thereof, 0.155mmol, retention time=11.5min).
[reference example 125]
1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (derived from optically active isomer A)
[formula 217]
Under with the dry ice-propanone cooling, to 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (optically active isomer A) (50.5mg, 0.141mmol) tetrahydrofuran (THF) (1.41ml) solution in feed ammonia, in solution, add the 30-40ml liquid ammonia.Under nitrogen atmosphere, (17.0mg 0.709mmol), stirs mixture 10 minutes to add sodium.At room temperature add saturated ammonium chloride solution (3), mixture is at room temperature stirred with the evaporation ammonia.Add 1N sodium hydroxide solution (12.0ml), use chloroform/methanol/water=7/3/1 (40ml * 1, the 20ml * 1) extraction of chloroform (40ml * 1,20ml * 1) and lower floor again.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, filtrate obtains 33mg (quantitatively) title compound through concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：5.58(1H，brs)，4.62(1H，brs)，3.47(3H，tt，J＝14.34，9.68Hz)，2.96-2.87(1H，m)，2.61-2.57(2H，m)，2.28-2.25(1H，m)，1.85(1H，dt，J＝16.42，6.62Hz)，1.45(9H，s)。
MS(ESI)m/z：225(M+H)
+。
[embodiment 25]
7-[1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body A)
[formula 218]
With triethylamine (0.0595ml, 0.426mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(51.2mg, (33.0mg is in dimethyl sulfoxide (DMSO) 0.135mmol) (0.284ml) solution 0.142mmol) to join 1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (derived from optically active isomer A) for inner complex.Mixture was at room temperature stirred 2 hours, stirred 14 hours at 40 ℃ again.With ethanol: the mixing solutions of water=4: 1 (5ml) and triethylamine (0.5ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (15ml), water (15ml) and salt solution (15ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 61.4mg gained resistates is dissolved in the concentrated hydrochloric acid (1ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (15ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.This basic solution is adjusted to pH 7.4 with hydrochloric acid, uses chloroform/methanol/water=7/3/1 (80ml * 3) extraction of chloroform (80ml), chloroform/methanol=10/1 (80ml) and lower floor again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is dissolved in hot ethanol (5ml) and 28% ammonia solution (1-2ml), removes by filter insolubles.Solvent evaporated under reduced pressure gradually heats simultaneously and stirs.In addition, ammonia and ethanol (3-5ml) component distillation (* 10).Concentrate ethanol, get off, at room temperature stir again and spend the night up to crystal settling.Filter the crystal of collecting precipitation,, at 60 ℃ of drying under reduced pressure, obtain the 9.65mg title compound then with ethanol and ether washing.
1H-NMR(400MHz，0.1N?NaOD)δ：8.40(1H，d，J＝3.19Hz)，7.69(1H，d，J＝14.46Hz)，5.62(1H，s)，5.12-4.96(1H，m)，4.50(1H，d，J＝12.50Hz)，4.04-4.01(2H，m)，3.60(5H，dd，J＝16.67，9.31Hz)，2.91(1H，s)，2.62-2.59(1H，m)，2.15-2.07(1H，m)，1.99-1.92(1H，m)，1.58-1.54(1H，m)，1.48-1.37(1H，m)。
C
21H
21F
2N
3O
41.5H
2The analytical calculation value of O: C, 56.75; H, 5.44; N, 99.45.Measured value: C, 56.53; H, 4.96; N, 9.01.
MS(ESI)；m/z：418(M+H)
+。
IR(ATR)v：2935，2852，2755，2657，2572，2103，1716，1614，1569，1531，1498，1463，1455，1361，1324，1116，1043，943，919，808cm
-1。
[reference example 126]
1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (derived from optically active isomer B)
[formula 219]
Under with the dry ice-propanone cooling, to 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (optically active isomer B) (54.7mg, 0.153mmol) tetrahydrofuran (THF) (1.53ml) solution in feed ammonia, in solution, add the 30-40ml liquid ammonia.Under nitrogen atmosphere, (18.4mg 0.767mmol), stirs mixture 10 minutes to add sodium.At room temperature add saturated ammonium chloride solution (10), mixture is at room temperature stirred with the evaporation ammonia.Add 1N sodium hydroxide solution (3-4ml), the gained mixture is through concentrating under reduced pressure.Add chloroform/methanol=10/1 (10-20ml).After the supersound process, remove by filter insolubles.Filtrate obtains the resistates that 150mg contains title compound through concentrating under reduced pressure, and it can be directly used in next reaction.
MS(ESI)m/z：225(M+H)
+。
[embodiment 26]
7-[1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body B)
[formula 220]
With triethylamine (0.0641ml, 0.460mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(58.0mg 0.161mmol) joins and contains 1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] suffering-5-alkene (derived from optically active isomer B) (150mg is in the resistates solution of dimethyl sulfoxide (DMSO) 0.153mmol) (0.306ml) inner complex.Mixture was at room temperature stirred 1.5 hours.(0.0641ml, 0.460mmol), the gained mixture stirred 1 day at 40 ℃ to add dimethyl sulfoxide (DMSO) (0.306ml) and triethylamine.With 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(174mg 0.483mmol) joins in the reaction soln inner complex, and the gained mixture stirred 15 hours at 40 ℃.With ethanol: the mixing solutions of water=4: 1 (5ml) and triethylamine (0.5ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (20ml), water (20ml) and salt solution (20ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 194mg gained resistates is dissolved in the concentrated hydrochloric acid (1ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (30ml * 5) washing, water layer is adjusted to pH12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform/methanol/water=7/3/1 (50ml) extraction of chloroform (80ml), chloroform/methanol=10/1 (80ml) and lower floor again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by PTLC purifying (chloroform/methanol/water of lower floor=7/3/1).Chloroform/methanol (10/1) is joined in the gained resistates, remove by filter insolubles.Filtrate decompression is concentrated.Ethanol (1ml) is joined in the gained resistates, mixture is at room temperature stirred spend the night.Add ether (2ml), filter the crystal of collecting precipitation,, at 50 ℃ of drying under reduced pressure, obtain the 2.38mg title compound then with ethanol and ether washing.
1H-NMR(400MHz，0.1N?NaOD)δ：8.50(1H，s)，7.70(1H，d，J＝14.46Hz)，5.62(1H，s)，5.05-4.90(1H，m)，4.65-4.59(1H，m)，4.11(1H，s)，3.93(1H，d，J＝14.95Hz)，3.70(1H，d，J＝10.05Hz)，3.62(3H，s)，3.53(1H，d，J＝10.79Hz)，3.00-2.82(1H，m)，2.67-2.56(1H，m)，2.15-2.12(1H，m)，2.00-1.95(1H，m)，1.72-1.58(2H，m)。
MS(ESI)；m/z：418(M+H)
+。
[reference example 127]
6-tert-butoxycarbonyl amino-8-benzyloxycarbonyl-8-aza-tricycle [4.3.0.0
1,3
] nonane (derived from
Optically active isomer A)
[formula 221]
Methylene dichloride (3.52ml) solution cools off with ice-acetone.Under nitrogen atmosphere, slowly add the 1.0M zinc ethyl hexane solution (0.88ml, 0.88mmol) and methylene iodide (0.071ml 0.881mmol), stirs mixture 20 minutes under cooling.Under cooling, (126mg, methylene dichloride 0.352mmol) (3.52ml) solution at room temperature stirred mixture 24 hours slowly to add 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.2.0] suffering-5-alkene (optically active isomer A).Under with the cooling of ice-acetone, add saturated sodium bicarbonate aqueous solution (10ml) and 10% hypo solution (10ml), stir the gained mixture, disappear up to vermilion red.Organic layer extracts with chloroform (50ml * 1,40ml * 1).Organic layer is with salt solution (80ml) washing, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Under nitrogen atmosphere, (384mg 1.76mmol) joins in the 212mg gained resistates successively with acetonitrile (7.04ml) and tert-Butyl dicarbonate.After at room temperature stirring 19 hours, reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 95.2mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.31(5H，m)，5.17-5.11(2H，m)，4.93(1H，brs)，4.21-4.11(1H，m)，3.75(1H，dd，J＝10.91，6.74Hz)，3.32-3.12(2H，m)，2.47-2.31(1H，m)，1.97-1.88(1H，m)，1.81-1.78(1H，m)，1.43(9H，s)，1.35-1.31(1H，m)，1.19-1.16(1H，m)，0.82-0.76(2H，m)。
MS(ESI)；m/z：395(M+Na)
+。
[reference example 128]
6-tert-butoxycarbonyl amino-8-benzyloxycarbonyl-8-aza-tricycle [4.3.0.0
1,3
] nonane (derived from
Optically active isomer B)
[formula 222]
Methylene dichloride (4.18ml) solution cools off with ice-acetone.Under nitrogen atmosphere, slowly add the 1.0M zinc ethyl hexane solution (1.05ml, 1.05mmol) and methylene iodide (0.0842ml 1.05mmol), stirs mixture 20 minutes under cooling.Under cooling, (150mg, methylene dichloride 0.418mmol) (4.18ml) solution at room temperature stirred mixture 22 hours slowly to add 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.2.0] suffering-5-alkene (optically active isomer B).Under with the cooling of ice-acetone, add saturated sodium bicarbonate aqueous solution (10ml) and 10% hypo solution (10ml), stir the gained mixture, disappear up to vermilion red.Organic layer extracts with chloroform (60ml * 1,50ml * 1).Organic layer is with salt solution (60ml) washing, through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.Under nitrogen atmosphere, (274mg 1.25mmol) joins in the 256mg gained resistates successively with acetonitrile (8.36ml) and tert-Butyl dicarbonate.After at room temperature stirring 13 hours, reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 84: 16 → 80: 20 → 75: 25), obtain the 113mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.40-7.29(5H，m)，5.13(2H，t，J＝6.74Hz)，4.93(1H，d，J＝16.18Hz)，4.23-4.09(1H，m)，3.75(1H，dd，J＝11.03，6.62Hz)，3.27-3.19(2H，m)，2.43(1H，brs)，1.98-1.88(1H，m)，1.82-1.74(2H，m)，1.43(9H，s)，1.37-1.22(1H，m)，1.22-1.14(1H，m)，0.81-0.77(2H，m)。
MS(ESI)；m/z：395(M+Na)
+。
[reference example 129]
6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0
1,3
] nonane (derived from optically active isomer A)
[formula 223]
Under nitrogen atmosphere, (47.6mg 50wt%) joins 6-tert-butoxycarbonyl amino-8-benzyloxycarbonyl-8-aza-tricycle [4.3.0.0 with 10% palladium carbon catalyst
1,3] (95.2mg is in methyl alcohol 0.255mmol) (2.55ml) solution for nonane (derived from optically active isomer A).After the former atmosphere of hydrogen exchange, mixture was at room temperature stirred 1 hour.Add 10% palladium carbon catalyst (28.6mg, 30wt%).After the former atmosphere of hydrogen exchange, mixture was at room temperature stirred 1 hour.After the former atmosphere of nitrogen replacement, reaction soln obtains the 56.0mg title compound by diatomite filtration and concentrating under reduced pressure, is the dark oil thing.
1H-NMR(400MHz，CDCl
3)δ：4.98(1H，brs)，3.63(1H，s)，3.46-3.44(1H，m)，2.92(2H，dd，J＝30.52，11.15Hz)，2.37(1H，brs)，2.00-1.96(1H，m)，1.76-1.70(1H，m)，1.44(9H，s)，1.35-1.25(1H，m)，1.21-1.15(1H，m)，0.86-0.69(2H，m)。
MS(ESI)；m/z：239(M+H)
+。
[embodiment 27]
7-[6-amino-8-aza-tricycle [4.3.0.0
1,3
] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body A)
[formula 224]
With triethylamine (0.0984ml, 0.705mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2(89.1mg 0.247mmol) joins 6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0 to inner complex
1,3] in dimethyl sulfoxide (DMSO) (0.470ml) solution of nonane (derived from optically active isomer A) 56.0mg (0.235mmol).The gained mixture stirred 19 hours at 35 ℃.With ethanol: the mixing solutions of water=4: 1 (5.0ml) and triethylamine (0.5ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (35ml) also with 10% citric acid solution (25ml), water (25ml) and salt solution (25ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1).Down 80.5mg gained resistates is dissolved in the concentrated hydrochloric acid (1ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (30ml * 4) washing, water layer is adjusted to pH12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH 7.4 with hydrochloric acid, uses chloroform (60ml * 2) and chloroform/methanol=10/1 (60ml * 3) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is by PTLC purifying (chloroform/methanol/water of lower floor=7/3/1).The gained resistates is dissolved in chloroform/methanol=10/1 (10ml).Remove by filter insolubles, then filtrate decompression is concentrated.The gained resistates is dissolved in the hot ethanol (20-30ml), then concentrating under reduced pressure and dry.Ethanol (0.5ml) and ether (5ml) are joined in the gained resistates, and the gained mixture carries out supersound process also with ice-cooled.Then, filter the crystal of collecting precipitation and wash with ether.Crystal obtains the 21.0mg title compound at 45 ℃ of drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.38(1H，d，J＝2.94Hz)，7.67(1H，d，J＝14.22Hz)，5.12-4.96(1H，m)，4.32-4.29(1H，m)，4.04-3.99(1H，m)，3.80(1H，d，J＝10.30Hz)，3.61(3H，s)，3.44(1H，d，J＝10.54Hz)，3.31(1H，d，J＝10.30Hz)，2.02-1.89(2H，m)，1.77(1H，dd，J＝12.62，8.46Hz)，1.58-1.24(4H，m)，0.82(2H，dt，J＝23.78，5.82Hz)。
C
22H
23F
2N
3O
4The analytical calculation value: C, 57.64; H, 5.72; F, 8.29; N, 9.17.Measured value: C, 57.70; H, 5.77; F, 8.57; N, 9.09.
MS(ESI)；m/z：432(M+H)
+。
IR(ATR)v：2935，2869，1725，1616，1432，1363，1319，1182，1137，1045，943，923，806cm
-1。
[reference example 130]
6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0
1,3
] nonane (derived from optically active isomer B)
[formula 225]
Under nitrogen atmosphere, (27.7mg 30wt%) joins 6-tert-butoxycarbonyl amino-8-benzyloxycarbonyl-8-aza-tricycle [4.3.0.0 with 10% palladium carbon catalyst
1,3] (92.3mg is in methyl alcohol 0.248mmol) (2.48ml) solution for nonane (derived from optically active isomer B).The gained mixture stirred 1 hour under nitrogen atmosphere, room temperature.(18.5mg, 20wt%), the gained mixture stirred 2.5 hours under nitrogen atmosphere, room temperature to add 10% palladium carbon catalyst.After the former atmosphere of nitrogen replacement, reaction soln obtains the resistates that 64.4mg contains title compound by diatomite filtration and concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：4.87(1H，brs)，3.50(1H，brs)，3.29(1H，d，J＝11.03Hz)，3.14-3.12(1H，m)，2.76(2H，dd，J＝19.12，11.28Hz)，2.47-1.66(3H，m)，1.43(9H，s)，1.32(1H，dd，J＝24.14，10.17Hz)，1.08-1.04(1H，m)，0.82-0.67(2H，m)。
MS(ESI)；m/z：239(M+H)
+。
[embodiment 28]
7-[6-amino-8-aza-tricycle [4.3.0.0
1,3
] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body B)
[formula 224]
With triethylamine (0.104ml, 0.745mmol) and 1-[(1R, 2S)-2-fluorine ring third-1-yl]-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2(89.5mg 0.248mmol) joins 64.4mg and contains 6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0 inner complex
1,3] in the resistates solution of dimethyl sulfoxide (DMSO) (0.496ml) of nonane (0.248mmol equivalent), the gained mixture stirred 17 hours at 35 ℃.With ethanol: the mixing solutions of water=4: 1 (5.0ml) and triethylamine (0.5ml) joins in the reaction soln, and mixture heating up was refluxed 1.5 hours.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (35ml) also with 10% citric acid solution (25ml), water (25ml) and salt solution (25ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1).Down 75.5mg gained resistates is dissolved in the concentrated hydrochloric acid (1ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (30ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH 7.4 with hydrochloric acid, uses chloroform (80ml * 1,70ml * 1,50ml * 1) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the hot ethanol (10ml), removes by filter insolubles.Solvent evaporated under reduced pressure gradually heats simultaneously and stirs.Concentrated solution is about 0.5ml up to ethanol then, gets back to room temperature then.Add ether (5ml), mixture is with ice-cooled.Then, filter the crystal of collecting precipitation, wash with ether again.Crystal obtains the 25.9mg title compound at 50 ℃ of drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.50(1H，s)，7.67(1H，d，J＝14.71Hz)，4.99-4.93(1H，m)，4.39(1H，dd，J＝10.30，3.43Hz)，4.09(1H，q，J＝6.21Hz)，3.87(1H，dd，J＝10.54，2.94Hz)，3.63(3H，s)，3.37(1H，d，J＝10.54Hz)，3.23(1H，d，J＝10.30Hz)，2.01-1.95(2H，m)，1.79-1.58(3H，m)，1.34-1.17(2H，m)，0.82(2H，dt，J＝22.22，5.94Hz)。
C
22H
23F
2N
3O
40.5H
2The analytical calculation value of O: C, 59.99; H, 5.49; F, 8.63; N, 9.54.Measured value: C, 60.28; H, 5.34; F, 8.57; N, 9.52.
MS(ESI)；m/z：432(M+H)
+。
IR(ATR)v：2937，2863，1716，1616，1508，1434，1321，1187，1120，1054，939，889，804cm
-1。
[reference example 131]
[(1R
*
, 6R
*
)-8-benzyl-8-azabicyclo [4.3.0] nonane-1-yl] methyl-formiate
[formula 227]
At room temperature, the trifluoroacetic acid of catalytic amount is joined 1-tetrahydrobenzene-1-methyl-formiate (25.0g, 178mmol) with N-benzyl-N-(methoxymethyl)-N-trimethyl silyl methylamine (46.6g, 196mmol) 1, in 2-ethylene dichloride (178ml) solution, mixture was at room temperature stirred 2 hours.(200ml) joins in the reaction soln with saturated sodium bicarbonate solution, uses chloroform (150ml * 1,100ml * 1) extraction again.Organic layer is with salt solution (450ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 85: 15 → 75: 25), obtain the 21.3g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.24(5H，m)，3.70-3.65(5H，m)，2.92(1H，d，J＝9.31Hz)，2.73-2.68(3H，m)，1.93(1H，td，J＝9.01，4.82Hz)，1.79-1.65(2H，m)，1.53-1.21(6H，m)。
MS(ESI)；m/z：274(M+H)
+。
[reference example 132]
[(1R
*
, 6R
*
)-8-benzyloxycarbonyl-8-azabicyclo [4.3.0] nonane-1-yl] methyl-formiate
[formula 228]
Under nitrogen atmosphere, (33.4ml 234mmol) joins [(1R with chloroformic acid benzyl ester
*, 6R
*)-8-benzyl-8-azabicyclo [4.3.0] nonane-1-yl] (21.3g in methylene dichloride 77.9mmol) (259ml) solution, at room temperature stirred mixture 15 hours methyl-formiate.Reaction soln is through concentrating under reduced pressure.Then, resistates (58.0g) is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 80: 20 → 75: 25), obtain the 17.5g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5H，m)，5.13(2H，m)，3.71(3H，d，J＝3.19Hz)，3.63(1H，dd，J＝10.91，8.21Hz)，3.52-3.28(3H，m)，2.72-2.64(1H，m)，1.93(1H，m)，1.75(1H，dq，J＝20.41，5.23Hz)，1.63-1.38(6H，m)。
MS(ESI)；m/z：318(M+H)
+。
[reference example 133]
[(1R
*
, 6R
*
)-8-benzyloxycarbonyl-8-azabicyclo [4.3.0] nonane-1-yl] formic acid
[formula 229]
Under nitrogen atmosphere, 1mol/L sodium hydroxide solution (70.8ml) and tetrahydrofuran (THF) (78.8ml) are joined [(1R
*, 6R
*)-8-benzyloxycarbonyl-8-azabicyclo [4.3.0] nonane-1-yl] (7.50g in methyl alcohol 23.6mmol) (78.8ml) solution, at room temperature stirred mixture 3 days methyl-formiate.Reaction soln is used ether (50ml * 2) washing then through concentrating under reduced pressure.Water layer down with 3mol/L hydrochloric acid (28ml) acidifying, is used ethyl acetate (100ml * 2) extraction ice-cooled then.Organic layer is with salt solution (250ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 6.70g title compound through concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5，m)，5.13(2H，m)，3.70(1H，dd，J＝10.91，4.78Hz)，3.51(2H，m)，3.40-3.30(1H，m)，2.68(1H，m)，2.00-1.96(1H，m)，1.78-1.76(1H，m)，1.65-1.60(1H，m)，1.51-1.45(5H，m)。
MS(ESI)；m/z：304(M+H)
+。
[reference example 134]
(1R
*
, 6S
*
)-8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane
[formula 230]
Under nitrogen atmosphere, (6.17ml, 44.2mmol) (6.19ml 28.7mmol) joins [(1R with two phenoxy group phosphoryl azides with triethylamine
*, 6R
*)-8-benzyloxycarbonyl-8-azabicyclo [4.3.0] nonane-1-yl] (6.70g in toluene 22.1mmol) (110ml) solution, stirs down ice-cooled formic acid simultaneously.Mixture was at room temperature stirred 40 minutes, stirred 1 hour at 90 ℃ again.Reaction soln is at room temperature used ethyl acetate (150ml) dilution, with saturated sodium bicarbonate solution (200ml), water (200ml) and salt solution (200ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.With 1,4-diox (55.0ml) and 6mol/L hydrochloric acid (55.0ml) join in the gained resistates, and the gained mixture stirred 2 hours at 50 ℃.Reaction soln is with water (55.0ml) distillation and concentrating under reduced pressure.Then, resistates and ethanol azeotropic drying (* 5).Methylene dichloride (110ml) is joined in the sedimentary white solid (7.41g).Under nitrogen atmosphere, (15.4ml, 110mmol) (9.65g 44.2mol), at room temperature stirred mixture 15 hours with two tert-butoxycarbonyls to add triethylamine.Reaction soln is through concentrating under reduced pressure, and adding ethyl acetate (150ml).Mixture water (200ml) and salt solution (200ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 83: 17 → 66: 34), obtain the 6.65g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.29(5H，m)，5.13(2H，s)，4.55(1H，d，J＝13.97Hz)，3.69(1H，d，J＝11.28Hz)，3.58-3.45(2H，m)，3.30(1H，ddd，J＝21.33，10.66，6.74Hz)，2.03-1.99(1H，m)，1.66-1.43(17H，m)。
MS(ESI)；m/z：374(M+H)
+。
[reference example 135]
(1R, 6S)-/(1S, 6R)-8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0]
Nonane (optically active isomer A, optically active isomer B)
[formula 231]
Racemic modification (1R
*, 6S
*)-8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (6.65g, 17.8mmol) carry out optical resolution (CHIRALPAK AD by the optically-active post, 20mm diameter * 250mm, hexane: Virahol=95: 5, flow velocity=20ml/min), obtain 8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (optically active isomer the A) (427mg of optically-active, 1.14mmol, retention time=14.2min) and optically active enantiomorph 8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (optically active isomer B) (415mg thereof, 1.11mmol, retention time=19.4min).
[reference example 136]
1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (derived from optically active isomer A)
[formula 232]
Under nitrogen atmosphere, (80.0mg, (400mg is in methyl alcohol 1.07mmol) (10.7ml) solution 20wt%) to join 8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (optically active isomer A) with 10% palladium carbon catalyst.After the former atmosphere of hydrogen exchange, mixture was stirred 1 hour under nitrogen atmosphere, room temperature.After the former atmosphere of nitrogen replacement, reaction soln obtains title compound (quantitatively) by diatomite filtration and concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：4.61(1H，brs)，3.18-3.12(2H，m)，3.02(1H，d，J＝11.28Hz)，2.81(1H，dd，J＝10.66，6.74Hz)，2.16(1H，brs)，2.01(1H，brs)，1.57-1.43(8H，m)，1.43(9H，s)。
MS(ESI)；m/z：241(M+H)
+。
[embodiment 29]
7-[1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third-1-
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body A)
[formula 233]
With triethylamine (0.407ml, 2.92mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine ring third-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (351mg, 0.972mmol) join 1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (derived from optically active isomer A) (277mg, 1.07mmol) dimethyl sulfoxide (DMSO) (1.94ml) solution in, the gained mixture stirred 17 hours at 35 ℃.With ethanol: the mixing solutions of water=4: 1 (20ml) and triethylamine (2ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (40ml) also with 10% citric acid solution (50ml), water (50ml) and salt solution (50ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 456mg gained resistates is dissolved in the concentrated hydrochloric acid (3.0ml) ice-cooled, gained solution at room temperature stirred 15 minutes.Reaction soln is adjusted to pH13.6 with saturated sodium hydroxide solution, and basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform/methanol/water=7/3/1 (150ml) extraction of chloroform (100ml), chloroform/methanol=10/1 (150ml * 1,100ml * 2) and lower floor again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the hot ethanol (67.5ml), removes by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Concentrated solution is 10ml up to ethanol, at room temperature stirs then and spends the night.Filter the crystal of collecting precipitation, then with ethanol and ether washing.Crystal obtains the 271mg title compound at 50 ℃ of drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.42(1H，d，J＝1.96Hz)，7.65(1H，d，J＝14.71Hz)，4.97(1H，dt，J＝49.76，17.89Hz)，4.05-4.00(1H，m)，3.84(1H，t，J＝7.48Hz)，3.71(1H，d，J＝10.30Hz)，3.60(4H，t，J＝12.01Hz)，3.36(1H，d，J＝8.33Hz)，2.01(1H，m)，1.77(2H，m)，1.60-1.41(8H，m)。
C
22H
25F
2N
3O
40.5H
2The analytical calculation value of O: C, 59.72; H, 5.92; F, 8.59; N, 9.50.Measured value: C, 59.91; H, 5.97; F, 8.68; N, 9.39.
MS(ESI)；m/z：434(M+H)
+。
IR(ATR)v：2927，2856，1724，1616，1508，1430，1324，1268，1186，1120，1049，925，877，806cm
-1。
[reference example 137]
1-tert-butoxycarbonyl amino-3-azabicyclo [4.3.0] nonane (derived from optically active isomer B)
[formula 234]
Under nitrogen atmosphere, (83.0mg, (415mg is in methyl alcohol 1.11mmol) (11.1ml) solution 20wt%) to join 8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (optically active isomer B) with 10% palladium carbon catalyst.After the former atmosphere of hydrogen exchange, mixture stirred 1 hour under nitrogen atmosphere, room temperature.After the former atmosphere of nitrogen replacement, reaction soln obtains title compound (quantitatively) by diatomite filtration and concentrating under reduced pressure.
1H-NMR(CDCl
3)δ：4.60(1H，brs)，3.17-3.12(2H，m)，3.02(1H，d，J＝11.52Hz)，2.81(1H，brs)，2.15(1H，brs)，2.00(1H，s)，1.63-1.36(8H，m)，1.43(9H，s)。
MS(ESI)；m/z：241(M+H)
+。
[embodiment 30]
7-[1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third-1-
Base]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid (7-bit substituent: different derived from optically-active
Structure body B)
[formula 235]
With triethylamine (0.422ml, 3.03mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine ring third-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (364mg, 1.01mmol) join 1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (derived from optically active isomer B) (273mg, 1.11mmol) dimethyl sulfoxide (DMSO) (1.94ml) solution in, the gained mixture stirred 17 hours at 35 ℃.With ethanol: the mixing solutions of water=4: 1 (20ml) and triethylamine (2ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (40ml) also with 10% citric acid solution (50ml), water (50ml) and salt solution (50ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 536mg gained resistates is dissolved in the concentrated hydrochloric acid (3.0ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (20ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH 7 with hydrochloric acid, uses chloroform/methanol=10/1 (150ml * 1,100ml * 2) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the hot ethanol (67.5ml), removes by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Concentrated solution is 10ml up to ethanol, at room temperature stirs then and spends the night.Filter the crystal of collecting precipitation and use ethanol and the ether washing.Crystal obtains the 315mg title compound at 50 ℃ of drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.45(1H，d，J＝1.47Hz)，7.64(1H，d，J＝14.95Hz)，5.04-4.84(1H，m)，4.06-3.99(2H，m)，3.88(1H，dd，J＝10.54，2.21Hz)，3.57(3H，s)，3.42(1H，d，J＝10.54Hz)，3.20(1H，d，J＝8.82Hz)，1.94(1H，m)，1.83(1H，m)，1.73(1H，m)，1.67-1.46(6H，m)，1.33(2H，m)。
C
22H
25F
2N
3O
40.75H
2The analytical calculation value of O: C, 59.12; H, 5.98; F, 8.50; N, 9.40.Measured value: C, 59.05; H, 6.12; F, 8.36; N, 9.20.
MS(ESI)；m/z：434(M+H)
+。
IR(ATR)v：2927，2859，1724，1616，1573，1509，1432，1369，1355，1319，1267，1118，1049，933，879，804cm
-1。
[reference example 138]
(3S, 4R)-3,4-diallyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester
[formula 236]
Ice-cooled down at salt, with allyl bromide 98 (1.36ml 16.1mmol) joins (3S)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] (4.05g is in tetrahydrofuran (THF) 12.3mmol) (41.0ml) solution and stir for tetramethyleneimine-3-t-butyl formate.Ice-cooled down at salt, (16.0ml 16.0mmol) also stirs the tetrahydrofuran solution of dropping 1M hexamethyl two silicon nitrine lithiums, and the gained mixture stirred 15 minutes under salt is ice-cooled.Saturated ammonium chloride solution (40ml) and water (20ml) are joined in the reaction soln, use ethyl acetate (40ml * 1,20ml * 1) extraction then.Organic layer is with salt solution (140ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 89: 11 → 88: 12 → 87: 13 → 83: 17 → 80: 20 → 75: 25), obtain the 2.02g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.32(5H，m)，5.77-5.62(2H，m)，5.48(1H，q，J＝7.11Hz)，5.13(2H，dd，J＝13.36，11.89Hz)，5.02(1H，t，J＝9.07Hz)，4.91(1H，dd，J＝5.52，2.76Hz)，3.21(1H，d，J＝10.54Hz)，3.09(1H，d，J＝10.79Hz)，2.56(1H，dd，J＝14.34，6.01Hz)，2.40(3H，d，J＝4.41Hz)，2.27(1H，dd，J＝13.73，8.33Hz)，1.50(3H，d，J＝7.11Hz)，1.40(9H，s)。
MS(ESI)；m/z：370(M+H)
+。
[reference example 139]
[(1S, 6R)-the 7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene-1-yl] first
Tert-butyl acrylate
[formula 237]
Under nitrogen atmosphere, with s-generation Grubbs catalyzer (91.9mg, 0.108mmol) join (3S, 4R)-3,4-diallyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (2.00g, 5.41mmol) methylene dichloride (54.1ml) solution in, mixture was at room temperature stirred 1 hour.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 75: 25 → 66: 34 → 50: 50), obtain the 1.61g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.21(5H，m)，5.75(1H，m)，5.67-5.62(1H，m)，5.49(1H，q，J＝7.19Hz)，3.22(2H，dd，J＝13.97，10.05Hz)，2.74(1H，dd，J＝16.42，5.15Hz)，2.62-2.54(1H，m)，2.49(1H，d，J＝5.39Hz)，2.42(1H，m)，2.15-2.08(1H，m)，1.48(3H，d，J＝7.11Hz)，1.18(9H，s)。
MS(ESI)；m/z：342(M+H)
+。
[reference example 140]
[(1S, 6R)-the 7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene-1-yl] first
Acid
[formula 238]
Under ice-cooled, (18.0ml) joins [(1S with trifluoroacetic acid, 6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene-1-yl] t-butyl formate (2.04g, 5.99mmol) methylene dichloride (18.0ml) solution in and stir, mixture was at room temperature stirred 1.5 hours.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (* 3).Down 1mol/L sodium hydroxide solution (15.0ml) is joined in the gained resistates ice-cooled, the gained mixture washs with ether (40ml * 2).Water layer is used 1mol/L hydrochloric acid (20ml) acidifying under ice-cooled.Then, filter the crystal of collecting precipitation also with 0.5mol/L hydrochloric acid, ethyl acetate and ether washing.The gained crystal spends the night at 50 ℃ of drying under reduced pressure, obtains the 1.40g title compound, is white crystal.The water layer of filtrate extracts with ethyl acetate (50ml).Merge organic layer, water (150ml) and salt solution (150ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 250mg title compound through concentrating under reduced pressure, is white crystal.
