CN101215288A - Novel beta-lactam compounds and process for producing the same - Google Patents

Novel beta-lactam compounds and process for producing the same Download PDF

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CN101215288A
CN101215288A CNA2008100051493A CN200810005149A CN101215288A CN 101215288 A CN101215288 A CN 101215288A CN A2008100051493 A CNA2008100051493 A CN A2008100051493A CN 200810005149 A CN200810005149 A CN 200810005149A CN 101215288 A CN101215288 A CN 101215288A
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methyl
solution
ester
300mhz
nmr
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砂川洵
久保田克巳
伊藤昌典
E·戈特斯奇
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Abstract

The present invention relates to a beta-lactam compound represented by the formula (1), a pharmaceutically acceptable salt or a non-toxic ester thereof, wherein R<1> is lower alkyl and the like; R<2> is H or lower alkyl; X is O, S or NH; m and n are respectively halogen and the like, and Y<2> is H, random substituted lower alkyl and the like. These compounds have excellent antibiotic activity to the Gram-positive bacteria, especially methicillin-resistant staphylococcus aureus and methicillin-resistant coagulase negative staphylococcus.

Description

Novel ' beta '-lactam compounds and preparation method thereof
The present invention is that international filing date is November 6 calendar year 2001 (international application no is PCT/JP01/09664), to enter national phase application number be 01821755.9 denomination of invention dividing an application for the patent application of " Novel ' beta '-lactam compounds and preparation method thereof ".
Invention field
The present invention relates to the Novel ' beta '-lactam compounds of following formula [1] expression.
Background technology
Along with third generation cephalosporin in wide clinical application, isolate gram positive bacterium again and again.Particularly isolate methicillinum resistance streptococcus aureus (Staphylococcus aureus) (being abbreviated as MRSA hereinafter) more continually, because be difficult to treat the communicable disease that is caused by MRSA, these bacteriums become the serious problems of clinical field.Although at present vancomycin has been widely used in the communicable disease that is caused by MRSA, owing to its side effect, it has the defective that is difficult to medication, and thinks along with its use will further increase the glycopeptide drug tolerant bacteria.In addition, report that recently isolated methicillinum resistance coagulase negative staphylococcus (MRCNS) increases.In the case, need safer the having excellent anti-MRSA activity and resist-the active medicine of MRCNS of exploitation.
Disclosure of the Invention
An object of the present invention is to provide gram positive bacterium, especially MRSA and MRCNS are had excellent antibiotic active beta-lactam antibiotics.
The present inventor has done a large amount of research, finds effectively resisting gram-positive bacterium of following formula [1] compound, especially MRSA and MRCNS is had excellent anti-microbial activity, and has finished the present invention.
Just the present invention relates to:
(1) 'beta '-lactam compounds of following formula [1] or its pharmacy acceptable salt or non-toxic ester;
Figure S2008100051493D00021
R wherein 1Low alkyl group for low alkyl group or hydroxyl replacement; R 2Be hydrogen atom or low alkyl group; X is Sauerstoffatom, sulphur atom or imino-(NH); M and n independently are that integer 0-4 and m and n sum are 0-4; Y 1Amino, lower alkoxy, low-grade alkyl amino, the carboxyl of optional protection, the optional formamyl that replaces or the optional low alkyl group that replaces for the hydroxyl of halogen atom, cyano group, optional protection, optional protection; Y 2For hydrogen atom, the optional low alkyl group that replaces, cyano group or-C (R 3)=NR 4(R wherein 3And R 4Independent is hydrogen atom, the optional amino or optional low alkyl group that replaces that replaces or protect, perhaps R 3And R 4Can mutually combine and constitute 5-unit to 7-unit heterocycle with the nitrogen-atoms that their connect), condition is 1-4 Y 1May reside on the same ring 2 Y 1May reside on the same carbon atom,
(2) 'beta '-lactam compounds of above-mentioned (1) or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 2,
(3) 'beta '-lactam compounds of above-mentioned (1) or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 3,
(4) 'beta '-lactam compounds of above-mentioned (1) or its pharmacy acceptable salt or non-toxic ester, wherein said 'beta '-lactam compounds is the 'beta '-lactam compounds of following formula [1a];
Figure S2008100051493D00022
R wherein 1, R 2, X, m, n, Y 1And Y 2Define the same,
(5) 'beta '-lactam compounds of above-mentioned (4) or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 2,
(6) 'beta '-lactam compounds of above-mentioned (4) or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 3,
(7) each 'beta '-lactam compounds or its pharmacy acceptable salt or non-toxic ester of above-mentioned (1)-(6), wherein X is a sulphur atom,
(8) each 'beta '-lactam compounds or its pharmacy acceptable salt or non-toxic ester, wherein R of above-mentioned (1)-(7) 1Be 1-(R)-hydroxyethyl,
(9) 'beta '-lactam compounds of a kind of preparation formula [1] or the method for its salt:
R wherein 1Low alkyl group for low alkyl group or hydroxyl replacement; R 2Be hydrogen atom or low alkyl group; X is Sauerstoffatom, sulphur atom or imino-(NH); M and n independently are that integer 0-4 and m and n sum are 0-4; Y 1Amino, lower alkoxy, low-grade alkyl amino, the carboxyl of optional protection, the optional formamyl that replaces or the optional low alkyl group that replaces for the hydroxyl of halogen atom, cyano group, optional protection, optional protection; Y 2For hydrogen atom, the optional low alkyl group that replaces, cyano group or-C (R 3)=NR 4(R wherein 3And R 4Independent is hydrogen atom, the optional amino or optional low alkyl group that replaces that replaces or protect, perhaps R 3And R 4Can mutually combine and constitute 5-unit to 7-unit heterocycle with the nitrogen-atoms that their connect), condition is 1-4 Y 1May reside on the same ring 2 Y 1May reside on the same carbon atom;
Described method is included in alkali and exists down, makes formula [2] compound:
Figure S2008100051493D00032
R wherein 1aThe low alkyl group that the low alkyl group that replaces for low alkyl group, hydroxyl or the hydroxyl of protected radical protection replace, R 2Define the same, R 5Be the blocking group of carboxyl, L is the active ester of hydroxyl,
React with formula [3] compound:
Figure S2008100051493D00041
Wherein m, n, X and Y 1Define the same, Y 3For hydrogen atom, the optional low alkyl group that replaces, cyano group or-C (R 3)=NR 4a(R wherein 3Define the same, R 4aBe hydrogen atom, the optional amino that replaces or protect, optional low alkyl group or the blocking group of imino-, the perhaps R that replaces 3And R 4aCan mutually combine and constitute 5-unit to 7-unit heterocycle) with the nitrogen-atoms that their connect;
Perhaps make thiolate reaction acquisition formula [4] compound of formula [2] compound and formula [3] compound:
Figure S2008100051493D00042
R wherein 1a, R 2, R 5, m, n, X, Y 1And Y 3Define the same,
Appropriate combination is selected from following suitable reactions and removes R then 5And Y 1Carboxy protective group: remove R 1aAnd Y 1Hydroxy-protective group, remove Y 3The amido protecting group, remove Y 1Amido protecting group (optional subsequently imino-Y 3The amino of removal blocking group) or remove Y 3The imino-blocking group,
(10) a kind of medicinal compositions, described medicinal compositions comprise 'beta '-lactam compounds or its pharmacy acceptable salt or the non-toxic ester of each elaboration of above (1)-(8),
(11) a kind of antibacterials, described medicine comprise 'beta '-lactam compounds or its pharmacy acceptable salt or the non-toxic ester of each elaboration of above (1)-(8).
Implement best mode of the present invention
Low alkyl group of the present invention comprises straight or branched C 1-C 6Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl and n-hexyl.
The low alkyl group that hydroxyl replaces comprises the hydroxyalkyl of 1-6 carbon atom, for example hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyl-1-methylethyl, 1-hydroxypropyl and 2-hydroxypropyl.Lower alkoxy comprises straight or branched C 1-C 6Alkoxyl group, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy and positive hexyloxy.Low-grade alkyl amino comprises by straight or branched C 1-C 6List or disubstituted amino that alkyl replaces, for example methylamino, ethylamino, n-propyl amino, sec.-propyl amino, normal-butyl amino, isobutylamino, tertiary butyl amino, n-pentyl amino, n-hexyl amino, methylethyl amino, dimethylamino, diethylamino, two (n-propyl) amino, two (sec.-propyls) amino, two (normal-butyls) amino, two (n-pentyls) amino and two (n-hexyl) amino.Halogen atom comprises fluorine atom, chlorine atom, bromine atoms and iodine atom.5-7 unit heterocycle comprises, for example 3, and 4-dihydro-2-H-pyrrole ring, 2,3,4,5-tetrahydro pyridine ring, 3,4,5,6-tetrahydrochysene-2-H-azepines ring etc.The substituting group of the optional low alkyl group that replaces comprise hydroxyl, lower alkoxy, lower alkylthio, low alkyl group sulfinyl, low alkyl group alkylsulfonyl, lower alkylcarbonyl, low alkyl group carbonyl oxygen base, elementary alkoxy carbonyl, carboxyl, halogen atom, cyano group ,-NR 6R 7(R wherein 6And R 7Independent is hydrogen atom or low alkyl group, perhaps R 6And R 7Can combine with nitrogen-atoms and constitute 5-7 unit ring, for example tetramethyleneimine, piperidines, azepine ring in heptan, morpholine, piperazine or N-low alkyl group piperazine) ,-CONR 6R 7(R wherein 6And R 7Define the same) ,-NR 6aCOR 7a(R wherein 6aAnd R 7aIndependent is hydrogen atom or low alkyl group) ,-OCONR 6R 7(R wherein 6And R 7Define the same) ,-SO2NR 6R 7(R wherein 6And R 7Define the same) ,-NR 6aSO 2NR 6R 7(R wherein 6a, R 6And R 7Define the same) ,-NR 6aCONR 6R 7(R wherein 6a, R 6And R 7Define the same) and-COOCH 2OCOR 8(R wherein 8Be low alkyl group).These substituting groups can be by suitable blocking group protection.Chemically may need only, the position of substitution is unrestricted, but has one or more substituting groups.
Lower alkylcarbonyl comprises straight or branched C 2-7Alkyl-carbonyl, for example methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, normal-butyl carbonyl, isobutyl-carbonyl, tertiary butyl carbonyl, n-pentyl carbonyl and n-hexyl carbonyl.Low alkyl group carbonyl oxygen base comprises straight or branched C 2-7Alkyl carbonyl oxy, for example methyl carbonyl oxygen base, ethyl oxy carbonyl, n-propyl carbonyl oxygen base, sec.-propyl carbonyl oxygen base, normal-butyl carbonyl oxygen base, isobutyl-carbonyl oxygen base, tertiary butyl carbonyl oxygen base, n-pentyl carbonyl oxygen base and n-hexyl carbonyl oxygen base.