1H-NMR(400MHz，CDCl
3)δ：7.23(5H，m)，5.81(1H，m)，5.69(1H，m)，5.51(1H，q，J＝7.11Hz)，3.27(1H，d，J＝10.05Hz)，3.18(1H，d，J＝10.05Hz)，2.74(1H，dd，J＝16.67，4.90Hz)，2.59(1H，m)，2.47(1H，m)，2.22(1H，d，J＝16.67Hz)，2.14(1H，brs)，1.49(3H，d，J＝7.11Hz)。
MS(ESI)；m/z：286(M+H)
+。
[reference example 141]
(1S, 6R)-1-amino-7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene
[formula 239]
Under nitrogen atmosphere, under ice-cooled, with triethylamine (1.61ml, 11.5mmol) and two phenoxy group phosphoryl azide (1.62ml, 7.52mmol) join [(1S, 6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene-1-yl] (1.65g, in toluene 5.78mmol) (28.9ml) solution and stir, the gained mixture stirred 30 minutes at 100 ℃ formic acid.Reaction soln is through concentrating under reduced pressure, and triethylamine and methylbenzene azeotropic distill (* 3).With 1,4-diox (14.4ml) and 4mol/L hydrochloric acid (14.4ml) join in the gained resistates, and the gained mixture stirred 6 hours at 50 ℃.Reaction soln water (30.0ml) dilutes and washs with ethyl acetate (50ml * 2).(55.0ml) joins in the water layer with the 1mol/L sodium hydroxide solution, uses chloroform (100ml * 1,80ml * 1) extraction again.Organic layer is with salt solution (150ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 1.24g title compound through concentrating under reduced pressure, is the amorphous thing.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.23(5H，m)，5.81-5.77(1H，m)，5.67-5.62(1H，m)，5.53(1H，q，J＝7.11Hz)，3.70(2H，s)，3.23(1H，d，J＝9.80Hz)，2.96(1H，d，J＝9.80Hz)，2.45(2H，m)，2.33(1H，m)，2.27-2.16(1H，m)，2.10(1H，dd，J＝16.79，5.02Hz)，1.50(3H，d，J＝7.11Hz)。
MS(ESI)；m/z：257(M+H)
+。
[reference example 142]
(1S, 6S)-1-amino-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene
[formula 240]
Toluene solution (2.87ml with 65% pair of (2-methoxy ethoxy) sodium aluminum hydride, 9.56mmol) join (1S, 6R)-1-amino-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene (612mg, 2.39mmol) toluene (11.9ml) solution in, the gained mixture stirred 1 hour at 80 ℃.Join in the reaction soln 5mol/L sodium hydroxide solution (15.0ml) and stirring down ice-cooled, use toluene (30ml * 2) extraction again.Organic layer is with salt solution (90ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 450mg title compound through concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.19(5H，m)，5.72-5.59(2H，m)，3.58(1H，q，J＝6.54Hz)，2.86(1H，d，J＝9.07Hz)，2.70(1H，dd，J＝9.56，8.09Hz)，2.54-2.48(2H，m)，2.22-1.73(5H，m)，1.33(3H，d，J＝6.62Hz)。
MS(ESI)；m/z：243(M+H)
+。
[reference example 143]
(1S, 6S)-1-tert-butoxycarbonyl amino-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems
-3-alkene
[formula 241]
Under nitrogen atmosphere, with tert-Butyl dicarbonate (689mg, 3.16mmol) join (1S, 6S)-1-amino-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene (450mg, 1.86mmol) methylene dichloride (9.3ml) solution in, mixture was at room temperature stirred 16 hours.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 66: 34 → 50: 50 → 25: 75 → 16: 84), obtain the 456mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.29-7.18(5H，m)，5.69-5.59(2H，m)，4.43(1H，s)，3.62(1H，q，J＝6.54Hz)，3.53(1H，d，J＝10.54Hz)，3.04(1H，dd，J＝8.95，7.23Hz)，2.89(1H，d，J＝18.38Hz)，2.60(1H，d，J＝11.03Hz)，2.52(1H，dd，J＝11.28，9.31Hz)，2.26-2.08(2H，m)，1.99-1.83(2H，m)，1.44(9H，s)，1.32(3H，d，J＝6.62Hz)。
MS(ESI)；m/z：343(M+H)
+。
[reference example 144]
(1S, 6S)-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane
[formula 242]
Under nitrogen atmosphere, with 10% palladium carbon catalyst (406mg, 100wt%) join (1S, 6S)-1-tert-butoxycarbonyl amino-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-(406mg is in ethanol 1.18mmol) (11.8ml) solution for 3-alkene.After the former atmosphere of hydrogen exchange, with mixture under nitrogen atmosphere, stirred 7 hours at 40 ℃-50 ℃.After the former atmosphere of nitrogen replacement, reaction soln obtains title compound (quantitatively) by diatomite filtration and concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：4.24(1H，brs)，3.59(1H，brs)，3.01(1H，dd，J＝9.80，7.60Hz)，2.67-2.62(2H，m)，2.52(1H，d，J＝11.28Hz)，1.79-1.53(9H，m)，1.44(9H，s)。
MS(ESI)；m/z：241(M+H)
+。
[embodiment 31]
7-[(1S, 6S)-1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring
Propyl group]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid
[formula 243]
With triethylamine (0.449ml, 3.22mmol) and 1-[(1R, 2S)-2-fluorine ring third-1-yl]-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (387mg, 1.07mmol) join (1S, 6S)-(301mg, in dimethyl sulfoxide (DMSO) 1.18mmol) (2.14ml) solution, the gained mixture stirred 15 hours at 35 ℃ 1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane.With ethanol: the mixing solutions of water=4: 1 (20ml) and triethylamine (2ml) joins in the reaction soln, and mixture heating up was refluxed 1.5 hours.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (40ml), water (40ml) and salt solution (40ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 506mg gained resistates is dissolved in the concentrated hydrochloric acid (3.0ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (20ml * 3) washing, water layer is adjusted to pH12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform (150ml) and chloroform/methanol=10/1 (100ml * 2) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the hot ethanol (45ml), removes by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Concentrated solution is 10ml up to ethanol, at room temperature stirs then and spends the night.Filter the crystal of collecting precipitation, then with ethanol and ether washing.Crystal obtains the 126mg title compound at 50 ℃ of-60 ℃ of drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.35(1H，d，J＝3.92Hz)，7.65(1H，d，J＝14.71Hz)，5.15-4.96(1H，m)，3.99(1H，dt，J＝10.21，4.47Hz)，3.62(3H，m)，3.54(3H，s)，3.44(1H，t，J＝8.46Hz)，3.27(1H，d，J＝9.56Hz)，1.87-1.28(11H，m)。
C
22H
25F
2N
3O
40.25H
2The analytical calculation value of O: C, 60.33; H, 5.87; F, 8.68; N, 9.59.Measured value: C, 60.27; H, 5.84; F, 8.60; N, 9.58.
MS(ESI)；m/z：434(M+H)
+。
IR(ATR)v：2929，2859，1722，1617，1508，1432，1363，1319，1045，925，804cm
-1。
[embodiment 32]
7-[(1S, 6S)-1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-8-cyano group-6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid
[formula 244]
Under nitrogen atmosphere, with triethylamine (478 μ l, 3.42mmol) and 8-cyano group-6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine ring third-1-yl]-1, the 4-dihydro-(384mg 1.14mmol) joins (1S to 4-Oxoquinoline-3-ethyl formate, 6S)-(302mg is in acetonitrile 1.26mmol) (2.28ml) solution for 1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane.Mixture was at room temperature stirred 1 hour, stirred 1 hour at 45 ℃ again.Reaction soln is through concentrating under reduced pressure.Then, resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 50: 50 → 40: 60 → 30: 70), obtain light yellow amorphous thing.1mol/L sodium hydroxide solution (4.64ml) is joined in ethanol (5.80ml) solution of 644mg amorphous thing down ice-cooled, mixture was at room temperature stirred 1 hour.Then, add tetrahydrofuran (THF) (8.70ml), mixture was at room temperature stirred 1 hour.(15ml) joins in the reaction soln with 10% citric acid solution, uses ethyl acetate (50ml * 1,40ml * 1) extraction then.Organic layer is with salt solution (80ml) washing, through anhydrous sodium sulfate drying and filtration.Filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 554mg gained resistates is dissolved in the concentrated hydrochloric acid (2ml) ice-cooled, gained solution at room temperature stirred 10 minutes.Solution washs with chloroform (25ml * 2).Reaction soln is adjusted to pH12.5 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform/methanol/water=7/3/1 (200ml * 3) extraction of lower floor again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Hot ethanol (80ml) and 28% ammoniacal liquor (5ml) are joined in the resistates, remove by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Ammonia and ethanol azeotropic are removed several times.Solution concentration to about 20ml, is at room temperature stirred then.Filter the crystal of collecting precipitation, then with ethanol and ether washing.Crystal spends the night at 50 ℃ of drying under reduced pressure, obtains the 341mg title compound, is pale yellow crystals.
1H-NMR(400MHz，0.1N?NaOD)δ：8.29(1H，d，J＝3.92Hz)，7.85(1H，d，J＝15.44Hz)，5.18(1H，ddd，J＝66.61，6.92，4.47Hz)，4.01-3.88(3H，m)，3.70-3.65(1H，m)，3.46(1H，t，J＝5.27Hz)，1.95-1.32(11H，m)。
C
22H
22F
2N
4O
31.25H
2The analytical calculation value of O0.25EtOH: C, 58.91; H, 5.71; F, 8.28; N, 12.21.Measured value: C, 58.71; H, 5.66; N, 11.96.
MS(ESI)；m/z：429(M+H)
+。
IR(ATR)v：3623，2938，2886，2202，1641，1610，1556，1535，1515，1490，1461，1353，1342，1301，1261cm
-1。
[embodiment 33]
7-[(1S, 6S)-1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-1-[(1R, 2S)-2-fluorine ring third
Base]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 245]
Under nitrogen atmosphere, with triethylamine (0.277ml, 1.98mmol) and 7-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (185mg, 0.663mmol) join (1S, 6S)-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane (175mg, 0.728mmol) dimethyl sulfoxide (DMSO) (1.33ml) solution in, the gained mixture stirred 12 days at 75 ℃.Reaction soln is used 10% citric acid solution (40ml), water (40ml) and saturated sodium hydroxide solution (40ml) washing then with ethyl acetate (45ml) dilution.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 260mg (0.578mmol) gained resistates is dissolved in the concentrated hydrochloric acid (2.5ml) ice-cooled, gained solution at room temperature stirred 10 minutes.After chloroform (50ml * 2) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform (100ml * 2) and chloroform/methanol=10/1 (100ml) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by PTLC purifying (using the chloroform/methanol/water=7/3/1 exhibition layer of lower floor).Collect the fluorescence part, add chloroform/methanol/water=7/3/1 (70ml) of lower floor.After the supersound process, leach silica gel.Filtrate is through concentrating under reduced pressure, vacuum-drying then.Ethanol (1ml), ether and 2-propyl alcohol are joined in the resistates.Add ether.Repeat supersound process and ice-cooled several times after, the gained mixture stirred 30 minutes at 40 ℃.After at room temperature stirring 2 hours, filter and collect crystal and, obtain the 88.7mg title compound, be pale yellow crystals through drying under reduced pressure.
1H-NMR(400MHz，0.1N?NaOD)δ：8.40(1H，d，J＝3.68Hz)，7.98(1H，d，J＝8.82Hz)，7.07(1H，d，J＝9.31Hz)，5.17-4.94(1H，m)，4.06(1H，dd，J＝13.97，5.64Hz)，3.55(2H，dd，J＝19.36，10.30Hz)，3.22(1H，t，J＝8.09Hz)，3.13(1H，d，J＝9.56Hz)，2.43(3H，s)，1.92-1.19(11H，m)。
C
22H
26FN
3O
30.25H
2The analytical calculation value of O: C, 65.41; H, 6.61; F, 4.70; N, 10.40.Measured value: C, 65.18; H, 6.60; N, 10.48.
MS(ESI)；m/z：400(M+H)
+。
IR(ATR)v：3380，2927，2863，1712，1614，1509，1428，1396，1359，1348，1340，1315，1301，1035，927cm
-1。
[embodiment 34]
10-[(1S, 6S)-1-amino-8-azabicyclo [4.3.0] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-
Methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid
[formula 246]
With triethylamine (0.208ml, 1.49mmol) and 9,10-two fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid-BF
2Inner complex (164mg, 0.498mmol) join (1S, 6S)-(126mg, in dimethyl sulfoxide (DMSO) 0.524mmol) (0.996ml) solution, the gained mixture stirred 15 hours at 35 ℃ 1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] nonane.With ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml) joins in the reaction soln, and mixture heating up was refluxed 3 hours.Reaction soln joins 10% citric acid solution (30ml) in the resistates then through concentrating under reduced pressure, uses ethyl acetate (30ml) extraction again.The interface portion chloroform extraction.Organic layer is water (30ml) and salt solution (30ml) washing respectively, through anhydrous sodium sulfate drying and filtration.Filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 169mg gained resistates is dissolved in the concentrated hydrochloric acid (1ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (20ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform (100ml * 2) and chloroform/methanol=10/1 (100ml * 3) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates (130mg) is dissolved among ethanol/28% ammoniacal liquor=7/1 (60ml), removes by filter insolubles.With filtrate heating and stir with evaporating solvent gradually.Ammonia and ethanol azeotropic are removed several times.Solution concentration to 10ml, is returned room temperature then.Filter the crystal of collecting precipitation, with ethanol and ether washing, drying under reduced pressure obtains the 109mg title compound then, is pale yellow crystals.
1H-NMR(400MHz，0.1N?NaOD)δ：8.30(1H，s)，7.51(1H，d，J＝14.46Hz)，4.62-4.54(1H，m)，4.45(1H，dd，J＝11.40，2.08Hz)，4.26(1H，dd，J＝11.28，2.21Hz)，3.74(1H，dd，J＝10.05，3.43Hz)，3.70-3.64(1H，m)，3.43(1H，t，J＝8.33Hz)，3.34(1H，d，J＝8.33Hz)，1.87-1.63(5H，m)，1.56-1.22(4H，m)，1.52(3H，d，J＝6.86Hz)。
C
21H
24FN
3O
40.25H
2The analytical calculation value of O: C, 62.13; H, 6.08; F, 4.68; N, 10.35.Measured value: C, 62.03; H, 6.10; N, 10.31.
MS(ESI)；m/z：402(M+H)
+。
IR(ATR)v：3590，3295，3222，2929，2883，1614，1554，1471，1344，1311，1259，1234，1110，1041，985，815cm
-1。
[reference example 145]
(1S, 6S)-8-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene
[formula 247]
Under nitrogen atmosphere, with chloroformic acid benzyl ester (0.600ml, 4.20mmol) join (1S, 6S)-1-tert-butoxycarbonyl amino-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene (479mg, 1.40mmol) methylene dichloride (4.66ml) solution in, mixture was at room temperature stirred 17 hours.Reaction soln is through concentrating under reduced pressure.Then, resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 75: 25 → 66: 34), obtain the 401mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.43-7.18(5H，m)，5.76-5.58(2H，m)，5.19-5.09(2H，m)，4.54-4.32(2H，m)，3.70(1H，dd，J＝18.02，7.97Hz)，3.17-2.97(3H，m)，2.39-1.47(4H，m)，1.41(9H，s)。
MS(ESI)；m/z：395(M+Na)
+。
[reference example 146]
(1S, 6S)-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene
[formula 248]
Under with dry ice-methyl alcohol cooling, to (1S, 6S)-1-tert-butoxycarbonyl amino-8-benzyloxycarbonyl-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-(400mg feeds ammonia and reaches 10 minutes 3-alkene in tetrahydrofuran (THF) 1.07mmol) (5.35ml) solution, add the 30-40ml liquid ammonia in solution.(128mg 5.34mmol), stirs mixture 10 minutes to add sodium.At room temperature add saturated ammonium chloride solution (15), mixture is at room temperature stirred with vaporized ammonia.Add 1mol/L sodium hydroxide solution (15.0ml), use chloroform (30ml * 2) extraction again.Water layer is through concentrating under reduced pressure.Add 1mol/L sodium hydroxide solution (5.0ml), use chloroform/methanol/water=7/3/1 (35ml * 2) extraction of lower floor again.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, filtrate obtains the 136mg title compound through concentrating under reduced pressure, is white amorphous thing.
1H-NMR(400MHz，CDCl
3)δ：5.74-5.63(2H，m)，4.44-4.36(1H，m)，3.12(1H，dd，J＝9.93，7.72Hz)，3.02-2.88(2H，m)，2.72(1H，t，J＝10.79Hz)，2.60(2H，d，J＝11.52Hz)，2.30(1H，t，J＝11.52Hz)，2.18-1.82(4H，m)，1.39(9H，s)。
MS(ESI)；m/z：239(M+H)
+。
[embodiment 35]
7-[(1S, 6S)-1-amino-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-3-alkene-8-yl]-6-fluoro-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 249]
With triethylamine (0.217ml, 1.55mmol) and 1-[(1R, 2S)-2-fluorine ring third-1-yl]-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (187mg, 0.518mmol) join (1S, 6S)-1-tert-butoxycarbonyl amino-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-(136mg, in dimethyl sulfoxide (DMSO) 0.571mmol) (2.04ml) solution, the gained mixture stirred 16 hours at 35 ℃ 3-alkene.With ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (30ml), water (30ml) and salt solution (30ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down 242mg gained resistates is dissolved in the concentrated hydrochloric acid (2.0ml) ice-cooled, gained solution at room temperature stirred 10 minutes.After chloroform (25ml * 3) washing, water layer is adjusted to pH12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform/methanol=10/1 (150ml * 1,75ml * 1,50ml * 1) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the 2-propyl alcohol (40ml) of heat, removes by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Solution concentration at room temperature stirs then and spends the night to 10ml.Filter the crystal of collecting precipitation, with 2-propyl alcohol and ether washing, drying under reduced pressure obtains the 129mg title compound then.
1H-NMR(400MHz，0.1N?NaOD)δ：8.36(1H，d，J＝3.68Hz)，7.66(1H，d，J＝14.46Hz)，5.88-5.72(2H，m)，5.15-4.94(1H，m)，4.05-3.98(1H，m)，3.80-3.61(3H，m)，3.57(3H，s)，3.45(1H，d，J＝9.31Hz)，2.48-1.97(5H，m)，1.55-1.48(1H，m)，1.45-1.29(1H，m)。
C
22H
23F
2N
3O
40.5H
2The analytical calculation value of OiPrOH: C, 59.99; H, 6.44; F, 7.59; N, 8.39.Measured value: C, 59.95; H, 6.30; F, 7.61; N, 8.25.
MS(ESI)；m/z：432(M+H)
+。
IR(ATR)v：2962，1725，1612，1450，1436，1386，1351，1309，1035，819cm
-1。
[reference example 147]
(3S, 4R)-3-allyl group-4-benzyloxymethyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate;
(3S, 4S)-3-allyl group-4-benzyloxymethyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate
[formula 250]
Ice-cooled down at salt, with allyl bromide 98 (11.0ml 79.1mmol) joins (3S)-3-allyl group-5-oxo-1-[(1R)-1-phenylethyl] (20.0g is in tetrahydrofuran (THF) 60.7mmol) (303ml) solution and stir for tetramethyleneimine-3-t-butyl formate.Ice-cooled down at salt, (78.9ml 78.9mmol) also stirs the tetrahydrofuran solution of dropping 1M hexamethyl two silicon nitrine lithiums, and the gained mixture stirred 10 minutes down ice-cooled.(300ml) joins in the reaction soln with saturated ammonium chloride solution, uses ethyl acetate (200ml) extraction then.Organic layer is with salt solution (600ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 84: 16 → 75: 25 → 66: 34), obtain the 9.81g title compound (3S, 4R)-isomer and 6.76g title compound (3R, 4S)-isomer.
(3S, 4R)-isomer:
1H-NMR(400MHz，CDCl
3)δ：7.39-7.21(10H，m)，5.75-5.59(1H，m)，5.51-5.41(1H，m)，5.17-5.08(1H，m)，5.06-4.97(1H，m)，4.71(1H，s)，4.50(1H，dd，J＝22.31，11.77Hz)，3.97-3.95(1H，m)，3.85-3.83(1H，m)，3.35-3.04(2H，m)，2.64-2.61(1H，m)，2.45-2.37(1H，m)，1.49(1H，dd，J＝7.11，4.66Hz)，1.42(3H，d，J＝7.35Hz)，1.28(9.H，s)。
MS(ESI)；m/z：450(M+H)
+。
(3R, 4S)-isomer:
1H-NMR(400MHz，CDCl
3)δ：7.27-6.96(10H，m)，5.76-5.65(1H，m)，5.52(1H，q，J＝7.03Hz)，5.17-5.12(2H，m)，4.42-4.35(2H，m)，3.50(1H，d，J＝10.05Hz)，3.04(1H，d，J＝10.05Hz)，2.52(1H，dd，J＝13.73，6.37Hz)，2.45(1H，t，J＝2.82Hz)，2.36(1H，dd，J＝13.73，8.09Hz)，1.51(3H，d，J＝7.11Hz)，1.38(9H，s)。
MS(ESI)；m/z：450(M+H)
+。
[reference example 148]
(3S, 4R)-4-benzyloxymethyl-3-hydroxyethyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate
[formula 251]
To (3S, 4R)-3-allyl group-4-benzyloxymethyl-5-oxo-1-[(1R)-the 1-phenylethyl] (8.00g, aerating oxygen reaches 10 minutes to tetramethyleneimine-3-t-butyl formate in methyl alcohol 17.8mmol) (177ml) solution.Under with dry ice-methyl alcohol cooling, feed ozone while stirring after 30 minutes, feed nitrogen and drive ozone away.Under with the cooling of ice-acetone, (1.68g, 44.4mmol), the gained mixture stirred 1.5 hours under cooling to add sodium borohydride.(150ml) joins in the reaction soln with saturated ammonium chloride solution, and methyl alcohol boils off by concentrating under reduced pressure.Mixture extracts with ethyl acetate (200ml * 1,150ml * 1).Organic layer is with salt solution (300ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 50: 50), obtain the 3.79g title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.22(5H，m)，5.46(1H，q，J＝7.03Hz)，4.50(2H，dd，J＝17.28，11.64Hz)，3.97(1H，dd，J＝9.80，4.41Hz)，3.84(1H，dd，J＝9.80，2.45Hz)，3.60(2H，t，J＝6.37Hz)，3.42(1H，d，J＝9.31Hz)，3.26(1H，d，J＝9.31Hz)，3.10(1H，dd，J＝4.41，2.45Hz)，2.11(1H，dt，J＝15.52，5.58Hz)，1.99-1.93(1H，m)，1.41(3H，d，J＝7.35Hz)，1.28(9H，s)。
MS(ESI)；m/z：454(M+H)
+。
[reference example 149]
(3S, 4R)-3-benzyloxymethyl-3-methane sulfonyl oxygen base ethyl-5-oxo-1-[(1R)-the 1-phenyl
Ethyl] tetramethyleneimine-3-t-butyl formate
[formula 252]
Under nitrogen atmosphere, with triethylamine (2.79ml, 19.9mmol) join (3S, 4R)-4-benzyloxymethyl-3-hydroxyethyl-5-oxo-1-[(1R)-the 1-phenylethyl] (4.57g is in methylene dichloride 10.0mmol) (50.0ml) solution for tetramethyleneimine-3-t-butyl formate.Under with the cooling of ice-acetone, (1.17ml 15.1mmol), at room temperature stirred mixture 15 minutes to add methane sulfonyl chloride.(150ml) joins in the reaction soln with water, uses chloroform (150ml * 1,80ml * 1) extraction again.Organic layer is with salt solution (200ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the resistates that 7.09g contains title compound through concentrating under reduced pressure, and it need not to be further purified and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.25(10H，m)，5.45(1H，q，J＝7.11Hz)，4.50(2H，dd，J＝17.16，11.52Hz)，4.23-4.20(1H，m)，4.14-4.11(1H，m)，3.99(1H，dd，J＝9.93，4.29Hz)，3.81(1H，dd，J＝9.93，2.57Hz)，3.37(1H，d，J＝9.56Hz)，3.25(1H，d，J＝9.56Hz)，3.08(1H，dd，J＝4.41，2.45Hz)，2.90(3H，s)，2.33-2.26(1H，m)，2.21-2.17(1H，m)，1.42(3H，d，J＝7.11Hz)，1.28(9H，s)。
MS(ESI)；m/z：532(M+H)
+。
[reference example 150]
(3S, 4R)-4-methylol-3-methane sulfonyl oxygen base ethyl-5-oxo-1-[(1R)-the 1-phenylethyl]
Tetramethyleneimine-3-t-butyl formate
[formula 253]
Under nitrogen atmosphere; with 20% hydroxide palladium carbon catalyst (7.09g; 100wt%) join (3S, 4R)-3-benzyloxymethyl-3-methane sulfonyl oxygen base ethyl-5-oxo-1-[(1R)-the 1-phenylethyl] in ethanol (100ml) solution of tetramethyleneimine-3-t-butyl formate (7.09g).After the former atmosphere of hydrogen exchange, mixture was stirred 1 hour under nitrogen atmosphere, room temperature, stirred 1 hour at 50 ℃ again.After the former atmosphere of nitrogen replacement, reaction soln is by diatomite filtration, and concentrating under reduced pressure and through drying under reduced pressure obtains the resistates that 4.49g contains title compound, and it need not to be further purified and just can be used for next step.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.25(5H，m)，5.48(1H，q，J＝7.03Hz)，4.30-4.19(2H，m)，4.11-3.96(2H，m)，3.34(2H，dd，J＝26.72，10.54Hz)，2.99(3H，s)，2.98-2.95(1H，m)，2.31-2.24(1H，m)，2.17-2.10(1H，m)，1.56(3H，d，J＝7.11Hz)，1.37(9H，s)。
MS(ESI)；m/z：442(M+H)
+。
[reference example 151]
(1S, 6R)-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-
Base } t-butyl formate
[formula 254]
Will (3S, 4R)-4-methylol-3-methane sulfonyl oxygen base ethyl-5-oxo-1-[(1R)-the 1-phenylethyl] pyridine (100ml) solution of tetramethyleneimine-3-t-butyl formate (4.49g) is under nitrogen atmosphere, stirred 15 hours at 50 ℃.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 50: 50 → 10: 90), obtain the 1.75g title compound, be white crystal.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.23(5H，m)，5.58(1H，q，J＝7.11Hz)，4.38(1H，d，J＝11.77Hz)，3.83-3.79(1H，m)，3.71(1H，dd，J＝12.01，3.92Hz)，3.42(1H，td，J＝12.01，2.21Hz)，3.04(1H，d，J＝10.05Hz)，2.96(1H，d，J＝9.80Hz)，2.62(1H，d，J＝3.43Hz)，1.97(1H，d，J＝14.22Hz)，1.75(1H，ddd，J＝15.44，10.79，3.19Hz)，1.54(3H，d，J＝7.11Hz)，1.44(9H，s)。
MS(ESI)；m/z：346(M+H)
+。
[reference example 152]
(1S, 6R}-{4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-
Base } formic acid
[formula 255]
Under ice-cooled, while stirring trifluoroacetic acid (6.63ml) is joined (1S, 6R)-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-yl } t-butyl formate (763mg, 2.21mmol) methylene dichloride (6.63ml) solution in, mixture was at room temperature stirred 1.5 hours.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (3 times).Down 1mol/L sodium hydroxide solution (20ml) is joined in the gained resistates ice-cooled, the gained mixture washs with ether (50ml * 2).Water layer down with 1mol/L hydrochloric acid (20ml) acidifying, is used ethyl acetate (60ml * 1,50ml * 1) extraction ice-cooled then.Merge organic layer, with salt solution (90ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 637mg title compound through concentrating under reduced pressure, is white crystal.
1H-NMR(400MHz，CDCl
3)δ：7.43-7.24(5H，m)，5.58(1H，q，J＝7.11Hz)，4.41(1H，d，J＝12.26Hz)，3.83(1H，dd，J＝12.13，2.82Hz)，3.70(1H，dd，J＝12.01，3.68Hz)，3.44(1H，td，J＝12.13，1.88Hz)，3.11(1H，d，J＝10.05Hz)，3.02(1H，d，J＝10.05Hz)，2.69(1H，d，J＝3.43Hz)，2.09-2.05(1H，m)，1.84-1.76(1H，m)，1.55(3H，d，J＝7.11Hz)。
MS(ESI)；m/z：290(M+H)
+。
[reference example 153]
(1S, 6R)-1-tert-butoxycarbonyl amino-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-nitrogen
Assorted dicyclo [4.3.0] nonane
[formula 256]
Under nitrogen atmosphere, under ice-cooled, while stirring with triethylamine (0.720ml, 5.16mmol) and two phenoxy group phosphoryl azide (0.723ml, 3.35mmol) join (1S, 6R)-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-yl } (747mg is in toluene 2.58mmol) (12.9ml) solution for formic acid.Mixture was at room temperature stirred 30 minutes, stirred 30 minutes at 100 ℃ then.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (3 times).With 1,4-diox (6.45ml) and 6mol/L hydrochloric acid (6.45ml) join in the gained resistates, and the gained mixture stirred 1 hour at 50 ℃.Reaction soln water (15ml) dilutes and washs with ethyl acetate (50ml * 2).Water layer down with the alkalization of 1mol/L sodium hydroxide solution, is used chloroform (50ml * 2) extraction ice-cooled again.Organic layer is with salt solution (80ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.Methylene dichloride (14.9ml) is joined in the gained resistates, and (813mg 3.73mmol), at room temperature stirred mixture 4 days to add tert-Butyl dicarbonate under nitrogen atmosphere.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 75: 25 → 60: 40 → 50: 50), obtain 470mg (51%) title compound.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.25(5H，m)，5.58(1H，q，J＝7.19Hz)，4.81(1H，brs)，4.31(1H，dd，J＝12.26，1.72Hz)，3.77(1H，td，J＝7.54，4.09Hz)，3.61(1H，dd，J＝12.26，3.92Hz)，3.48(2H，m)，3.09(1H，d，J＝10.05Hz)，2.39(1H，brs)，2.16-2.05(1H，m)，1.81(1H，ddd，J＝15.26，10.85，3.62Hz)，1.53(3H，d，J＝7.11Hz)，1.39(9H，s)。
MS(ESI)；m/z：361(M+H)
+。
[reference example 154]
(1S, 6R)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-7-sulfo--8-nitrogen
Assorted dicyclo [4.3.0] nonane
[formula 257]
Lawesson's reagent is joined (1S, 6R)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-7-oxo-8-azabicyclo [4.3.0] nonane (470mg, 1.30mmol) tetrahydrofuran (THF) (13.0ml) solution in, the gained mixture stirred 2.5 hours at 60 ℃.Reaction soln is through concentrating under reduced pressure.(hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 80: 20 → 75: 25 → 66: 34), obtain containing the resistates of title compound, it can be directly used in next step to the gained resistates by the silica gel column chromatography purifying.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.29(5H，m)，6.97(1H，dt，J＝12.83，4.60Hz)，6.44(1H，q，J＝7.03Hz)，4.39(1H，d，J＝9.31Hz)，3.87-3.82(3H，m)，3.72-3.57(2H，m)，2.70(1H，brs)，2.03-1.94(1H，m)，1.90-1.79(1H，m)，1.60(3H，d，J＝7.11Hz)，1.36(9H，s)。
MS(ESI)；m/z：377(M+H)
+。
[reference example 155]
(1S, 6R)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-the 8-azabicyclo
[4.3.0] nonane
[formula 258]
Under nitrogen atmosphere, Raney nickel (14.2ml) is joined (1S, 6R)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-ethanol (28.4ml) solution of 7-sulfo--8-azabicyclo [4.3.0] nonane (700mg) in.Mixture is vigorous stirring 1 hour at room temperature.Reaction soln obtains 423mg title compound (quantitatively) by diatomite filtration and concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.20(5H，m)，4.66(1H，brs)，3.75-3.40(4H，m)，2.90(2H，s)，2.78-2.69(2H，m)，2.20-1.96(3H，m)，1.41(9H，s)，1.34(3H，d，J＝6.59Hz)。
MS(ESI)；m/z：347(M+H)
+。
[reference example 156]
(1S, 6S)-1-tert-butoxycarbonyl amino-4-oxabicyclo [4.3.0] nonane
[formula 259]
Under nitrogen atmosphere, (205mg) joins (1S with 10% palladium carbon catalyst, 6R)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-(205mg is in ethanol 0.592mmol) (5.92ml) solution for 8-azabicyclo [4.3.0] nonane.After the former atmosphere of hydrogen exchange, mixture was stirred 45 minutes under nitrogen atmosphere, room temperature, stirred 1 hour at 50 ℃ again.After the former atmosphere of nitrogen replacement, reaction soln is by diatomite filtration and concentrating under reduced pressure.Under nitrogen atmosphere, 10% palladium carbon catalyst (205mg) is joined in ethanol (5.92ml) solution of gained resistates.After the former atmosphere of hydrogen exchange, mixture was stirred 16 hours at 50 ℃.After the former atmosphere of nitrogen replacement, reaction soln is by diatomite filtration and concentrating under reduced pressure.Under nitrogen atmosphere, 20% hydroxide palladium carbon catalyst (205mg) is joined in ethanol (5.92ml) solution of gained resistates.After the former atmosphere of hydrogen exchange, with mixture under nitrogen atmosphere, stirred 1 hour at 50 ℃.After the former atmosphere of nitrogen replacement, reaction soln is by diatomite filtration, and concentrating under reduced pressure and drying under reduced pressure obtain the 128mg title compound, are shallow vermilion red oily matter.