Elementary alkoxy carbonyl comprises straight or branched C 2-7Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, n-pentyloxy carbonyl and positive hexyloxy carbonyl.
The low alkyl group of lower alkylthio, low alkyl group sulfinyl and low alkyl group alkylsulfonyl partly comprises straight or branched C 1-C 6Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl and n-hexyl.
Tetramethyleneimine, piperidines and azepan that the substituting group of the optional formamyl that replaces comprises 1 or 2 low alkyl groups, constitutes with the nitrogen-atoms of carbamyl amine.
The substituting group of the optional amino that replaces comprises 1 or 2 low alkyl groups, and the amino of replacement comprises tetramethyleneimine, piperidines and the azepan that the nitrogen-atoms with carbamyl amine constitutes.
Choose the 5-7 unit heterocyclic substituting group that replaces wantonly and comprise, for example low alkyl group, hydroxyl, lower alkoxy, lower alkylcarbonyl, low alkyl group carbonyl oxygen base, elementary alkoxy carbonyl, carboxyl and halogen atom and cyano group.
The blocking group of carboxyl can be any GPF (General Protection False group; but the straight or branched low alkyl group of a preference such as 1-5 carbon atom (methyl for example; ethyl; sec.-propyl; the tertiary butyl etc.); the junior alkyl halides of 1-5 carbon atom (2-iodo ethyl for example; 2; 2,2-three chloro ethyls); the alkoxy methyl of 1-5 carbon atom (methoxymethyl for example; ethoxyl methyl; the isobutoxy methyl); the lower aliphatic acyloxy methyl of 1-5 carbon atom (acetoxy-methyl for example; the propionyloxy methyl; the butyryl acyloxy methyl; oxy acid methyl neopentyl); 1-(C 1-C 5) low-grade alkenyl (for example allyl group, 3-methacrylic), diphenyl-methyl or the phthalidyl of lower alkoxy carbonyl oxygen base ethyl (for example 1-oxyethyl group carbonyl oxygen base ethyl), replacement or unsubstituted aralkyl (for example benzyl, to methoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl), a 3-7 carbon atom.
Hydroxyl or amino blocking group can be any GPF (General Protection False group; the elementary alkoxy carbonyl (for example tert-butoxycarbonyl) of preferred 1-5 carbon atom; the halo alkoxy carbonyl of 1-5 carbon atom (2-iodo ethoxy carbonyl for example; 2; 2,2-three chloro ethoxy carbonyls); the replacement of 3-7 carbon atom or unsubstituted lower alkanols allyloxycarbonyl (for example allyloxy carbonyl); replace or unsubstituted aromatic alkoxy carbonyl (benzyloxycarbonyl for example; to methoxyl group benzyloxy base carbonyl; adjacent nitro benzyloxycarbonyl; to the nitro benzyloxycarbonyl) or trialkylsilkl (three silyls for example; three disilanyl-s; tertiary butyl dimethyl silanyl).
In the 'beta '-lactam compounds of formula [1a], Y 1Preferred substituents be C 1-3Alkyl (for example methyl, ethyl, sec.-propyl etc.), hydroxymethyl, chloro methyl, fluoro methyl, methoxymethyl, formamyl oxygen ylmethyl, urea groups methyl, sulphonamide methyl, sulfamoylamino group methyl, formamyl etc., Y 2The preferred hydrogen atom of preferred substituents, C 1-3Alkyl (for example methyl, ethyl, sec.-propyl etc.), iminomethyl (CH=NH) ,-C (CH 3)=NH etc.
Pharmacy acceptable salt with following formula [1] compound is conventional non-toxic salts.Such salt comprises intramolecularly carboxylate salt, mineral alkali (for example sodium, potassium, calcium, magnesium, aluminium) salt, organic bases (for example three second ammoniums, pyridine, di-isopropyl ammonium) salt or constitutes molecule inner salt with the positively charged ion (quaternary ammonium ion) of 3 side chains.Intramolecularly alkali salt, mineral acid (for example hydrochloric acid, sulfuric acid, phosphoric acid) salt or organic acid (for example formic acid, acetate, oxalic acid, methylsulfonic acid, Phenylsulfonic acid) salt are arranged for instance.
Be included in acceptable ester on the conventional pharmaceutical of 2 carboxyls of carbamyl antibacterials with the non-toxic ester of following formula [1], described ester can be the ester in the easy hydrolysis of live body, for example contains the ester of acetoxy-methyl, 1-(oxyethyl group carbonyl oxygen base) ethyl and phthalidyl.
The lactam compound of formula [1] or its pharmacy acceptable salt or non-toxic ester can be its acid anhydrides, hydrate or solvate forms.
Below more specifically exemplary illustration prepares the method for The compounds of this invention.
Formula [4] compound:
Figure S2008100051493D00071
R wherein 1a, R 2, R 5, m, n, X, Y 1And Y 3Define the samely, can be prepared as follows:
In the presence of alkali, in inert solvent, make formula [2] compound:
Figure S2008100051493D00072
R wherein 1a, R 2, R 5The same with the L definition, react with formula [3] compound:
Figure S2008100051493D00081
Wherein m, n, X, Y 1And Y 3Define the samely, perhaps in inert solvent, make the thiolate reaction of formula [2] compound and formula [3] compound.
The active ester of hydroxyl comprises, for example replace or the haloalkyl sulphonate of the low alkyl group sulphonate (methanesulfonate ester, ethylsulfonic acid ester etc.) of unsubstituted aromatic yl sulphonate (for example benzene sulfonate, p-toluenesulfonic esters, p-nitrophenyl sulphonate, to the bromobenzene sulphonate etc.), a 1-5 carbon atom, a 1-5 carbon atom (for example trifluoromethane sulfonic acid ester etc.), aryl phosphate ester (for example diphenyl phosphoester etc.) or halogenide for example muriate, bromide, iodide, it is the ester with hydrogen halide.Preferred hydroxyl activity ester can be p-toluenesulfonic esters, methanesulfonates, triflate and diphenyl phosphoester.
Be used in the presence of alkali, making the inert solvent of formula [2] compound and formula [3] compound reaction acquisition formula [4] compound to comprise for example mixture of two  alkane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, acetonitrile, benzene, toluene, hexamethylphosphoramide or these solvents.
Alkali for example comprises mineral alkali (for example yellow soda ash, salt of wormwood, sodium hydride, potassium hydride KH) or organic bases (for example pyridine, dimethyl aminopyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU)).Especially preferred alkali is DBU.Should use the alkali of capacity that reaction is carried out, use the 1-3 equivalent of mercaptan compound [3] consumption usually.
Should use the mercaptan compound [3] of capacity that reaction is carried out, its consumption can be excessive greatly, but use the 1-2 equivalent of compound [2] consumption usually.
The temperature of reacting is-78 ℃～+ 60 ℃, and preferred temperature is-40 ℃～+ 40 ℃.In addition, after reaction was finished, thus obtained product separated by vitochemical routine techniques.
Be used to make the inert solvent of thiolate reaction acquisition formula [4] compound of formula [2] compound and formula [3] compound to comprise for example mixture of two  alkane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, acetonitrile, benzene, toluene, hexamethylphosphoramide or these solvents.
In above reaction, should use the thiolate of capacity that reaction is carried out, its consumption can be excessive greatly, but use the 1-2 equivalent of compound [2] consumption usually.
The temperature of reacting is-78 ℃～+ 60 ℃, and more preferably temperature is-40 ℃～+ 40 ℃.After reaction was finished, thus obtained product separated by vitochemical routine techniques.
Prepare described thiolate by mercaptan compound [3] and alkali reaction.Alkali comprises for example mineral alkali (for example sodium hydride, potassium hydride KH), metal alcoholate (for example potassium tert.-butoxide, sodium methylate) or metal amide (sodium amide, diisopropylaminoethyl lithium, disilane lithium amide (lithiumdisilazide)).
The 'beta '-lactam compounds of formula [1] by as following acquisition: with compound [4] react in a conventional manner, with following reaction with the removal R 5And Y 1The carboxy protective group optional combination or carry out simultaneously, for example remove R 1aOr Y 1Hydroxy-protective group, remove Y 1The amido protecting group, remove Y 3Amido protecting group (imino-ization has been removed the amino of blocking group subsequently) or remove Y 3The imino-blocking group.
Remove these blocking groups with acid, alkali or reductive agent according to well-known method, referring to for example T.W.Greene:Protective Groups in Organic Synthesis, J.Wiley﹠amp; Sons Inc.1981.The preferred trifluoroacetic acid of acid, formic acid, boron trifluoride, aluminum chloride etc. or these sour mixtures.Alkali preferred alkali metal carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metalsulphide (sodium sulphite, potassium sulphide etc.) or tetrabutylammonium fluoride.Method of reducing comprises for example usefulness zinc and acetate hydrogenation, uses hydrogen and hydrogenations such as carbon-palladium or platinum.Here also can use palladium (0) compound.
Solvent can comprise for example mixture of water, alcohol (for example methyl alcohol, ethanol), ether (for example tetrahydrofuran (THF), two  alkane), lipid acid (for example acetate) or these solvents for reaction there not being any solvent of disadvantageous effect.By suitably reduction or rising temperature of reaction might suppress or promote reaction.Preferred-30 ℃～+ 40 ℃ of range of reaction temperature.After reaction was finished, thus obtained product separated by vitochemical routine techniques, for example by the neutralization reaction mixture, it was handled with column chromatographies such as absorbing resin, collected the part that comprises required compound, then the lyophilize product.
The compound of general formula (2) is known, can prepare with JP63-55514 B disclosed method.
The mercaptan compound of general formula (3) is according to following flow preparation: contain the cyclic amine derivatives (B) of unsaturated ester part with suitable amino acid preparation, be translated into thyroidan derivative (C) then.If desired, available opticity intermediate preparation opticity thyroidan derivative (C).
Figure S2008100051493D00101
R wherein aBe the optional low alkyl group that replaces, R bBe the blocking group of amino, p is integer 0 or 1.
When compd B begins preparation by compd A, use the method for JP1-233270 B introduction.When Compound C begins preparation by compd B, prepare Compound C according to currently known methods, for example K.Hofmann, Heterocyclic Chemistry vol.6 (1953), J.V.Metzger, the same vol.34 (1979), I.J.Turchi, the same vol.45 (1986), IntersciencePublishers, Inc. or A.R.Katritzky, Advances in Heterocyclic Chemistry, vol.32 (1982), Academic Press or its combined method.
Above-mentioned formula [1] compound has 4-, 5-based on carbapenem ring and the optically active isomer of 6-position unsymmetrical carbon, is shown below:
Figure S2008100051493D00102
Only with a molecular formula conveniently to represent all these isomer.When being, should therefore not be interpreted as limitation of the scope of the invention, the scope of the invention comprises all isomer and based on the isomer mixture of each unsymmetrical carbon.In addition, preferred isomers is following isomer: work as R 2During for hydrogen atom, 5 carbon atoms have the isomer of R configuration, for example (5R, 6R) compound or (5R, 6S) compound; Work as R 2During for alkyl, 4 carbon atoms have the R configuration, and 5 carbon atoms have the isomer of S configuration, for example (4R, 5S, 6S) compound or (4R, 5S, 6R) compound.In addition, work as R 1During for the 1-hydroxyethyl, compound [1] can shown in following formula, be the isomer of R configuration at 8 preferably at 8 isomer that R configuration or S configuration are arranged.It also has because substituting group Y 1Isomer.
The isomer for preparing above-mentioned configuration with the corresponding separately isomer of precursor compound [2] and [3].
Formula of the present invention [1] compound is to contain the pyrrolidine dithiocarbamate group and at 3 Novel ' beta '-lactam compounds that different substituents is arranged of carbapenem ring, these compounds have very strong anti-microbial activity and useful as drug.
Following table 1 provides the representative compounds example of the formula [1] that obtains by the present invention.
Table 1-1
Compound R 1R 2X
Figure S2008100051493D00121
Numbering
1 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00122
2 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00123
3 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00124
4 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00125
5 CH(OH)CH 3 CH 3 S
6 CH(OH)CH 3 CH 3 S
7 CH 2CH 3 CH 3 O
Figure S2008100051493D00128
8 CH 2OH H NH
Figure S2008100051493D00129
Table 1-2
Compound
R 1 R 2 X
Figure S2008100051493D00131
Numbering
9 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00132
10 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00133
11 CH(OH)CH 3 CH 3 S
12 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00135
13 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00136
14 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00137
15 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00138
16 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00139
Table 1-3
Compound R 1R 2X
Figure S2008100051493D00141
Numbering
17 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00142
18 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00143
19 CH(OH)CH 3 CH 3 S
20 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00145
21 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00146
22 CH(OH)CH 3 CH 3 S
23 CH(OH)CH 3 CH 3 S
24 CH(OH)CH 3 CH 3 S
Table 1-4
Compound R 1R 2X
Figure S2008100051493D00151
Numbering
25 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00152
26 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00153
27 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00154
28 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00155
29 CH(OH)CH 3 CH 3 S
30 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00157
31 CH(OH)CH 3 CH 3 S
32 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00159
Table 1-5
Compound R 1R 2X
Figure S2008100051493D00161
Numbering
33 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00162
34 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00163
35 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00164
36 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00165
37 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00166
38 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00167
39 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00168
40 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00169
Table 1-6
Compound R 1R 2X
Figure S2008100051493D00171
Numbering
41 CH(OH)CH 3 CH 3 S
42 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00173
43 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00174
44 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00175
45 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00176
46 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00177
47 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00178
48 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00179
Table 1-7
Compound R 1R 2X
Numbering
49 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00182
50 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00183
51 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00184
52 CH(OH)CH 3 CH 3 NH
Figure S2008100051493D00185
53 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00186
54 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00187
55 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00188
56 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00189
Table 1-8
Compound R 1R 2X
Figure S2008100051493D00191
Numbering
57 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00192
58 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00193
59 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00194
60 CHMe 2 CH 3 O
Figure S2008100051493D00195
61 CH 2CH 3 H NH
Figure S2008100051493D00196
62 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00197
63 CH(OH)CH 3 CH 3 S
64 CH(OH)CH 3 CH 3 S
Figure S2008100051493D00199
Table 1 compound has steric isomer as mentioned above, and these exemplary compounds also comprise their all isomer.
Novel ' beta '-lactam compounds of the present invention with following formula [1] expression has anti-microbial activity to many different malignant bacterias, described bacterium comprises for example streptococcus aureus of gram positive bacterium, staphylococcus epidermidis (Staphylococcus epidermidis), streptococcus pyogenes (streptococcus pyogenes), streptococcus pneumoniae (Streptococcus pneumoniae), enterococcus faecalis (Enterococcus faecalis) and gram negative bacterium be intestinal bacteria (Escherichia coli) for example, proteus (Proteus), pneumobacillus (Klebsiellapneumoniae), hemophilus influenzae (Haemophilus influenzae), gonococcus (Neisseria gonorrhoeae), branhamella (Branhamella) especially has very strong anti-microbial activity to gram positive bacterium and MRSA and MRCNS.
Further, each compound of The compounds of this invention [1] is inequality to a certain extent, reduced but more nervus centralis side effect and the physicochemical property of having improved compound [1] more for example as medicine should possess water-soluble.These character are characteristic properties of the present invention.
Well-known a kind of kidney enzyme dehydropeptidase-I (DHP-I) is the carbapenem compounds of hydrolysis natural origin easily, but the part The compounds of this invention that also is carbapenem compounds is stable to DHP-I, therefore The compounds of this invention can use separately, but the DHP-I inhibitor can be used with The compounds of this invention if desired.
When being used for the treatment of by bacterial communicable disease as anti-bacterial drug, the The compounds of this invention medication is passed through for example with oral medication or for example intravenous injection of parenteral medication, intramuscularly or internal rectum medications such as tablet, capsule, pulvis, syrups.
Above-mentioned suitable administration form can be prepared as follows: activeconstituents is mixed with conventional pharmaceutically acceptable carrier, vehicle, tackiness agent, stablizer etc.When with the injection form medication, wherein can add pharmaceutically acceptable buffer reagent, solubilizing agent, isotonic agent etc.
The dosage of compound [1] is according to variations such as symptom, age, body weight, administration form, medicine frequencies, but the common consumption of grownup is 100～3000mg/ days, can once give or be divided into some dose units and give.In addition, if desired, the dosage of compound [1] can increase or reduce.
The present invention is described more specifically by embodiment, but should not be interpreted as limitation of the present invention.
Below abbreviation is used for embodiment.
PNB: to nitrobenzyl
PMB: to methoxy-benzyl
Ph: phenyl
TMS: three silyls
TBDMS: the tertiary butyl (dimethyl) silyl
The ALOC:(allyloxy) carbonyl
The Z:(benzyloxy) carbonyl
Me: methyl
Et: ethyl
IPr: sec.-propyl
T-Bu: the tertiary butyl
Bn: benzyl
MOM: methoxymethyl
MS: methylsulfonyl
Tf: trifyl
THF: tetrahydrofuran (THF)
DMF:N, dinethylformamide
DBU:1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
Embodiment 1
Figure S2008100051493D00221
A) at 0 ℃, THF solution (1 M with two (trimethyl silane) lithium amides (lithiumhexamethyldisilazide), 0.20ml, 0.20mmol) adding (2S)-2-methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-2, (54mg, THF 0.20mmol) (0.20ml)/DMF (0.20ml) suspension stir mixture 25 minutes 5-dihydro-1H-pyrroles-1-allyl carboxylate.In reaction mixture, add (4R at 0 ℃; 5R; 6S)-(3-[(two phenoxy group phosphonos) oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 0.76g; 0.40mmol), solution was left standstill 15 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate) and is obtained (4R, 5S, 6S)-and 3-[(4-{ (5S)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (85mg, 70%).
1H?NMR(300MHz，CDCl 3)δ?0.09(9H，s)，1.06-1.10(3H，m)，1.15-1.40(6H，m)，3.21-3.24(1H，m)，3.40-3.59(1H，m)，4.15-4.22(2H，m)，4.37-4.85(7H，m)，5.15-5.48(4H，m)，5.87-6.02(2H，m)，6.31-6.36(1H，m)，7.09-7.12(1H，m)。
B) at 0 ℃, at (4R, 5S, 6S)-and 3-[(4-{ (5S)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(85mg adds entry in THF 0.14mmol) (6ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 3 then, stirred 10 minutes.Add sodium bicarbonate aqueous solution in the reaction soln, twice of ethyl acetate extraction of reaction mixture.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate=1/2) and is obtained light yellow unbodied (4R, 5S, 6S)-and 3-[(4-{ (5S)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (60mg, 80%).
C) (4R, 5S, 6S)-and 3-[(4-{ (5S)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (70mg, 0.1 add acetate (19 μ l) and tri-butyl tin hydride (0.32ml in methylene dichloride 3mmol) (2ml) solution, 1.2mmol), two (triphenylphosphine) Palladous chlorides (II) of adding at room temperature (91mg, 0.013mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(5S)-5-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (26.9mg).
IR(KBr)3406，2969，1760，1599，1391cm -1
1H?NMR(300MHz，D 2O)δ?0.94(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.4Hz)，1.38(3H，d，J＝6.8Hz)，3.10-3.24(1H，m)，3.35(1H，dd，J＝2.6，6.0Hz)，4.05-4.15(2H，m)，4.23-4.37(2H，m)，6.25(1H，s)，7.50(1H，s)。
Embodiment 2
Figure S2008100051493D00241
A) according to the same procedure of embodiment 1, with (2R)-2-methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate is as mercaptan compound, obtain (4R thus, 5S, 6S)-and 3-[(4-{ (5R)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ?0.11(9H，s)，1.08-1.12(3H，m)，1.22-1.25(3H，m)，1.37-1.43(3H，m)，3.24(1H，dd，J＝6.2，2.9Hz)，3.37-3.58(1H，m)，4.17-4.24(2H，m)，4.40-4.87(7H，m)，5.21-5.50(4H，m)，5.91-6.05(2H，m)，6.34-6.38(1H，m)，7.10-7.14(1H，m)。
B) (4R, 5 S, 6S)-and 3-[(4-{ (5R)-1-[(allyloxy) carbonyl]-5-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (42mg, 0.070mmol) ethyl acetate (4ml) solution in add entry, with 2N hydrochloric acid pH value of solution is adjusted to about 2 then.Stir after 10 minutes, add THF in the solution again, with solution stirring 20 minutes.Add saturated sodium bicarbonate aqueous solution in the mixture that obtains, twice of ethyl acetate extraction of solution.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.Removal of solvent under reduced pressure.At 0 ℃, in methylene dichloride (2ml) solution of resistates (37.6mg), add tri-butyl tin hydride (0.17ml), acetate (10 μ l) and two (triphenylphosphine) Palladous chloride (5mg), mixture was stirred 10 minutes at uniform temp.(50mM, pH 7,25ml) and methylene dichloride (20ml) to add phosphate buffered saline buffer in the reaction mixture.Isolate water layer, dichloromethane layer water extracting twice.The water layer that merges methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(5R)-5-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ?0.92(3H，d，J＝7.2Hz)，1.10(3H，d，J＝6.4Hz)，1.3?1(3H，d，J＝6.8Hz)，3.10-3.20(1H，m)，3.32(1H，dd，J＝5.9，2.9Hz)，4.03-4.28(4H，m)，6.23(1H，br?s)，7.45(1H，s)。
Embodiment 3
A) at 0 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 1.26ml, 1.26mmol) adding (6S)-6-methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-3, (373mg, THF 1.26mmol) (15ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 4.80g; 2.52mmol), solution was left standstill 60 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate) and is obtained (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (590mg, 76%).