1H-NMR(400MHz，CDCl
3)δ：4.83(1H，brs)，3.68-3.57(4H，m)，3.30-3.19(3H，m)，3.00-2.98(1H，m)，2.14-1.96(3H，m)，1.44(9H，s)。
MS(ESI)；m/z：243(M+H)
+。
[embodiment 36]
7-[(1S, 6R)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 260]
With triethylamine (0.198ml, 1.42mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (171mg, 0.474mmol) join (1S, 6R)-(126mg, in dimethyl sulfoxide (DMSO) 0.520mmol) (0.948ml) solution, the gained mixture stirred 16 hours at 35 ℃ 8-azepine-1-tert-butoxycarbonyl amino-4-oxabicyclo [4.3.0] nonane.With ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in ethyl acetate (30ml) also with 10% citric acid solution (30ml), water (30ml) and salt solution (30ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Under ice-cooled, (0.694ml 3v/w) joins in methylene dichloride (2.31ml) solution of 125mg gained resistates, and mixture was at room temperature stirred 1 hour with trifluoroacetic acid while stirring.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (* 3).Down the hydrochloric acid (20.0ml) of pH1 is joined in the gained resistates ice-cooled, the gained mixture is with ether (40ml * 4) washing.Water layer is adjusted to pH12 with the 1mol/L sodium hydroxide solution down ice-cooled.Basic solution is adjusted to pH7.4 with 1mol/L hydrochloric acid, uses chloroform (100ml * 2) and chloroform/methanol=10/1 (100ml) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in the hot ethanol (10ml), removes by filter insolubles.Evaporating solvent gradually heats simultaneously and stirs.Concentration residue is 3-4ml up to ethanol, at room temperature stirs then and spends the night.Filter the crystal of collecting precipitation,, at 60 ℃ of drying under reduced pressure, obtain the 20.5mg title compound then with ethanol and ether washing.
1H-NMR(400MHz，0.1N?NaOD)δ：8.45(1H，s)，7.68(1H，d，J＝14.71Hz)，5.08-4.92(1H，m)，4.07(1H，dd，J＝13.73，6.13Hz)，3.92(1H，dd，J＝12.50，3.68Hz)，3.83(4H，dd，J＝13.85，8.95Hz)，3.73-3.58(6H，m)，2.20-2.13(1H，m)，2.06-1.99(1H，m)，1.68-1.49(3H，m)。
C
21H
23F
2N
3O
50.75H
2The analytical calculation value of O: C, 56.18; H, 5.50; N, 9.36.Measured value: C, 56.15; H, 5.46; N, 9.65.
MS(ESI)；m/z：436(M+H)
+。
IR(ATR)v：2937，2892，2856，1724，1625，1515，1454，1324，1137，1099，1054，985，927，887，802cm
-1。
[reference example 157]
(3S, 4S)-4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl] pyrroles
Alkane-3-t-butyl formate
[formula 261]
To (3S, 4S)-3-allyl group-4-benzyloxymethyl-5-oxo-1-[(1R)-the 1-phenylethyl] (6.76g, aerating oxygen reaches 5 minutes to tetramethyleneimine-3-t-butyl formate in methyl alcohol 15.0mmol) (150ml) solution.Under with dry ice-methyl alcohol cooling, feed ozone while stirring after 1.5 hours, feed nitrogen and drive ozone away.Under cooling, (5.64ml 76.8mmol), stirs mixture 19 hours to add methyl-sulfide.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 75: 25 → 66: 34 → 50: 50), obtain the 4.58g title compound, be transparent oily matter.
1H-NMR(400MHz，CDCl
3)δ：9.74(1H，s)，7.37-7.15(5H，m)，5.47(1H，q，J＝7.19Hz)，4.42(2H，s)，3.92(1H，dd，J＝9.80，3.68Hz)，3.81(1H，dd，J＝9.56，6.62Hz)，3.68(1H，d，J＝10.54Hz)，3.21(1H，t，J＝8.58Hz)，3.13(1H，d，J＝10.54Hz)，2.70(1H，dd，J＝6.37，3.68Hz)，2.61(1H，d，J＝17.16Hz)，1.50(3H，d，J＝7.11Hz)，1.27(9H，s)。
MS(ESI)；m/z：452(M+H)
+。
[reference example 158]
(3S, 4S)-4-benzyloxymethyl-3-carboxyl methyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine
-3-t-butyl formate
[formula 262]
Under ice-cooled, the 2-methyl-2-butene is joined (3S, 4S)-and 4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl] (4.58g in trimethyl carbinol 10.1mmol) (25.2ml) solution, stirs the gained mixture to tetramethyleneimine-3-t-butyl formate.(2.29g, (4.10g in water 26.3mmol) (20.2ml) solution, prepares solution respectively 25.3mmol) to join the SODIUM PHOSPHATE, MONOBASIC dihydrate with Textone.Down this solution is joined in the above-mentioned solution ice-cooled, mixture was at room temperature stirred 1 hour.Filter the solid of collecting precipitation, water and hexane wash at 40 ℃ of drying under reduced pressure, obtain the 3.93g title compound then, are the white powder crystal.
1H-NMR(400MHz，CDCl
3)δ：7.30-7.14(5H，m)，5.48(1H，q，J＝7.03Hz)，4.42(2H，s)，3.90(1H，dd，J＝9.68，3.55Hz)，3.82(1H，dd，J＝9.56，6.13Hz)，3.69(1H，d，J＝10.54Hz)，3.27(1H，d，J＝10.79Hz)，3.10(1H，d，J＝16.18Hz)，2.70(1H，dd，J＝6.13，3.68Hz)，2.58(1H，d，J＝16.18Hz)，1.79(1H，brs)，1.52(3H，d，J＝7.11Hz)，1.29(9H，s)。
MS(ESI)；m/z：468(M+H)
+。
[reference example 159]
(3S, 4S)-3-carboxyl methyl-4-methylol-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-first
Tert-butyl acrylate
[formula 263]
Under nitrogen atmosphere, (3.93g) joins (3S with 10% palladium carbon catalyst, 4S)-4-benzyloxymethyl-3-carboxyl methyl-5-oxo-1-[(1R)-the 1-phenylethyl] (3.93g is in methyl alcohol 8.41mmol) (84.0ml) solution for tetramethyleneimine-3-t-butyl formate.After the former atmosphere of hydrogen exchange, mixture was stirred 3 days under nitrogen atmosphere, room temperature.After the former atmosphere of nitrogen replacement, reaction soln obtains the 2.54g title compound by diatomite filtration and concentrating under reduced pressure.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.27(5H，m)，5.44(1H，q，J＝7.11Hz)，3.88(1H，dd，J＝11.28，7.60Hz)，3.80(1H，dd，J＝11.28，5.39Hz)，3.69(1H，d，J＝10.79Hz)，3.26(1H，d，J＝10.79Hz)，3.05(1H，d，J＝16.91Hz)，2.68(1H，dd，J＝7.35，5.39Hz)，2.59(1H，d，J＝16.91Hz)，1.53(3H，d，J＝7.11Hz)，1.28(9H，s)。
MS(ESI)；m/z：378(M+H)
+。
[reference example 160]
(1S, 6S)-4-oxa--3,7-dioxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems
Alkane-1-yl } t-butyl formate
[formula 264]
Under nitrogen atmosphere, with triethylamine (1.32ml, 9.46mmol) and 2,4,6-trichloro-benzoyl chloride (1.16ml, 7.45mmol) join (3S, 4S)-3-carboxyl methyl-4-methylol-5-oxo-1-[(1R)-the 1-phenylethyl] (2.54g is in tetrahydrofuran (THF) 6.73mmol) (44.8ml) solution for tetramethyleneimine-3-t-butyl formate.After at room temperature stirring 30 minutes, add again toluene (179ml) and 4-Dimethylamino pyridine (1.23g, 10.1mmol).After at room temperature stirring 18 hours, reaction soln washs with ethyl acetate (100ml) dilution and with 1mol/L hydrochloric acid (150ml), water (150ml), saturated sodium bicarbonate solution (150ml), water (150ml) and salt solution (150ml).Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 66: 34 → 50: 50 → 34: 66 → 25: 75), obtain the 2.06g title compound.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.27(5H，m)，5.43(1H，q，J＝7.19Hz)，4.76-4.72(2H，m)，3.34-3.20(3H，m)，2.90(1H，dd，J＝10.42，7.97Hz)，2.56(1H，d，J＝16.91Hz)，1.52(3H，d，J＝7.35Hz)，1.24(9H，s)。
MS(ESI)；m/z：360(M+H)
+。
[reference example 161]
(1S, 6S)-3-acetoxyl group-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-the 8-azabicyclo
[4.3.0] nonane-1-yl } t-butyl formate
[formula 265]
Under with dry ice-methyl alcohol cooling, while stirring with the hexane solution (1.65ml of 0.97mol/L diisobutyl aluminium hydride, 1.60mmol) join { (1S, 6S)-4-oxa--3, the 7-dioxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-yl } (500mg is in methylene dichloride 1.39mmol) (6.95ml) solution for t-butyl formate.After stirring 1 hour under the cooling, and the hexane solution of adding 0.97mol/L diisobutyl aluminium hydride (0.716ml, 0.695mmol).After stirring 2 hours under the cooling, (0.338ml is 4.18mmol) with 4-Dimethylamino pyridine (204mg, (3.5ml) solution of methylene dichloride 1.67mmol) and diacetyl oxide (0.526ml, methylene dichloride 5.56mmol) (1.8ml) solution to add pyridine.Mixture was stirred 1 hour under cooling, carry out ice-cooledly then, and add saturated chlorination four ammoniums (tetraammonium chloride) solution (20ml).After 30 minutes, reaction soln extracts with ethyl acetate (50ml * 1,40ml * 1) in ice-cooled stirring down.Organic layer washs with 10% citric acid (60ml) water (60ml), saturated sodium bicarbonate solution (60ml) and salt solution (60ml).Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 60: 40 → 50: 50), obtain the 350mg title compound, be white solid.
1H-NMR(400MHz，CDCl
3)δ：7.35-7.23(5H，m)，5.74(1H，dd，J＝7.35，4.17Hz)，5.45(1H，dd，J＝20.84，10.42Hz)，4.29-4.14(2H，m)，2.70-2.60(2H，m)，2.09(3H，s)，1.67(1H，dd，J＝12.62，7.23Hz)，1.48(3H，d，J＝7.11Hz)，1.23(9H，s)。
MS(ESI)；m/z：404(M+H)
+。
[reference example 162]
(1S, 5S)-3-azepine-4, the 10-dioxo-3-[(1R)-and the 1-phenylethyl]-7,9-two oxatricyclos
[6.2.1.0
1,5
] undecane
[formula 266]
Will (1S, 6S)-3-acetoxyl group-7-oxa--8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-yl } (663mg, acetonitrile 1.64mmol) (8.20ml) solution cools off with ice-acetone t-butyl formate.Under nitrogen atmosphere, add triethyl silicane (0.787ml, 4.93mmol) and trifluoromethanesulfonic acid (trimethyl silyl) ester (0.595ml, 3.29mmol), the stirring 15 minutes under cooling of gained mixture.(50ml) joins in the reaction soln with saturated sodium bicarbonate solution, uses ethyl acetate (100ml * 1,60ml * 1) extraction then.Organic layer water (50ml) and salt solution (100ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 75: 25 → 66: 34 → 50: 50 → 34: 66), obtain the 413mg title compound, be transparent oily matter.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.17(5H，m)，5.45(1H，q，J＝7.03Hz)，4.25(1H，dd，J＝11.28，4.17Hz)，4.18-4.10(1H，m)，3.97-3.92(2H，m)，3.31-3.25(2H，m)，2.61(1H，dd，J＝10.66，4.29Hz)，2.19(1H，d，J＝13.24Hz)，1.80(1H，td，J＝12.62，4.66Hz)，1.48(3H，d，J＝7.11Hz)。
[reference example 163]
(1S, 6S)-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-
Base } formic acid
[formula 267]
Will (1S, 5S)-3-azepine-4, the 10-dioxo-3-[(1R)-and the 1-phenylethyl]-7,9-two oxatricyclo [6.2.1.0
1,5] (413mg, methylene dichloride 1.44mmol) (7.20ml) solution cools off with dry ice-methyl alcohol undecane.Under nitrogen atmosphere, add triethyl silicane (0.690ml, 4.32mmol) and the dichloromethane solution of 1.0mol/L titanium tetrachloride (2.88ml, 2.88mmol), the gained mixture stirred 30 minutes under cooling.(50ml) joins in the reaction soln with saturated sodium bicarbonate solution, and the gained mixture washs with ethyl acetate (100ml * 2).Water layer is used chloroform (100ml * 1,60ml * 1) extraction again with 6mol/L hydrochloric acid and 1mol/L hcl acidifying.Organic layer water (100ml) and salt solution (150ml) washing are then through anhydrous sodium sulfate drying and filtration.Filtrate obtains the 235mg title compound again through concentrating under reduced pressure and through drying under reduced pressure, is white crystal.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.23(5H，m)，5.46(1H，d，J＝7.35Hz)，4.26(1H，dd，J＝11.03，4.41Hz)，3.97-3.91(2H，m)，3.33-3.24(3H，m)，2.60(1H，dd，J＝10.66，4.29Hz)，2.19(1H，d，J＝12.50Hz)，1.85-1.67(2H，m)，1.49(3H，d，J＝7.11Hz)。
MS(ESI)；m/z：290(M+H)
+。
[reference example 164]
(1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-nitrogen
Assorted dicyclo [4.3.0] nonane
[formula 268]
Under nitrogen atmosphere, under ice-cooled, while stirring with triethylamine (0.330ml, 2.36mmol) and two phenoxy group phosphoryl azide (0.330ml, 1.53mmol) join [(1S, 6S)-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4.3.0] nonane-1-yl] (340mg is in toluene 1.18mmol) (5.90ml) solution for formic acid.Mixture was at room temperature stirred 30 minutes, stirred 1 hour at 100 ℃ then.Reaction soln is through concentrating under reduced pressure, and triethylamine and methylbenzene azeotropic distill (* 3).With 1,4-diox (2.95ml) and 6mol/L hydrochloric acid (2.95ml) join in the gained resistates, and the gained mixture stirred 1 hour at 50 ℃.Reaction soln water (9.0ml) dilutes and washs with ether (40ml * 2).Water layer down with the alkalization of 1mol/L sodium hydroxide solution, is used chloroform (80ml * 1,60ml * 1) extraction ice-cooled again.Organic layer water (80ml) and salt solution (80ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.Methylene dichloride (5.90ml) is joined in the gained resistates, under nitrogen atmosphere, add tert-Butyl dicarbonate (773mg, 3.54mmol.Mixture was at room temperature stirred 14 hours, stirred 7 hours at 50 ℃ again, and the adding tert-Butyl dicarbonate (515mg, 2.36mmol).After 17 hours, reaction soln is through concentrating under reduced pressure 50 ℃ of stirrings.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 80: 20 → 66: 34 → 60: 40), obtain the 320mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.34-7.23(5H，m)，5.44(1H，q，J＝6.95Hz)，4.53(1H，brs)，4.16-4.11(1H，m)，3.81(1H，dd，J＝12.13，3.80Hz)，3.62(3H，tt，J＝14.83，6.37Hz)，3.15(1H，d，J＝10.30Hz)，2.69(1H，dd，J＝11.52，4.41Hz)，1.71(1H，td，J＝12.68，4.98Hz)，1.49(3H，d，J＝7.11Hz)，1.26(9H，s)。
MS(ESI)；m/z：361(M+H)
+。
[reference example 165]
(1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-the 8-azabicyclo
[4.3.0] nonane
[formula 269]
Will (1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-(331mg, tetrahydrofuran (THF) 0.918mmol) (3.0ml) solution cools off with ice-acetone 8-azabicyclo [4.3.0] nonane.Under nitrogen atmosphere, (3.83ml 4.59mmol), at room temperature stirred mixture 19 hours the tetrahydrofuran solution of adding 1.2mol/L borane.With after the cooling of ice-acetone, (3.83ml 4.59mmol), at room temperature stirred mixture 1 hour the tetrahydrofuran solution of adding 1.2mol/L borane under nitrogen atmosphere once more.Reaction soln is through concentrating under reduced pressure.Then, add ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml), reflux mixture heating up 1.5 hours.Reaction soln is through concentrating under reduced pressure, and (50ml) joins in the resistates with saturated sodium bicarbonate solution, uses chloroform (50ml * 1,40ml * 1) extraction again.Organic layer salt water washing is again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → → 90: 10 → 60: 40 → 50: 50 → 34: 66 → 25: 75 → 16: 84 → 10: 90 → 5: 95 → 2: 98 → 0: 100), obtain the 255mg title compound.
1H-NMR(400MHz，CDCl
3)δ：7.31-7.21(5H，m)，4.35(1H，s)，3.81(2H，ddd，J＝22.43，11.64，4.04Hz)，3.62(2H，td，J＝11.95，2.37Hz)，3.49(1H，t，J＝11.52Hz)，3.37(1H，d，J＝10.05Hz)，2.91(1H，t，J＝8.33Hz)，2.55-2.42(2H，m)，2.17(1H，t，J＝5.88Hz)，1.56-1.50(1H，m)，1.47(9H，s)，1.32(3H，d，J＝6.37Hz)。
MS(ESI)；m/z：347(M+H)
+。
[reference example 166]
(1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--8-dicyclo [4.3.0] nonane
[formula 270]
Under nitrogen atmosphere, 20% hydroxide palladium carbon catalyst (262mg) is joined (1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--8-[(1R)-the 1-phenylethyl]-(262mg is in ethanol 0.756mmol) (7.56ml) solution for 8-azabicyclo [4.3.0] nonane.After the former atmosphere of hydrogen exchange, with mixture under nitrogen atmosphere, stirred 2.5 hours at 45 ℃.After the former atmosphere of nitrogen replacement, reaction soln through concentrating under reduced pressure and through drying under reduced pressure, obtains the 183mg title compound by diatomite filtration.
1H-NMR(400MHz，CDCl
3)δ：4.33(1H，brs)，3.95(1H，dd，J＝11.64，4.29Hz)，3.84(1H，dd，J＝12.50，4.66Hz)，3.72(1H，q，J＝7.03Hz)，3.62-3.55(2H，m)，3.49(1H，t，J＝11.64Hz)，3.06(1H，dd，J＝9.93，7.97Hz)，2.68-2.57(3H，m)，2.13-2.04(1H，m)，1.57(1H，td，J＝12.93，4.74Hz)，1.45(9H，s)。
MS(ESI)；m/z：243(M+H)
+。
[embodiment 37]
7-[(1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 271]
With triethylamine (0.165ml, 1.18mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (142mg, 0.393mmol) join (1S, 6S)-(142mg in dimethyl sulfoxide (DMSO) 0.421mmol) (0.787ml) solution, at room temperature stirred mixture 14 hours 1-tert-butoxycarbonyl amino-4-oxa--8-dicyclo [4.3.0] nonane.With ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (30ml), water (30ml) and salt solution (30ml) washing.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Under ice-cooled, (0.975ml 3v/w) joins in methylene dichloride (3.25ml) solution of 174mg gained resistates, and mixture was at room temperature stirred 2 hours with trifluoroacetic acid while stirring.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (* 3).Down 1N hydrochloric acid (25.0ml) is joined in the gained resistates ice-cooled, the gained mixture washs with ether (50ml * 5).Water layer is adjusted to pH12 with the 1mol/L sodium hydroxide solution down ice-cooled.Basic solution is adjusted to pH7.4 with 1mol/L hydrochloric acid, uses chloroform (100ml * 2,50ml * 2) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is dissolved in chloroform/methanol=10/1, removes by filter insolubles.Filtrate is through concentrating under reduced pressure and be dissolved in hot ethanol.Evaporating solvent gradually heats simultaneously and stirs.Then, concentrated solution is about 10ml up to ethanol, at room temperature stirs 3 hours.Filter the crystal of collecting precipitation, then with ethanol and ether washing.Crystal is spent the night at 50 ℃ of drying under reduced pressure, obtain the 55.3mg title compound.
1H-NMR(400MHz，0.1N?NaOD)δ：8.36(1H，d，J＝3.68Hz)，7.67(1H，d，J＝14.46Hz)，5.15-4.96(1H，m)，4.00(3H，ddd，J＝20.71，11.03，4.53Hz)，3.84-3.63(4H，m)，3.58(3H，s)，3.53(1H，t，J＝8.58Hz)，3.39(1H，d，J＝9.31Hz)，2.32-2.20(1H，m)，1.99-1.85(2H，m)，1.58-1.43(1H，m)，1.43-1.27(1H，m)。
C
21H
23F
2N
3O
50.25H
2The analytical calculation value of O: C, 57.33; H, 5.38; N, 9.55.Measured value: C, 57.55; H, 5.40; N, 9.47.
MS(ESI)；m/z：436(M+H)
+。
IR(ATR)v：3052，2927，2869，1727，1614，1594，1508，1446，1428，1363，1322，1110，1078，1043，989，948，910，809cm
-1。
[embodiment 38]
7-[(1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-yl]-8-cyano group-6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid
[formula 272]
Under nitrogen atmosphere, with triethylamine (0.263ml, 1.88mmol) and 8-cyano group-6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine ring third-1-yl]-1, the 4-dihydro-(211mg 0.627mmol) joins (1S to 4-Oxoquinoline-3-ethyl formate, 6S)-(151mg is in acetonitrile 0.628mmol) (1.25ml) solution for 1-tert-butoxycarbonyl amino-4-oxa--8-azabicyclo [4.3.0] nonane.Mixture was at room temperature stirred 18 hours.Reaction soln is through concentrating under reduced pressure.Then, the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 60: 40 → 50: 50 → 34: 66 → 25: 75 → 16: 84).1mol/L sodium hydroxide solution (1.94ml) is joined in ethanol (2.42ml) solution of gained resistates down ice-cooled, mixture was at room temperature stirred 1 hour.(30ml) joins in the reaction soln with 10% citric acid solution, uses ethyl acetate (40ml * 1,30ml * 1) extraction then.Organic layer is with salt solution (45ml) washing, then through anhydrous sodium sulfate drying and filtration.Filtrate is again through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Under ice-cooled, (1.38ml 3v/w) joins in methylene dichloride (4.58ml) solution of 243mg gained resistates, and mixture was at room temperature stirred 2.5 hours with trifluoroacetic acid while stirring.Reaction soln is through concentrating under reduced pressure.Then, down the hydrochloric acid of pH1 is joined in the gained resistates ice-cooled, the gained mixture is with chloroform (40ml * 3) washing.Water layer is adjusted to pH12 with the 1mol/L sodium hydroxide solution down ice-cooled.Basic solution is adjusted to pH7.4 with 1mol/L hydrochloric acid, uses chloroform (100ml * 1,70ml * 1,50ml * 1) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Water layer is through concentrating under reduced pressure.The gained resistates is dissolved in chloroform/methanol=10/1, removes by filter insolubles (* 2).The resistates that derives from organic layer and water layer is respectively by PTLC purifying (chloroform/methanol/water of lower floor=7/3/1).They are merged, be dissolved in the methylene dichloride (20ml) again, methylene dichloride and ethanol azeotropic are removed (3 times).Ethanol (5ml) is joined in the gained resistates, and the gained mixture cools off then through supersound process.Filter the solid of collecting precipitation,, and, obtain the 122mg title compound at 60 ℃ of drying under reduced pressure with ethanol and ether washing.
1H-NMR(400MHz，0.1N?NaOD)δ：8.30(1H，d，J＝3.92Hz)，7.90(1H，d，J＝15.44Hz)，5.19(1H，dd，J＝63.24，3.43Hz)，4.06-3.97(5H，m)，3.81-3.74(3H，m)，3.58(1H，d，J＝10.30Hz)，2.33-2.31(1H，m)，2.03-1.73(3H，m)，1.61-1.49(1H，m)。
C
21H
20F
2N
4O
40.25H
2The analytical calculation value of O: C, 58.00; H, 4.75; F, 8.74; N, 12.88.Measured value: C, 58.07; H, 4.60; F, 8.70; N, 12.74.
MS(ESI)；m/z：431(M+H)
+。
IR(ATR)v：3081，2960，2873，2211，1725，1629，1446，1400，1307，1261，927，912，804cm
-1。
[embodiment 39]
7-[(1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-yl]-1-[(1R, 2S)-the 2-fluorine
Cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 273]
Under nitrogen atmosphere, with triethylamine (0.0737ml, 0.528mmol) and 7-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (49.0mg, 0.175mmol) join (1S, 6S)-1-tert-butoxycarbonyl amino-4-oxa--8-azabicyclo [4.3.0] nonane (42.2mg, 0.176mmol) dimethyl sulfoxide (DMSO) (0.352ml) solution in, the gained mixture stirred 2 days at 75 ℃.(0.147ml 1.06mmol) joins in the reaction soln, and the gained mixture stirred 4 days at 75 ℃ with dimethyl sulfoxide (DMSO) (0.352ml) and triethylamine.(0.147ml 1.06mmol) joins in the reaction soln, and the gained mixture stirred 2 days at 75 ℃ with dimethyl sulfoxide (DMSO) (0.352ml) and triethylamine.With 7-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (24.6mg, 0.0881mmol) and triethylamine (0.147ml 1.06mmol) joins in the reaction soln, and mixture was stirred 5 days.Reaction soln is used 10% citric acid solution (25ml), water (25ml) and saturated sodium hydroxide solution (25ml) washing then with ethyl acetate (30ml) dilution.In addition, again from 10% citric acid solution and the water of washing of washing, with ethyl acetate (40ml) extraction organic layer.Merge organic layer,, then filtrate decompression is concentrated through anhydrous sodium sulfate drying and filtration.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Under ice-cooled, (0.402ml 3v/w) joins in methylene dichloride (1.32ml) solution of 67.5mg gained resistates, and mixture was at room temperature stirred 1 hour with trifluoroacetic acid while stirring.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (* 3).Down 6mol/L hydrochloric acid is joined in the gained resistates ice-cooled, the gained mixture washs with chloroform (30ml * 5).Water layer is adjusted to pH12 with the 1mol/L sodium hydroxide solution down ice-cooled.Basic solution is adjusted to pH7.4 with 1mol/L hydrochloric acid, uses chloroform (100ml * 2) and chloroform/methanol=10/1 (50ml) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates is by PTLC purifying (chloroform/methanol/water of lower floor=7/3/1) and concentrating under reduced pressure.The gained resistates is dissolved in the hot ethanol, removes by filter insolubles.Filtrate is dissolved in the hot ethanol (1ml) through concentrating under reduced pressure, through supersound process, and cools off with frozen water.Then, the gained slurries wash with ether (10ml).After at room temperature stirring is spent the night, filter the crystal of collecting precipitation,, at 60 ℃ of drying under reduced pressure, obtain the 12.4mg title compound then with ethanol and ether washing.
1H-NMR(400MHz，0.1N?NaOD)δ：8.41(1H，d，J＝3.68Hz)，8.00(1H，d，J＝8.58Hz)，7.09(1H，d，J＝8.82Hz)，5.16-4.96(1H，m)，4.10-3.95(3H，m)，3.83-3.77(2H，m)，3.66(1H，d，J＝9.80Hz)，3.59(1H，t，J＝10.91Hz)，3.26(2H，dd，J＝15.32，8.70Hz)，2.45(3H，s)，2.33-2.23(1H，m)，2.02-1.87(3H，m)，1.68-1.57(1H，m)，1.33-1.21(1H，m)。
C
21H
24FN
3O
41.5H
2The analytical calculation value of O: C, 58.87; H, 6.35; N, 9.81.Measured value: C, 58.97; H, 5.98; N, 9.40.
MS(ESI)；m/z：402(M+H)
+。
IR(ATR)v：2937，2865，1710，1608，1508，1428，1388，1349，1315，1257，794cm
-1。
[reference example 167]
(3S)-3-ethoxycarbonyl methoxy methyl-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate
[formula 274]
With (3S)-3-methylol-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (2.0g, 6.26mmol) and bromoethyl acetate (2.09g 12.52mmol) is dissolved in the tetrahydrofuran (THF) (40ml).At 0 ℃, (0.33g 7.51mmol), at room temperature stirred mixture 18 hours to add sodium hydride.At 0 ℃, (100ml) joins in the reaction soln with saturated ammonium chloride solution, uses ethyl acetate (300ml) extraction then.Organic layer water (100ml) and salt solution (100ml) washing are again through anhydrous sodium sulfate drying.After the filtration, with solvent removed under reduced pressure.The gained resistates obtains the 1.74g title compound by silica gel column chromatography purifying (40% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.30(5H，m)，5.49(1H，q，J＝6.99Hz)，4.21(2H，q，J＝7.15Hz)，4.08(2H，s)，3.68(2H，brs)，3.46(1H，d，J＝10.24Hz)，3.31(1H，d，J＝10.24Hz)，2.80(1H，d，J＝17.07Hz)，2.56(1H，d，J＝17.07Hz)，1.53(3H，d，J＝7.32Hz)，1.35(9H，s)，1.28(3H，t，J＝7.19Hz)。
MS(EI)m/z：406(M+H)
+。
[reference example 168]
(1S)-3-oxa--7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4,3,0] ninth of the ten Heavenly Stems-5-alkene-1-
Base } t-butyl formate
[formula 275]
With (3S)-3-ethoxycarbonyl methoxy methyl-5-oxo-1-[(1R)-1-phenylethyl] (9.31g 25.9mmol) is dissolved in the tetrahydrofuran (THF) (200ml) tetramethyleneimine-3-t-butyl formate.Under nitrogen atmosphere, at 0 ℃, drip the tetrahydrofuran solution (64.7ml) of 1M hexamethyl two silicon nitrine lithiums, mixture was stirred 1.5 hours.Add saturated ammonium chloride solution (300ml), use ethyl acetate (900ml) extraction then.Organic layer water (300ml) and salt solution (100ml) washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the tetrahydrofuran (THF) (200ml).At 0 ℃, (1.27g 33.67mmol), stirs mixture 1 hour to add sodium borohydride.(200ml) joins in the reaction soln with saturated ammonium chloride solution, uses ethyl acetate (600ml) extraction then.Organic layer water (200ml) and salt solution (200ml) washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (40% ethyl acetate/hexane).Enriched material is dissolved in the methylene dichloride (150ml).The adding triethylamine (5.69ml, 41.02mmol), at-10 ℃, the dropping methane sulfonyl chloride (1.90ml, 24.61mmol).Stir after 1 hour, (200ml) joins in the reaction soln with saturated ammonium chloride solution, uses ethyl acetate (600ml) extraction then.Organic layer water (200ml) and salt solution (200ml) washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the toluene (150ml).(12.24ml, 82.03mmol), the gained mixture stirred 15 hours at 40 ℃ to add DBU.Reaction soln adds saturated ammonium chloride solution (150ml) then through concentrating under reduced pressure, then with ethyl acetate (400ml) extraction.Organic layer water (150ml) and salt solution (150ml) washing are again through anhydrous sodium sulfate drying.After the filtration, with solvent removed under reduced pressure.The gained resistates obtains the 3.28g title compound by silica gel column chromatography purifying (75% ethyl acetate/hexane), is colorless solid.
1H-NMR(400MHz，CDCl
3)δ：7.32-7.29(5H，m)，6.60(1H，t，J＝2.32Hz)，5.57(1H，q，J＝7.16Hz)，4.50-4.45(2H，m)，4.24(1H，dd，J＝18.55，2.44Hz)，3.26(1H，d，J＝10.25Hz)，3.21(1H，d，J＝10.01Hz)，3.13(1H，d，J＝10.01Hz)，1.51(3H，d，J＝7.08Hz)，1.27(9H，s)。
MS(EI)m/z：344(M+H)
+。
[reference example 169]
(1S, 6S)-3-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4,3,0] nonane-1-
Base } t-butyl formate;
(1S, 6R)-3-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [43,0] nonane-1-
Base } t-butyl formate
[formula 276]
Will (1S)-3-oxa--7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4,3,0] ninth of the ten Heavenly Stems-5-alkene-1-yl } (231mg 0.67mmol) is dissolved in the tetrahydrofuran (THF) t-butyl formate.(100mg), the gained mixture stirred 4 hours under nitrogen atmosphere to add 10% palladium-carbon (50% is wet).Remove by filter catalyzer, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (20% ethyl acetate/hexane → 50%), obtain the 187mg title compound (1S, 6S)-isomer (colorless solid) and 44mg title compound (1S, 6R)-isomer (colorless solid).
(1S, 6S)-isomer:
1H-NMR(400MHz，CDCl
3)δ：7.29-7.24(5H，m)，5.48(1H，q，J＝7.24Hz)，4.41(1H，d，J＝10.24Hz)，4.10(1H，dd，J＝10.98，4.39Hz)，3.38-3.33(2H，m)，3.17(1H，d，J＝9.76Hz)，3.08(1H，d，J＝10.00Hz)，2.28-2.19(2H，m)，1.96-1.92(1H，m)，1.46(3H，d，J＝7.32Hz)，1.23(9H，s)。
MS(EI)m/z：346(M+H)
+。
(1S, 6R)-isomer:
1H-NMR(400MHz，CDCl
3)δ：7.36-7.26(5H，m)，5.54(1H，q，J＝7.07Hz)，4.12(1H，d，J＝11.71Hz)，3.82-3.77(1H，m)，3.39(1H，m)，3.29(1H，d，J＝11.71Hz)，3.02(1H，t，J＝4.63Hz)，2.91(2H，dd，J＝18.29，10.24Hz)，2.03-2.01(2H，m)，1.53(3H，d，J＝7.07Hz)，1.41(9H，s)。
MS(EI)m/z：346(M+H)
+。
[(1S, 6S)-3-oxa--8-benzyloxycarbonyl-8-azabicyclo [4,3,0] nonane-1-yl] formic acid uncle fourth
Ester
[formula 277]
Under nitrogen atmosphere, with [(1S, 6S)-3-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4,3,0] nonane-1-yl] t-butyl formate (3.36g, 9.73mmol) be dissolved in the tetrahydrofuran (THF) (50ml), drip the tetrahydrofuran solution (48.63ml) of 1M borane-tetrahydrofuran complex.Stir after 3 days, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 2 hours at 80 ℃.Reaction soln adds saturated ammonium chloride solution (100ml) then through concentrating under reduced pressure, uses ethyl acetate (300ml) extraction again.Organic layer water (100ml) and salt solution (100ml) washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with resistates by short silica gel column chromatography purifying (35% ethyl acetate/hexane).The gained crude product is dissolved in 1, in the 2-ethylene dichloride (18ml).(3.40g, 19.91mmol), the gained mixture stirred 1 day at 40 ℃ to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 2.39g title compound by silica gel column chromatography purifying (35% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.24(5H，m)，5.14(2H，s)，3.88(1H，dd，J＝20.63，11.84Hz)，3.77-3.54(6H，m)，3.48(1H，t，J＝10.50Hz)，3.41-3.33(1H，m)，2.81-2.70(1H，m)，1.93-1.80(1H，m)，1.44(9H，s)。
MS(EI)m/z：384(M+Na)
+。
[reference example 171]
(1S, 6R)-8-benzyloxycarbonyl-3-oxa--8-azabicyclo [4,3,0] nonane-1-yl } formic acid uncle fourth
Ester
[formula 278]
Under nitrogen atmosphere, with { (1S, 6R)-3-oxa--7-oxo-8-[(1R)-the 1-phenylethyl]-8-azabicyclo [4,3,0] nonane-1-yl } t-butyl formate (709mg, 2.05mmol) be dissolved in the tetrahydrofuran (THF) (20ml), and drip the tetrahydrofuran solution (10.26ml) of 1M borane-tetrahydrofuran complex.Stir after 3 days, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 2 hours at 80 ℃.Reaction soln adds saturated ammonium chloride solution (80ml) then through concentrating under reduced pressure, uses ethyl acetate (240ml) extraction again.Organic layer water (80ml) and salt solution (80ml) washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (35% ethyl acetate/hexane).The gained flow point is through concentrating under reduced pressure, and resistates is dissolved in 1,2-ethylene dichloride (4ml).(788mg, 4.62mmol), the gained mixture stirred 4 days at 40 ℃ to add benzyloxycarbonyl chlorine.Reaction soln is through concentrating under reduced pressure, and resistates obtains the 435mg title compound by silica gel column chromatography purifying (40% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.33-7.28(5H，m)，5.13(2H，d，J＝3.42Hz)，4.48(1H，dd，J＝20.75，10.50Hz)，4.10-4.07(1H，m)，3.77(1H，dd，J＝24.05，11.11Hz)，3.62-3.52(2H，m)，3.38(1H，td，J＝11.66，2.77Hz)，3.22(1H，dd，J＝10.50，6.84Hz)，3.07(1H，dd，J＝10.99，3.42Hz)，2.24-2.21(1H，m)，1.98-1.96(1H，m)，1.63-1.60(1H，m)，1.44(9H，s)。
MS(EI)；m/z：384(M+Na)
+。
[reference example 172]
[(1S, 6R)-1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl] first
Acid benzyl ester
[formula 279]
Will (1S, 6S)-8-benzyloxycarbonyl-3-oxa--8-azabicyclo [4,3,0] nonane-1-yl } (2.30g 6.94mmol) is dissolved in the methylene dichloride (20ml) t-butyl formate.Add trifluoroacetic acid (10ml), mixture was stirred 1 day.Reaction soln adds 1N sodium hydroxide solution (100ml) through concentrating under reduced pressure, and the gained mixture washs with chloroform.Chloroform (200ml * 2) extraction is used in water layer hydrochloric acid soln acidifying again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the acetonitrile (40ml).Under nitrogen atmosphere, at 0 ℃, add 1, the 1-carbonyl is two-and (1.55g 9.53mmol), stirs mixture 1 hour the 1H-imidazoles, at room temperature feeds ammonia then.Add ethyl acetate and water, the salt water washing of gained mixture.Organic layer is through anhydrous sodium sulfate drying and filtration.After the solvent evaporated under reduced pressure, the gained resistates is by short silica gel column chromatography purifying (ethyl acetate).The gained crude product is dissolved in the trimethyl carbinol (50ml).(3.98g, 8.97mmol), the gained mixture is under nitrogen atmosphere, 80 ℃ of stirrings 1 hour to add lead tetraacetate.(3.52g 41.86mmol) joins in the reaction soln with ethyl acetate, and the gained mixture passes through diatomite filtration with sodium bicarbonate.Then, filtrate is with saturated sodium bicarbonate aqueous solution and salt water washing, again through anhydrous sodium sulfate drying.After the filtration, with solvent removed under reduced pressure.The gained resistates obtains the 1.70g title compound by silica gel column chromatography purifying (30% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.31(5H，m)，5.13(2H，s)，4.66(1H，d，J＝7.57Hz)，3.86-3.57(7H，m)，3.36(1H，dq，J＝23.01，5.45Hz)，2.63-2.55(1H，m)，1.87-1.79(1H，m)，1.54-1.50(1H，m)，1.43(9H，s)。
MS(EI)m/z：399(M+Na)
+。
[reference example 173]
(1S, 6S)-1-tert-butoxycarbonyl amino-3-oxa--8-dicyclo [4,3,0] nonane-8-yl } the formic acid benzyl
Ester
[formula 280]
Will (1S, 6R)-8-benzyloxycarbonyl-3-oxa--8-dicyclo [4,3,0] nonane-1-yl } (725mg 2.01mmol) is dissolved in the methylene dichloride (20ml) t-butyl formate.Add trifluoroacetic acid (4ml), mixture was stirred 15 hours.Reaction soln adds 1N sodium hydroxide solution (50ml) through concentrating under reduced pressure, and the gained mixture washs with chloroform.Chloroform (50ml * 2) extraction is used in water layer hydrochloric acid soln acidifying again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure, and the gained resistates is dissolved in the toluene (20ml).Under nitrogen atmosphere, (406mg, 4.01mmol) (740mg, 2.61mmol), the gained mixture stirred 1.5 hours at 110 ℃ with two phenoxy group phosphoryl azides to add triethylamine.Reaction soln is through concentrating under reduced pressure.Then, add diox (20ml) and 6N hydrochloric acid (20ml), the gained mixture stirred 2 hours at 50 ℃.Concentrating under reduced pressure and with the ethanol component distillation after, add 1N sodium hydroxide solution (50ml), use chloroform (100ml * 2) extraction again.Through anhydrous sodium sulfate drying and after filtering, with solvent removed under reduced pressure.(2189mg 10.03mmol) joins in the gained resistates, and the gained mixture stirred 1.5 hours at 50 ℃ with tert-Butyl dicarbonate.Reaction soln obtains the 623mg title compound by silica gel column chromatography purifying (60% ethyl acetate/hexane), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.52-7.26(5H，m)，5.13(2H，s)，4.55(1H，dd，J＝19.51，11.22Hz)，4.45(1H，d，J＝10.73Hz)，4.25(1H，t，J＝12.44Hz)，4.13-4.08(1H，m)，3.70-3.62(1H，m)，3.36-3.34(1H，m)，3.16-3.09(3H，m)，2.02-1.97(1H，m)，1.69-1.62(2H，m)，1.43(9H，s)。
MS(EI)m/z：399(M+Na)
+。
[reference example 174]
(1S, 6R)-1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane
[formula 281]
Will [(1S, 6R)-1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl] (401mg 1.07mmol) is dissolved in the methyl alcohol (20ml) benzyl formate.(200mg), the gained mixture stirred 2.5 hours under nitrogen atmosphere to add 10% palladium-carbon (50% is wet).Remove by filter catalyzer, then filtrate decompression is concentrated.Add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure obtains the 256mg title compound, is colorless solid.
MS(EI)m/z：243(M+H)
+。
[embodiment 40]
7-[(1S, 6R)-1-amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 282]
Will (1S, 6R)-(252mg 1.04mmol) is dissolved in the dimethyl sulfoxide (DMSO) (8ml) 8-azepine-1-tert-butoxycarbonyl amino-3-oxabicyclo [4,3,0] nonane.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (450.6mg, 1.25mmol) and triethylamine (315.7mg, 3.12mmol), the gained mixture stirred 17 hours at 40 ℃.Then, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 5 hours at 80 ℃.Solvent evaporated under reduced pressure joins 10% citric acid solution in the resistates then, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained flow point is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH 8 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates washs with ethanol and ether and through drying under reduced pressure, obtains the 302mg title compound, is pale yellow crystals.
mp：132-134℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.41(1H，s)，7.66(1H，d，J＝14.63Hz)，4.99(1H，d，J＝63.90Hz)，4.04-4.03(2H，m)，3.91-3.88(1H，m)，3.82(2H，t，J＝11.22Hz)，3.68-3.62(2H，m)，3.59(3H，s)，3.51(1H，d，J＝11.95Hz)，3.37(1H，d，J＝10.98Hz)，2.23-2.20(1H，m)，1.93-1.91(1H，m)，1.57-1.47(3H，m)。
C
21H
23F
2N
3O
50.5H
2O 0.4CHCl
3The analytical calculation value: C, 55.42; H, 5.30; N, 9.06; F, 8.19.Measured value: C, 55.19; H, 5.19; N, 9.09; F, 8.32.
MS(EI)m/z：436(M+H)
+。
IR(ATR)v：2943，2887，2845，1720，1622，1516，1452，1346，1323，1275cm
-1。
[embodiment 41]
7-[(1S, 6R)-1-amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 283]
Will (1S, 6R)-(187mg 0.77mmol) is dissolved in the dimethyl sulfoxide (DMSO) (4ml) 1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid-BF
2Inner complex (316.5mg, 0.92mmol) and triethylamine (93.6mg 0.92mmol), stirs mixture 14 days.Then, 90% aqueous ethanol (18ml) and triethylamine (2ml) are joined in the reaction soln, the gained mixture stirred 2 hours at 80 ℃.Solvent evaporated under reduced pressure joins 10% citric acid solution in the gained resistates, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, with solvent removed under reduced pressure.Then, resistates is by PTLC purifying (5% methyl alcohol/chloroform), and the gained flow point is dissolved in the concentrated hydrochloric acid and with chloroform and washs 2 times.Water layer is adjusted to pH 12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.9 with hydrochloric acid then, uses 5% methyl alcohol/chloroform extraction again 2 times.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.Filter the crystal of collecting precipitation and, obtain the 51mg title compound, be clear crystal through drying under reduced pressure.
mp：158-160℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.44(1H，d，J＝3.17Hz)，7.67(1H，d，J＝14.16Hz)，5.01(1H，d，J＝64.94Hz)，4.16(1H，t，J＝6.71Hz)，4.07(1H，dt，J＝9.93，4.46Hz)，4.01(1H，d，J＝10.01Hz)，3.95-3.92(1H，m)，3.85(1H，d，J＝11.96Hz)，3.62-3.54(1H，m)，3.47(1H，d，J＝11.72Hz)，3.17(1H，d，J＝9.77Hz)，3.06(1H，d，J＝10.01Hz)，2.48(3H，s)，2.20-2.15(1H，m)，1.89-1.82(1H，m)，1.65-1.60(2H，m)，1.26-1.19(1H，m)。
C
21H
23F
2N
3O
40.75H
2The analytical calculation value of O0.25EtOH: C, 58.10; H, 5.90; N, 9.45; F, 8.55.Measured value: C, 58.35; H, 5.86; N, 9.19; F, 8.53.
MS(EI)m/z：420(M+H)
+。
IR(ATR)v：3365，2945，2839，1716，1616，1510，1466，1454，1431，1342，1311，1265，1215cm
-1。
[reference example 175]
(1S, 6S)-1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane
[formula 284]
Will (1S, 6S)-1-tert-butoxycarbonyl amino-3-oxa--8-dicyclo [4,3,0] nonane-8-yl } (610mg 1.62mmol) is dissolved in the methyl alcohol (20ml) benzyl formate.Adding 10% palladium-carbon (50% is wet) (200mg), stirs mixture 3 hours under nitrogen atmosphere.Remove by filter catalyzer, then filtrate decompression is concentrated.Add the 1N sodium hydroxide solution, use chloroform extraction again.Through anhydrous sodium sulfate drying and after filtering, solvent evaporated under reduced pressure obtains the 362mg title compound, is colorless solid.
MS(EI)m/z：243(M+H)
+。
[embodiment 42]
10-[(1S, 6S)-1-amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl]-9-fluoro-2, the 3-dihydro
-3-methyl-(S)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid
[formula 285]
Will (1S, 6S)-(147.7mg 0.61mmol) is dissolved in the dimethyl sulfoxide (DMSO) (2.5ml) 1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane.Add 9,10-two fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid-BF
2Inner complex (211.3mg, 0.64mmol) and triethylamine (185.7mg, 1.83mmol), the gained mixture stirred 18 hours at 40 ℃.Then, 90% aqueous ethanol (33ml) and triethylamine (3ml) are joined in the reaction mixture, it was stirred 4 hours at 80 ℃.Solvent evaporated under reduced pressure also adds 10% citric acid solution, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained flow point is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.4 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is dissolved in ethanol-ammoniacal liquor, with heating of gained solution and stirring.After ammonia steamed, filter the crystal of collecting precipitation and, obtain the 180mg title compound, be clear crystal through drying under reduced pressure.
mp：＞300℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.31(1H，s)，7.51(1H，d，J＝14.63Hz)，4.58(1H，d，J＝7.07Hz)，4.45(1H，dd，J＝11.34，1.83Hz)，4.27(1H，d，J＝11.22Hz)，4.08(1H，dd，J＝11.22，3.66Hz)，3.93(1H，d，J＝10.49Hz)，3.78(1H，dd，J＝10.37，3.05Hz)，3.75-3.68(1H，m)，3.55(1H，d，J＝10.98Hz)，3.49-3.43(2H，m)，3.29(1H，d，J＝10.00Hz)，2.04-2.01(1H，m)，1.81-1.72(2H，m)，1.52(3H，d，J＝6.59Hz)。
C
20H
22FN
3O
51.5H
2The analytical calculation value of O: C, 55.81; H, 5.85; N, 9.76; F, 4.41.Measured value: C, 55.80; H, 5.89; N, 9.74; F, 4.34.
MS(EI)m/z：404(M+H)
+。
IR(ATR)v：3498，3407，3224，3045，2956，2877，1616，1573，1523，1473，1379，1352，1306，1261cm
-1。
[embodiment 43]
7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4,3,0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 286]
Will (1S, 6S)-(108.8mg 0.45mmol) is dissolved in the dimethyl sulfoxide (DMSO) (4ml) 8-azepine-1-tert-butoxycarbonyl amino-3-oxabicyclo [4,3,0] nonane.Add 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-BF
2Inner complex (210.7mg, 0.58mmol) and triethylamine (136.3mg, 1.35mmol), the gained mixture stirred 18 hours at 40 ℃.Then, 90% aqueous ethanol (30ml) and triethylamine (3ml) are joined in the reaction soln, the gained mixture stirred 5 hours at 80 ℃.Solvent evaporated under reduced pressure, and 10% citric acid solution joined in the resistates, ethyl acetate extraction used then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained crude product is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH 7.4 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates passes through from the ethyl alcohol recrystallization purifying, and through drying under reduced pressure, obtains the 121mg title compound, is pale yellow crystals.
mp：190-192℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.36(1H，d，J＝3.66Hz)，7.65(1H，d，J＝14.40Hz)，5.06(1H，dd，J＝64.09，3.54Hz)，4.09(1H，dd，J＝11.35，4.03Hz)，4.02-3.95(2H，m)，3.67-3.51(8H，m)，3.24(1H，d，J＝10.25Hz)，2.14-2.11(1H，m)，1.88-1.71(2H，m)，1.54-1.48(1H，m)，1.36-1.32(1H，m)。
C
21H
23F
2N
3O
50.25H
2The analytical calculation value of O: C, 57.33; H, 5.38; N, 9.55; F, 8.64.Measured value: C, 57.28; H, 5.39; N, 9.27; F, 8.48.
MS(EI)m/z：436(M+H)
+。
IR(ATR)v：3502，3374，3091，2948，2881，2850，1716，1617，1513，1450，1365，1321，1309，1268，1223cm
-1。
[embodiment 44]
7-[(1S, 6S)-1-amino-3-oxa--8-azabicyclo [4,3,0] nonane-8-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 287]
Will (1S, 6S)-(184.7mg 0.76mmol) is dissolved in the dimethyl sulfoxide (DMSO) (4ml) 1-tert-butoxycarbonyl amino-3-oxa--8-azabicyclo [4,3,0] nonane.Add 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (289.4mg, 0.84mmol) and triethylamine (115.7mg 1.14mmol), stirs mixture 7 days.Then, 90% aqueous ethanol (22ml) and triethylamine (2ml) are joined in the reaction soln, the gained mixture stirred 2 hours at 75 ℃.Solvent evaporated under reduced pressure also adds 10% citric acid solution, uses ethyl acetate extraction then.Organic layer water and salt water washing are again through anhydrous sodium sulfate drying.After the filtration, solvent evaporated under reduced pressure, and with the gained resistates by short silica gel column chromatography purifying (3% methyl alcohol/chloroform).The gained flow point is dissolved in the concentrated hydrochloric acid and with chloroform and washs.Water layer is adjusted to pH12 at 0 ℃ with aqueous sodium hydroxide solution, is adjusted to pH7.5 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and filtration, then with solvent removed under reduced pressure.The gained resistates is dissolved in ethanol-ammoniacal liquor, with solution heating and stirring.After ammonia steamed, filter the crystal of collecting precipitation and, obtain the 94.7mg title compound, be clear crystal through drying under reduced pressure.
mp：159-161℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.42(1H，s)，7.67(1H，d，J＝14.15Hz)，5.03(1H，d，J＝60.24Hz)，4.10-4.08(2H，m)，3.96(1H，d，J＝10.49Hz)，3.82(1H，d，J＝9.27Hz)，3.68(1H，t，J＝10.49Hz)，3.61(1H，d，J＝10.49Hz)，3.49(1H，t，J＝11.10Hz)，3.26(1H，t，J＝8.17Hz)，3.08(1H，d，J＝9.51Hz)，2.45(3H，s)，2.21-2.18(1H，m)，1.84-1.57(3H，m)，1.23(1H，d，J＝26.10Hz)。
C
21H
23F
2N
3O
41.25H
2The analytical calculation value of O: C, 57.07; H, 5.82; N, 9.51; F, 8.60.Measured value: C, 56.87; H, 5.99; N, 9.49; F, 8.43.
MS(EI)m/z：420(M+H)
+。
IR(ATR)v：3518，3251，3059，2935，2885，1720，1614，1540，1508，1441，1387，1358，1325，1306，1273cm
-1。
[reference example 176]
Methylsulfonic acid (5,6-dihydro-4H-pyrans-2-yl) methyl esters
[formula 288]
Ice-cooled down at salt, in 15 minutes, with methane sulfonyl chloride (17.9ml, 232mmol) be added drop-wise to (5,6-dihydro-4H-pyrans-2-yl) methyl alcohol (25.51g, 193mmol) [referring to Synlett, the 5th the volume, the 533rd page (1997)] and triethylamine (40.4ml is in methylene dichloride 290mmol) (600ml) solution.After stirring 2 hours under the same temperature, add triethylamine (18.8ml, 135mmol) and methane sulfonyl chloride (7.5ml, 97mmol), gained mixture restir 30 minutes.(300ml) joins in the reaction soln with water, uses ethyl acetate (1.5L) extraction then.Gained organic layer water (300ml) and salt solution (300ml) washing.Organic layer filters solvent evaporated under reduced pressure then through anhydrous sodium sulfate drying.The rough title compound of gained need not purifying and just can be used for next reaction.
[reference example 177]
2-azido methyl-5,6-dihydro-4H-pyrans
[formula 289]
(15.1g 232mmol) joins the N of rough methylsulfonic acid (5,6-dihydro-4H-pyrans-2-yl) methyl esters (about 193mmol), in dinethylformamide (350ml) solution, mixture is at room temperature stirred 20 hours with water (35ml) and sodiumazide.(300ml) joins in the reaction soln with water, uses ethyl acetate (1.5L) extraction then.Gained organic layer water (3 * 200ml) and salt solution (200ml) washing.Organic layer is through anhydrous sodium sulfate drying, and filtration and solvent evaporated under reduced pressure are to about 300ml then.The rough title compound solution of gained need not purifying and just can be used for next reaction.
[reference example 178]
2-amino methyl-5,6-dihydro-4H-pyrans
[formula 290]
(35.4g 135mmol) joins rough 2-azido methyl-5 successively, and in the 6-dihydro-4H-pyrans (about 193mmol), the gained mixture heats in 60 ℃ of oil baths and stirred 2 hours with tetrahydrofuran (THF) (500ml), water (50ml) and triphenyl phosphine.(1L) joins in the reaction soln with ethyl acetate, removes water layer.Then, organic layer is through anhydrous sodium sulfate drying and filtration, solvent evaporated under reduced pressure.The rough title compound of gained need not to be further purified and just can be used for next reaction.
[reference example 179]
2-(trityl amino) methyl-5,6-dihydro-4H-pyrans
[formula 291]
With triethylamine (37.7ml, 270mmol) and trityl chloride (41.4g 149mmol) joins rough 2-amino methyl-5 successively, in methylene dichloride (500ml) solution of 6-dihydro-4H-pyrans (about 193mmol), mixture is at room temperature stirred 11 hours.Reaction soln is with methylene dichloride (500ml) dilution, and water (2 * 500ml) and salt solution (500ml) washing, then through anhydrous sodium sulfate drying and filtration.Solvent evaporated under reduced pressure.Then, resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=5: 95 → 10: 90), obtain 22.2g (4 steps, 32%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.16-7.49(15H，m)，4.81(1H，brs)，3.97(2H，t，J＝5.1Hz)，2.66(2H，brs)，2.02-2.04(2H，m)，1.76-1.82(2H，m)。
[reference example 180]
2-(trityl amino) methyl-3,4,5,6-tetrahydrochysene-2H-pyrans-3-alcohol
[formula 292]
At room temperature, in 20 minutes, with the tetrahydrofuran solution (1M of borane-tetrahydrofuran complex, 187ml, 187mmol) be added drop-wise to 2-(trityl amino) methyl-5, (22.2g is in tetrahydrofuran (THF) 62.4mmol) (180ml) solution for 6-dihydro-4H-pyrans.After at room temperature stirring 2.5 hours, reaction soln carries out ice-cooled, and dropping 3N sodium hydroxide solution in 10 minutes (208ml, 624mmol).Under same temperature, (69ml 629mmol), at room temperature stirred mixture 1 hour again to drip 31% superoxol in 10 minutes then.(2 * 300ml) extract reaction soln with ether.Organic layer water (300ml) that merges and salt solution (300ml) washing are then through anhydrous sodium sulfate drying and filtration.Solvent evaporated under reduced pressure, then resistates is suspended in dichloromethane/hexane (1: 1, in mixed solvent 80ml).Remove by filter insolubles, filtrate obtains 18.54g (80%) title compound through reduction vaporization then, is light yellow gluey solid.
1H-NMR(400MHz，CDCl
3)δ：7.41-7.46(6H，m)，7.26-7.33(6H，m)，7.18-7.23(3H，m)，3.81-3.84(1H，m)，3.73-3.76(1H，m)，3.60-3.66(1H，m)，3.25-3.32(1H，m)，3.05-3.10(1H，m)，2.64(1H，dd，J＝11.6，7.7Hz)，2.35(1H，dd，J＝11.7，4.9Hz)，2.13-2.21(1H，m)，1.83-1.86(1H，m)，1.62-1.68(1H，m)，1.38-1.48(1H，m)。
[reference example 181]
2-(trityl amino) methyl-5,6-dihydro-2H-pyrans-3 (4H)-ketone
[formula 293]
Under nitrogen atmosphere, at room temperature, with sulphur trioxide-pyridine complex (23.7g, dimethyl sulfoxide (DMSO) 149mmol) (150ml) solution joins 2-(trityl amino) methyl-3,4,5,6-tetrahydrochysene-2H-pyrans-3-alcohol (18.54g, 49.6mmol) and triethylamine (45ml is in dimethyl sulfoxide (DMSO) 323mmol) (150ml) solution.Mixture was stirred 10 hours under same temperature.Reaction soln is poured in the frozen water (1L), used ethyl acetate (2 * 1L) extractions then.Then, merge organic layer and water (2 * 1L) and salt solution (1L) wash.The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is by silica gel column chromatography purifying (ethyl acetate: hexane=5: 95 → 10: 90 → 20: 80), obtain 9.56g (52%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.44-7.47(6H，m)，7.15-7.28(9H，m)，3.93-4.00(2H，m)，3.65-3.72(1H，m)，2.41-2.61(4H，m)，1.99-2.20(2H，m)。
[reference example 182]
6-(trityl amino) methyl-7-oxa--1,3-diaza spiro [4.5] decane-2,4-diketone
[formula 294]
Under nitrogen atmosphere, with 2-(trityl amino) methyl-5,6-dihydro-2H-pyrans-3 (4H)-ketone (9.56g, 25.7mmol), sodium cyanide (2.52g, 51.4mmol), ammonium chloride (2.75g, 51.4mmol), volatile salt (10.18g, 128.7mmol), the mixture of strong aqua (50ml) and ethanol (50ml) stirred 4.5 hours in 60 ℃ of oil baths.Add volatile salt (10.18g, 128.7mmol), with mixture restir 19.5 hours under same temperature.The gained reaction soln is through concentrating under reduced pressure, and (300ml 100ml) extracts resistates with ethyl acetate.Then, merge organic layer and water (2 * 100ml) and salt solution (100ml) wash.The gained organic layer is through anhydrous magnesium sulfate drying and filtration.Then, solvent evaporated under reduced pressure obtains 11.35g (quantitatively) title compound, is colourless amorphous thing.
1H-NMR(400MHz，CDCl
3)δ：7.65(1H，s)，7.38-7.49(6H，m)，7.15-7.30(9H，m)，5.79(1H，s)，3.97(1H，dm，J＝13.2Hz)，3.68(1H，dd，J＝7.1，5.1Hz)，3.51(1H，dt，J＝11.2，4.4Hz)，2.34(1H，dd，J＝12.1，5.0Hz)，2.18-2.23(1H，m)，2.05-2.14(1H，m)，1.81(1H，brd，J＝13.4Hz)，1.55-1.70(2H，m)。
[reference example 183]
(2R
*
, 3R
*
)-3-amino-2-(tert-butoxycarbonyl amino) methyl-3,4,5,6-tetrahydrochysene-2H-pyrans-3-
Formic acid
[formula 295]
At room temperature, with 6-(trityl amino) methyl-7-oxa--1,3-diaza spiro [4.5] decane-2, (10.69g 24.2mmol) is dissolved in the trifluoroacetic acid (50ml) the 4-diketone, and mixture was stirred 15 minutes.(50ml) joins in the reaction soln with water, solvent evaporated under reduced pressure.Then, (200ml) joins in the resistates with water, and (2 * 100ml) wash the gained mixture with ether.
(40g 1.0mol) joins in the gained solution (about 250ml), gained mixture reflux 16 hours in 130 ℃ of oil baths with sodium hydroxide.Reaction soln carries out ice-cooled, adds concentrated hydrochloric acid then gradually and is adjusted to pH 7.0, solvent evaporated under reduced pressure.
The gained resistates is suspended in 1N sodium hydroxide solution (75ml) and 1, in the 4-diox (150ml).(52.8g 242mmol), stirs mixture 5 days under same temperature at room temperature to add tert-Butyl dicarbonate.Solvent is through concentrating under reduced pressure.Then, resistates is suspended in the 1N sodium hydroxide solution (300ml), (3 * 300ml) wash the gained mixture with diisopropyl ether.Down concentrated hydrochloric acid is joined in the gained water layer gradually ice-cooled, water layer is adjusted to pH7.0.Solvent evaporated under reduced pressure.Resistates is suspended in the methyl alcohol (100ml), removes by filter most of sodium-chlor (2 times) then.Then, resistates obtains 1.21g (three steps, 18%) title compound by ion exchange resin HP-20 purifying (using methanol-eluted fractions), is light brown solid.
1H-NMR(400MHz，0.1N?NaOD)δ：3.99-4.03(1H，m)，3.69-3.73(1H，m)，3.53(1H，t，J＝12.0Hz)，3.00-3.12(2H，m)，2.00-2.06(1H，m)，1.70-1.87(2H，m)，1.52-1.56(1H，m)，1.43(9H，s)。
[reference example 184]
(2R
*
, 3R
*
)-3-(benzyloxycarbonyl amino)-2-(tert-butoxycarbonyl amino) methyl-3,4,5,6-four
Hydrogen-2H-pyrans-3-formic acid
[formula 296]
Under ice-cooled, (1.49g 5.98mmol) joins (2R with N-(benzyloxycarbonyloxy base) succinimide
*, 3R
*)-3-amino-2-(tert-butoxycarbonyl amino) methyl-3,4,5,6-tetrahydrochysene-2H-pyrans-3-formic acid (1.09g, 3.99mmol) and triethylamine (1.11ml in tetrahydrofuran (THF) 7.96mmol) (10ml)/water (10ml) solution, at room temperature stirred mixture 15 hours.Reaction soln washs with ethyl acetate (150ml) dilution and with 1N hydrochloric acid (50ml).The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.Resistates is by silica gel column chromatography purifying (methyl alcohol: chloroform=2: 98 → 5: 95), be dissolved in then in the 1N sodium hydroxide solution (50ml) and (2 * 20ml) wash to remove remaining benzylalcohol with ether.The gained water layer is adjusted to pH 1-2 with concentrated hydrochloric acid, uses methylene dichloride (2 * 80ml) extractions again.Merge organic layer, through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure obtains 1.08g (66%) title compound, is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.28(5H，m)，5.53(1H，brs)，5.20-5.07(2H，m)，4.94(1H，brs)，3.99(1H，dd，J＝11.1，4.5Hz)，3.65(1H，m)，3.55-3.30(2H，m)，3.17(1H，m)，2.59(1H，m)，2.06(1H，m)，1.73(1H，m)，1.57-1.51(1H，m)，1.43(9H，m)。
MS(ESI)；m/z：309(M-Boc+2H)
+。
[reference example 185]
(1R
*
, 6R
*
)-6-(benzyloxycarbonyl amino)-2-oxa--7-oxo-8-azabicyclo [4.3.0] nonane
[formula 297]
At room temperature, with (2R
*, 3R
*)-3-(benzyloxycarbonyl amino)-2-(tert-butoxycarbonyl amino) methyl-3,4,5, (1.08g 2.64mmol) is dissolved in 1 of 4N hydrogenchloride, in the 4-dioxane solution to 6-tetrahydrochysene-2H-pyrans-3-formic acid.Mixture was stirred 20 minutes under same temperature, then with solvent removed under reduced pressure.The gained resistates is Yu diox component distillation (2 times) obtains 921mg (quantitatively) resistates.
With 691mg (2.00mmol) gained resistates and N, (1.75ml 10.0mmol) is dissolved in the methylene dichloride (25ml) the N-diisopropylethylamine.At room temperature, (1.02g 4.01mmol), stirs mixture 18 hours under same temperature to add two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides.Reaction soln is used 1N hydrochloric acid (30ml), water (30ml), saturated sodium bicarbonate solution (30ml) and salt solution (30ml) washing more successively with chloroform (50ml) dilution.The gained organic layer is through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure at room temperature.Resistates is by silica gel column chromatography purifying (methyl alcohol: chloroform=2: 98 → 5: 95), obtain 834mg (quantitatively) title compound, be light brown colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.23(5H，m)，5.60(1H，brs)，5.42(1H，brs)，5.12(2H，s)，4.06(1H，dd，J＝11.7，5.4Hz)，3.67-3.55(2H，m)，3.43-3.38(1H，m)，3.33(1H，t，J＝4.2Hz)，2.76-2.68(1H，m)，1.94-1.82(1H，m)，1.65-1.55(2H，m)。
MS(ESI)；m/z：291(M+H)
+。
[reference example 186]
(1R
*
, 6R
*
)-8-benzyl-6-(benzyloxycarbonyl amino)-2-oxa--7-oxo-8-azabicyclo
[4.3.0] nonane
[formula 298]
Under ice-cooled, (55% mineral oil dispersion, 111mg 2.54mmol) join (1R with sodium hydride
*, 6R
*The N of)-6-(benzyloxycarbonyl amino)-2-oxa--7-oxo-8-azabicyclo [4.3.0] nonane (818mg, about 1.96mmol) in the dinethylformamide solution, stirs mixture 20 minutes under same temperature.Then, (0.304ml 2.56mmol), at room temperature stirred mixture 20 minutes to add bromotoluene.Reaction soln is poured in 10% citric acid solution (30ml), used ethyl acetate (100ml) extraction then.Gained organic layer water (2 * 30ml) and salt solution (30ml) washing, through anhydrous sodium sulfate drying and filter, then with solvent removed under reduced pressure.Resistates is by silica gel column chromatography purifying (ethyl acetate: chloroform=50: 50 → methyl alcohol: chloroform=1: 99 → 2: 98), obtain 224mg (0.59mmol, three steps, 30%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.16(5H，m)，5.38(1H，brs)，5.20-5.09(2H，m)，4.46(2H，s)，4.02(1H，dd，J＝11.5，5.7Hz)，3.57-3.50(2H，m)，3.23(1H，t，J＝9.2Hz)，3.13(1H，dd，J＝9.2，6.7Hz)，2.75(1H，m)，1.94-1.84(1H，m)，1.68-1.61(1H，m)，1.56-1.53(1H，m)，
MS(ESI)；m/z：381(M+H)
+。
[reference example 187]
(1R
*
, 6R
*
)-6-amino-8-benzyl-2-oxa--7-oxo-8-azabicyclo [4.3.0] nonane
[formula 299]
(50% is wet, 80mg) joins (1R with 10% palladium carbon catalyst
*, 6R
*(220mg, in methyl alcohol 0.58mmol) (10ml) solution, the gained mixture stirred 1.5 hours under nitrogen atmosphere, room temperature)-8-benzyl-6-(benzyloxycarbonyl amino)-2-oxa--7-oxo-8-azabicyclo [4.3.0] nonane.Filtering reacting solution, filtrate obtain 143mg (quantitatively) title compound through concentrating under reduced pressure, are the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.24(5H，m)，4.58(1H，d，J＝15.1Hz)，4.38(1H，d，J＝14.9Hz)，4.09(1H，dd，J＝11.6，5.5Hz)，3.58-3.40(3H，m)，3.17(1H，dd，J＝8.1，6.1Hz)，2.53(2H，brs)，2.15-2.04(2H，m)，1.79-1.72(1H，m)，1.60-1.55(1H，m)。
MS(ESI)；m/z：247(M+H)
+。
[reference example 188]
(1R
*
, 6S
*
)-8-benzyl-6-(tert-butoxycarbonyl amino)-2-oxa--8-azabicyclo [4.3.0] ninth of the ten Heavenly Stems
Alkane
[formula 300]
Under ice-cooled, (65mg 1.71mmol) joins (1R with lithium aluminum hydride
*, 6R
*(140mg in tetrahydrofuran (THF) 0.57mmol) (6ml) solution, at room temperature stirred mixture 30 minutes)-6-amino-8-benzyl-2-oxa--7-oxo-8-azabicyclo [4.3.0] nonane.Reaction soln carries out ice-cooled.Add entry (0.06ml), 15% sodium hydroxide solution (0.06ml) and water (0.18ml) successively carefully, mixture is at room temperature stirred spend the night.Then, add anhydrous magnesium sulfate, mixture was stirred 10 minutes.The gained mixture concentrates filtrate decompression then by diatomite filtration.