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.06-1.12(3H，m)，1.24(3H，d，J＝6.0Hz)，1.29-1.32(3H，m)，2.37-2.45(1H，m)，2.46-2.59(1H，m)，2.46-2.59(1H，m)，3.00-3.12(1H，m)，3.24(1H，dd，J＝6.4，2.9Hz)，3.42-3.61(1H，m)，4.16-4.40(3H，m)，4.62-4.87(5H，m)，5.20-5.50(4H，m)，5.90-6.04(2H，m)，6.61-6.64(1H，m)，7.10-7.13(1H，m)。
B) at 0 ℃, at (4R, 5S, 6S)-3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(640mg adds entry in THF 1.04mmol) (30ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 3 then, stirred 10 minutes.Add sodium bicarbonate aqueous solution in the reaction soln, twice of ethyl acetate extraction of reaction mixture.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate=1/2) and is obtained light yellow unbodied (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (547mg, 97%).
C) (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (270mg, 0.49mmol) methylene dichloride (10ml) solution in add acetate (73 μ l) and tri-butyl tin hydride (1.23ml, 4.6mmol), two (triphenylphosphine) Palladous chlorides (II) of adding at room temperature (36mg, 0.051mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-5%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(6S)-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (151.5mg).
IR(KBr)3409，2971，1760，1596，1390，1264，1148，1028cm -1 1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.0Hz)，1.10(3H，d，J＝5.7Hz)，1.32(3H，d，J＝6.8Hz)，2.58-2.63(2H，m)，3.09-3.26(2H，m)，3.30-3.34(1H，m)，3.42-3.51(1H，m)，4.01-4.11(3H，m)，6.28(1H，s)，7.44(1H，s)。
Embodiment 4
Figure S2008100051493D00271
A) according to the same procedure of embodiment 1, with (6R)-6-methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester is as mercaptan compound, obtain (4R thus, 5S, 6S)-and 3-[(4-{ (6R)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.09(9H，s)，1.04-1.10(3H，m)，1.15-1.29(6H，m)，2.34-2.57(2H，m)，2.96-3.11(1H，m)，3.19-3.24(1H，m)，3.38-3.58(1H，m)，4.13-4.38(3H，m)，4.59-4.85(5H，m)，5.16-5.48(4H，m)，5.85-6.02(2H，m)，6.61(1H，m)，7.08-7.10(1H，m)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-and 3-[(4-{ (6R)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain thus (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(6R)-the 6-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.89-0.91(3H，m)，1.09(3H，d，J＝6.4Hz)，1.33(3H，d，J＝7.0Hz)，2.58-2.67(2H，m)，3.07-3.35(3H，m)，3.43-3.53(1H，m)，4.00-4.12(3H，m)，6.28(1H，s)，7.44(1H，s)。
IR(KBr)3422，1771cm -1
Embodiment 5
Figure S2008100051493D00281
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.62ml, 0.62mmol) adding (6S)-6-sec.-propyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-3, (202mg, THF 0.62mmol) (1.0ml) solution stir mixture 15 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 2.37g; 1.2mmol), solution was left standstill 16 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, (hexane/ethyl acetate: 1/5 → 1/3) purification obtains (4R to resistates with silica gel chromatography, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-6-sec.-propyl-1,2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (0.24g, 61%).
1H?NMR(300MHz，CDCl 3)δ0.00(9H，s)，0.88-1.00(9H，m)，1.11-1.14(3H，m)，1.87(1H，sesq)，J＝7.3Hz，2.22-2.48(2H，m)，2.88-3.14(2H，m)，3.27-3.47(1H，m)，3.97-4.77(8H，m)，5.06-5.38(4H，m)，5.77-5.93(2H，m)，6.71(1H，brs)，6.99(1H，brs)。
B) at 0 ℃, at (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-6-sec.-propyl-1,2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(204mg adds entry in THF 0.32mmol) (20ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, adds 1N hydrochloric acid then.PH value of solution is adjusted to about 3, stirred 1 hour.Add sodium bicarbonate aqueous solution in the reaction soln, twice of ethyl acetate extraction of reaction mixture.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates (0.25g) is dissolved in methylene dichloride (25ml).Add in the solution acetate (46 μ l, 0.80mmol) and tri-butyl tin hydride (0.86ml, 3.2mmol), then room temperature add two (triphenylphosphine) Palladous chlorides (II) (22.5mg, 0.032mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6S)-6-sec.-propyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (74.2mg, purity 95%, yield 50%).
1H NMR (300MHz, D 2O) δ 0.90-0.95 (9H, m), 1.09 (3H, d, J=6.4Hz), 1.93 (1H, 1.5 peaks, J=6.6Hz), 2.59-2.67 (2H, m), 3.06-3.23 (2H, m), 3.29-3.34 (1H, m), 3.46-3.53 (1H, m), 3.72-3.77 (1H, m), 4.04-4.11 (2H, m), 6.40 (1H, s), 7.45 (1H, s).
IR(KBr)3362，2968，1760，1599，1390cm -1
Embodiment 6
Figure S2008100051493D00301
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.29ml, 0.29mmol) adding (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2-sulfydryl-1,3-thiazole-4-yl)-3, (122mg, THF 0.29mmol) (4.3ml) solution stir mixture 10 minutes 6--dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 1.09g; 0.58mmol), solution was left standstill 19 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in THF (5.65ml).0-5 ℃ of THF solution that in solution, adds acetate (215 μ l) and tetrabutylammonium fluoride (1M, 1.5ml, 1.5mmol).React after 20 hours, in reaction mixture, add frozen water, the mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate=1/3 → contain the chloroform of 10% methyl alcohol) and is obtained (4R, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (110mg, 68%).
IR(KBr)3426，2933，1772，1700，1559，1457，1136cm -1 1H?NMR(300MHz，CDCl 3)δ1.10(3H，d，J＝7.3Hz)，1.31(3H，d，J＝6.2Hz)，2.50(1H，d，J＝17.4Hz)，2.62-2.73(1H，m)，3.25(1H，d，J＝2.8，7.0Hz)，3.45-3.96(4H，m)，4.17-4.27(2H，m)，4.41-4.86(6H，m)，5.19-5.47(4H，m)，5.87-6.03(2H，m)，6.63(1H，s)，7.11(1H，s)。
B) (4R, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (110mg, 0.20mmol) methylene dichloride (15ml) solution in add acetate (28 μ l) and tri-butyl tin hydride (0.54ml, 2.6mmol), at room temperature add then two (triphenylphosphine) Palladous chlorides (II) (14mg, 0.020mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2R)-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (51mg, yield 54%). 1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.0Hz)，1.09(3H，d，J＝6.4Hz)，2.35-2.65(2H，m)，3.08-3.18(1H，m)，3.30-3.44(2H，m)，3.60(1H，dd，J＝6.8，12.5Hz)，3.72-3.82(3H，m)，4.03-4.13(2H，m)，6.38(1H，s)，7.41(1H，s)。
Embodiment 7
Figure S2008100051493D00321
A) at 0-5 ℃, with sodium hydride (60w/w%, 13.3mg, 0.33mmol) adding (2S)-2-(hydroxymethyl)-4-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (purity 70%, 139mg, 0.33mmol) THF (1.0ml)/DMF (0.5ml) mixture, mixture was stirred 10 minutes.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 1.27g; 0.67mol), solution was left standstill 16 hours at refrigerator.In reaction soln, add frozen water, with 1N hydrochloric acid pH value of solution is adjusted to 3 at 0-5 ℃.After mixture stirred 30 minutes, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with tlc (chloroform that contains 10% methyl alcohol) and is obtained (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (87mg, 46%).
1H?NMR(300MHz，CDCl 3)δ0.99(3H，d，J＝7.3Hz)，1.21(3H，d，J＝6.0Hz)，2.38-2.63(2H，m)，3.15(1H，dd，J＝2.8，6.8Hz)，3.37-3.85(4H，m)，4.30-4.65(5H，m)，4.73(1H，dd，J＝5.3，13.2Hz)，5.10-5.37(4H，m)，5.78-5.93(2H，m)，6.54(1H，brs)，7.01(1H，s)。
B) (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (28mg, 0.05mmol) methylene dichloride (4ml) solution in add acetate (7.2 μ l) and tri-butyl tin hydride (135ml, 0.50mmol), at room temperature add then two (triphenylphosphine) Palladous chlorides (II) (3.5mg, 0.005mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2S)-2-(hydroxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (3.9mg).
1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.0Hz)，1.09(3H，d，J＝6.4Hz)，2.20-2.33(1H，m)，2.44-2.53(1H，m)，3.08-3.73(7H，m)，4.02-4.13(2H，m)，6.39(1H，s)，7.37(1H，s)。
Embodiment 8
Figure S2008100051493D00331
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.58ml, 0.58mmol) adding (2R)-4-(2-sulfydryl-1,3-thiazole-4-yl)-2-methyl-3, (172mg, THF 0.58mmol) (2.0ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 2.21g; 1.2mmol), solution was left standstill 16 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, (hexane/ethyl acetate: 1/4 → 1/3) purification obtains (4R to resistates with silica gel chromatography, 5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (137mg, 38%). 1H?NMR(300MHz，CDCl 3)δ0.10(9H，s)，1.07(3H，d，J＝7.3Hz)，1.17(3H，d，J＝6.8Hz)，1.21(3H，d，J＝6.2Hz)，2.28(1H，d，J＝17.2Hz)，2.67-2.79(1H，m)，3.22(1H，dd，J＝2.7，6.2Hz)，3.56(1H，dd，J＝7.3，9.9Hz)，3.77-3.87(1H，m)，4.15-4.23(2H，m)，4.42-4.53(1H，m)，4.60-4.85(5H，m)，5.18-5.48(4H，m)，5.88-6.02(2H，m)，6.64(1H，brs)，7.06(1H，s)。
B) at 0 ℃, at (4R, 5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(137mg adds entry in THF 0.22mmol) (20ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to about 3 then.With solution stirring 10 minutes.Add sodium bicarbonate aqueous solution in the reaction soln, twice of ethyl acetate extraction of reaction mixture.Organic layer washs with saturated nacl aqueous solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in the methylene dichloride (3ml).In solution, add acetate (3 μ l) and tri-butyl tin hydride (0.59ml, 22mmol), at room temperature add then two (triphenylphosphine) Palladous chlorides (II) (15.6mg, 0.02mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2R)-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (59.3mg).
IR(KBr)3428，2971，1758，1602，1391，1263cm -1
1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.1Hz)，1.10(3H，d，J＝6.2Hz)，1.32(3H，d，J＝6.4Hz)，2.30-2.45(1H，m)，2.67-2.78(1H，m)，3.09-3.18(1H，m)，3.31-3.34(1H，m)，3.41-3.52(1H，m)，3.77(2H，brs)，4.05-4.13(2H，m)，6.35(1H，m)，7.42(1H，m)。
Embodiment 9
Figure S2008100051493D00351
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.30ml, 0.30mmol) adding (2S)-4-(2-sulfydryl-1,3-thiazole-4-yl)-2-methyl-3, (89mg, THF 0.30mmol) (2.0ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 1.2g; 0.60mmol), solution was left standstill 16 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, (hexane/ethyl acetate: 1/4 → 1/3) purification obtains (4R to resistates with silica gel chromatography, 5S, 6S)-and 3-[(4-{ (2S)-1-[(allyloxy) carbonyl]-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (87mg, 47%).