The gained resistates is dissolved in the methylene dichloride (3ml).(252mg 1.15mmol), at room temperature stirred mixture 4 hours to add tert-Butyl dicarbonate.After the solvent evaporated under reduced pressure, the gained resistates is again by PTLC purifying (methyl alcohol: chloroform=2: 98), obtain 50mg (0.152mmol, two steps, 26%) title compound, be the water white transparency colloidal solid.
1H-NMR(400MHz，CDCl
3)δ：7.30-7.20(5H，m)，4.93(1H，brs)，4.02(1H，dd，J＝11.6，5.2Hz)，3.81(2H，s)，3.61-3.48(3H，m)，3.07(1H，t，J＝8.0Hz)，2.71-2.67(2H，m)，2.52(1H，m)，1.90-1.55(3H，m)，1.47(9H，s)。
MS(ESI)；m/z：333(M+H)
+。
[embodiment 45]
7-[(1R
*
, 6S
*
)-6-amino-2-oxa--8-azabicyclo [4.3.0] nonane-3-yl]-1-cyclopropyl-6-
Fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 301]
(50% is wet, 50mg) joins (1R with 10% palladium carbon catalyst
*, 6S
*(50mg, in methyl alcohol 0.152mmol) (10ml) solution, the gained mixture stirred 1.5 hours under nitrogen atmosphere, room temperature)-8-benzyl-6-(tert-butoxycarbonyl amino)-2-oxa--8-azabicyclo [4.3.0] nonane.Remove by filter catalyzer, solvent evaporated under reduced pressure obtains 45mg (1R then
*, 6S
*)-6-(tert-butoxycarbonyl amino)-2-oxa--8-azabicyclo [4.3.0] nonane.
With gained (1R
*, 6S
*)-6-(tert-butoxycarbonyl amino)-2-oxa--8-azabicyclo [4.3.0] nonane (45mg), 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (572mg, 1.67mmol), triethylamine (0.128ml, 0.92mmol) and the mixture of dimethyl sulfoxide (DMSO) (0.5ml) in 40 ℃ of oil baths, stirred 19 hours.Then, ethanol (16ml), water (4ml) and triethylamine (2ml) are joined in the reaction soln gained mixture reflux and stirring 2.5 hours in 110 ℃ of oil baths.Solvent evaporated under reduced pressure joins 10% citric acid solution (20ml) in the gained resistates then, uses ethyl acetate (60ml) extraction again.Organic layer water (20ml * 2) and salt solution (20ml) washing are through anhydrous sodium sulfate drying and filtration.Then, solvent evaporated under reduced pressure.At room temperature, the gained resistates is dissolved in the concentrated hydrochloric acid (10ml).The gained acidic solution moves in the separating funnel, uses chloroform (5 * 30ml, 3 * 50ml) washings again.Water layer is adjusted to pH12.0 with the 10mol/L sodium hydroxide solution down ice-cooled, is adjusted to pH7.4 with hydrochloric acid then.Then, solvent evaporated under reduced pressure.Resistates is suspended in the methyl alcohol and filters, and filtrate is through reduction vaporization.Then, resistates is suspended in the methyl alcohol once more and filters, and filtrate is through reduction vaporization.The gained resistates is by PTLC purifying (lower floor's solvent chloroform: methyl alcohol: water=7: 3: 1), with further crystallization of ether and purifying, obtain 10mg (16%) title compound, be buff powder.
1H-NMR(400MHz，CDCl
3)δ：8.78(1H，s)，7.79(1H，d，J＝12.9Hz)，4.20-3.60(5H，m)，3.58(3H，s)，3.50-3.40(3H，m)，2.02(2H，m)，1.80-1.60(2H，m)，1.35-1.05(3H，m)，0.81(1H，m)。
C
21H
24FN
3O
50.25H
2O0.25Et
2The analytical calculation value of O: C, 59.99; H, 6.18; N, 9.54.Measured value: C, 59.94; H, 5.94; N, 9.12.
MS(EI)m/z：417(M
+)。
HRMS (FAB) C
21H
24FN
3O
5Calculated value: 417.1700.Measured value: 417.1695.
[embodiment 46]
(3S)-10-[6-amino-8-aza-tricycle [4.3.0.01,3] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-
Methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid
[formula 302]
With triethylamine (0.266ml, 1.91mmol) and (3S)-9,10-two fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid-BF
2(209mg 0.635mmol) joins 6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0 to inner complex
1,3] (160mg, in dimethyl sulfoxide (DMSO) 0.666mmol) (1.27ml) solution, the gained mixture stirred 16 hours at 35 ℃ nonane.With ethanol: the mixing solutions of water=4: 1 (10ml) and triethylamine (1ml) joins in the reaction soln, and mixture heating up was refluxed 2.5 hours.Reaction soln joins 10% citric acid solution (40ml) in the resistates then through concentrating under reduced pressure, uses ethyl acetate (50ml) extraction then.The interface portion chloroform extraction.Organic layer is water (40ml) and salt solution (40ml) washing respectively, through anhydrous sodium sulfate drying and filtration.Filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99.5: 0.5 → 99: 1 → 98: 2 → 96: 4 → 92: 8).Down gained resistates (224mg) is dissolved in the concentrated hydrochloric acid (1.5ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (25ml * 3) washing, water layer is adjusted to pH12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform (80ml * 3,60ml * 1) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Resistates (190mg) is dissolved in the hot ethanol (about 100ml), removes insolubles by fluted filter paper filtering.Heating is also stirred filtrate, boils off solvent gradually.Concentrated solution at room temperature stirs then and spends the night to about 10-20ml.Filter the crystal of collecting precipitation and use ethanol and the ether washing.Crystal spends the night at 60 ℃ of drying under reduced pressure, obtains the 120mg title compound, is pale yellow crystals.
1H-NMR(0.1N?NaOD)δ：8.32(1H，s)，7.53(1H，d，J＝14.46Hz)，4.61-4.59(1H，m)，4.48(1H，dd，J＝11.52，1.96Hz)，4.32-4.30(2H，m)，3.85(1H，dd，J＝10.54，2.70Hz)，3.49(1H，d，J＝9.80Hz)，3.29(1H，d，J＝10.30Hz)，1.95-1.91(2H，m)，1.75(1H，dd，J＝12.50，8.58Hz)，1.52(3H，d，J＝6.86Hz)，1.31-1.17(3H，m)，0.82-0.76(2H，m)。
C
21H
22FN
3O
4The analytical calculation value: C, 63.15; H, 5.55; F, 4.76; N, 10.52.Measured value: C, 62.94; H, 5.53; F, 4.62; N, 10.40.
MS(ESI)m/z：400(M+H)
+。
IR(ATR)：3370，2933，2877，1708，1618，1523，1463，1444，1396，1353，1311，1274，1228，1145，1085，1045，985，970，956，860，831，800cm
-1。
[reference example 189]
(3S)-3-(3-oxo-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid uncle fourth
Ester
[formula 303]
Under nitrogen atmosphere, methylene dichloride (35ml) is cooled off with dry ice-methyl alcohol.Add oxalyl chloride (3.45ml, 39.5mmol) and dimethyl sulfoxide (DMSO) (4.68ml, 66.0mmol), the stirring 15 minutes under cooling of gained mixture.Adding (3S)-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] (the gained mixture stirred 1 hour under cooling tetramethyleneimine-3-t-butyl formate for 4.58g, methylene dichloride 13.2mmol) (31ml) solution.(11.1ml, 79.5mmol), the gained mixture stirred 1 hour under cooling, at room temperature stirred then 1 hour to add triethylamine under cooling.(100ml) joins in the reaction soln with saturated ammonium chloride solution, uses chloroform (100ml * 1,80ml * 1) extraction again.Organic layer is with salt solution (120ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 60: 40 → 50: 50 → 40: 60 → 34: 66 → 25: 75), obtain the 4.59g title compound, be white crystal.
1H-NMR(CDCl
3)δ：9.76(1H，s)，7.35-7.24(5H，m)，5.49(1H，q，J＝7.19Hz)，3.34(1H，d，J＝10.05Hz)，3.13(1H，d，J＝10.05Hz)，2.94(1H，d，J＝16.91Hz)，2.44(2H，dt，J＝11.52，4.72Hz)，2.29(1H，d，J＝16.91Hz)，2.12-2.05(1H，m)，1.99-1.91(1H，m)，1.52(3H，d，J＝7.11Hz)，1.32(9H，s)。
MS(ESI)m/z：346(M+H)
+。
[reference example 190]
(3S)-3-(3-oxo-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate
[formula 304]
Under nitrogen atmosphere, with 1,8-two azo dicyclos [5.4.0]-7-undecylene (2.17ml, 14.5mmol) and Ai Shenmozeer salt (Eschenmoser salt) (3.66g, 19.8mmol) join (3S)-3-(3-oxo-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] in methylene dichloride (88.0ml) solution of tetramethyleneimine-3-t-butyl formate, mixture was at room temperature stirred 16 hours.Then, (1.22g 6.59mmol), at room temperature stirred mixture 3 hours to add Ai Shenmozeer salt.(150ml) joins in the reaction soln with saturated ammonium chloride solution, uses chloroform (100ml * 1,150ml * 1) extraction again.Organic layer is with salt solution (200ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 60: 40 → 50: 50 → 34: 66), obtain the 3.14g title compound, be white crystal.
1H-NMR(CDCl
3)δ：9.51(1H，s)，7.34-7.24(5H，m)，6.31(1H，s)，6.12(1H，s)，5.47(1H，q，J＝7.08Hz)，3.31(1H，d，J＝10.50Hz)，3.22(1H，d，J＝10.25Hz)，2.89(1H，d，J＝17.09Hz)，2.75-2.64(2H，m)，2.41(1H，d，J＝17.09Hz)，1.51(3H，d，J＝7.08Hz)，1.30(9H，s)。
MS(ESI)m/z：358(M+H)
+。
[reference example 191]
(3S)-3-(3-hydroxyl-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-
T-butyl formate
[formula 305]
Under nitrogen atmosphere, with ethanol (43.9ml) join sodium borohydride (644mg, 17.0mmol) in, the gained mixture cools off with ice-acetone.Under cooling, add the cesium chloride heptahydrate (6.55g, 17.6mmol) and (3S)-3-(3-oxo-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (3.14g, 6.55mmol).Mixture was stirred 1 hour under cooling, add then the cesium chloride heptahydrate (1.64g, 4.40mmol) and sodium borohydride (166mg, 4.39mmol).Mixture was stirred 30 minutes under cooling, carry out ice-cooled then.(150ml) joins in the reaction soln with saturated ammonium chloride solution.Mixture is through concentrating under reduced pressure and remove ethanol.Mixture extracts with ethyl acetate (150ml * 1,100ml * 1).Organic layer is with salt solution (200ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 90: 10 → 66: 34 → 50: 50 → 34: 66 → 25: 75 → 17: 83 → 5: 95), obtain the 2.83g title compound.
1H-NMR(CDCl
3)δ：7.35-7.23(5H，m)，5.49(1H，q，J＝7.11Hz)，5.15(1H，d，J＝1.23Hz)，4.87(1H，d，J＝1.23Hz)，3.98(2H，d，J＝6.37Hz)，3.33(1H，d，J＝10.30Hz)，3.22(1H，d，J＝10.30Hz)，2.94(1H，d，J＝17.16Hz)，2.62(1H，d，J＝14.95Hz)，2.46(1H，d，J＝15.44Hz)，2.44(1H，d，J＝17.16Hz)，1.72(1H，t，J＝6.25Hz)，1.52(3H，d，J＝7.11Hz)，1.32(9H，s)。
MS(ESI)m/z：360(M+H)
+。
[0751]
[reference example 192]
(3S)-3-(3-bromo-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-first
Tert-butyl acrylate
[formula 306]
Under the frozen water cooling, under nitrogen atmosphere, with carbon tetrabromide (3.24g, 9.77mmol) and triphenyl phosphine (2.57g 9.80mmol) joins (3S)-3-(3-hydroxyl-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] in methylene dichloride (113ml) solution of tetramethyleneimine-3-t-butyl formate.Mixture stirred 15 minutes under the frozen water cooling, and concentrating under reduced pressure desolvates to remove then.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 80: 20 → 75: 25 → 66: 34), obtain the 3.22g title compound, be white crystal.
1H-NMR(CDCl
3)δ：7.34-7.22(5H，m)，5.48(1H，q，J＝7.19Hz)，5.26(1H，s)，4.89(1H，s)，3.88(2H，s)，3.36(1H，d，J＝10.05Hz)，3.21(1H，d，J＝10.30Hz)，2.99(1H，d，J＝16.91Hz)，2.72(1H，d，J＝15.44Hz)，2.57(1H，d，J＝15.44Hz)，2.44(1H，d，J＝16.91Hz)，1.51(3H，d，J＝7.35Hz)，1.30(9H，s)。
MS(ESI)m/z：422(M
+)。
[reference example 193]
[(1S, 5S)-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-aza-bicyclo [3.3.0] octane
-1-yl] t-butyl formate
[formula 307]
Under with the cooling of ice-acetone, under nitrogen atmosphere, THF solution (9.15ml with 1M hexamethyl two silicon nitrine lithiums, 9.15mmol) join (3S)-3-(3-bromo-2-methylene radical-1-propyl group)-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (3.22g, 7.62mmol) tetrahydrofuran (THF) (76.2ml) solution in, mixture was stirred 10 minutes.(120ml) joins in the reaction soln with 10% citric acid solution, uses ethyl acetate (100ml * 2) extraction then.Organic layer is with salt solution (200ml) washing, again through anhydrous sodium sulfate drying.After the filtration, filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 83: 17 → 80: 20 → 75: 25), obtain the 2.47g title compound, be white crystal.
1H-NMR(CDCl
3)δ：7.34-7.23(5H，m)，5.46(1H，q，J＝7.11Hz)，4.88(2H，d，J＝1.72Hz)，3.31(1H，d，J＝10.30Hz)，3.13(2H，t，J＝6.37Hz)，3.08(2H，d，J＝10.30Hz)，2.89(1H，d，J＝15.69Hz)，2.72(2H，d，J＝6.13Hz)，2.30(1H，d，J＝15.93Hz)，1.47(3H，d，J＝7.11Hz)，1.35(9H，s)。
MS(ESI)m/z：342(M+H)
+。
[reference example 194]
[(1S, 5S)-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane
-1-yl] formic acid
[formula 308]
Under ice-cooled, while stirring trifluoroacetic acid (26.0ml) is joined [(1S, 5S)-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-aza-bicyclo [3.3.0] octane-1-yl] t-butyl formate (2.47g, 8.66mmol) methylene dichloride (26.0ml) solution in, mixture was at room temperature stirred 1 hour.Reaction soln is through concentrating under reduced pressure, and trifluoroacetic acid and methylbenzene azeotropic distill (* 3).Down 1mol/L sodium hydroxide solution (15.0ml) is joined in the gained resistates ice-cooled, the gained mixture washs with ether (60ml * 2).Water layer down with 6mol/L hydrochloric acid (4ml) acidifying, is used ethyl acetate (100ml * 2) extraction ice-cooled then.Merge organic layer, water (100ml) and salt solution (100ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 2.15g title compound through concentrating under reduced pressure, is white crystal.
1H-NMR(CDCl
3)δ：7.36-7.24(5H，m)，5.48(1H，q，J＝7.03Hz)，4.93(2H，s)，3.40(1H，d，J＝10.30Hz)，3.27(1H，dd，J＝7.48，4.78Hz)，3.16(1H，d，J＝10.54Hz)，3.02(1H，d，J＝15.93Hz)，2.77(2H，d，J＝5.39Hz)，2.38(1H，d，J＝15.93Hz)，1.50(3H，d，J＝7.11Hz)。
MS(ESI)m/z：342(M+H)
+。
[reference example 195]
(1S, 5S)-1-amino-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0]
Octane
[formula 309]
Under nitrogen atmosphere, under ice-cooled, while stirring with triethylamine (0.489ml, 3.50mmol) and two phenoxy group phosphoryl azide (0.491ml, 2.28mmol) join [(1S, 5S)-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-yl] (500mg is in toluene 1.75mmol) (8.75ml) solution for formic acid.Mixture was at room temperature stirred 30 minutes, stirred 30 minutes at 100 ℃ then.Reaction soln is through concentrating under reduced pressure, and triethylamine and methylbenzene azeotropic are removed (* 3).With 1,4-diox (4.37ml) and 6mol/L hydrochloric acid (4.37ml) join in the gained resistates, and the gained mixture stirred 1 hour at 50 ℃.Reaction soln water (18.0ml) dilutes and washs with ether (60ml * 2).Water layer is used chloroform (80ml * 1,70ml * 1) extraction again with the alkalization of 1mol/L sodium hydroxide solution.Organic layer water (80ml) and salt solution (80ml) washing are again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 238mg title compound through concentrating under reduced pressure.
1H-NMR(CDCl
3)δ：7.38-7.24(5H，m)，5.53(1H，q，J＝7.11Hz)，4.92(2H，brs)，3.25(1H，d，J＝10.05Hz)，2.79-2.73(3H，m)，2.58(1H，dd，J＝9.44，4.04Hz)，2.40(2H，dd，J＝35.17，15.57Hz)，1.48(3H，d，J＝7.11Hz)。
MS(ESI)m/z：257(M+H)
+。
[reference example 196]
(1S, 5R)-1-amino-7-methylene radical-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane
[formula 310]
Toluene solution (0.539ml with 65% pair of (2-methoxy ethoxy) sodium aluminum hydride, 1.79mmol) join (1S, 5S)-1-amino-7-methylene radical-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane (115mg, 0.449mmol) toluene (2.24ml) solution in, mixture was at room temperature stirred 30 minutes, stirred 30 minutes at 80 ℃ again.While stirring 5mol/L sodium hydroxide solution (15.0ml) is joined in the reaction soln down ice-cooled, use toluene (30ml * 1,20ml * 1) extraction again.Organic layer salt water washing is again through anhydrous sodium sulfate drying.After the filtration, filtrate obtains the 106mg title compound through concentrating under reduced pressure.
1H-NMR(CDCl
3)δ：7.38-7.19(5H，m)，4.80-4.78(2H，m)，3.14(1H，q，J＝6.45Hz)，2.78(1H，t，J＝8.21Hz)，2.65-2.56(2H，m)，2.47(1H，d，J＝14.71Hz)，2.33(1H，d，J＝9.07Hz)，2.22(1H，d，J＝14.95Hz)，2.13-2.06(3H，m)，1.31(3H，d，J＝6.62Hz)。
MS(ESI)m/z：243(M+H)
+。
[reference example 197]
(1S, 5R)-1-tert-butoxycarbonyl amino-7-methylene radical-3-[(1R)-the 1-phenylethyl]-the 3-azepine is two
Ring [3.3.0] octane
[formula 311]
Under nitrogen atmosphere, with tert-Butyl dicarbonate (191mg, 0.875mmol) join (1S, 5R)-1-amino-7-methylene radical-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane (106mg, 0.437mmol) methylene dichloride (2.18ml) solution in, mixture was at room temperature stirred 22 hours.Reaction soln is through concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 88: 12 → 84: 16 → 80: 20 → 75: 25), obtain the 203mg title compound, be transparent oily matter.
1H-NMR(CDCl
3)δ：7.29-7.22(5H，m)，4.86(1H，brs)，4.79(2H，d，J＝7.84Hz)，3.16(1H，q，J＝6.45Hz)，2.92(1H，d，J＝9.07Hz)，2.76(4H，t，J＝8.58Hz)，2.67-2.57(4H，m)，2.40(2H，d，J＝9.56Hz)，2.08-1.99(2H，m)，1.43(9H，s)，1.31(3H，d，J＝6.62Hz)。
MS(ESI)m/z：343(M+H)
+。
[reference example 198]
(1S, 5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-7-methylene radical-3-azabicyclo
[3.3.0] octane
[formula 312]
Under nitrogen atmosphere, with chloroformic acid benzyl ester (0.250ml, 1.75mmol) join and contain (1S, 5R)-1-tert-butoxycarbonyl amino-7-methylene radical-3-[(1R)-1-phenylethyl]-resistates (200mg of 3-azabicyclo [3.3.0] octane, be equivalent to 0.437mmol) methylene dichloride (1.94ml) solution in, mixture was at room temperature stirred 15 hours, stirred 4 hours at 40 ℃ again.Reaction soln is through concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 87: 13 → 86: 14 → 83: 17 → 80: 20 → 75: 25), obtain the 95.1mg title compound, be transparent oily matter.
1H-NMR(CDCl
3)δ：7.36-7.30(7H，m)，5.12(2H，s)，4.92(2H，d，J＝8.82Hz)，4.67(1H，brs)，3.74-3.72(2H，m)，3.56(1H，d，J＝11.77Hz)，3.27-3.24(1H，m)，2.72-2.68(4H，m)，2.19-2.17(1H，m)，1.43(9H，s)。
MS(ESI)m/z：373(M+H)
+。
[reference example 199]
(1S, 5R)-amino spiral shell (3-azabicyclo [3.3.0] octane of 3-benzyloxycarbonyl-1-tert-butoxycarbonyl
-7,1 '-cyclopropane)
[formula 313]
In open system, under the frozen water cooling, (50% aqueous mixture 6g) joins in the two layers of solution of 40% potassium hydroxide solution (18ml) and ether (60ml), the diethyl ether solution of preparation diazomethane with N-methyl-N '-nitro-N-nitrosoguanidine.
In open system, under ice-cooled, (5.26mg 0.0234mmol) joins (1S with acid chloride, 5R)-(175mg is in ether 0.469mmol) (4.69ml) solution for 3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-7-methylene radical-3-azabicyclo [3.3.0] octane.Down the diethyl ether solution (20ml) of the diazomethane that before prepared is slowly joined in this solution ice-cooled, mixture was at room temperature stirred 16 hours.Behind diatomite filtration, filtrate decompression is concentrated.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5 → 90: 10 → 88: 12 → 87: 13 → 86: 14 → 85: 15 → 83: 17 → 80: 20 → 75: 25), obtain the 138mg title compound, be transparent oily matter.
1H-NMR(CDCl
3)δ：7.38-7.28(5H，m)，5.13(2H，s)，4.80(1H，d，J＝9.31Hz)，3.77-3.72(3H，m)，3.37-3.35(1H，m)，2.66(1H，s)，2.05-1.97(3H，m)，1.60(1H，s)，1.43(10H，s)，0.47-0.46(4H，m)。
MS(ESI)m/z：387(M+H)
+。
[reference example 200]
(1S, 5R)-the amino spiral shell of 1-tert-butoxycarbonyl (3-azabicyclo [3.3.0] octane-7,1 '-cyclopropane)
[formula 314]
Under nitrogen atmosphere, with 10% palladium carbon catalyst (45.6mg, 30wt%) join (1S, 5R)-the 3-benzyloxycarbonyl-amino spiral shell (3-azabicyclo [3.3.0] octane-7 of 1-tert-butoxycarbonyl, 1 '-cyclopropane) (152mg is in methyl alcohol 0.393mmol) (3.93ml) solution.After the former atmosphere of hydrogen exchange, mixture was at room temperature stirred 30 minutes.After the former atmosphere of nitrogen replacement, reaction soln obtains the 97.9mg title compound by diatomite filtration and concentrating under reduced pressure, is transparent oily matter.
MS(ESI)m/z：253(M+H)
+。
[embodiment 47]
7-[(1S, 5R)-the amino spiral shell of 1-(3-azabicyclo [3.3.0] octane-7,1 '-cyclopropane)-the 3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine ring third-1-yl]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid
[formula 315]
With triethylamine (0.162ml, 0.388mmol) and 1-[(1R, 2S)-2-fluorine ring third-1-yl]-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (140mg, 0.388mmol) join (1S, 5R)-the amino spiral shell of 1-tert-butoxycarbonyl (3-azabicyclo [3.3.0] octane-7,1 '-cyclopropane) (97.9mg, 0.388mmol) dimethyl sulfoxide (DMSO) (0.776ml) solution in, the gained mixture stirred 14 hours at 35 ℃.With ethanol: the mixing solutions of water=4: 1 (10.0ml) and triethylamine (1.0ml) joins in the reaction soln, and mixture heating up was refluxed 1 hour.Reaction soln is through concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate (30ml) also with 10% citric acid solution (30ml), water (30ml) and salt solution (30ml) washing.Organic layer filters then through anhydrous sodium sulfate drying, and filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (chloroform: methyl alcohol=100: 0 → 99: 1 → 98: 2).Down gained resistates (165mg) is dissolved in the concentrated hydrochloric acid (1.0ml) ice-cooled, gained solution at room temperature stirred 15 minutes.After chloroform (25ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH 7.4 with hydrochloric acid, uses chloroform (80ml * 5) and chloroform/methanol=10/1 (60ml * 1) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Gained is dissolved in resistates in the hot ethanol (20ml), removes insolubles by fluted filter paper filtering.Heating is also stirred filtrate, boils off solvent gradually.Concentrated solution at room temperature stirs then and spends the night to about 5ml.Filter the crystal of collecting precipitation and use ethanol and the ether washing.Crystal spends the night at 50 ℃ of drying under reduced pressure, obtains the 86.0mg title compound, is pale yellow crystals.
1H-NMR(0.1N?NaOD)δ：8.46(1H，s)，7.70(1H，d，J＝14.15Hz)，5.06-5.04(1H，m)，4.09-4.04(1H，m)，3.92-3.86(1H，m)，3.70-3.68(4H，m)，3.58(1H，d，J＝10.73Hz)，3.53-3.49(1H，m)，2.54-2.46(1H，m)，2.15-2.09(1H，m)，1.86-1.76(2H，m)，1.67-1.46(3H，m)，0.57-0.45(4H，m)。
C
23H
25F
2N
3O
40.5H
2The analytical calculation value of O: C, 60.79; H, 5.77; F, 8.36; N, 9.25.Measured value: C, 60.82; H, 5.73; F, 8.17; N, 9.23.
MS(ESI)m/z：446(M+H)
+。
IR(ATR)：2931，2850，1725，1616，1508，1434，1342，1315，1270，1209，1186，1120，1052，1014，987，927，881，850，806，746cm
-1。
[embodiment 48]
7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-yl]-1-cyclopropyl-6,8-two fluoro-1,4-
Dihydro-4-Oxoquinoline-3-formic acid
[formula 316]
With 10% palladium carbon catalyst (M, about 50% is wet, 72.6mg) join (+)-(1S, 5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] octane (363mg, 1.01mmol) methyl alcohol (10.1ml) solution in, in the rubber sacculus, under nitrogen atmosphere, the gained mixture was at room temperature stirred 45 minutes.Remove by filter catalyzer, solvent evaporated under reduced pressure then obtains 229mg and contains that (1S 5R)-resistates of 1-(tert-butoxycarbonyl amino)-3-azabicyclo [3.3.0] octane, is the water white transparency colloidal solid.
Under nitrogen atmosphere, with triethylamine (0.423ml, 3.03mmol) and 1-cyclopropyl-6,7,8-three fluoro-8-methoxyl groups-1, (272mg 0.960mmol) joins (1S that contains of above acquisition to 4-dihydro-4-Oxoquinoline-3-formic acid, 5R)-acetonitrile (3.84ml) solution of the resistates (229mg) of 1-tert-butoxycarbonyl amino-3-azabicyclo [3.3.0] octane in, mixture heating up was refluxed 6 hours.Reaction soln carries out ice-cooled, filters the crystal of collecting precipitation then and uses acetonitrile and the ether washing.Crystal spends the night at 50 ℃ of drying under reduced pressure.Down gained resistates (410mg) is dissolved in the concentrated hydrochloric acid (3ml) ice-cooled, gained solution at room temperature stirred 15 minutes then.After chloroform (40ml * 3) washing, water layer is adjusted to pH 12 with saturated sodium hydroxide solution.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform (80ml * 2) and chloroform/methanol=10/1 (100ml * 6) extraction again.Organic layer concentrates filtrate decompression then through anhydrous sodium sulfate drying and filtration.Hot ethanol (150ml) and 28% ammoniacal liquor (3-5ml) are joined in the resistates, remove insolubles by fluted filter paper filtering.Evaporating solvent gradually heats simultaneously and stirs.Ammonia and ethanol azeotropic are removed several times.Concentrated solution at room temperature stirred 4 hours then to about 10ml.Filter the crystal of collecting precipitation and use ethanol and the ether washing.Crystal spends the night at 45 ℃ of drying under reduced pressure, obtains the 289mg title compound, is pale yellow crystals.
1H-NMR(0.1N?NaOD)δ：8.44(1H，s)，7.62(1H，d，J＝13.73Hz)，3.97-3.86(2H，m)，3.59(1H，d，J＝10.30Hz)，3.49(1H，d，J＝10.30Hz)，3.32(1H，d，J＝5.64Hz)，2.31-2.26(1H，m)，2.02(1H，dt，J＝20.43，7.48Hz)，1.90-1.84(1H，m)，1.81-1.74(2H，m)，1.70-1.63(1H，m)，1.51-1.48(1H，m)，1.19(2H，t，J＝7.11Hz)，1.07(2H，s)。
C
20H
21F
2N
3O
30.75H
2The analytical calculation value of O: C, 59.62; H, 5.63; F, 9.43; N, 10.43.Measured value: C, 59.69; H, 5.58; F, 9.31; N, 10.35.
MS?(ESI)m/z：390(M+H)
+。
IR(ATR)：2956，1612，1573，1542，1508，1459，1402，1351，1317，1274，1201，1166，1106，1031，979，817，732cm
-1。
[reference example 201]
(3S, 4S)-3-allyl group-4-(t-butyldimethylsilyl oxygen base) methyl-2-oxo
-1-[(1R)-and the 1-phenylethyl] tetramethyleneimine
[formula 317]
With (4S)-4-(t-butyldimethylsilyl oxygen base) methyl-2-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine (333.5g, 1.00mol) and allyl bromide 98 (90.9ml 1.05mol) is dissolved in the tetrahydrofuran (THF) (1.10L).At-15 ℃, (1.10L, 1.10mol), the gained mixture stirred 1 hour at-5 ℃ to drip hexamethyl two silicon nitrine lithiums (tetrahydrofuran solution of 1.0M).Reaction soln saturated ammonium chloride solution and ethyl acetate extraction.Then, organic layer salt water washing is again through anhydrous sodium sulfate drying.Then, solvent evaporated under reduced pressure.Resistates is handled (hexane: ethyl acetate=4: 1 → 2: 1), obtain the 327g title compound, be colourless syrup shape thing through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.42-7.32(5H，m)，5.93-5.80(1H，m)，5.57(1H，q，J＝7.1Hz)，5.22-5.12(2H，m)，3.56(1H，dd，J＝10.0，4.9Hz)，3.48-3.43(1H，m)，3.34(1H，dd，J＝10.3，8.1Hz)，2.82(1H，dd，J＝9.8，5.9Hz)，2.65-2.57(1H，m)，2.48-2.40(2H，m)，2.32-2.24(1H，m)，1.59(3H，d，J＝7.6Hz)，0.86(9H，s)，0.00(6H，s)。
[reference example 202]
(3S, 4S)-3-allyl group-4-(t-butyldimethylsilyl oxygen base) methyl isophthalic acid-[(1R)-the 1-phenyl
Ethyl] tetramethyleneimine
[formula 318]
Under nitrogen atmosphere, in 1 hour, with 65%Red-Al
TMToluene solution (788ml, 2.63mol) be added drop-wise to (3S, 4S)-3-allyl group-4-(t-butyldimethylsilyl oxygen base) methyl-2-oxo-1-[(1R)-the 1-phenylethyl] (327g is in toluene 875mmol) (1500ml) solution for tetramethyleneimine.Reaction soln stirred 5 hours at 45 ℃, was cooled to 0 ℃ and add 20% (+)-Seignette salt tetrahydrate solution (2.00L) then.Reaction soln is poured in ethyl acetate and the saline mixture, used ethyl acetate extraction then.Organic layer salt water washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure then.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=20: 1 → 4: 1), obtain the 213g title compound, be colourless syrup shape thing.
1H-NMR(400MHz，CDCl
3)δ：7.29-7.10(5H，m)，5.73-5.63(1H，m)，4.97-4.87(2H，m)，3.49(2H，d，J＝6.8Hz)，3.09(1H，q，J＝6.6Hz)，2.57-2.49(2H，m)，2.39(1H，t，J＝8.5Hz)，2.20-2.13(1H，m)，2.09-2.00(2H，m)，1.91-1.83(1H，m)，1.78-1.68(1H，m)，1.28(3H，d，J＝6.6Hz)，0.85(9H，s)，0.27(6H，d，J＝1.0Hz)。
[reference example 203]
(3S, 4S)-3-allyl group-1-benzyloxycarbonyl-4-hydroxymethyl pyrrolidine
[formula 319]
Will (3S, 4S)-3-allyl group-4-(t-butyldimethylsilyl oxygen base) methyl isophthalic acid-[(1R)-and the 1-phenylethyl] (213g 592mmol) is dissolved in the methylene dichloride (420ml) tetramethyleneimine.(169.2ml, 1.19mol), the gained mixture stirred 10 hours at 55 ℃, at room temperature stirred then 14 hours to drip chloroformic acid benzyl ester.(250ml 250mmol) joins in the reaction soln, and mixture was at room temperature stirred 24 hours with the ethanolic soln of 1M hydrochloric acid again.Reaction soln saturated sodium bicarbonate solution and ethyl acetate extraction.Then, organic layer salt water washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure then.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 1 → 1: 1), obtain the 140g title compound, be light yellow oil.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.25(5H，m)，5.75(1H，brs)，5.13-5.02(4H，m)，3.76-3.54(4H，m)，3.31-3.23(1H，m)，3.15-3.07(1H，m)，2.32-2.26(1H，m)，2.14-2.03(3H，m)。
[reference example 204]
(3S, 4S)-4-allyl group-1-benzyloxycarbonyl tetramethyleneimine-3-t-butyl formate
[formula 320]
(48.0ml 559mmol) is dissolved in the methylene dichloride (1000ml) with the oxalyl dichloro.At-70 ℃, (39.7ml 559mmol), stirs mixture 15 hours to drip dimethyl sulfoxide (DMSO).Will (3S, 4S)-(140g, methylene dichloride 508mmol) (400ml) drips of solution is added in the reaction soln 3-allyl group-1-benzyloxycarbonyl-4-hydroxymethyl pyrrolidine, and mixture was stirred 50 minutes.(354ml 2.54mol) is added drop-wise in the reaction soln, and the gained mixture stirred 10 minutes at-10 ℃ then with triethylamine.Reaction soln water and dichloromethane extraction.Then, organic layer salt water washing is through anhydrous magnesium sulfate drying and concentrating under reduced pressure.
The gained resistates is dissolved in the mixing solutions of the trimethyl carbinol (250ml) and tetrahydrofuran (THF) (750ml).(538ml, 5.08mol), then at 0 ℃, (60.3g, 533mmol) (238g, the suspension of water 1.52mol) (250ml) at room temperature stirred mixture 20 hours with the SODIUM PHOSPHATE, MONOBASIC dihydrate to add Textone to add the 2-methyl-2-butene.Reaction soln adds the 1N hydrochloric acid soln then through concentrating under reduced pressure, uses extracted with diethyl ether again.Organic layer is with 5% hypo solution and salt water washing, then through anhydrous magnesium sulfate drying and concentrating under reduced pressure.
The gained resistates is dissolved in the methylene dichloride (1000ml).Drip N, (509g, 2.54mol), the gained mixture stirred 4 hours at 50 ℃ N '-di-isopropyl-O-tertiary butyl isourea, at room temperature stirred then 15 hours.Leach precipitated solid, then filtrate decompression is concentrated.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=10: 1 → 4: 1), obtain the 126g title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.31(5H，m)，5.81-5.65(1H，m)，5.14-5.07(2H，m)，5.06-5.00(2H，m)，3.77-3.63(2H，m)，3.58-3.49(1H，m)，3.13-3.01(1H，m)，2.71-2.59(1H，m)，2.48(1H，brs)，2.36-2.26(1H，m)，2.16-2.04(1H，m)，1.45(9H，s)。
[reference example 205]
(3S, 4R)-1-benzyloxycarbonyl-4-(1-formyl radical vinyl) tetramethyleneimine-3-t-butyl formate
[formula 321]
Will (3S, 4S)-(70.0g 203mmol) is dissolved in the mixing solutions of tetrahydrofuran (THF) (350ml) and water (350ml) 4-allyl group-1-benzyloxycarbonyl tetramethyleneimine-3-t-butyl formate.(86.7g 406mmol) and perosmic anhydride (catalytic amount), at room temperature stirred mixture 20 hours to add sodium metaperiodate successively.10% sodium sulfite solution is joined in the reaction soln, use dichloromethane extraction again.Organic layer water and salt water washing are then through anhydrous magnesium sulfate drying and concentrating under reduced pressure.
The gained resistates is dissolved in the methylene dichloride (700ml).Drip N, (56.3g, 305mmol) with 1, (33.4ml 223mmol), at room temperature stirred mixture 59 hours 8-two azo dicyclo [5.4.0] undecylenes N-dimethylated methylene base ammonium iodide.Saturated ammonium chloride solution is joined in the reaction soln, use ethyl acetate extraction then.Organic layer salt water washing is then through anhydrous sodium sulfate drying and concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=24: 1 → 4: 1), obtain the 56.7g title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：9.55(1H，d，J＝5.1Hz)，7.40-7.28(5H，m)，6.38(1H，d，J＝2.0Hz)，6.15(1H，d，J＝3.2Hz)，5.13(2H，d，J＝4.1Hz)，3.89-3.74(2H，m)，3.60(1H，t，J＝9.6Hz)，3.49-3.41(1H，m)，3.29(1H，dt，J＝30.0，9.7Hz)，3.15-3.07(1H，m)，1.41(9H，s)。
[reference example 206]
(3S, 4R)-1-benzyloxycarbonyl-4-[1-(methylol) vinyl] tetramethyleneimine-3-t-butyl formate
[formula 322]
(57.0g 153mmol) is dissolved in the ethanol (700ml) with Cerium II Chloride (III) heptahydrate.At 0 ℃, (5.79g 153mmol), stirs mixture 10 minutes to add sodium borohydride.At 0 ℃, will (3S, 4R)-(55.0g, ethanol 153mmol) (700ml) drips of solution is added in the reaction soln 1-benzyloxycarbonyl-4-(1-formyl radical vinyl) tetramethyleneimine-3-t-butyl formate, and mixture was at room temperature stirred 3 hours.Reaction soln is with 10% citric acid solution, water and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.The gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=24: 1 → 2: 1), obtain the 42.2g title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.28(5H，m)，5.20(1H，brs)，5.17-5.10(2H，m)，5.04(1H，d，J＝5.4Hz)，4.16-4.09(3H，m)，3.87-3.77(2H，m)，3.52(1H，dd，J＝17.2，8.9Hz)，3.29(1H，q，J＝10.9Hz)，3.18-2.98(2H，m)，1.43(9H，s)。
[reference example 207]
(3S, 4R)-1-benzyloxycarbonyl-4-[1-(brooethyl) vinyl] tetramethyleneimine-3-t-butyl formate
[formula 323]
Will (3S, 4R)-1-benzyloxycarbonyl-4-[1-(methylol) vinyl] (30.0g 83.0mmol) is dissolved in the methylene dichloride (300ml) tetramethyleneimine-3-t-butyl formate.Add triphenyl phosphine (23.2g, 87.2mmol) and carbon tetrabromide (29.4g 87.2mmol), at room temperature stirred mixture 30 minutes.Reaction soln is through concentrating under reduced pressure.Then, the gained resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=100: 1 → 1: 1), obtain the 26.9g title compound, be colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.30(5H，m)，5.34(1H，s)，5.16-5.12(3H，m)，3.99(2H，q，J＝10.6Hz)，3.91-3.78(2H，m)，3.59-3.53(1H，m)，3.34-3.22(2H，m)，3.08-2.96(1H，m)，1.44(9H，s)。
[reference example 208]
(1S, 5S)-3-benzyloxycarbonyl-6-methylene radical-3-azabicyclo [3.2.0] heptane-1-t-butyl formate
[formula 324]
With (3S, 4R)-and 1-benzyloxycarbonyl-4-[1-(brooethyl) vinyl] tetramethyleneimine-3-t-butyl formate (22.8g, 53.7mmol) and 1,3-dimethyl-3,4,5, (19.5ml 161mmol) is dissolved in the mixing solutions of tetrahydrofuran (THF) (220ml) and toluene (220ml) 6-tetrahydrochysene-2 (1H)-pyrimidone.At-78 ℃, (80.6ml 80.6mmol), at room temperature stirred mixture 5 minutes then to drip hexamethyl two silicon nitrine lithiums (tetrahydrofuran solution of 1.0M).Reaction soln saturated ammonium chloride solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is handled (hexane: ethyl acetate=24: 1 → 2: 1), obtain the 8.34g title compound, be colourless syrup shape thing through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.37-7.24(5H，m)，5.14(2H，d，J＝2.4Hz)，4.98-4.88(2H，m)，3.93-3.76(2H，m)，3.66(1H，d，J＝11.7Hz)，3.59-3.54(1H，m)，3.45-3.38(1H，m)，3.24(1H，dt，J＝16.4，2.6Hz)，2.67-2.57(1H，m)，1.46(9H，s)。
[reference example 209]
(1S, 5S, 6R)-3-benzyloxycarbonyl-6-methylol-3-azabicyclo [3.2.0] heptane-1-formic acid uncle fourth
Ester/(1S, 5S, 6S)-3-benzyloxycarbonyl-6-methylol-3-azabicyclo [3.2.0] heptane-1-formic acid uncle
Butyl ester
[formula 325]
Will (1S, 5S)-(2.00g 5.82mmol) is dissolved in the tetrahydrofuran (THF) (40ml) 3-benzyloxycarbonyl-6-methylene radical-3-azabicyclo [3.2.0] heptane-1-t-butyl formate.(17.5ml 8.73mmol), stirs mixture 2 hours then to drip assorted dicyclo [3.3.1] the nonane losser (dimmer) (tetrahydrofuran solution of 0.5M) of 9-boron.At 0 ℃, (3.49ml 10.5mmol) is added drop-wise in the reaction soln with 30% aqueous hydrogen peroxide solution (2.47ml), then mixture is at room temperature stirred 16 hours with the 3M sodium hydroxide solution.Reaction soln water and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is handled (hexane: ethyl acetate=100: 1 → 1: 2) through silica gel column chromatography, obtain 1.58g isomer A (isomer that polarity is lower) title compound and 50.0mg isomer B (isomer that polarity is higher) title compound, be colourless syrup shape thing.
Isomer A;
1H-NMR (400MHz, CDCl
3) δ: 7.40-7.30 (5H, m), 5.17 (2H, s), 4.00 (1H, d, J=12.4Hz), 3.75-3.54 (4H, m), 3.42 (1H, d, J=11.7Hz), 3.29 (1H, dd, J=12.6,7.9Hz), 3.09 (1H, t, J=8.2Hz), 2.74-2.64 (1H, m), 2.67-2.54 (1H, m), 1.47 (9H, s).
Isomer B;
1H-NMR (400MHz, CDCl
3) δ: 7.39-7.28 (5H, m), 5.17 (2H, s), 3.86-3.56 (6H, m), 3.38 (1H, dd, J=11.6,6.0Hz), 2.85-2.78 (1H, m), 2.32-2.22 (1H, m), 2.19-2.09 (1H, m), 1.45 (9H, s).
[reference example 210]
(1S, 5S)-3-benzyloxycarbonyl-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-1-t-butyl formate
(derived from isomer A)
[formula 326]
Will (1S, 5S)-(1.51g 4.18mmol) is dissolved in the methylene dichloride (30ml) 3-benzyloxycarbonyl-6-methylol-3-azabicyclo [3.2.0] heptane-1-t-butyl formate (isomer A).(1.28ml, 9.20mmol) (746 μ l 8.36mmol), stir mixture 15 minutes then with the chloromethyl SULPHURYL CHLORIDE to drip triethylamine at 0 ℃.At 0 ℃, reaction soln saturated ammonium chloride solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
The gained resistates is dissolved in the tetrahydrofuran (THF) (20ml).At 0 ℃, (16.7ml 16.7mmol), stirs mixture 16 hours then to drip tetrabutyl ammonium fluoride (tetrahydrofuran solution of 1.0M).Reaction soln is through concentrating under reduced pressure.Resistates is handled (hexane: ethyl acetate=100: 1 → 1: 1), obtain the 1.01g title compound, be colourless syrup shape thing through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.40-7.31(5H，m)，5.18(2H，s)，4.48-4.26(2H，m)，3.99(1H，d，J＝12.7Hz)，3.72(1H，brs)，3.43(1H，d，J＝12.6Hz)，3.31(1H，dd，J＝13.2，7.8Hz)，3.11(1H，t，J＝8.0Hz)，2.96-2.79(1H，m)，2.62-2.53(1H，m)，1.69-1.60(1H，m)，1.48(9H，s)。
[reference example 211]
(1S, 5S)-3-benzyloxycarbonyl-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-1-t-butyl formate
(derived from isomer B)
[formula 327]
Will (1S, 5S)-3-benzyloxycarbonyl-6-methylol-3-azabicyclo [3.2.0] heptane-1-t-butyl formate (isomer B) (180mg, 498 μ mol) is dissolved in the methylene dichloride (4ml).At 0 ℃, (153 μ l 1.10mmol) with chloromethyl SULPHURYL CHLORIDE (89.0 μ l, 996 μ mol), stir mixture 15 minutes then to drip triethylamine.Reaction soln at 0 ℃ with saturated ammonium chloride solution and ethyl acetate extraction.Then, organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
The gained resistates is dissolved in the tetrahydrofuran (THF) (4ml).At 0 ℃, (1.99ml 1.99mmol), stirs mixture 2 hours then to drip tetrabutyl ammonium fluoride (tetrahydrofuran solution of 1.0M).Reaction soln is through concentrating under reduced pressure.Resistates is handled (hexane: ethyl acetate=100: 1 → 1: 1), obtain the 80.6mg title compound, be colourless syrup shape thing through silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：7.40-7.31(5H，m)，5.17(2H，s)，4.52-4.31(2H，m)，3.89-3.56(3H，m)，3.38(1H，dd，J＝12.0，6.6Hz)，2.89(1H，t，J＝5.6Hz)，2.40-2.25(2H，m)，2.06-2.02(1H，m)，1.46(9H，s)。
[reference example 212]
(1S, 5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo
[3.2.0] heptane (derived from isomer A)
[formula 328]
Under ice-cooled, (4ml) is added drop-wise to (1S with trifluoroacetic acid, 5S)-3-benzyloxycarbonyl-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-1-t-butyl formate (derived from isomer A) (887mg, 2.44mmol) methylene dichloride (4ml) solution in, mixture was at room temperature stirred 2 hours.Reaction soln ice-cooled following, joins the 1M sodium hydroxide solution in the resistates then through concentrating under reduced pressure.Solution washs with ether, and ice-cooled following, water layer is adjusted to pH 2-3 with concentrated hydrochloric acid, uses chloroform extraction more then.Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
With 1,1 '-carbonyl is two-and (594mg 3.66mmol) joins in acetonitrile (16ml) solution of gained resistates the 1H-imidazoles, and mixture was stirred 1 hour.Feed ammonia in the reaction soln and reach 1.5 hours.Then, water is joined in the reaction soln, use chloroform extraction again.Organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
(2.16g 4.88mmol) joins in the trimethyl carbinol (16ml) solution of gained resistates, and the gained mixture heats and stirred 15 minutes at 80 ℃ with lead tetraacetate.Allow after its cooling, sodium bicarbonate (2.50g) and ether are joined in the reaction soln, the gained mixture stirred 30 minutes down ice-cooled.Remove insolubles by diatomite filtration, filtrate is used saturated sodium bicarbonate solution and salt water washing then.Organic layer is through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=7: 1 → 1: 1), obtain the 754mg title compound, be colourless syrup shape thing.
1H-NMR(400MHz，CDCl
3)δ：7.40-7.29(5H，m)，5.16(2H，s)，4.89-4.79(1H，m)，4.53-4.27(2H，m)，3.91(1H，d，J＝12.5Hz)，3.77(1H，d，J＝11.5Hz)，3.51-3.40(1H，m)，3.33-3.26(1H，m)，3.00-2.86(2H，m)，2.37-2.23(1H，m)，1.87(1H，dd，J＝13.1，6.7Hz)，1.45(9H，s)。
[reference example 213]
(1S, 5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo
[3.2.0] heptane (derived from isomer B)
[formula 329]
Under ice-cooled, (3ml) is added drop-wise to (1S with trifluoroacetic acid, 5S)-3-benzyloxycarbonyl-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-1-t-butyl formate (derived from isomer B) (660mg, 1.82mmol) methylene dichloride (3ml) solution in, mixture was at room temperature stirred 2 hours.Reaction soln ice-cooled following, joins the 1M sodium hydroxide solution in the resistates then through concentrating under reduced pressure.Solution washs with ether, and ice-cooled following, water layer is adjusted to pH 2-3 with concentrated hydrochloric acid, uses chloroform extraction more then.Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
With 1,1 '-carbonyl is two-and (443mg 2.73mmol) joins in acetonitrile (12ml) solution of gained resistates the 1H-imidazoles, and mixture was stirred 1 hour.Feed ammonia in the reaction soln and reach 1.5 hours.Then, water is joined in the reaction soln, use chloroform extraction again.Organic layer salt water washing is through anhydrous sodium sulfate drying and concentrating under reduced pressure.
(1.61g 3.64mmol) joins in the trimethyl carbinol (12ml) solution of gained resistates, and the gained mixture heats and stirred 15 minutes at 80 ℃ with lead tetraacetate.Allow after its cooling, sodium bicarbonate (2.00g) and ether are joined in the reaction soln, the gained mixture stirred 30 minutes down ice-cooled.Leach insolubles by diatomite, filtrate is used saturated sodium bicarbonate solution and salt water washing then.Organic layer is through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (hexane: ethyl acetate=16: 1 → 1: 1), obtain the 590mg title compound, be colourless syrup shape thing.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.30(5H，m)，5.15(2H，s)，4.89-4.74(1H，m)，4.58-4.32(2H，m)，3.91(1H，d，J＝11.7Hz)，3.76-3.46(3H，m)，2.83-2.66(1H，m)，2.31(1H，dd，J＝10.7，8.8Hz)，2.19-2.05(2H，m)，1.43(9H，s)。
[reference example 214]
(1S, 5R)-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derives
From isomer A)
[formula 330]
Will (1S, 5R)-(625mg 1.65mmol) is dissolved in the tetrahydrofuran (THF) (12ml) 3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derived from isomer A).(200mg), the gained mixture stirred 1 hour under nitrogen atmosphere to add 20% palladium hydroxide-carbon (50% is wet).Remove by filter catalyzer, then filtrate decompression is concentrated.Down the 1M sodium hydroxide solution is joined in the resistates ice-cooled, use chloroform extraction again.Organic layer obtains the 403mg title compound through anhydrous sodium sulfate drying and concentrating under reduced pressure, is colourless syrup shape thing.
1H-NMR(400MHz，CDCl
3)δ：4.89-4.78(1H，m)，4.66-4.39(2H，m)，3.15(1H，d，J＝11.5Hz)，3.07-2.78(4H，m)，2.71(1H，d，J＝10.3Hz)，2.34-2.26(1H，m)，1.90(1H，dd，J＝12.7，8.3Hz)，1.46(9H，s)。
[reference example 215]
(1S, 5R)-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derives
From isomer B)
[formula 331]
Will (1S, 5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derived from isomer B) (305mg, 806 μ mol) is dissolved in the tetrahydrofuran (THF) (6ml).(100mg), the gained mixture stirred 1 hour under nitrogen atmosphere to add 20% palladium hydroxide-carbon (50% is wet).Remove by filter catalyzer, then filtrate decompression is concentrated.Down the 1M sodium hydroxide solution is joined in the resistates ice-cooled, use chloroform extraction again.Organic layer obtains the 196mg title compound through anhydrous sodium sulfate drying and concentrating under reduced pressure, is colourless syrup shape thing.
1H-NMR(400MHz，CDCl
3)δ：4.82(1H，brs)，4.58-4.39(2H，m)，3.16(1H，d，J＝11.2Hz)，3.06(1H，dd，J＝11.1，5.2Hz)，2.85(2H，dd，J＝19.3，11.7Hz)，2.65-2.53(1H，m)，2.27-1.86(3H，m)，1.44(9H，s)。
[embodiment 49]
7-[(1S, 5R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid (spreads out
Be conigenous isomer A)
[formula 332]
With triethylamine (143 μ l, 1.03mmol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (309mg, 855 μ mol) join (1S, 5R)-tetramethylene sulfone (3ml) solution of 1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derived from isomer A) (209mg, 855 μ mol) in.The gained mixture stirred 87 hours at 40 ℃.Ethanol (20ml), water (2ml) and triethylamine (0.5ml) are joined in the reaction soln, mixture heating up was refluxed 2 hours.After the solvent evaporated under reduced pressure, the gained resistates is used 10% citric acid solution and ethyl acetate extraction again.Then, organic layer washes with water 3 times and uses the salt water washing, through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is handled (chloroform: methyl alcohol=99: 1 → 9: 1) through silica gel column chromatography.Down gained oily matter (1.02g) is dissolved in the concentrated hydrochloric acid (5ml) ice-cooled, gained solution at room temperature stirred 15 minutes.Reaction soln washs 5 times with chloroform, and water layer is adjusted to pH11 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.(use the chloroform of lower floor: methyl alcohol: water=7: 3: 1 conduct exhibition layer solvents), the gained flow point is through concentrating under reduced pressure then by the PTLC purifying for resistates.The gained resistates obtains the 120mg title compound from ethyl alcohol recrystallization, is white solid.
mp：122-125℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.47(1H，brs)，7.74(1H，d，J＝13.4Hz)，5.00(1H，d，J＝64.5Hz)，4.70-4.49(2H，m)，4.09-4.01(1H，m)，3.75-3.54(6H，m)，3.14(1H，d，J＝10.5Hz)，3.02-2.89(1H，m)，2.65(1H，t，J＝7.8Hz)，2.16(1H，t，J＝11.8Hz)，2.00(1H，dd，J＝12.7，7.8Hz)，1.67-1.41(2H，m)。
C
21H
22F
3N
3O
42.5H
2The analytical calculation value of O: C, 52.28; H, 5.64; N, 8.71.Measured value: C, 52.03; H, 5.50; N, 8.47.
IR(KBr)v：3404，2963，1731，1619，1579，1541，1452，1392，1360，1320，1293，1270，1053cm
-1。
[embodiment 50]
7-[(1S, 5R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid (spreads out
Be conigenous isomer B)
[formula 333]
With triethylamine (135 μ l, 967 μ mol) and 6,7-two fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-formic acid-BF
2Inner complex (291mg, 806 μ mol) join (1S, 5R)-tetramethylene sulfone (2ml) solution of 1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derived from isomer B) (196mg, 806 μ mol) in.The gained mixture stirred 111 hours at 40 ℃.Ethanol (10ml), water (1ml) and triethylamine (0.5ml) are joined in the reaction soln, mixture heating up was refluxed 1 hour.After the solvent evaporated under reduced pressure, the gained resistates is used 10% citric acid solution and ethyl acetate extraction again.Then, organic layer washes with water 3 times and uses and the salt water washing, through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is handled (chloroform: methyl alcohol=99: 1 → 9: 1) through silica gel column chromatography.Down gained oily matter (515mg) is dissolved in the concentrated hydrochloric acid (5ml) ice-cooled, solution at room temperature stirred 15 minutes then.Reaction soln washs 5 times with chloroform, and water layer is adjusted to pH11 with saturated sodium hydroxide solution then.Basic solution is adjusted to pH7.4 with hydrochloric acid, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.(use the chloroform of lower floor: methyl alcohol: water=7: 3: 1 conduct exhibition layer solvents), the gained flow point is through concentrating under reduced pressure then by the PTLC purifying for resistates.The gained resistates obtains the 125mg title compound from ethyl alcohol recrystallization, is white solid.
mp：193-195℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，brs)，7.73(1H，d，J＝13.7Hz)，4.98(1H，d，J＝65.2Hz)，4.68-4.48(2H，m)，4.10-4.04(1H，m)，3.76-3.67(5H，m)，3.58-3.52(1H，m)，3.22(1H，d，J＝10.5Hz)，2.46-2.41(1H，m)，2.40-2.22(2H，m)，1.96-1.87(1H，m)，1.69-1.44(2H，m)。
C
21H
22F
3N
3O
4The analytical calculation value: C, 57.66; H, 5.07; F, 13.03; N, 9.61.Measured value: C, 57.42; H, 5.07; F, 12.98; N, 9.53.
IR(KBr)v：3393，3086，3063，3034，2954，2930，2897，2872，1720，1621，1514，1452，1395，1365，1344，1318，1288，1273，1186，1123，1108，1060，1038，1020cm
-1。
[embodiment 51]
7-[(1S, 5R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-formic acid (is derived
From isomer A)
[formula 334]
Under argon atmospher, with (1S, 5R)-1-(tert-butoxycarbonyl amino)-6-methyl fluoride-3-azabicyclo [3.2.0] heptane (derived from isomer A) (157mg, 643 μ mol), 7-bromo-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-ethyl formate (226mg, 643 μ mol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (273mg, 438 μ mol), three (dibenzalacetones) close two palladiums (0) (134mg, 146 μ mol) and cesium carbonate (381mg, 1.17mmol) De diox (5.00ml) solution at room temperature stirred 30 minutes, stirred 16 hours at 100 ℃ again.Water is joined in the reaction soln, use ethyl acetate and chloroform extraction then.Then, organic layer is through anhydrous sodium sulfate drying.After the solvent evaporated under reduced pressure, the gained resistates is handled (hexane: ethyl acetate=7: 1 → ethyl acetate) by silica gel column chromatography.
At 0 ℃, 1N sodium hydroxide solution (1.21ml) is joined in the light yellow foamy ethanol of gained (5ml) solution, mixture was at room temperature stirred 30 hours.At 0 ℃, 10% citric acid solution is joined in the reaction soln, use ethyl acetate extraction then.Organic layer is through anhydrous sodium sulfate drying, then concentrating under reduced pressure.
At 0 ℃, the gained resistates is dissolved in the concentrated hydrochloric acid (5ml).Mixture was stirred 15 minutes, then with chloroform washing 5 times.Water layer is adjusted to pH12 with saturated sodium hydroxide solution at 0 ℃, is adjusted to pH 7.4 with hydrochloric acid then, uses chloroform extraction again.Organic layer is through anhydrous sodium sulfate drying, then concentrating under reduced pressure.Resistates is by PTLC purifying (use the chloroform of lower floor: methyl alcohol: a layer solvent opened up in water=conduct in 7: 3: 1).Then, the gained flow point obtains the 28.5mg title compound from ethyl alcohol recrystallization, is white solid.
mp：130-133℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.46(1H，d，J＝3.2Hz)，7.73(1H，d，J＝13.8Hz)，5.01(1H，d，J＝64.2Hz)，4.78-4.46(2H，m)，4.13-4.06(1H，m)，3.91-3.84(1H，m)，3.51(1H，d，J＝9.6Hz)，3.34(1H，d，J＝11.0Hz)，2.99-2.87(2H，m)，2.71-2.64(4H，m)，2.24-2.12(2H，m)，1.66-1.55(1H，m)，1.29-1.16(1H，m)。
C
21H
22F
3N
3O
32.25H
2The analytical calculation value of O0.25IPA: C, 54.77; H, 6.02; F, 11.95; N, 8.81.Measured value: C, 54.82, H, 5.71; F, 11.84; N, 8.85.
IR(KBr)v：3414，2970，1723，1616，1580，1546，1508，1458，1434，1394，1363，1320，1103，1023cm
-1。
[reference example 216]
2-(4-bromo-2,5-two fluoro-3-methyl benzoyls)-3-dimethylamino ethyl propenoate
[formula 335]
With 2, (10.7g 42.4mmol) is dissolved in the toluene (160ml) 5-two fluoro-4-bromo-3-tolyl acids.Add thionyl chloride (5.00ml, 63.9mmol) and dimethyl formamide (5.0ml), with mixture heating up backflow 2 hours.Solvent evaporated under reduced pressure is dissolved in resistates in the tetrahydrofuran (THF) (300ml).Add 3-dimethylamino ethyl propenoate (7.30ml, 50.9mmol) and triethylamine (7.60ml, 54.5mmol), with mixture heating up backflow 3 hours.Solvent evaporated under reduced pressure joins methylene dichloride and water in the resistates, separates each layer.Then, organic layer is through anhydrous sodium sulfate drying, solvent evaporated under reduced pressure.Resistates is by flash column chromatography purifying (hexane: ethyl acetate=2: 1 → 1: 1 → 1: 2), obtain title compound (11.35g), be yellow oil.
1H-NMR(CDCl
3)δ：7.81-7.74(1H，m)，7.27-7.16(1H，m)，4.00(2H，q，J＝7.1Hz)，3.31(3H，br?s)，2.89(3H，br?s)，2.35(3H，d，J＝2.9Hz)，0.97(3H，t，J＝7.1Hz)。
[reference example 217]
7-bromo-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
Ethyl ester
[formula 336]
(4-bromo-2,5-two fluoro-3-methyl benzoyls)-(11.4g 30.2mmol) is dissolved in the methylene dichloride (200ml) 3-dimethylamino ethyl propenoate with 2-.Add (1R, 2S)-(8.24g 33.3mmol), is cooled to-25 ℃ with the gained mixture to 2-fluorine cyclopropylamine tosylate.At-25 ℃, (6.60ml 47.4mmol) is added drop-wise in the reaction soln, and the gained mixture stirred 1 hour at-15 ℃, stirred 2.5 hours at 0 ℃ again with triethylamine.Solvent evaporated under reduced pressure joins ethyl acetate and water in the resistates, separates each layer.Organic layer salt water washing is again through anhydrous sodium sulfate drying.Solvent evaporated under reduced pressure obtains amino acrylates, is yellow oil.The gained amino acrylates is dissolved in N, in the dinethylformamide (350ml).(19.8g 60.9mmol), at room temperature stirred mixture 12 hours to add cesium carbonate.Solvent evaporated under reduced pressure joins ethyl acetate and water in the resistates, separates each layer.Organic layer is with salt water washing and through anhydrous sodium sulfate drying, solvent evaporated under reduced pressure.Resistates is by flash column chromatography purifying (hexane: ethyl acetate=9: 1 → 1: 1 → 1: 2), obtain title compound (2.98g), be colourless powder.
1H-NMR(CDCl
3)δ：8.56(1H，d，J＝3.2Hz)，8.06(1H，d，J＝8.1Hz)，4.98-4.73(1H，m)，4.40(2H，q，J＝7.1Hz)，3.91-3.82(1H，m)，2.85(3H，s)，1.61-1.22(2H，m)，1.41(3H，t，J＝7.1Hz)。
[reference example 218]
7-[(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-
Base]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
Ethyl ester
[formula 337]
Under argon atmospher, with (1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane (318mg, 1.21mmol), 7-bromo-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-ethyl formate (426mg, 1.10mmol), 1,1 '-two (diphenylphosphino) ferrocene (183mg, 0.331mmol), three (dibenzalacetones) close two palladiums (0) (101mg, 0.110mmol) and cesium carbonate (718mg, 2.20mmol the mixture of) De diox (5.51ml) at room temperature stirred 30 minutes, stirred 11 hours at 100 ℃ again.The mixture dilute with water is also used ethyl acetate and chloroform extraction (3 *).The organic layer that merges is through anhydrous sodium sulfate drying, and underpressure distillation removes and desolvates.Resistates obtains the 436mg title compound by silica gel flash column chromatography purifying (ethyl acetate/hexane=10: 90 → 50: 50 → 67: 33 → ethyl acetate), is light yellow foam.
1H-NMR(400MHz，CDCl
3)δ：8.54(1H，d，J＝2.9Hz)，7.96(1H，d，J＝12.9Hz)，4.99(1H，brs)，4.94-4.72(1H，m)，4.39(2H，q，J＝7.1Hz)，3.91-3.79(2H，m)，3.62(2H，s)，3.49-3.41(1H，m)，2.91-2.76(1H，m)，2.62(3H，s)，2.42-2.12(4H，m)，1.45(9H，s)，1.61-1.43(1H，m)，1.41(3H，t，J＝7.1Hz)，1.34-1.21(1H，m)。
MS(ESI)m/z：568(M+H)
+。
[reference example 219]
7-[(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-
Base]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 338]
At 0 ℃, to 7-[(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-yls]-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, (436mg is in ethanol 0.769mmol) (5ml) solution for 4-dihydro-8-methyl-4-Oxoquinoline-3-ethyl formate, add 1mol/L aqueous sodium hydroxide solution (0.845ml), mixture was at room temperature stirred 13 hours.At 0 ℃, in mixture, add 1mol/L aqueous sodium hydroxide solution (0.845ml) again, mixture was at room temperature stirred 4 hours.Add 10% aqueous citric acid solution in mixture, ethanol is removed in underpressure distillation.Residue diluted with water is also used dichloromethane extraction (3x).The organic layer that merges is through anhydrous sodium sulfate drying, and underpressure distillation removes and desolvates.Resistates obtains the 342mg title compound by silica gel flash column chromatography purifying (ethyl acetate/hexane=1: 3 → 1: 1 → 2: 1 → ethyl acetate), is colourless foam shape thing.