1H?NMR(300MHz，CDCl 3)δ0.09(9H，s)，1.10(3H，d，J＝7.1Hz)，1.18(3H，d，J＝7.0Hz)，1.21(3H，d，J＝6.2Hz)，2.28(1H，d，J＝16.3Hz)，2.67-2.79(1H，m)，3.22(1H，dd，J＝2.9，6.2Hz)，3.46(1H，dd，J＝7.4，9.9Hz)，3.75-3.86(1H，m)，4.15-4.23(2H，m)，4.42-4.53(1H，m)，4.59-4.86(5H，m)，5.16-5.48(4H，m)，5.88-6.03(2H，m)，6.64(1H，brs)，7.08(1H，s)。
B) at 0 ℃, at (4R, 5S, 6S)-3-[(4-{ (2S)-1-[(allyloxy) carbonyl]-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(87mg adds entry (7ml) in THF 0.14mmol) (10ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 3 then, stirred 1 hour.Add sodium bicarbonate aqueous solution in the reaction soln, twice of ethyl acetate extraction of reaction mixture.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in the methylene dichloride (2ml).In solution, add acetate (20 μ l) and tri-butyl tin hydride (0.38ml, 1.4mmol), at room temperature add then two (triphenylphosphine) Palladous chlorides (II) (9.8mg, 0.014mmol).After 10 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the reaction mixture impouring.After mixture separates with separating funnel, organic layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2S)-the 2-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (59.3mg).
IR(KBr)3392，2970，1758，1599，1391，1263cm -1
1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.1Hz)，1.09(3H，d，J＝6.4Hz)，1.26(3H，d，J＝6.4Hz)，2.24-2.37(1H，m)，2.60-2.71(1H，m)，3.07-3.18(1H，m)，3.28-3.38(2H，m)，3.68(2H，brs)，4.03-4.10(2H，m)，6.35(1H，m)，7.39(1H，m)。
Embodiment 10
Figure S2008100051493D00371
A) according to the same procedure of embodiment 1, with (2S)-2-(methoxymethyl)-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(methoxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.09(3H，d，J＝7.3Hz)，1.24(3H，d，J＝6.2Hz)，2.54(1H，d，J＝16.8Hz)，2.63-2.73(1H，m)，3.24(1H，dd，J＝6.2，2.9Hz)，3.39-3.48(2H，m)，3.34(3H，s)，3.50-3.64(1H，m)，3.70-3.87(1H，m)，4.18-4.26(2H，m)，4.48-4.88(6H，m)，5.20-5.51(4H，m)，5.90-6.04(2H，m)，6.68(1H，br?s)，7.12(1H，s)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(methoxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain thus (4R, 5S, 6S)-6-[(1R)-the 1-[(hydroxyethyl)-3-(4-[(2S)-2-(methoxymethyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.1Hz)，1.09(3H，d，J＝6.4Hz)，2.38-2.49(1H，m)，2.59-2.66(1H，m)，3.09-3.20(1H，m)，3.30(3H，s)，3.31-3.33(1H，m)，3.48-3.65(3H，m)，3.73(2H，br?s)，4.03-4.12(2H，m)，6.37(1H，s)，7.40(1H，s)。
Embodiment 11
Figure S2008100051493D00381
A) according to the same procedure of embodiment 1, with (2S)-2-(fluoro methyl)-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.10(3H，d，J＝7.3Hz)，1.24(3H，d，J＝6.0Hz)，2.57(1H，d，J＝16.7Hz)，2.69-2.80(1H，m)，3.24(1H，dd，J＝6.2，2.9Hz)，3.49-3.60(1H，m)，3.78-3.94(1H，m)，4.08-4.99(10H，m)，5.22-5.50(4H，m)，5.90-6.04(2H，m)，6.69(1H，br?s)，7.14(1H，s)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain thus (4R, 5S, 6S)-3-(4-[(2S)-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-[(hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.3Hz)，1.10(3H，d，J＝6.2Hz)，2.24-2.33(1H，m)，2.43-2.49(1H，m)，3.12-3.19(1H，m)，3.30-3.33(1H，m)，3.53-3.56(2H，m)，4.05-4.12(2H，m)，4.31-4.39(1H，m)，4.46-4.54(1H，m)，6.40-6.43(1H，m)，7.36(1H，s)。
Embodiment 12
A) according to the same procedure of embodiment 1, with (2R)-2-(fluoro methyl)-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.13(3H，d，J＝7.3Hz)，1.24(3H，d，J＝6.0Hz)，2.57(1H，d，J＝16.9Hz)，2.69-2.80(1H，m)，3.25(1H，dd，J＝6.2，2.7Hz)，3.44-3.59(1H，m)，3.78-3.94(1H，m)，4.11-5.00(10H，m)，5.22-5.50(4H，m)，5.90-6.05(2H，m)，6.68(1H，br?s)，7.15(1H，s)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain thus (4R, 5S, 6S)-3-(4-[(2R)-2-(fluoro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-[(hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.1Hz)，1.10(3H，d，J＝6.2Hz)，2.38-2.50(1H，m)，2.55-2.63(1H，m)，3.09-3.19(1H，m)，3.31-3.34(1H，m)，3.48-3.62(1H，m)，3.68-3.72(2H，m)，4.04-4.12(2H，m)，4.40-4.45(1H，m)，4.55-4.61(1H，m)，6.39-6.42(1H，m)，7.40(1H，s)。
Embodiment 13
Figure S2008100051493D00401
A) at 0 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.19ml, 0.19mmol) adding (2S)-2-(chloro methyl)-4-(2-sulfydryl-1,3-thiazole-4-yl)-3, (64mg, THF 0.19mmol) (1.0ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 0.74g; 0.38mmol), solution was left standstill 15 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate) and is obtained (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (54mg, 43%).
1H?NMR(300MHz，CDCl 3)δ0.11(9H，s)，1.07(3H，d，J＝7.4Hz)，1.21(3H，d，J＝6.0Hz)，2.68-2.75(2H，m)，3.22(1H，dd，J＝2.7，6.4Hz)，3.47-3.60(3H，m)，3.73-3.90(1H，m)，4.15-4.22(2H，m)，4.42-4.86(6H，m)，5.20-5.35(3H，m)，5.45(1H，dd，J＝1.5，17.2Hz)，5.88-6.03(2H，m)，6.65(1H，brs)，7.12(1H，s)。
B) at 0 ℃, at (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(54mg adds entry (7ml) in THF 0.083mmol) (4ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 2 then, stirred 15 minutes.Add saturated sodium bicarbonate aqueous solution in the reaction mixture.Solution is adjusted to pH7.5, uses twice of ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in methylene dichloride (2ml).(5.8mg 0.014mmol), stirs mixture 10 minutes in same temperature to add acetate (12 μ l), tri-butyl tin hydride (0.23ml) and two (triphenylphosphine) Palladous chloride at 0 ℃ in solution.Add in the reaction mixture phosphate buffered saline buffer (50mM, pH7,25ml) and methylene dichloride (20ml).After isolating water layer, the extraction of dichloromethane layer water, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2S)-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (22.5mg, 46%).
IR(KBr)3398，2968，1760,1601，1389，1264cm -1
1H?NMR(300MHz，D 2O)δ0.91(3H，d，J＝7.1Hz)，1.08(3H，d，J＝6.2Hz)，2.67-2.75(2H，m)，3.14(1H，dd，J＝7.3，9.7Hz)，3.31(1H，dd，J＝2.8，5.9Hz)，3.75-3.95(5H，m)，4.02-4.11(2H，m)，6.37(1H，m)，7.43(1H，m)。
Embodiment 14
Figure S2008100051493D00421
A) at-70 ℃, hexane solution (1.56M with n-Butyl Lithium, 68ml, 0.11mmol) adding (2S)-2-{[(aminocarboxyl) the oxygen base] methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (37.8mg, THF 0.11mmol) (1.0ml)/DMF (0.5ml) solution.Mixture is risen to 0 ℃, stirred then 15 minutes.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 0.42g; 0.22mmol), solution was left standstill 13 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography (hexane/ethyl acetate) and is obtained rough (4R, 5S, 6S)-3-{[4-((2S)-1-[(allyloxy) carbonyl]-the 2-{[(aminocarboxyl) the oxygen base] methyl }-1,2,3,6-tetrahydrochysene-4-pyridyl)-1,3-thiazoles-2-yl] sulfenyl }-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (154mg).
At 0 ℃ to thus obtained rough (4R, 5S, 6S)-3-{[4-((2S)-1-[(allyloxy) carbonyl]-the 2-{[(aminocarboxyl) the oxygen base] methyl }-1,2,3,6-tetrahydrochysene-4-pyridyl)-and 1,3-thiazoles-2-yl] sulfenyl }-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-add entry in THF (4ml) solution of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 2 then, stirred 15 minutes.Add saturated sodium bicarbonate aqueous solution in the reaction mixture.Solution is adjusted to pH7.5, uses twice of ethyl acetate extraction.Organic layer washs with saturated nacl aqueous solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in methylene dichloride (2ml).(21.8mg 0.014mmol), stirs mixture 10 minutes in same temperature to add acetate (47 μ l), tri-butyl tin hydride (0.84ml) and two (triphenylphosphine) Palladous chloride at 0 ℃ in solution.Add in the reaction mixture phosphate buffered saline buffer (50mM, pH7,25ml) and methylene dichloride (20ml).After isolating water layer, the extraction of dichloromethane layer water, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-and 3-{[4-((2S)-2-{[(aminocarboxyl) oxygen base] methyl }-1,2,3,6-tetrahydrochysene-4-pyridyl)-1,3-thiazoles-2-yl] sulfenyl }-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (10.6mg).
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.4Hz)，2.54-2.80(2H，m)，3.15-3.21(1H，m)，3.68-3.86(3H，m)，4.08-4.38(5H，m)，6.41(1H，s)，7.46(1H，s)。
Embodiment 15
Figure S2008100051493D00441
A) according to the same procedure of embodiment 8, use 4-[(2S)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-thiol obtains (4R, 5S thus as mercaptan compound, 6S)-and 3-(4-[(2S)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.10(9H，s)，1.05(3H，d，J＝7.1Hz)，1.21(6H，d，J＝6.2Hz)，2.24-2.36(1H，m)，2.41(3H，s)，2.50-2.61(1H，m)，2.69-3.00(2H，m)，3.19-3.22(1H，m)，3.47-3.53(1H，m)，4.15-4.20(2H，m)，4.46-4.85(3H，m)，5.25(1H，d，J＝10.4Hz)，5.44(1H，dd，J＝1.4，17.0Hz)，5.96(1H，ddd，J＝5.1，10.4，17.0Hz)，6.61(1H，s)，7.07(1H，s)。
B) according to the same procedure utilization (4R of embodiment 8,5S, 6S)-and 3-(4-[(2S)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-3-(4-[(2S) and-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
IR(KBr)3393，2970，1749，1601，1393，1266cm -1
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.5Hz)，1.13(3H，d，J＝6.2Hz)，1.32(3H，d，J＝6.2Hz)，2.47-2.58(1H，m)，2.74-2.88(1H，m)，2.79(3H，s)，3.11-3.23(1H，m)，3.32-3.38(1H，m)，3.75-3.93(1H，m)，4.09-4.15(2H，m)，6.33(1H，s)，7.47(1H，s)。
Embodiment 16
A) according to the same procedure of embodiment 8, with [(2S)-1-methyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-1,2,3,6-tetrahydrochysene-2-pyridyl] the methyl carboxylic acids allyl ester is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2S)-2-({ [(allyloxy) carbonyl] oxygen base } methyl)-1-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.10(9H，s)，1.07(3H，d，J＝7.3Hz)，1.21(3H，d，J＝6.2Hz)，2.37-2.65(2H，m)，2.48(3H，s)，2.88-3.00(1H，m)，3.19-3.29(2H，m)，3.37-3.55(2H，m)，4.15-4.24(4H，m)，4.61-4.85(4H，m)，5.17-5.48(4H，m)，5.79-6.00(2H，m)，6.65(1H，s)，7.08(1H，s)。
B) according to the same procedure utilization (4R of embodiment 8,5S, 6S)-3-(4-[(2S)-2-({ [(allyloxy) carbonyl] oxygen base } methyl)-1-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2S)-2-(hydroxymethyl)-1-methyl isophthalic acid, 2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
IR(KBr)3489，1758，1598，1393cm -1
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.1Hz)，1.13(3H，d，J＝6.4Hz)，2.62-2.75(5H，m)，3.13-3.22(1H，m)，3.28-3.33(1H，m)，3.53-3.74(2H，m)，3.82-4.16(5H，m)，6.33(1H，s)，7.48(1H，s)。
Embodiment 17
Figure S2008100051493D00461
A) according to the same procedure of embodiment 1, with (2S)-2-methyl-3-(2-sulfenyl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate is as mercaptan compound, obtain (4R thus, 5S, 6S)-and 3-[(4-{ (2S)-1-[(allyloxy) carbonyl]-2-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.12(3H，d，J＝7.1Hz)，1.23(3H，d，J＝6.2Hz)，1.44-1.50(3H，m)，3.25(1H，dd，J＝6.0，2.7Hz)，3.42-3.58(1H，m)，4.12-4.48(4H，m)，4.60-4.89(4H，m)，4.98-5.08(1H，m)，5.22-5.51(4H，m)，5.91-6.05(2H，m)，6.36-6.37(1H，m)，7.18-7.26(1H，m)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-and 3-[(4-{ (2S)-1-[(allyloxy) carbonyl]-2-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2S)-2-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.1Hz)，1.07(3H，d，J＝6.4Hz)，1.35(3H，d，J＝6.6Hz)，3.02-3.12(1H，m)，3.31(1H，dd，J＝6.0，2.7Hz)，3.97-4.13(4H，m)，6.20(1H，s)，7.53(1H，s)。
Embodiment 18
Figure S2008100051493D00471
A) according to the same procedure of embodiment 1, with (2R)-2-methyl-3-(2-sulfenyl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate is as mercaptan compound, obtain (4R thus, 5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-2-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.07-1.10(3H，m)，1.23-1.26(3H，m)，1.44-1.50(3H，m)，3.23-3.30(1H，m)，3.53-3.62(1H，m)，4.12-4.48(4H，m)，4.60-4.89(4H，m)，4.99-5.08(1H，m)，5.22-5.51(4H，m)，5.90-6.05(2H，m)，6.33-6.37(1H，m)，7.18-7.26(1H，m)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-2-methyl-2,5-dihydro-1H-pyrroles-3-yl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2R)-2-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.1Hz)，1.10(3H，d，J＝6.4Hz)，1.36(3H，d，J＝6.8Hz)，3.05-3.22(1H，m)，3.33(1H，dd，J＝5.9，2.7Hz)，3.96-4.14(4H，m)，6.22(1H，s)，7.53(1H，s)。
Embodiment 19
Figure S2008100051493D00481
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.16ml, 0.16mmol) adding (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(2-sulfydryl-1,3-thiazole-4-yl)-2, (67mg, THF 0.16mmol) (1.0ml) solution stir mixture 20 minutes 5-dihydro-1H-pyrroles-1-allyl carboxylate.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 0.62g; 0.32mmol), solution was left standstill 12 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, (hexane/ethyl acetate: 1/5 → 1/3) purification obtains the mixture of even joint compound and POCA (initial feed) to resistates with silica gel chromatography.(1M, 0.96ml 0.96mmol), react after 20 hours, add frozen water in reaction mixture, the solution ethyl acetate extraction at 0-5 ℃ of THF solution that adds acetate (92 μ l) and tetrabutylammonium fluoride in mixture.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, purify obtains (4R to resistates with silica gel chromatography (hexane/ethyl acetate: 1/3 → contain the chloroform of 10% methyl alcohol), 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (83mg, 95%).
1H?NMR(300MHz，CDCl 3)δ1.10(3H，d，J＝7.3Hz)，1.32(3H，d，J＝6.1Hz)，3.22-3.28(1H，m)，3.53-3.64(1H，m)，3.72-3.80(1H，m)，3.93-4.47(6H，m)，4.58-4.88(4H，m)，5.12-5.48(4H，m)，5.80-6.05(2H，m)，6.38(1H，s)，7.31(1H，s)。
B) at 0 ℃ to (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (33mg, 0.06mmol) methylene dichloride (3ml) solution in add acetate (8.6 μ l, 0.15mmol), tri-butyl tin hydride (165ml, 0.61mmol) and two (triphenylphosphine) Palladous chloride (4.2mg, 0.006mmol), stirred 3 minutes in same temperature.Add in the reaction mixture phosphate buffered saline buffer (50mM, pH7.0,25ml) and methylene dichloride (5ml).After isolating water layer, dichloromethane layer water extracting twice, water layer methylene dichloride (3ml) washed twice.The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 1-3%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (12.3mg, 48%).
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝6.8Hz)，1.10(3H，d，J＝5.7Hz)，3.12-3.19(1H，m)，3.30-3.35(1H，m)，3.73-4.13(7H，m)，6.36(1H，s)，7.55(1H，s)。
Embodiment 20
A) according to the same procedure of embodiment 6, with (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(2-sulfenyl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ1.21(3H，d，J＝7.1Hz)，1.33(3H，d，J＝6.2Hz)，3.27(1H，dd，J＝6.9，2.7Hz)，3.42-3.60(1H，m)，3.76-4.50(7H，m)，4.66-4.89(4H，m)，5.06-5.50(5H，m)，5.91-6.05(2H，m)，6.43-6.46(1H，m)，7.35-7.40(1H，m)。
B) according to the same procedure utilization (4R of embodiment 6,5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.3Hz)，1.09(3H，d，J＝6.4Hz)，3.05-3.16(1H，m)，3.32(1H，dd，J＝6.0，2.9Hz)，3.81-3.93(2H，m)，4.03-4.19(4H，m)，4.87-4.90(1H，m)，6.36(1H，s)，7.60(1H，s)。
Embodiment 21
Figure S2008100051493D00511
A) according to the same procedure of embodiment 1, with (2R)-2-(methoxymethyl)-3-(2-sulfenyl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(methoxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.11(3H，d，J＝7.3Hz)，1.23(3H，d，J＝6.1Hz)，3.21-3.30(4H，m)，3.37-3.53(1H，m)，3.74-3.93(2H，m)，4.12-4.49(4H，m)，4.60-4.89(4H，m)，5.04-5.09(1H，m)，5.22-5.51(4H，m)，5.91-6.05(2H，m)，6.47(1H，s)，7.37-7.42(1H，m)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(methoxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2R)-2-(methoxymethyl)-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.0Hz)，1.09(3H，d，J＝6.6Hz)，3.07-3.13(1H，m)，3.18(1H，s)，3.31-3.34(1H，m)，3.66-3.69(2H，m)，3.97-4.12(4H，m)，6.34(1H，s)，7.58(1H，s)。
Embodiment 22
Figure S2008100051493D00521
A) according to the same procedure of embodiment 1, use 4-[(5S)-1,5-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-mercaptan is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(5S) and-1,5-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.11-0.12(9H，s)，1.04-1.09(3H，m)，1.17-1.28(6H，m)，2.52(3H，s)，2.55-2.63(1H，m)，3.21-3.25(1H，m)，3.49-3.62(3H，m)，4.09-4.25(3H，m)，4.60-4.87(3H，m)，5.17-5.50(4H，m)，5.85-6.04(1H，m)，6.28-6.30(1H，m)，7.05-7.27(1H，m)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-and 3-(4-[(5S)-1,5-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-and 3-(4-[(5S)-1,5-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.93(3H，d，J＝7.1Hz)，1.11(3H，d，J＝6.2Hz)，1.34(3H，d，J＝6.8Hz)，2.81(3H，s)，3.13-3.18(1H，m)，3.34(1H，dd，J＝6.2，2.8Hz)，4.03-4.14(3H，m)，4.21-4.30(1H，m)，4.38-4.45(1H，m)，6.22(1H，s)，7.47(1H，s)。
Embodiment 23
Figure S2008100051493D00531
A) according to the same procedure of embodiment 1, use 4-[(2R)-1,2-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-mercaptan is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2R) and-1,2-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.11(9H，s)，1.08(3H，d，J＝7.4)，1.25(3H，d，J＝6.2)，1.30(3H，d，J＝6.2)，2.53(3H，s)，3.23(1H，dd，J＝6.6，2.7)，3.39-3.47(1H，m)，3.53-3.63(1H，m)，3.80-3.98(2H，m)，4.16-4.26(2H，m)，4.56-4.87(2H，m)，5.25-5.50(2H，m)，5.87-6.04(1H，m)，6.29-6.31(1H，m)，7.18(1H，s)。
B) according to the same procedure utilization (4R of embodiment 2,5S, 6S)-and 3-(4-[(2R)-1,2-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-and 3-(4-[(2R)-1,2-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.4Hz)，1.37(3H，d，J＝6.6Hz)，2.80(3H，s)，3.13-3.23(1H，m)，3.35(1H，dd，J＝6.0，2.9Hz)，3.84-3.89(1H，m)，4.06-4.15(2H，m)，4.21-4.27(1H，m)，4.45-4.51(1H，m)，6.21(1H，s)，7.55(1H，s)。
Embodiment 24
Figure S2008100051493D00541
A) according to the same procedure of embodiment 1, use 4-[(2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-thiol is as mercaptan compound, obtain (4R thus, 5S, 6S)-3-(4-[(2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ-0.03(3H，s)，0.00(3H，s)，0.12(9H，s)，0.86(9H，s)，1.09(3H，d，J＝7.3Hz)，1.23(3H，d，J＝6.2Hz)，2.59(3H，s)，3.23(1H，dd，J＝6.4，2.9Hz)，3.41-3.58(2H，m)，3.67-3.97(4H，m)，4.16-4.26(2H，m)，4.65-4.88(2H，m)，5.18-5.51(2H，m)，5.82-6.04(1H，m)，6.46(1H，s)，7.41(1H，s)。
B) with (4R, 5S, 6S)-3-(4-[(2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (106mg, 0.16mmol) THF (2.7ml) solution 0 ℃ of cooling, in solution, add acetate (0.073ml, 1.28mmol) and the THF solution (1M of tetrabutylammonium fluoride, 0.64ml, 0.64mmol).Solution was stirred 1 hour at uniform temp, left standstill 63 hours at refrigerator then.In reaction mixture, add entry, solution ethyl acetate extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is purified with silica gel chromatography, then according to embodiment 1.c) same procedure obtain (4R behind the allyl reaction through taking off, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(2R)-2-(hydroxymethyl)-1-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.98(3H，d，J＝7.3Hz)，1.13(3H，d，J＝6.4Hz)，2.97(3H，s)，3.09-3.19(1H，m)，3.36(1H，dd，J＝6.0，2.9Hz)，3.87-4.02(3H，m)，4.06-4.15(2H，m)，4.40-4.45(1H，m)，6.38(1H，s)，7.63(1H，s)。
Embodiment 25
Figure S2008100051493D00561
A) at 0 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 1.24ml, 1.24mmol) adding 2-methyl-5-(2-sulfydryl-1,3-thiazole-4-yl)-3, (368mg, THF 1.24mmol) (2.4ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-and 3-[(two phenoxy group phosphonos) the oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 4.73g; 2.5mmol), solution was left standstill 13 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, (hexane/ethyl acetate: 4/1 → 3/1) purification obtains (4R to resistates with silica gel chromatography, 5S, 6S)-and the 3-[(4-{1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (544mg, 71%).