1H-NMR(CDCl
3)δ：14.98(1H，s)，8.78(1H，d，J＝2.9Hz)，7.95(1H，d，J＝12.7Hz)，5.03-4.77(2H，m)，4.02-3.87(2H，m)，3.77-3.64(2H，m)，3.57-3.49(1H，m)，2.98-2.83(1H，m)，2.66(3H，s)，2.43-2.12(4H，m)，1.70-1.53(1H，m)，1.46(9H，s)，1.40-1.26(1H，m)。
MS(ESI)m/z：540(M+H)
+。
[embodiment 52]
7-[(1S, 5R)-1-amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-yls]-the 6-fluorine
-1-[(1R, 2S)-2-(the fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 339]
At 0 ℃, with 7-[(1S, 5R)-1-tert-butoxycarbonyl amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-yls]-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, (414mg 0.767mmol) is dissolved in the concentrated hydrochloric acid (4ml) 4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid, and the gained mixture stirred 1 hour at 0 ℃.Obtained aqueous solution is with chloroform washs (3 *).The gained mixture alkalizes to pH12 with saturated aqueous sodium hydroxide solution at 0 ℃, is neutralized to pH7.4 then.Solution chloroform extraction (5 *).The organic layer that merges is through anhydrous sodium sulfate drying, and underpressure distillation removes and desolvates.Resistates obtains the 219mg title compound from ethyl alcohol recrystallization, is white solid.
Fusing point: 211-212 ℃.
1H-NMR(400MHz，0.1N?NaOD)δ：8.52-8.46(1H，m)，7.79-7.67(1H，m)，5.12-4.88(1H，m)，4.18-4.05(1H，m)，3.91-3.79(1H，m)，3.68-3.55(1H，m)，3.52-3.40(1H，m)，3.36-3.25(1H，m)，2.71-2.58(4H，m)，2.45-2.28(2H，m)，2.24-2.12(1H，m)，1.97-1.85(1H，m)，1.69-1.54(1H，m)，1.38-1.17(1H，m)。
C
21H
21F
4N
3O
30.2H
2The analytical calculation value of O: C, 56.93; H, 4.87; N, 9.49; F, 17.15.Measured value: C, 56.91, H, 4.83; N, 9.47; F, 17.55.
MS(ESI)m/z：440(M+H)
+。
IR(ATR)v：3391，3061，2962，2871，1714，1615，1510，1460，1434，1356，1336，1301，1235，1207，1177，1157，1140，1075，1061，1045，1015cm
-1。
[reference example 220]
(3S)-4-chloro-3-(3-hydroxyl-1-propyl group)-5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-formic acid
The tert-butyl ester
[formula 340]
Under nitrogen atmosphere, at-78 ℃, to (3S)-3-[3-(t-butyldimethylsilyl oxygen base) third-1-yl]-the 5-oxo-1-[(1R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (960mg, 2.08mmol) THF (15ml) solution in add the THF solution (2.29ml of 1.0M two (trimethyl silyl) Lithamide, 2.29mmol), mixture was stirred 30 minutes.Then, (333mg 2.50mmol), stirs mixture 1 hour at-60 ℃, stirs 10 minutes at 0 ℃ again to add N-chlorosuccinimide.In this mixture, add saturated aqueous ammonium chloride and ethyl acetate.Isolating organic layer water and salt water washing.Solution is through anhydrous sodium sulfate drying, and solvent is removed through underpressure distillation.At 0 ℃, in the THF of this resistates (20ml) solution, add acetate (0.24ml, 4.16mmol) and the THF solution of 1.0M tetrabutyl ammonium fluoride (4.16ml 4.16mmol), at room temperature stirred mixture 16 hours.In mixture, add 10% aqueous citric acid solution and ethyl acetate.Isolating organic layer water and salt water washing.Solution is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates obtains the 506mg title compound by silica gel flash column chromatography purifying (ethyl acetate/hexane=1: 1 → 1: 2), is light yellow oil.
1H-NMR(CDCl
3)δ：7.34-7.26(5H，m)，5.49-5.40(1H，m)，4.75(1H，s)，3.68-3.61(2H，m)，3.39-3.34(2H，m)，3.24(0.75H，d，J＝10.0Hz)，3.14(0.25H，d，J＝10.9Hz)，1.95-1.80(2H，m)，1.68-1.40(2H，m)，1.52(3H，d，J＝7.1Hz)，1.28(9H，s)。
[reference example 221]
(1S, 5R)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base
T-butyl formate
[formula 341]
At 0 ℃, to (3S)-4-chloro-3-(3-hydroxyl third-1-yl)-5-oxo-1-[(1R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate (500mg, 1.31mmol) methylene dichloride (10ml) solution in add carbon tetrabromide (434mg, 1.31mmol) and triphenyl phosphine (344mg, 1.31mmol).After mixture at room temperature stirred 2 hours, with carbon tetrabromide (143mg, 0.431mmol) and triphenyl phosphine (114mg 0.434mmol) joins in the gained mixture.Stir after 2 hours, add carbon tetrabromide (72mg, 0.216mmol) and triphenyl phosphine (57mg, 0.217mmol), with mixture stirring 16 hours.Decompression steams solvent.Resistates obtains colorless oil by short silica gel flash column chromatography purifying (15% ethyl acetate/hexane).Under nitrogen atmosphere, at-78 ℃, (1.46ml, 1.46mmol), reaction mixture was warming up to 0 ℃ to the THF solution of adding 1.0M two (trimethyl silyl) Lithamide in 2 hours in the THF of this oily matter (12ml) solution.In this mixture, add saturated aqueous ammonium chloride and ethyl acetate.Isolating organic layer water and salt water washing.Solution is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates obtains the 337mg title compound by silica gel flash column chromatography purifying (15% ethyl acetate/hexane), is light yellow solid.
1H-NMR(CDCl
3)δ：7.37-7.26(5H，m)，5.54(1H，q，J＝7.1Hz)，3.51(1H，d，J＝10.7Hz)，3.02(1H，d，J＝10.7Hz)，2.76-2.71(1H，m)，2.52-2.45(1H，m)，2.38-2.30(1H，m)，2.02-1.96(1H，m)，1.74-1.60(2H，m)，1.53(3H，d，J＝7.1Hz)，1.45(9H，s)。
[reference example 222]
(1S, 5R)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base
Formic acid
[formula 342]
At room temperature, will (1S, 5R)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base t-butyl formate (332mg, 0.912mmol) and methylene dichloride (4ml) mixture of trifluoroacetic acid (2ml) stirring 14.5 hours.Decompression steams solvent.In resistates, add ether (3ml), filter collecting precipitation then, obtain the 245mg title compound, be colorless solid.
1H-NMR(CDCl
3)δ：7.38-7.26(5H，m)，5.50(1H，q，J＝7.1Hz)，3.53(1H，d，J＝10.7Hz)，3.07(1H，d，J＝10.8Hz)，2.78-2.73(1H，m)，2.63-2.56(1H，m)，2.41-2.33(1H，m)，2.05-2.01(1H，m)，1.79-1.63(2H，m)，1.54(3H，d，J＝7.1Hz)。
[reference example 223]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-nitrogen
Assorted dicyclo [3.3.0] octane
[formula 343]
At 80 ℃, with (1S, 5R)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane-1-base formic acid (239mg, 0.777mmol), triethylamine (0.215ml, 1.55mmol) and two phenoxy group phosphoryl azides (0.184ml, toluene 0.855mmol) (6ml) solution stirring 30 minutes.Decompression steams solvent.To 1 of resistates, add 6N aqueous hydrochloric acid (5ml) in 4-diox (5ml) solution.Mixture was stirred 5 hours at 50 ℃.Decompression steams solvent.In resistates, add the 1N aqueous sodium hydroxide solution.Solution CHCl
3Extract 2 times, the organic layer of merging is through anhydrous sodium sulfate drying, and decompression steams solvent.With resistates and tert-Butyl dicarbonate (847mg, mixture 3.89mmol) stirred 3 hours at 50 ℃, mixture obtains the 222mg title compound by silica gel flash column chromatography purifying (15% ethyl acetate/hexane), is colorless oil.
1H-NMR(CDCl
3)δ：7.37-7.26(5H，m)，5.50(1H，q，J＝6.9Hz)，5.25(1H，brs)，3.66(1H，brd，J＝10.0Hz)，2.96(1H，d，J＝6.8Hz)，2.76-2.69(1H，m)，2.55-2.51(1H，m)，2.18-2.08(1H，m)，1.98-1.84(2H，m)，1.51(3H，d，J＝7.1Hz)，1.65-1.50(1H，m)，1.40(9H，s)。
[reference example 224]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-3-[(1R)-the 1-phenylethyl]-the 3-azabicyclo
[3.3.0] octane
[formula 344]
Under nitrogen atmosphere, at room temperature, to (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-4-oxo-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane (217mg, 0.573mmol) THF (10ml) solution in add 1.0M borane-THF complex compound THF solution (1.72ml, 1.72mmol).Stir after 14 hours, and the THF solution of adding 1.0M borane-THF complex compound (0.86ml, 0.86mmol).Mixture is warming up to 50 ℃ and stirred 18 hours.In mixture, add once more 1.0M borane-THF complex compound THF solution (0.86ml, 0.86mmol).Mixture was stirred 24 hours at 50 ℃.After being cooled to 0 ℃, in mixture, add entry (1ml), EtOH (9ml) and triethylamine (1ml).Mixture is warming up to 80 ℃ and stirred 2 hours.Decompression steams solvent.In resistates, add saturated aqueous ammonium chloride and ethyl acetate.Isolating organic layer water and salt water washing.Solution is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates obtains the 67.3mg title compound by silica gel flash column chromatography purifying (10% ethyl acetate/hexane), is colorless oil.
1H-NMR(CDCl
3)δ：7.29-7.19(5H，m)，5.53(1H，brs)，3.22(1H，q，J＝6.8Hz)，3.07(1H，brd，J＝8.8Hz)，2.93(1H，brd，J＝8.7Hz)，2.82-2.71(1H，m)，2.64-2.57(1H，m)，2.27-2.15(2H，m)，2.09-2.06(2H，m)，1.74-1.67(2H，m)，1.55(9H，s)，1.31(3H，d，J＝6.6Hz)。
[reference example 225]
(1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-3-azabicyclo [3.3.0] octane
[formula 345]
Under nitrogen atmosphere, with (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-3-[(1R)-the 1-phenylethyl]-3-azabicyclo [3.3.0] octane (63.0mg, 0.173mmol), 10%Pd-C (50wt%, M, methyl alcohol 32mg) (6ml) mixture at room temperature stirred 4 hours, stirred 19 hours at 40 ℃ again.After removing by filter catalyzer, filtrate steams through decompression.
MS(ESI)m/z：261(M+H)
+。
[embodiment 53]
7-[(1R, 5R)-1-amino-5-chloro-3-azabicyclo [3.3.0] octane-3-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine ring third-1-yl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 346]
With (1R, 5R)-1-(tert-butoxycarbonyl amino)-5-chloro-3-azabicyclo [3.3.0] octane (45.0mg, 0.173mmol), 6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropane]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-boron difluoride complex compound (62.3mg, 0.173mmol) and triethylamine (0.0598ml, the mixture of methyl-sulphoxide 0.433mmol) (3ml) stirred 45 hours at 45 ℃.In mixture, add entry (1ml), EtOH (9ml) and triethylamine (1ml).Mixture was stirred 1.5 hours at 80 ℃.After being cooled to room temperature, decompression steams solvent.In resistates, add 10% aqueous citric acid solution and ethyl acetate.Isolating organic layer H
2O and salt water washing.Solution is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates is by TLC purifying (5%MeOH/CHCl
3), obtain the compound that 48.0mg N-Boc protects, be yellow oil.In this oily matter, add hydrochloric acid, mixture was at room temperature stirred 30 minutes.Mixture alkalizes to pH 12 with aqueous sodium hydroxide solution, is neutralized to pH 7.8 at 0 ℃ then.Solution chloroform extraction 2 times.The organic layer that merges is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates obtains the 33.9mg title compound through drying under reduced pressure, is light yellow solid.
Fusing point: 161-163 ℃.
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，s)，7.70(1H，d，J＝14.2Hz)，5.07-4.85(1H，m)，4.19-4.08(2H，m)，3.92(1H，d，J＝11.8Hz)，3.76-3.63(5H，m)，2.48-2.41(1H，m)，2.30-2.25(1H，m)，2.08-1.87(4H，m)，1.70-1.51(2H，m)，1.19(1.8H，t，J＝7.2Hz)。
C
21H
22ClF
4N
3O
30.6EtOH the analytical calculation value: C, 55.38; H, 5.36; N, 8.73; F, 7.89; Cl, 7.36.Measured value: C, 55.24, H, 4.91; N, 8.85; F, 8.27; Cl, 6.92.
MS(ESI)m/z：454(M+H)
+。
IR(ATR)v：3384，3075，2880，1728，1621，1513，1453，1360，1318，1188，1136，1120，1103，1056cm
-1。
[embodiment 54]
7-[6-amino-8-aza-tricycle [4.3.0.0
1,3
] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
-1-yl]-8-methyl-4-oxo-1, and 4-dihydroquinoline-3-formic acid (7: derivative, derived from optically-active
Isomer A)
[formula 347]
Close two palladiums (0) (332mg to three (dibenzalacetones), 0.363mmol) and 4, two (phenylbenzene) phosphino-s-9 of 5-, 9-dimethyl xanthene (462mg, 0.798mmol) 1, add 7-bromo-6-fluoro-1-[(1R in 4-diox (9.06ml) solution, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-ethyl formate (350mg, 0.906mmol), 6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0
1,3] nonane (and 216mg, 0.906mmol) and cesium carbonate (355mg, 1.09mmol), with mixture under nitrogen atmosphere, stirred 22 hours at 90 ℃.Reaction mixture water (80ml) dilutes and extracts with ethyl acetate (90ml).Organic layer is with saturated sodium-chloride water solution (80ml) washing, through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (chloroform-methanol; 100: 0 → 99: 1 → 98: 2), obtain light yellow solid.Add 1mol/L aqueous sodium hydroxide solution (1.50ml) in this solid ethanol (3.32ml) solution in ice bath, mixture was at room temperature stirred 14 hours.Add 1mol/L aqueous hydrochloric acid (1.50ml) in this reaction soln in ice bath, organic layer is through concentrating under reduced pressure.Aqueous solution water (30ml) dilutes and extracts with ethyl acetate (40ml).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (chloroform-methanol; 100: 0 → 99: 1 → 98: 2), obtain light yellow solid.In ice bath, the gained solid is dissolved in the concentrated hydrochloric acid (1.0ml), the aqueous solution washs with chloroform (25ml * 3).Add saturated sodium hydroxide solution in water layer, regulate pH to 12.0, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Solution extracts with chloroform (120ml * 1,80ml * 2).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates obtains title compound 68.1mg (18%) by from the ethyl alcohol recrystallization purifying, is light yellow solid.
mp：145-149℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.43(1H，d，J＝3.2Hz)，7.70(1H，d，J＝14.2Hz)，5.12-4.92(1H，m)，4.29(1H，d，J＝9.2Hz)，4.12-4.07(1H，m)，3.91-3.88(1H，m)，3.24(1H，d，J＝9.6Hz)，3.08(1H，d，J＝9.2Hz)，2.54(3H，s)，2.08-1.97(1H，m)，1.92-1.87(1H，m)，1.79-1.74(1H，m)，1.65-1.55(1H，m)，1.32-1.19(3H，m)，0.84-0.76(2H，m)。
C
22H
23F
2N
3O
31.5H
2The analytical calculation value of O: C, 59.72; H, 5.92; F, 8.59; N, 9.50.Measured value: C, 59.72; H, 5.65; F, 59.08; N, 9.47.
MS(ESI)m/z：416(M+H)
+。
IR(ATR)：2939，2867，1719，1612，1542，1507，1460，1428，1354，1314，1284，1184，1136，1024，967，921，884，806cm
-1。
[embodiment 55]
7-[6-amino-8-aza-tricycle [4.3.0.0
1,3
] nonane-8-yl]-1-[(1R, 2S)-2-fluorine ring third-1-
Base]-8-methyl-4-oxo-1, and 4-dihydroquinoline-3-formic acid (7: derivative, derived from rotational isomerism
Body A)
[formula 348]
Under nitrogen atmosphere, to 6-tert-butoxycarbonyl amino-8-aza-tricycle [4.3.0.0
1,3] nonane (290mg, 1.22mmol) dimethyl sulfoxide (DMSO) (2.42ml) solution in add triethylamine (0.507ml, 3.63mmol) and 7-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (337mg, 1.21mmol), mixture was stirred 13 days at 70 ℃.Reaction soln washs with the ethyl acetate dilution and with 10% aqueous citric acid solution (50ml), water (60ml) and saturated sodium-chloride water solution (60ml).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (chloroform-methanol; 100: 0 → 99: 1 → 98: 2 → 95: 5), obtain light yellow solid.In ice bath, solid is dissolved in the concentrated hydrochloric acid (1.0ml), the aqueous solution washs with chloroform (30ml * 5).Add saturated aqueous sodium hydroxide solution in water layer, regulate pH to 12.0, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Solution extracts with chloroform (80ml * 4) and 10% methyl alcohol-chloroform (80ml * 1,50ml * 1).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates obtains title compound 138mg (29%) by from the ethyl alcohol recrystallization purifying, is light yellow solid.
Mp:＞254 ℃ (decomposition).
1H-NMR(400MHz，0.1N?NaOD)δ：8.42(1H，d，J＝3.9Hz)，8.00(1H，d，J＝9.3Hz)，7.14(1H，d，J＝9.0Hz)，5.13-4.94(1H，m)，4.32(1H，d，J＝10.0Hz)，4.10-4.04(1H，m)，3.73(1H，d，J＝10.3Hz)，3.23(1H，d，J＝10.0Hz)，3.00(1H，d，J＝10.3Hz)，2.46(3H，s)，2.04-1.92(2H，m)，1.79-1.73(1H，m)，1.66-1.55(1H，m)，1.35-1.17(3H，m)，0.86-0.77(2H，m)。
C
22H
24FN
3O
30.25H
2The analytical calculation value of O: C, 65.74; H, 6.14; F, 4.73; N, 10.45.Measured value: C, 65.84; H, 6.28; F, 5.00; N, 10.41.
MS(ESI)m/z：398(M+H)
+。
IR(ATR)：3376，3030，2989，2929，2858，1703，1614，1547，1510，1450，1430，1387，1354，1337，1313，1295，1266，1230，1189，1177，1153，1138，1090，1079，1054，1022，998，990，923cm
-1。
[embodiment 56]
7-{ (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.2.0] heptane-3-yl }-the 6-fluorine
-1-[(1R, 2S)-2-fluorine ring third-1-yl]-8-methyl-4-oxo-1,4-dihydroquinoline-3-formic acid
[formula 349]
Under nitrogen atmosphere, close two palladiums (0) (414mg to three (dibenzalacetones), 0.452mmol) and 4, two (phenylbenzene) phosphino-s-9 of 5-, 9-dimethyl xanthene (522mg, 0.902mmol) 1, add 7-bromo-6-fluoro-1-[(1R in 4-diox (20.0ml) solution, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, and 4-dihydro-4-Oxoquinoline-3-ethyl formate (1.28g, 3.31mmol), (1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.2.0] heptane (693mg, 3.01mmol) and cesium carbonate (1.96g 6.02mmol), stirs mixture 14 hours at 95 ℃.Reaction mixture water (100ml) dilutes and extracts with ethyl acetate (100ml * 2).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (normal hexane-ethyl acetate; 100: 0 → 95: 5 → 90: 10 → 75: 25 → 5: 95 → 0: 100), obtain light yellow solid.Add 1mol/L aqueous sodium hydroxide solution (5.98ml) in this solid ethanol (15.9ml) solution in ice bath, mixture was at room temperature stirred 13 hours.Add 1mol/L aqueous hydrochloric acid (5.98ml) in this reaction soln in ice bath, organic layer is through concentrating under reduced pressure.Aqueous solution water (80ml) dilutes and extracts with ethyl acetate (100ml * 1,80ml * 1).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (chloroform-methanol; 100: 0 → 99: 1 → 98: 2 → 97: 3 → 96: 4 → 95: 5 → 94: 6 → 93: 7), obtain light yellow solid.In ice bath, the gained solid is dissolved in the concentrated hydrochloric acid (3.0ml), the aqueous solution washs with chloroform (40ml * 4).Add saturated sodium hydroxide solution in water layer, with pH regulator to 12.0, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Gained solution extracts with chloroform (250ml * 4).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates obtains title compound 690mg (56%) by from the ethyl alcohol recrystallization purifying, is light yellow solid.
Mp:＞272 ℃ (decomposition).
1H-NMR(400MHz，0.1N?NaOD)δ：8.49(1H，d，J＝2.2Hz)，7.70(1H，dd，J＝13.2，4.2Hz)，5.08-4.88(1H，m)，4.12-4.06(1H，m)，3.69-3.56(2H，m)，3.42-3.39(1H，m)，3.21-3.18(1H，m)，2.64(3H，d，J＝5.1Hz)，2.54-2.39(1H，m)，2.31-2.20(1H，m)，2.12-1.93(2H，m)，1.66-1.56(1H，m)，1.32-1.19(1H，m)。
C
20H
20F
3N
3O
3The analytical calculation value: C, 58.96; H, 4.95; F, 13.99; N, 10.31.Measured value: C, 58.76; H, 4.88; F, 14.11; N, 10.28.
MS(ESI)m/z：408(M+H)
+。
IR(ATR)：3089，2980，2936，2862，2837，1719，1614，1544，1506，1474，1454，1432，1350，1318，1268，1231，1213，1181，1159，1140，1093，1058，1047，1021，1009，977，962，930，898，864，837，805cm
-1。
[embodiment 57]
7-[6-amino-8-aza-tricycle [4.3.0.0
1,3
] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third
-1-yl]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-formic acid mesylate
[formula 350]
To 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine ring third-1-yl]-8-methoxyl group-4-oxo-1, (2.24g adds methylsulfonic acid (0.316ml in the suspension of ethanol 4.82mmol) (48.2ml) to 4-dihydroquinoline-3-formic acid, 4.87mmol), mixture was at room temperature stirred 15 hours.Add entry (5ml) in this reaction soln, the gained mixture is through concentrating under reduced pressure.In this resistates, add 2-propyl alcohol (20ml), mixture was at room temperature stirred 15 hours.Filter the solid of collecting precipitation.Solid washs with excessive 2-propyl alcohol, obtains title compound 2.41g (95%), is light yellow solid.
mp：202-204℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.39(1H，d，J＝2.9Hz)，7.64(1H，d，J＝14.4Hz)，5.09-4.93(1H，m)，4.21(1H，dd，J＝10.0，2.7Hz)，3.97(1H，dt，J＝10.0，4.6Hz)，3.72(1H，dd，J＝10.6，2.7Hz)，3.53(3H，s)，3.39(1H，d，J＝10.3Hz)，3.18(1H，d，J＝10.3Hz)，2.83(3H，s)，1.99-1.85(2H，m)，1.73(1H，dd，J＝12.2，8.5Hz)，1.56-1.46(1H，m)，1.39-1.23(2H，m)，1.17-1.13(1H，m)，0.79-0.74(2H，m)。
C
22H
23F
2N
3O
4CH
4O
3S0.5H
2The analytical calculation value of O: C, 51.49; H, 5.26; F, 7.08; N, 7.83; S, 5.98.Measured value: C, 51.21; H, 5.20; F, 7.44; N, 7.82; S, 6.00.
MS(ESI)m/z：432(M+H)
+。
IR(ATR)：3412，2944，2878，1694，1617，1597，1536，1513，1437，1361，1330，1315，1297，1273，1219，1167，1135，1109，1040，952，925，883，805cm
-1。
[embodiment 58]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-
The fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid mesylate
[formula 351]
To 7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid (4.50g, 10.7mmol) ethanol (90ml) suspension in add methylsulfonic acid (0.695ml, 10.7mmol), mixture was at room temperature stirred 30 minutes.Mixture water (20ml) dilutes, and steams through decompression.Purifying obtains the 4.96g title compound to resistates by slurrying in the 2-propyl alcohol, is buff powder.
1H-NMR(400MHz，0.1N?NaOD)δ：8.48(1H，d，J＝2.9Hz)，7.72(1H，d，J＝13.7Hz)，5.11-4.86(1H，m)，4.15-4.07(1H，m)，3.93-3.81(1H，m)，3.60-3.31(3H，m)，2.82(3H，s)，.62(3H，s)，2.16-1.98(3H，m)，1.92-1.55(4H，m)，1.33-1.19(1H，m)。
MS(FAB)；m/z：422(M+H)
+。
C
21H
22F
3N
3O
3CH
3SO
3H1.75H
2The analytical calculation value of O: C, 48.13; H, 5.42; F, 10.38; N, 7.65; S, 5.84.Measured value: C, 47.81; H, 5.09; F, 10.43; N, 7.63; S, 5.75.
IR(ATR)v：3442，2871，1709，1615，1509，1432，1370，1319，1265，1161，1038，971，929，892，853，806cm
-1。
[reference example 226]
(3aS)-and 1-hydroxyl-6-oxo-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) [3,4-c] pyrroles-3a-first also
Tert-butyl acrylate
[formula 352]
With (3aS, 7aS)-the 1-oxo-2-[(R)-the 1-phenylethyl]-1,2,3, the 7a-tetrahydropyrans also [3,4-c] pyrroles-3a-t-butyl formate (4.0g, 11.6mmol), N-methylmorpholine-N-oxide compound (2.95g, 22.0mmol) and the mixture of perosmic anhydride (catalytic amount) be dissolved in the trimethyl carbinol (20ml) and the water (10ml), at room temperature stirred 3 days.Reaction mixture is with the AcOEt dilution and add 10% sodium thiosulfate solution.Separate each layer, water layer extracts with AcOEt.The saturated NaHCO of extraction liquid that merges
3The aqueous solution, salt water washing, dry (Na
2SO
4) and vacuum concentration, obtain Vandyke brown oily matter (4.4g).Crude product (2.6g) is dissolved in tetrahydrofuran (THF) (60ml) and the water (30ml), adds sodium periodate (2.6g).Reaction mixture at room temperature stirred 18 hours, with AcOEt and water dilution.Separate each layer, water layer extracts with AcOEt.The saturated NaHCO of extraction liquid that merges
3The aqueous solution, salt water washing, dry (Na
2SO
4) and vacuum concentration.Resistates is dissolved in ethanol and tetrahydrofuran (THF) (20ml; 17: 3) in, drip the 1N NaOH aqueous solution (5.2ml) at 0 ℃.Mixture was at room temperature stirred 3 hours, and then add the 1N NaOH aqueous solution (2.2ml), reaction mixture restir 1 hour.After the solvent removed in vacuo, the gained resistates distributes between AcOEt and water, the water layer extraction.The saturated NaHCO of extraction liquid that merges
3The aqueous solution, salt water washing, dry (Na
2SO
4) and vacuum concentration.The gained resistates is by the silica gel chromatography purifying, and the hexane wash-out with 50%AcOEt obtains title compound (1.10g), is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.25(5H，m)，5.71(1H，d，J＝7.3Hz)，5.66-5.44(1.2H，m)，4.96(0.2H，d，J＝7.3Hz)，4.49(0.8H，d，J＝9.6Hz)，4.25(0.2H，d，J＝9.6Hz)，4.00(0.2H，d，J＝9.2Hz)，3.90(0.8H，d，J＝9.2Hz)，3.64(0.8H，d，J＝7.3Hz)，3.38-3.24(3H，m)，1.54-1.38(12H，m)。
MS(ESI)m/z：348(M+H)
+。
[reference example 227]
(3S)-3,4-two (methylol)-5-oxo-1-[(R)-1-phenylethyl] tetramethyleneimine-3-t-butyl formate
[formula 353]
To (3aS)-1-hydroxyl-6-oxo-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) [3,4-c] pyrroles-3a-t-butyl formate (350mg, tetrahydrofuran (THF) 1.01mmol) and ethanol (10ml also; 4: 1) cooling solution (20 ℃) in add sodium borohydride in batches (38.0mg 1.00mmol), stir mixture 5.5 hours under same temperature.Reaction mixture is dissolved in AcOEt and the water through vacuum concentration.Separate each layer, water layer extracts with AcOEt.The extraction liquid salt water washing that merges, dry (Na
2SO
4) and vacuum concentration.Resistates is by the silica gel chromatography purifying, and the hexane wash-out with 90%AcOEt obtains title compound (153mg), is colorless oil.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.25(5H，m)，5.50(1H，q，J＝7.0Hz)，4.19-3.80(4H，m)，3.40-3.05(5H，m)，1.52(3H，d，J＝7.0Hz)，1.40(9H，s)。
MS(ESI)m/z：350(M+H)
+。
[reference example 228]
(3aS)-and 6-oxo-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) [3,4-c] pyrroles-3a-t-butyl formate also
[formula 354]
To (3S)-3,4-two (methylol)-5-oxo-1-[(R)-the 1-phenylethyl] tetramethyleneimine-3-t-butyl formate (710mg, 2.03mmol) and triphenyl phosphine (450mg, 2.64mmol) cooling (0 ℃) solution of tetrahydrofuran (THF) (10ml) in, drip 40% diethyl azodiformate toluene solution (1.06ml, 2.33mmol).Allow reaction mixture be warming up to room temperature and stirred 6 hours.Mixture is through vacuum concentration.Resistates is by the silica gel chromatography purifying, and the hexane wash-out with 40%AcOEt obtains title compound (435mg), is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.39-7.25(5H，m)，5.48(1H，q，J＝7.2Hz)，4.32-4.26(1H，m)，4.01(1H，d，J＝9.6Hz)，3.97-3.91(1H，m)，3.85(1H，d，J＝9.6Hz)，3.43(1H，d，J＝10.1Hz)，3.37-3.32(1H，m)，3.26(1H，d，J＝10.1Hz)，1.54(3H，d，J＝6.9Hz)，1.38(9H，br?s)。
MS(ESI)m/z：332(M+H)
+。
[reference example 229]
[(3aS)-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) is [3,4-c] pyrroles-3a-yl also] carboxylamine uncle fourth
Ester
[formula 355]
To [(3aS)-6-oxo-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) also [3,4-c] pyrroles-3a-yl] t-butyl carbamate (820mg, 2.47mmol) methylene dichloride (8ml) solution in add trifluoroacetic acid (8ml), mixture was at room temperature stirred 2 hours.Solvent removed in vacuo is also drained with pump, obtains white solid (680mg).
At 0 ℃, with 1,1 '-carbonyl is two-and (480mg 2.94mmol) joins in acetonitrile (10ml) solution of crude product (540mg) the 1H-imidazoles, and mixture was stirred 1 hour under same temperature, is warming up to room temperature then.Ammonia is fed reaction mixture reach 30 minutes, solvent is through vacuum concentration.The gained resistates is dissolved in the methylene dichloride, with 1N HCl, saturated NaHCO
3The aqueous solution and salt water washing, dry (Na
2SO
4) and vacuum concentration, obtain white solid (536mg).
(1.73g 3.90mmol), ℃ reaches mixture heating up to 100 at 5 hours to add lead tetraacetate in the suspension of the trimethyl carbinol (20ml) of white solid (536mg).Allow reaction mixture be cooled to room temperature,, and add sodium bicarbonate (3g) with ether (200ml) dilution.Stir after 30 minutes, leach precipitation.Vacuum concentrated filtrate, resistates are dissolved in the methylene dichloride, use saturated NaHCO
3The aqueous solution and salt water washing, dry (Na
2SO
4) and vacuum concentration.Obtain crude product (620mg, white solid).
Trifluoroacetic acid (6ml) is joined in methylene dichloride (6ml) solution of crude product (200mg), reaction mixture was stirred 1 hour, then solvent removed in vacuo and drain with pump.Products therefrom can be used for next step.
(2.3mmol), gained mixture heating up to 60 ℃ reaches 1 hour for 65% toluene solution, 690 μ L slowly to add two (2-methoxy ethoxy) sodium aluminum hydrides in toluene (6ml) solution of this product.Reaction mixture is cooled to room temperature, adds the 5N NaOH aqueous solution then and stirs 1 hour.Separate each layer, water layer extracts with toluene.The extraction liquid salt water washing that merges, dry (Na
2SO
4) and vacuum concentration.Crude product (540mg) need not purifying and just can use.