1H?NMR(300MHz，CDCl 3)δ0.09(9H，s)，1.06-1.22(9H，m)，2.04-2.15(1H，m)，2.58-2.70(1H，m)，3.22(1H，dd，J＝2.7，6.0Hz)，3.40-3.60(1H，m)，3.82-3.93(1H，m)，4.13-4.23(2H，m)，4.60-4.86(6H，m)，5.19-5.33(3H，m)，5.45(1H，d，J＝17.0Hz)，5.89-6.02(2H，m)，6.72(1H，brs)，7.10(0.5H，s)，7.11(0.5H，s)。
B) at 0 ℃, at (4R, 5S, 6S)-the 3-[(4-{1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1,3-thiazoles-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(544mg adds entry in THF 0.88mmol) (4ml) solution to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, with 1N hydrochloric acid pH value of solution is adjusted to approximately 3 then, stirred 1 hour.Add saturated sodium bicarbonate aqueous solution in the reaction mixture, solution is adjusted to pH7.5.Twice of ethyl acetate extraction of solution.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in methylene dichloride (10ml).0 ℃ in solution, add acetate (126 μ l), tri-butyl tin hydride (2.4ml, 8.9mmol) and two (triphenylphosphine) Palladous chlorides (61.8mg 0.088mmol), stirs mixture 5 minutes at uniform temp.Add in the reaction mixture phosphate buffered saline buffer (50mM, pH7.0,25ml) and methylene dichloride (20ml).After isolating water layer, dichloromethane layer water extracting twice, water layer washs with methylene dichloride (3ml).The organic solvent of pressure reducing and steaming water layer, resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-{[4-(6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl)-1, the 3-thiazol-2-yl] sulfenyl }-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (230mg, 62%).
1H?NMR(300MHz，D 2O)δ0.90(3H，d，J＝7.1Hz)，1.08(3H，d，J＝6.2Hz)，1.27(3H，d，J＝6.6Hz)，2.16-2.29(1H，m)，2.47-2.58(1H，m)，3.11(1H，dd，J＝7.3，9.5Hz)，3.30(1H，dd，J＝2.7，5.9Hz)，3.34-3.46(1H，m)，3.88-4.10(4H，m)，6.50(1H，brs)，7.36(1H，s)。
Embodiment 26
Figure S2008100051493D00581
A) according to the same procedure of embodiment 8, use 4-[(2R)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-thiol obtains (4R, 5S thus as mercaptan compound, 6S)-and 3-(4-[(2R)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1 R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
B) according to the same procedure utilization (4R of embodiment 8,5S, 6S)-and 3-(4-[(2R)-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, obtain (4R thus, 5S, 6S)-3-(4-[(2R) and-1,2-dimethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
Reference example
An example of the mercaptan compound of preparation formula [3] expression is described as follows.
Reference example 1
Figure S2008100051493D00591
A) obtain (2S)-N-(allyloxy carbonyl)-2-methyl-4-ethoxy carbonyl-3-pyrroline with hydrochloric acid L-alanine methyl ester as initial feed according to the method for preparing N-(tert-butoxycarbonyl)-2-methyl-4-ethoxy carbonyl-3-pyrroline (JP 1-233270B).
1H?NMR(300MHz，CDCl 3)δ1.22-1.40(6H，m)，4.24(2H，q，J＝6.9Hz)，4.29-4.49(2H，m)，4.56-4.84(3H，m)，5.23(1H，d，J＝10.4Hz)，5.32(1H，d，J＝17.4Hz)，5.89-6.02(1H，m)，6.62-6.67(1H，m)。
B) at-70 ℃, to (2S)-N-(allyloxy carbonyl)-2-methyl-4-ethoxy carbonyl-3-pyrroline (0.44g, 1.8mmol) and bromochloromethane (0.19ml adds the hexane solution (1.59M of n-Butyl Lithium in THF 2.9mmol) (3.7ml) solution, 1.7ml, 2.7mmol).After 20 minutes (10g) and phosphate buffered saline buffer (pH7.0, mixture 10ml) are iced in the mixture impouring.Add ethyl acetate in the mixture, after mixture separates with separating funnel, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates is purified with silica gel chromatography and is obtained (2S)-(4-chloro ethanoyl)-2-methyl-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (151mg).
1H?NMR(300MHz，CDCl 3)δ1.37-1.42(3H，m)，4.30-4.70(6H，m)，4.80-4.95(1H，m)，5.18-5.24(1H，m)，5.26-5.34(1H，m)，5.86-5.99(1H，m)，6.64-6.68(1H，m)。
IR(KCl)1683，1649，1629，1404cm -1
C) at 0-5 ℃, (2S)-(4-chloro ethanoyl)-2-methyl-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (0.15g, add in methyl alcohol 0.62mmol) (2ml) solution thioisonicotinamide (5mg) and ammonium dithiocarbamate (82mg, 0.74mmol).Temperature is risen to room temperature, stirred the mixture 15 minutes, then stirred 1 hour at 55-60 ℃.Removal of solvent under reduced pressure, resistates obtains (2S)-2-methyl-4-(2-sulfydryl-1,3-thiazoles-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (60mg, 34%) with washing with alcohol.
1H?NMR(300MHz，CDCl 3)δ1.34-1.39(3H，m)，4.32-4.53(2H，m)，4.61-4.66(2H，m)，4.72-4.85(1H，m)，5.22(1H，d，J＝10.4Hz)，5.27-5.35(1H，m)，5.87-6.09(2H，m)，6.37(0.5H，s)，6.40(0.5H，s)。
Reference example 2
Figure S2008100051493D00601
A) hydrochloric acid L-alanine methyl ester (100mg, 0.72mmol) DMF (2.5ml) suspension in add salt of wormwood (500mg, 3.6mmol), potassiumiodide (60mg, 0.36mmol) and 4-bromo ethyl lactate (0.103ml, 0.72mmol), the gained mixture stirred 2 hours at 60 ℃.(0.103ml, 0.70mmol), the gained mixture stirs more than 2 hours at uniform temp to add 4-bromo ethyl lactate again in mixture.Add entry in the reaction mixture, mixture ethyl acetate extraction three times merge organic layer.The organic layer that merges is water, saturated sodium-chloride water solution washing successively, uses dried over mgso.Organic solvent is removed in decompression, and resistates is dissolved in chloroform (5ml).At room temperature, (0.25ml, 1.44mmol) (0.15ml 1.42mmol), stirs mixture 1 hour with the carbonochloridic acid allyl ester to add diethyl propyl group ethamine in the solution.After in reaction mixture, adding entry, use the separating funnel separating mixture, twice of chloroform extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Organic solvent is removed in decompression, and resistates is purified with silica gel chromatography and obtained the N-[(allyloxy) carbonyl]-N-(4-oxyethyl group-4-oxo butyl)-L-alanine methyl ester (134mg).
1H?NMR(300MHz，CDCl 3)δ1.26(3H，t，J＝7.1Hz)，1.49(3H，d，J＝7.4Hz)，1.80-1.98(2H，m)，2.30-2.40(2H，m)，3.12-3.27(1H，m)，3.38-3.51(1H，m)，3.71(3H，s)，4.13(2H，q，J＝7.1Hz)，4.45-4.62(3H，m)，5.18-5.33(2H，m)，5.81-6.00(1H，m)。
B) rise to 60 ℃ potassium tert.-butoxide (3.42g, add the N-[(allyloxy in THF suspension 30mol)) carbonyl]-N-(4-oxyethyl group-4-oxo butyl)-L-alanine methyl ester (4.60g, THF 15mmol) (30ml) solution, stir after 1 minute, with reaction soln impouring biphosphate sodium water solution (1M, 50ml).Solution is adjusted to pH 2-3, in solution, adds ethyl acetate.Behind the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Organic solvent is removed in decompression, resistates is purified with silica gel chromatography and is obtained 1-allyl group 4-ethyl (2S)-2-methyl-3-oxo-1,4-piperidines dicarboxylic ester (2.03g) and 1-allyl group 4-methyl (2S)-2-methyl-3-oxo-1,4-piperidines dicarboxylic ester (1.20g).