Tert-Butyl dicarbonate (589mg) is joined in methylene dichloride (6ml) solution of crude product, mixture was stirred 18 hours solvent removed in vacuo.Resistates is by the silica gel chromatography purifying, and the hexane wash-out with 30%AcOEt obtains title compound (150mg), is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.31-7.21(5H，m)，5.00(1H，s)，4.09-3.78(3H，m)，3.53(1H，dd，J＝8.7，4.6Hz)，3.27(1H，q，J＝6.7Hz)，2.78-2.65(3H，m)，2.50-2.36(2H，m)，1.42(9H，s)，1.33(3H，d，J＝6.4Hz)。
MS(ESI)m/z：333(M+H)
+。
[reference example 230]
(3aS)-(tetrahydrofuran (THF) is [3,4-c] pyrroles-3a-yl also) t-butyl carbamate
[formula 356]
Will [(3aS)-5-[(R)-1-phenylethyl] tetrahydrofuran (THF) [3,4-c] pyrroles-3a-yl also] t-butyl carbamate (and 355mg, 1.06mmol) be dissolved in the diox (10ml) and add 20% palladium hydroxide catalyzer (the 20wt.% palladium on carbon, wet; Catalytic amount).Mixture is under nitrogen atmosphere, 40 ℃ of vigorous stirring 24 hours.Remove by filter after the catalyzer, filtrate decompression is concentrated.Resistates is dissolved in methylene dichloride, and with the 1N NaOH aqueous solution and salt water washing.Organic layer is through anhydrous sodium sulfate drying, and solvent removed in vacuo obtains rough title compound (243mg), is colourless syrup shape thing.
MS(ESI)m/z：229(M+H)
+。
[embodiment 59]
7-[(3aS)-3a-amido tetrahydrofuran [3,4-c] pyrroles-5-yl also]-6-fluoro-1-[(1R, 2S)-2-fluorine ring
Propyl group]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 357]
To 6,7-two fluoro-1-[(2S, 1R)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-boron difluoride complex compound (426mg, 1.18mmol) dimethyl sulfoxide (DMSO) (6ml) solution in, add (S)-(tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third is [c] pentalene-3a-yl also) t-butyl carbamate (270mg, 1.18mmol) and triethylamine (0.50ml, 3.54mmol), the gained mixture stirred 17 hours at 40 ℃.Reaction soln is dissolved in enriched material in second alcohol and water (9: the 1) mixing solutions (150ml) through vacuum concentration.After adding triethylamine (5ml), mixture heating up was refluxed 5 hours.Reaction mixture is through concentrating under reduced pressure, and enriched material is dissolved among the AcOEt (100ml * 2), and washs with 10% aqueous citric acid solution (100ml) and salt solution (100ml).Organic layer is through anhydrous sodium sulfate drying, and decompression steams solvent.By the silica gel column chromatography purifying (CHCl of 3%MeOH
3) after, in ice bath, the gained solid being dissolved in the concentrated hydrochloric acid (5ml), the aqueous solution washs with chloroform (50mlx 3).Add the 10mol/L aqueous sodium hydroxide solution in water layer, regulate pH to 12.0, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Solution extracts with chloroform (100ml * 6), and the extraction liquid of merging is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates is further purified from ethyl alcohol recrystallization by the preparative chromatography purifying again, and drying under reduced pressure obtains title compound (220mg) then, is pale yellow crystals.
mp：201-202℃。
1H-NMR(400MHz，CDCl
3)δ：8.76(1H，d，J＝1.4Hz)，7.87(1H，d，J＝12.8Hz)，4.92-4.71(1H，m)，4.27(1H，dd，J＝9.2，7.3Hz)，3.93-3.57(11H，m)，2.57-2.49(1H，m)，1.68-1.47(2H，m)。
C
20H
21F
2N
3O
5H
2The analytical calculation value of O: C, 54.67; H, 5.28; N, 9.56; F, 8.65.Measured value: C, 54.52; H, 5.18; N, 9.58; F, 8.73.
MS(ESI)m/z：422(M+H)
+。
IR(ATR)v：3301，2974，2847，1722，1614，1580，1516，1447，1403，1378，1365，1355，1340，1316，1289，1265cm
-1。
[embodiment 60]
7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-
The fluorine cyclopropane]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid
[formula 358]
Close two palladiums (0) (7.75g to three (dibenzalacetones), 8.46mmol), 4,5-two (phenylbenzene) phosphino--9,9-dimethyl xanthene (14.7g, 25.4mmol), 7-bromo-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-ethyl formate (14.2g, 36.8mmol) and (1R, 5S)-1-(tert-butoxycarbonyl amino)-5-fluoro-3-azabicyclo [3.3.0] octane (6.90g, 28.2mmol) 1, add cesium carbonate (18.4g in 4-diox (345ml) solution, 56.5mmol), the gained mixture is under nitrogen atmosphere, stirred 23 hours at 110 ℃.Reaction mixture water (400ml) dilutes and extracts with ethyl acetate (600ml * 1,250ml * 1).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (chloroform-methanol; 100: 0 → 99.5: 0.5 → 99.25: 0.75 → 99: 1), obtain solid.In ice bath, in this solid ethanol (273ml) solution, add 1mol/L aqueous sodium hydroxide solution (68.2ml), mixture was at room temperature stirred 1 hour.In this reaction soln, add ethanol (327ml) and 1mol/L aqueous sodium hydroxide solution (27.3ml), mixture was at room temperature stirred 13 hours.In ice bath, in this reaction soln, add 1mol/L aqueous hydrochloric acid (95.5ml), organic layer is through concentrating under reduced pressure.Aqueous solution water (150ml) dilutes and extracts with chloroform (250ml * 1,150ml * 1).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is by silica gel column chromatography purifying (normal hexane-ethyl acetate; 100: 0 → 2: 1 → 1: 1 → 1: 1.5 → 1: 1.7 → 1: 1.85 → 1: 2 → 1: 5 → 1: 9 → 0: 100), obtain light yellow solid.In ice bath, solid is dissolved in the concentrated hydrochloric acid (30ml), the aqueous solution washs with chloroform (100ml * 5).In water layer, add saturated sodium hydroxide solution, regulate pH to 12.0.Add entry (1.8L) in this solution, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Solution extracts with chloroform (1.5l * 1,800ml * 1).Organic layer is through anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates is light yellow solid by from 2-propyl alcohol/methyl alcohol=10/1 recrystallization and purifying obtains title compound 6.14g (52%).All spectroscopic datas of this compound all prove very consistent with those of embodiment 17.
[reference example 231]
(3aS)-the 6-oxo-5-[(R)-the 1-phenylethyl]-5,6-dihydro-4H-furo [3,4-c] pyrroles-3a-first
Tert-butyl acrylate
[formula 359]
At-10 ℃, to (3aS)-(tetrahydrofuran (THF) also [3,4-c] pyrroles-3a-yl) t-butyl formate (8.80g, 25.0mmol) and methylene dichloride (75ml) solution of triethylamine (7.8ml) in drip methane sulfonyl chloride (3.13ml, 40.0mmol), mixture was stirred 1.5 hours under same temperature, and then add triethylamine (7.8ml).Reaction mixture is heated to 40 ℃ and stirred 5 days.After being cooled to room temperature, solvent removed in vacuo, resistates is by the silica gel chromatography purifying, and the mixing solutions wash-out with AcOEt, hexane and triethylamine (40: 60: 0.5) obtains title compound (2.56g, white solid).
1H-NMR(400MHz，CDCl
3)δ：7.38-7.25(5H，m)，7.08(1H，s)，5.48(1H，q，J＝6.9Hz)，5.03(1H，d，J＝9.6Hz)，4.25(1H，d，J＝9.6Hz)，3.43(1H，d，J＝10.1Hz)，3.26(1H，d，J＝10.1Hz)，1.38(3H，d，J＝6.9Hz)，1.30(9H，s)。
MS(ESI)m/z：330(M+H)
+。
[reference example 232]
(S)-and 6-oxo-5-[(R)-1-phenylethyl] tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third also [c] and encircle penta 2
Alkene-3a-t-butyl formate
[formula 360]
At-10 ℃, to the zinc ethyl (hexane solution of 1M, 22.3ml) methylene dichloride (75ml) solution in drip methylene iodide (1.79ml, 22.3mmol), mixture was stirred 15 minutes under same temperature, at-10 ℃, adding (S)-6-oxo-5-[(R)-the 1-phenylethyl]-5, the dichloromethane solution of 6-dihydro-4H-furo [3,4-c] pyrroles-3a-t-butyl formate, the gained compound at room temperature stirred 8 hours.Reaction mixture is with 10% aqueous citric acid solution quencher.Separate each layer, the water layer dichloromethane extraction.The saturated NaHCO of organic layer that merges
3The aqueous solution and salt water washing, dry (Na
2SO
4) and vacuum concentration.Resistates is by the silica gel chromatography purifying, and the hexane wash-out with 30%AcOEt obtains title compound (1.96g), is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.38-7.25(5H，m)，5.54(1H，q，J＝7.0Hz)，4.45(1H，d，J＝9.2Hz)，4.24(1H，dd，J＝5.5，2.8Hz)，4.14(1H，d，J＝9.2Hz)，3.51(1H，d，J＝10.1Hz)，3.40(1H，d，J＝10.1Hz)，1.73-1.67(1H，m)，1.58-1.53(4H，m)，1.33(9H，s)。
MS(ESI)m/z：344(M+H)
+。
[reference example 233]
[(S)-5-[(R)-1-phenylethyl] tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third is [c] pentalene-3a-also
Base] t-butyl carbamate
[formula 361]
To (S)-6-oxo-5-[(R)-1-phenylethyl] tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third [c] pentalene-3a-t-butyl formate (880mg also, 2.56mmol) methylene dichloride (7ml) solution in add trifluoroacetic acid (8ml), mixture was at room temperature stirred 2 hours.Solvent removed in vacuo obtains white solid (800mg).
At-0 ℃, with 1,1 '-carbonyl is two-and (677mg 4.18mmol) joins in acetonitrile (15ml) solution of white solid (800mg) the 1H-imidazoles, and mixture was stirred 1 hour under same temperature, allows it be warming up to room temperature then.Ammonia fed reach 30 minutes in the reaction mixture, solvent is through vacuum concentration.The gained resistates is dissolved in the methylene dichloride, with 1N HCl, saturated NaHCO
3The aqueous solution and salt water washing, dry (Na
2SO
4) and vacuum concentration, obtain white solid (750mg).
(558mg, 1.26mmol), gained mixture heating up to 100 ℃ reaches 5 hours to add lead tetraacetate in the suspension of the trimethyl carbinol (5ml) of white solid (120mg).Allow reaction mixture be cooled to room temperature, with ether (50ml) dilution and adding sodium bicarbonate (1g).Stir after 30 minutes, leach solid.Filtrate is removed through vacuum, and resistates is dissolved in the methylene dichloride, uses saturated NaHCO
3The aqueous solution and salt water washing, dry (Na
2SO
4) and vacuum concentration.Crude product just need not to be further purified and can use.
Trifluoroacetic acid (6ml) is joined in methylene dichloride (5ml) solution of crude product, reaction mixture was stirred 1 hour, solvent removed in vacuo is drained with pump then.Products therefrom can be used for next step.
(2.0mmol), gained mixture heating up to 60 ℃ reaches 1 hour for 65% toluene solution, 600 μ L slowly to add two (2-methoxy ethoxy) sodium aluminum hydrides in toluene (4ml) solution of this product.Reaction mixture is cooled to room temperature and adds the 5N NaOH aqueous solution, stirred then 1 hour.Separate each layer, water layer extracts with toluene.The extraction liquid salt water washing that merges, dry (Na
2SO
4) and vacuum concentration.Crude product just need not to be further purified and can use.
Tert-Butyl dicarbonate (163mg) is joined in methylene dichloride (6ml) solution of crude product, mixture was stirred 18 hours solvent removed in vacuo.Resistates is by the silica gel chromatography purifying, and the hexane wash-out with 25%AcOEt obtains title compound (140mg), is white solid.
1H-NMR(400MHz，CDCl
3)δ：7.36-7.19(5H，m)，4.92(1H，s)，4.20(1H，d，J＝9.6Hz)，3.98-3.85(2H，m)，3.43(1H，q，J＝6.6Hz)，2.99(1H，d，J＝8.7Hz)，2.81-2.62(3H，m)，1.40(9H，s)，1.35(3H，d，J＝6.6Hz)，1.19(1H，d，J＝6.4Hz)，0.91(1H，t，J＝5.7Hz)。
MS(ESI)m/z：345(M+H)
+。
[reference example 234]
(S)-(tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third is [c] pentalene-3a-yl also) t-butyl carbamate
[formula 362]
Will [(S)-5-[(R)-1-phenylethyl] tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third [c] pentalene-3a-yl also] t-butyl carbamate (480mg, 1.39mmol) be dissolved in the diox (10ml) and add 20% palladium hydroxide catalyzer (the 20wt.% palladium on carbon, wet; Catalytic amount).With mixture vigorous stirring 3 days under nitrogen atmosphere, room temperature.Remove by filter after the catalyzer, filtrate decompression is concentrated.Resistates is dissolved in the methylene dichloride, with the 1N NaOH aqueous solution and salt water washing.Organic layer obtains rough title compound (280mg, white solid) through anhydrous sodium sulfate drying and solvent removed in vacuo.
MS(ESI)m/z：241(M+H)
+。
[embodiment 61]
7-[(3aS)-3a-amino-5-azepine-oxa-tetrahydrochysene ring pentalene-5-yl]-the 6-fluorine
-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid
[formula 363]
To 6,7-two fluoro-1-[(2S, 1R)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid-boron difluoride complex compound (361mg, 1.00mmol) dimethyl sulfoxide (DMSO) (5ml) solution in add (S)-(tetrahydrochysene-2-oxa--5-nitrogen heterocyclic third is [c] pentalene-3a-yl also) t-butyl carbamate (250mg, 1.08mmol) and triethylamine (0.50ml 3.54mmol), at room temperature stirred mixture 2 days.Reaction soln is through vacuum concentration, and enriched material is dissolved in the mixing solutions (150ml) of second alcohol and water (9: 1).After adding triethylamine (5ml), mixture heating up was refluxed 5 hours.Reaction mixture is through concentrating under reduced pressure, and enriched material is dissolved among the AcOEt (100ml * 2), and washs with 10% aqueous citric acid solution (100ml) and salt solution (100ml).Organic layer is through anhydrous sodium sulfate drying, and decompression steams solvent.By the silica gel chromatography purifying (CHCl of 5%MeOH
3) after, resistates is dissolved in the concentrated hydrochloric acid (5ml) in the ice bath, the aqueous solution is with chloroform (50ml * 3) washing.Add the 10mol/L aqueous sodium hydroxide solution in water layer, regulate pH to 12.0, alkaline aqueous solution is adjusted to pH 7.4 with hydrochloric acid.Solution extracts with chloroform (100ml * 6), and the extraction liquid of merging is through anhydrous sodium sulfate drying, and decompression steams solvent.Resistates is by the preparative chromatography purifying, and again by being further purified from ethyl alcohol recrystallization, drying under reduced pressure obtains title compound (135mg) then, is light yellow needle-like crystal.
mp：189-191℃。
1H-NMR(400MHz，0.1N?NaOD)δ：8.42(1H，d，J＝2.8Hz)，7.71(1H，d，J＝13.8Hz)，5.13-4.89(1H，m)，4.17-4.01(4H，m)，3.94(1H，dd，J＝10.5，2.3Hz)，3.67(3H，s)，3.64-3.47(3H，m)，1.63-1.37(3H，m)，1.02(1H，dd，J＝7.8，5.5Hz)。
C
21H
21F
2N
3O
51.25H
2The analytical calculation value of O: C, 55.32; H, 5.20; N, 9.22; F, 8.33.Measured value: C, 55.48; H, 5.12; N, 9.00; F, 8.61.
MS(ESI)m/z：434(M+H)
+。
IR(ATR)v：3358，3076，2941，2879，1721，1620，1513，1437，1367，1323，1274cm
-1。
[experimental example 1]
According to the standard method of Japanese chemotherapy meeting (Japanese Society of Chemotherapy) defined, measured the anti-microbial activity of The compounds of this invention.The results are shown in MIC (μ g/ml) (table 2).
For the MIC value with The compounds of this invention compares, table 2 has provided the 7-[3-(R) that discloses among the WO02/40478-(the amino cyclopropyl of 1-) tetramethyleneimine-1-yl simultaneously]-8-cyano group-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1, following formula), the MIC value of levofloxacin (LVFX), Ciprofloxacin (CPFX) and Moxifloxacin (MXFX) 4-dihydro-4-Oxoquinoline-3-formic acid (control drug 1:.
The concrete illustrational compound of " description of association area " part at EP-A-343524 is representative with the following formula:
[formula 364]
Has in two optically active isomers of its 7-bit substituent.It is the compound of representative that the present inventor has synthesized with the following formula:
[formula 365]
It has (1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-base, just high activity isomer of its 7-bit substituent.Verified, in the mouse bone marrow cells micronucleus test, after intravenously gives, be that the compound of representative is positive to inducing of micronucleus with formula 365.That is to say that this compound is considered to have genetoxic (genotoxic).In addition, find also in the mouse Phototoxicity experiment that after intravenously gave, this compound was positive to phototoxicity.On the other hand, find that embodiment is 11 described, in above two tests, all be negative as the compound of representative compounds of the present invention.That is to say that described compound is considered to weak genetoxic and does not have phototoxicity, is foolproof as the human medicine therefore.
Claims (46)
1. one kind is compound, its salt or the hydrate of representative with following formula (I),
R wherein
1Represent hydrogen atom, have the alkyl of 1-6 carbon atom, have the cycloalkyl of 3-6 carbon atom, perhaps derived from the substituted carbonyl of amino acid, dipeptides or tripeptides; Described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, cyano group, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;
R
2Represent hydrogen atom, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;
R
3And R
4The independent alkyl of representing hydrogen atom or having 1-6 carbon atom, described alkyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom;
R
5Represent hydrogen atom, halogen atom, alkyl with 1-6 carbon atom, alkoxyl group with 1-6 carbon atom, thiazolinyl with 2-6 carbon atom, alkynyl with 2-6 carbon atom, have 3-6 carbon atom and can have substituent cycloalkyl, have 6-10 carbon atom and can have substituent aryl and maybe can have substituent heteroaryl, described alkyl, thiazolinyl and alkynyl can be straight or brancheds, described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, alkylthio and alkoxyl group with 1-6 carbon atom with 1-6 carbon atom, and described thiazolinyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom;
R
6And R
7The carbon atom that is connected with them is combined together to form 4-7 unit ring texture, described ring texture representative forms the part-structure that condenses ring-type (dicyclo) structure with pyrrolidine ring, the first ring texture of described 4-7 can contain two keys also can contain Sauerstoffatom or the sulphur atom composed atom as ring
R
5Can be methylene radical, its can with R
6Be combined together to form 3 yuan and condense the ring-type structure division, and this condenses ring texture and can be positioned at the described other parts that condense ring-type (dicyclo) structure, and the described ring that forms as mentioned above can be positioned at the described other parts that condense ring-type (dicyclo) structure, and described 4-7 unit ring texture can have one or more following substituting groups that are selected from: have 1-6 carbon atom and also can have substituent alkyl, have 1-6 carbon atom and can have substituent alkoxyl group, have 2-6 carbon atom and can have substituent thiazolinyl, have 2-6 carbon atom and can have substituent alkynyl, have 3-6 carbon atom and can have substituent cycloalkyl, can have substituent outer methylene radical, can have substituent spirane base, have 6-10 carbon atom and can have substituent aryl, can have substituent heteroaryl, have 1-6 carbon atom and can have substituent Alkoximino, halogen atom, hydroxyl, cyano group and oxyimino; Perhaps have 2-5 carbon atom polymethylene chain can in conjunction with and form spiro system; With
The Q representative is the part-structure of representative with following formula (II):
R wherein
8Representative have 1-6 carbon atom alkyl, have 2-6 carbon atom thiazolinyl, have alkyl that the halogen of 1-6 carbon atom replaces, have 3-6 carbon atom also can have substituent cycloalkyl, can have substituent halogen replacement phenyl, can have substituent halogen replacement heteroaryl, have the alkoxyl group of 1-6 carbon atom or have the alkylamino of 1-6 carbon atom;
R
9Represent hydrogen atom or have the alkylthio of 1-6 carbon atom, perhaps R
9And R
8The atom that links to each other with them is combined together to form ring texture, and described ring texture can contain the composed atom of sulphur atom as ring, and the alkyl of halogen replacement that can have the alkyl that contains 1-6 carbon atom or contain 1-6 carbon atom is as substituting group;
R
10Represent hydrogen atom, phenyl, acetoxy-methyl, valeryl oxygen ylmethyl, ethoxy carbonyl, choline base, dimethyl aminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo butyl, have 1-6 carbon atom alkyl, have the alkoxy methyl of 2-7 carbon atom or by the alkylidene group with 1-6 carbon atom and phenyl and the phenylalkyl that forms;
R
11Represent hydrogen atom, amino, hydroxyl, thiol group, halogenated methyl or have the alkyl of 1-6 carbon atom, described amino can have one or two and be selected from following substituting group: formyl radical, have the alkyl of 1-6 carbon atom and have the acyl group of 2-5 carbon atom;
X
1Represent halogen atom or hydrogen atom;
A
1Represent nitrogen-atoms or be the part-structure of representative with following formula (III):
X wherein
2The methyl or the halogenated methoxy that represent hydrogen atom, have the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, cyano group, halogen atom, halogen replace, perhaps X
2And R
8Be combined together to form ring texture with their precursor skeleton connection portion, described ring texture can contain Sauerstoffatom, nitrogen-atoms or the sulphur atom composed atom as ring, and can be had 1-6 carbon atom and can have substituent alkyl replacement; With
A
2And A
3Represent nitrogen-atoms or carbon atom separately, and A
1, A
2, A
3, R
8And A
2With A
3The carbon atom that is connected is represented following part-structure together:
＞C＝C(-A
1＝)-N(-R
8)-
Or following part-structure:
＞N-C(-A
1＝)＝C(-R
8)-。
2. the compound of claim 1, its salt or hydrate are that the compound of representative is to be the compound of representative with the following formula with formula (I) wherein:
Or be the compound of representative with the following formula:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7With Q such as claim 1 definition.
3. the compound or its salt of claim 1 or its hydrate are that the compound of representative is to be the compound of representative with the following formula with formula (I) wherein:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7With Q such as claim 1 definition.
4. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) are the structure of representative:
Or be the structure of representative with the following formula:
R wherein
8, R
9, R
10, R
11, X
1And A
1Such as claim 1 definition.
5. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) are the structure of representative:
R wherein
8, R
9, R
10, R
11, X
1And A
1Such as claim 1 definition.
6. claim 1,2 or 3 compound, its salt or hydrate, wherein in formula (I), R
1And R
2The hydrogen atom of respectively doing for oneself.
7. claim 1,2 or 3 compound, its salt or hydrate, wherein in formula (I), R
1And R
2In one be hydrogen atom, another is to be selected from following substituting group: methyl, ethyl, sec.-propyl, fluoro ethyl, cyano ethyl, cyclopropyl and cyclobutyl.
8. each compound, its salt or hydrate among the claim 1-7, wherein in formula (I), R
3And R
4The hydrogen atom of respectively doing for oneself.
9. each compound, its salt or hydrate among the claim 1-8, wherein in formula (I), R
5Be hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, sec.-propyl, cyclopropyl, methyl fluoride, fluoro ethyl, trifluoromethyl, methoxymethyl, vinyl, ethynyl, methoxyl group, Ben Ji Huo oxazole-2-base.
10. each compound, its salt or hydrate among the claim 1-9 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 4 yuan of rings, and it can be replaced by one or more substituting groups.
11. each compound, its salt or hydrate among the claim 1-9 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, it can be replaced by one or more substituting groups.
12. each compound, its salt or hydrate in claim 1-9 and 11 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is to contain two keys as 5 yuan of rings or 6 yuan of rings of forming structure, and it can be replaced by one or more substituting groups.
13. each compound, its salt or hydrate among claim 1-9 and the 11-12 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is to contain Sauerstoffatom 5 yuan of composed atom rings or 6 yuan of rings as ring.
14. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the cis-condensed-bicyclic structure of representative:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7With Q such as claim 1 definition.
15. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the trans-condensed-bicyclic structure of representative:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7With Q such as claim 1 definition.
16. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R
6And R
7The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, R
5And R
6Be combined together to form two key part-structures, the gained ring texture is representative with the following formula:
R wherein
1, R
2, R
3, R
4, R
7As above define with Q.
17. each compound, its salt or hydrate among the claim 1-16 are among the part-structure Q of representative with formula (II) in formula (I) wherein, X
1Be hydrogen atom or fluorine atom.
18. each compound, its salt or hydrate among the claim 1-17 are among the part-structure Q of representative with formula (II) in formula (I) wherein, X
1Be fluorine atom.
19. each compound, its salt or hydrate among the claim 1-18 are among the part-structure Q of representative with formula (II) in formula (I) wherein, A
1Be nitrogen-atoms.
20. each compound, its salt or hydrate among the claim 1-18 are among the part-structure Q of representative with formula (II) in formula (I) wherein, A
1For being the part-structure of representative with formula (III).
21. each compound, its salt or hydrate among the claim 1-18, wherein in formula (III), X
2Be methyl, ethyl, methoxyl group, difluoro-methoxy, cyano group or chlorine atom.
22. each compound, its salt or hydrate among the claim 1-18, wherein in formula (III), X
2Be methyl or methoxy.
23. each compound, its salt or hydrate among the claim 1-22 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8Be 1,2-is suitable-the 2-halogenated cyclopropyl.
24. each compound, its salt or hydrate among the claim 1-22 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8Single 1 for stereochemistry, 2-is suitable-the 2-halogenated cyclopropyl.
25. the compound of claim 24, its salt or hydrate are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
81,2-is suitable-the 2-halogenated cyclopropyl be (1R, 2S)-the 2-halogenated cyclopropyl.
26. the compound of claim 25, its salt or hydrate are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
8(1R, 2S)-the 2-halogenated cyclopropyl be (1R, 2S)-2-fluorine cyclopropyl.
27. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, Q is for being the compound of representative with the following formula:
R wherein
9, R
10, R
11And X
1Such as claim 1 definition, Y
0Be methyl or methyl fluoride.
28. each compound, its salt or hydrate among the claim 1-27 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
9Be hydrogen atom.
29. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, Q is to be the compound of representative with following formula (IV):
R wherein
10And X
1Such as claim 1 definition, Y
0Be methyl or methyl fluoride.
30. the compound or its salt of claim 29 or its hydrate, wherein in formula (IV), Y
0Be methyl.
31. each compound, its salt or hydrate among the claim 1-30 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R
10Be hydrogen atom.
32. each compound, its salt or hydrate among the claim 1-31 are that the compound of representative is a stereochemistry simplification compound with formula (I) wherein.
33. the compound of claim 1, its salt or hydrate, wherein in formula (I), Q has following structure:
(1) 7-carboxyl-9-cyclopropyl-3-fluoro-6 (H)-6-oxo pyridine [1,2-a] pyrimidine-4-base also;
(2) 3-carboxyl-1-cyclopropyl-7-fluoro-9-methyl-4 (H)-4-oxo quinolizine-8-base;
(3) 5-carboxyl-9-fluoro-2,3-dihydro-3-(R)-methyl-6 (H)-6-oxo pyrans is [2,3,4-ij] quinolizine-10-base also;
(4) 1-(6-amino-3,5-difluoro pyridine-2-yl)-8-chloro-3-carboxyl-6-fluoro-1,4-dihydro-4-quinoline-7-base;
(5) 1-(6-amino-3,5-difluoro pyridine-2-yl)-3-carboxyl-6-fluoro-1,4-dihydro-8-methyl-4-quinoline-7-base;
(6) 6-carboxyl-9-fluoro-3-(R)-methyl fluoride-2,3-dihydro-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;
(7) 6-carboxyl-9-fluoro-2,3-dihydro-3-(S)-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;
(8) 8-amino-6-carboxyl-9-fluoro-2,3-dihydro-3-(S)-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;
(9) 3-carboxyl-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-Oxoquinoline-7-base;
(10) 3-carboxyl-8-chloro-1-cyclopropyl-1,4-dihydro-4-Oxoquinoline-7-base;
(11) 3-carboxyl-8-cyano group-1-cyclopropyl-6-fluoro-1,4-dihydro-4-Oxoquinoline-7-base;
(12) 3-carboxyl-8-cyano group-1-cyclopropyl-1,4-dihydro-4-Oxoquinoline-7-base;
(13) 3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;
(14) 3-carboxyl-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;
(15) 3-carboxyl-1-cyclopropyl-6-fluoro-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;
(16) 3-carboxyl-1-cyclopropyl-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;
(17) 3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;
(18) 3-carboxyl-1-cyclopropyl-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;
(19) 5-amino-3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;
(20) 5-amino-3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;
(21) 3-carboxyl-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;
(22) 3-carboxyl-8-chloro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;
(23) 3-carboxyl-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;
(24) 3-carboxyl-8-cyano group-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;
(25) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;
(26) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;
(27) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;
(28) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;
(29) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;
(30) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;
(31) 5-amino-3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base; Or
(32) 5-amino-3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base.
34. the compound of claim 1, its salt or hydrate, wherein in formula (I), the part-structure that replaces on Q has following structure:
(1) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(2) (1S, 5S, 6R)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(3) (1S, 5S, 6S)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;
(4) (1S, 5S)-1-amino-6,6-two fluoro-3-azabicyclo [3.2.0] heptane-3-bases;
(5) (1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;
(6) (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;
(7) (1S, 5R, 6R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;
(8) (1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;
(9) spiral shell [(1S, 5S)-1-amino-3-azabicyclo [3.2.0] heptane-6,1 '-cyclopropane]-the 3-base;
(10) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-base;
(11) (1S, 5S)-1-amino-3-azabicyclo [3.3.0] octane-3-base;
(12) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(13) (1R, 5R)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(14) (1S, 5R, 6S)-1-amino-6-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(15) (1S, 5R)-1-amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-bases;
(16) (1S, 5R, 7S)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(17) (1S, 5R, 7R)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;
(18) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;
(19) (1S, 5R)-1-amino-7-methyl-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;
(20) (1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;
(21) (1S)-1-amino-6-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;
(22) (1R, 5R)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;
(23) (1R, 5S)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;
(24) (1R, 5R)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;
(25) (1R, 5S)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;
(26) 6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-base;
(27) (1S, 5R)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;
(28) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;
(29) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-7-alkene-3-base;
(30) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-8-alkene-3-base;
(31) (1S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene-3-base;
(32) (1R, 6S)-1-amino-5-oxa--8-azabicyclo [4.3.0] nonane-8-base;
(33) (1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-base; Or
(34) (1S, 6S)-1-amino-3-oxa--8-azabicyclo [4.3.0] nonane-8-base.
35. the compound of following formula (I), its salt or hydrate:
(1) 7-[(1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(2) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(3) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(4) 10-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(5) 7-[(1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(6) 7-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(7) 10-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(8) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(9) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(10) 10-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(11) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(12) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(13) 10-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(14) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(15) 10-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(16) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(17) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(18) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(19) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(20) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(21) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(22) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(23) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(24) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(25) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(26) 7-[(1S)-1-amino-5-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(27) 10-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(28) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(29) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(30) 7-[6-amino-8-aza-tricycle [4.3.0.0
1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(31) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(32) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(33) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(34) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;
(35) 10-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;
(36) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(37) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;
(38) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;
(39) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid; Or
(40) 10-[(1S, 6S)-1-amino-8-azepine-3-oxa--dicyclo [4.3.0] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid.
36. medicine that comprises among the claim 1-34 each compound, its salt or hydrate as activeconstituents.
37. antibacterials that comprise among the claim 1-34 each compound, its salt or hydrate as activeconstituents.
38. a medicine that is used for the treatment of infection, described pharmaceutical pack contain compound, its salt or hydrate that right requires among the 1-34 each as activeconstituents.
39. a method that is used for the treatment of disease, described method comprise that the compound, its salt or the hydrate that give among the claim 1-34 each are as activeconstituents.
40. a method that is used for the treatment of infection, described method comprise that the compound, its salt or the hydrate that give among the claim 1-34 each are as activeconstituents.
41. a method of producing medicine, described method comprise that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.
42. a method of producing antibacterials, described method comprise that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.
43. a production is used for the treatment of the method for the medicine of infection, described method comprises that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.
44. each compound, its salt or the hydrate purposes in producing medicine among the claim 1-34.
45. each compound, its salt or the purposes of hydrate in the production antibacterials among the claim 1-34.
46. each compound, its salt or hydrate are used for the treatment of purposes in the medicine of infection in production among the claim 1-34.
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| JP2007074991 | 2007-03-22 | ||
| PCT/JP2007/075434 WO2008082009A2 (en) | 2007-01-05 | 2007-12-28 | Fused substituted aminopyrrolidine derivative |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718695A (en) * | 2012-06-25 | 2012-10-10 | 华东师范大学 | Method for synthesizing aza-bicyclo octane [3.3.0] derivatives |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926831A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN105541853A (en) * | 2016-02-04 | 2016-05-04 | 成都大学 | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718695A (en) * | 2012-06-25 | 2012-10-10 | 华东师范大学 | Method for synthesizing aza-bicyclo octane [3.3.0] derivatives |
| CN102718695B (en) * | 2012-06-25 | 2014-04-02 | 华东师范大学 | Method for synthesizing aza-bicyclo octane [3.3.0] derivatives |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
| CN103524487B (en) * | 2013-09-29 | 2015-12-02 | 南京优科生物医药研究有限公司 | A kind of preparation method of Sitafloxacin |
| CN104926712A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926831A (en) * | 2014-03-20 | 2015-09-23 | 上海医药工业研究院 | Telaprevir synthesis intermediate and preparation method thereof |
| CN104926712B (en) * | 2014-03-20 | 2018-03-23 | 上海医药工业研究院 | Synthesize intermediate of VX-960 and preparation method thereof |
| CN105541853A (en) * | 2016-02-04 | 2016-05-04 | 成都大学 | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof |
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| CN101622240B (en) | 2014-07-23 |
| ZA200903997B (en) | 2010-04-28 |
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