1-allyl group 4-ethyl (2S)-2-methyl-3-oxo-1,4-piperidines dicarboxylic ester
1H?NMR(300MHz，CDCl 3)δ1.31(3H，t，J＝7.1Hz)，1.40(3H，d，J＝7.0Hz)，2.25-2.42(2H，m)，2.86-3.08(1H，m)，4.07-4.28(1H，m)，4.23(2H，q，J＝7.1Hz)，4.57-4.72(3H，m)，5.20-5.34(2H，m)，5.88-6.00(1H，m)，12.2(1H，s)。
1-allyl group 4-methyl (2S)-2-methyl-3-oxo-1,4-piperidines dicarboxylic ester
1H?NMR(300MHz，CDCl 3)δ1.40(3H，d，J＝6.8Hz)，2.25-2.42(2H，m)，2.86-3.03(1H，m)，3.78(3H，s)，4.07-4.28(1H，m)，4.57-4.72(3H，m)，5.20-5.34(2H，m)，5.88-6.01(1H，m)，12.1(1H，s)。
C) 1-allyl group 4-ethyl (2S)-2-methyl-3-oxo-1,4-piperidines dicarboxylic ester (1.40g, add in methyl alcohol 5.2mmol) (27ml) solution acetate (0.36ml, 6.3mmol) and sodium cyanoborohydride (0.39g, 6.3mmol), mixture was at room temperature stirred 1 hour.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained 1-allyl group 4-ethyl (2S)-3-hydroxy-2-methyl-1,4-piperidines dicarboxylic ester (1.36g).With methylene dichloride (24ml) solution of this compound-30 ℃ of coolings, in solution, add methylsulfonyl chloride (0.58ml, 7.5mmol), triethylamine (1.4ml, 10.0ml) and dimethyl aminopyridine (61mg, 0.50mmol).Mixture stirred 20 minutes at 0 ℃, was poured in the 1N hydrochloric acid, with solution chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates is dissolved in toluene (10ml) and methylene dichloride (5ml).(2.3ml, 15.4mmol), solution at room temperature stirred 5 hours to add DBU in solution.Add entry in the reaction soln, behind the separating funnel separating mixture, the water layer ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates is purified with silica gel chromatography and is obtained 1-allyl group 4-ethyl (6S)-6-methyl-3, the compound (409mg) of 6-dihydro-1,4 (2H)-pyridine dicarboxylate (825mg) and a kind of intermediate methylsulfonylization.
1H?NMR(300MHz，CDCl 3)δ1.27(3H，d，J＝7.0Hz)，1.30(3H，t，J＝7.1Hz)，2.23-2.36(1H，m)，2.40-2.46(1H，m)，2.80-2.96(1H，m)，4.14-4.29(3H，m)，4.57-4.72(3H，m)，5.20-5.34(2H，m)，5.87-6.01(1H，m)，6.82(1H，s)。
D) at-90 ℃, at 1-allyl group 4-ethyl (6S)-6-methyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylates (200mg, 0.79mmol) and bromochloromethane (0.082ml adds the hexane solution (1.59M of n-Butyl Lithium in THF 1.3mmol) (4ml) solution, 0.74ml, 1.2mmol).After 20 minutes, with reaction mixture impouring ice (5g) and phosphate buffer soln (pH7.0,10ml).Add ethyl acetate in the solution, behind the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates is purified with silica gel chromatography and is obtained (6S)-4-(chloro ethanoyl)-6-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (167mg).
1H?NMR(300MHz，CDCl 3)δ1.32(3H，d，J＝7.0Hz)，2.18-2.31(1H，m)，2.49-2.56(1H，m)，2.80-2.94(1H，m)，4.16-4.31(1H，m)，4.39(1H，d，J＝14.1Hz)，4.42(1H，d，J＝14.1Hz)，4.60-4.64(2H，m)，4.74-4.83(1H，m)，5.20-5.34(2H，m)，5.86-6.02(1H，m)，6.73(1H，s)。
E) at 0-5 ℃; at (6S)-4-(chloro ethanoyl)-6-methyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (167mg, add in methyl alcohol 0.65mmol) (2ml) solution thioisonicotinamide (5mg) and thiocarbamate ammonium (87mg, 0.79mmol).Temperature rises to room temperature, and mixture was stirred 15 minutes.Add ethanol (4ml) in the mixture, solution under agitation refluxed 3 hours.Removal of solvent under reduced pressure, resistates are dissolved in the 1N aqueous sodium hydroxide solution.Solution washs with ether.The water layer of solution is adjusted to pH 2-3 with 6N hydrochloric acid, water layer ethyl acetate extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and decompression is removed organic solvent and obtained (6S)-6-methyl-4-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (115mg).
1H?NMR(300MHz，CDCl 3)δ1.29(3H，d，J＝6.9Hz)，2.20-2.28(1H，m)，2.38-2.50(1H，m)，2.83-3.05(1H，m)，4.25-4.33(1H，m)，4.60-4.65(2H，m)，4.66-4.78(1H，m)，5.21-5.35(2H，m)，5.89-6.02(2H，m)，6.40(1H，s)。
Reference example 3
Figure S2008100051493D00631
A) at-30 ℃, (35g adds triethylamine (17ml in THF 102mol) (500ml) solution to N-(benzyloxy) carbonyl-D-L-glutamic acid 5-tert-butyl ester, 122mmol), (12ml 122mmol), stirs mixture at uniform temp then to add chloro ethyl formate.(11.6g, water 306mmol) (51ml) solution stir mixture 30 minutes to add sodium borohydride at-30 ℃ in mixture then.Solution is risen to 0 ℃ then, stirred 30 minutes.Add entry in the reaction mixture, solution ethyl acetate extraction three times, organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and vacuum is removed organic solvent.Resistates silica gel (210g) chromatography (hexane/ethyl acetate: 3/2 → 1/1) purification obtains (4R)-4-{[(benzyloxy) carbonyl] amino }-the 5-hydroxypentanoic acid tert-butyl ester (16.5g, 50%).
1H?NMR(300MHz，CDCl 3)δ1.40(9H，s)，1.67-1.91(2H，m)，2.19-2.38(2H，m)，2.61(1H，brs)，3.48-3.70(3H，m)，5.06(2H，s)，5.17(1H，brs)，7.25-7.36(5H，m)。
B) ice-cooled following, (4R)-and the 4-{[(benzyloxy) carbonyl] amino }-the 5-hydroxypentanoic acid tert-butyl ester (15.05g, 46.5mmol) methylene dichloride (150ml) solution in add 4-dimethylaminopyridine (120mg, 1mmol), diisopropylethylamine (26ml, 150mmol) with chloro dimethyl cellosolve (12ml, 150mmol), mixture is risen to room temperature.After 10 hours under ice bath cooling, with frozen water and 1N hydrochloric acid with the mixture pH regulator to about 3.After adding saturated sodium-chloride water solution, use the separating funnel separating mixture, organic layer washes with water once, uses the saturated sodium-chloride water solution washed twice.The organic layer dried over mgso, decompression is removed organic solvent and is obtained (4R)-4-{[(benzyloxy) carbonyl] amino }-5-(methoxymethoxy) the valeric acid tert-butyl ester (16.87g, 99%).
1H?NMR(300MHz，CDCl 3)δ1.41(9H，s)，1.75-1.92(2H，m)，2.22-2.35(2H，m)，3.31(3H，s)，3.47-3.58(2H，m)，3.75-3.86(1H，m)，4.58(2H，s)，5.02(1H，brd，J＝8.1Hz)，5.07(2H，s)，7.26-7.37(5H，m)。
C) (4R)-and the 4-{[(benzyloxy) carbonyl] amino }-(16.42g adds 10%Pd-C (1.7g) in methyl alcohol 44mmol) (164ml) solution to 5-(methoxymethoxy) the valeric acid tert-butyl ester, and mixture was stirred 3.5 hours under nitrogen atmosphere.Remove by filter catalyzer, solvent removed in vacuo obtains (4R)-4-amino-5-(methoxymethoxy) valeric acid tert-butyl ester (10.87g, 106%).
1H?NMR(300MHz，CDCl 3)δ1.41(9H，s)，1.89(2H，q，J＝7.1Hz)，2.41(2H，t，J＝7.5Hz)，3.24-3.33(2H，m)，3.36(3H，s)，3.53(1H，dd，J＝6.8，10.1Hz)，3.68(1H，dd，J＝3.8，10.3Hz)，4.57-4.83(5H，m)。
D) at room temperature, to (4R)-4-amino-5-(methoxymethoxy) valeric acid tert-butyl ester (2.33g, 10mmol) and diisopropylethylamine (2.6ml, dripping bromine is for methyl acetate (1.4ml in methyl alcohol 15mmol) (70ml) solution, methyl alcohol 15mmol) (10ml) solution, mixture stirred 1 hour at 60 ℃.In mixture, add again the monobromo-acetic acid methyl esters (0.5ml, 5mmol) and diisopropylethylamine (0.9ml, 5mmol).Stir after 1 hour, mixture is cooled to room temperature, solvent removed in vacuo.Resistates is dissolved in chloroform (50ml), in solution, drip the carbonochloridic acid allyl ester (2.15ml, 20mmol), drip then diisopropylethylamine (3.5ml, 20mmol).Mixture was stirred 1 hour at uniform temp, again stirring at room 1 hour.Under the ice bath cooling, in mixture, add entry.Mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Organic solvent is removed in decompression, resistates is purified with silica gel (51g) chromatography (hexane/ethyl acetate: 2/1～hexane/ethyl acetate: 1: 1) and is obtained (4R)-4-{[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino }-5-(methoxymethoxy) the valeric acid tert-butyl ester (3.01g, 77%).
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.78-1.91(2H，m)，2.31-2.37(2H，m)，3.33(3H，s)，3.62(2H，t，J＝6.8Hz)，3.71(1.8H，s)，3.72(1.2H，s)，3.99(2H，s)，4.22-4.38(1H，m)，4.52-4.66(4H，m)，5.15-5.35(2H，m)，5.81-5.97(1H，m)。
E) at potassium tert.-butoxide (299mg, 2.66mmol) THF (26ml) suspension in add (4R)-4-{[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino-5-(methoxymethoxy) the valeric acid tert-butyl ester (0.52g, 1.33mmol) THF (2.5ml) solution, mixture was stirred 1 minute.After being cooled to 0 ℃, with reaction mixture impouring dilute hydrochloric acid.PH value of solution is adjusted to about 3, add saturated sodium-chloride water solution after, the solution ethyl acetate extraction.Organic layer is water, saturated sodium-chloride water solution washing successively.The organic layer dried over mgso, organic solvent is removed in decompression.Resistates silica gel (15g) chromatography (hexane/ethyl acetate: 3/1) purification obtains the 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-5-oxo-1,4-piperidines dicarboxylic ester (0.26g, 54%).
1H?NMR(300MHz，CDCl 3)δ1.50(9H，s)，2.29-2.44(2H，m)，3.33(3H，s)，3.49-3.76(3H，m)，4.31-4.48(1H，m)，4.56-4.70(5H，m)，5.22(1H，d，J＝10.4Hz)，5.31(1H，d，J＝17.4Hz)，5.94(1H，ddd，J＝5.1，10.4，17.2Hz)，12.23(1H，s)。
F) the 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-5-oxo-1,4-piperidines dicarboxylic ester (1.21g, 3.4mmol) methyl alcohol (40ml) solution in add acetate (0.235ml, 4.1mmol) and sodium cyanoborohydride (0.255g, 4.1mmol), mixture at room temperature stirred 20 minutes.Solvent removed in vacuo judges with TLC whether initial feed exhausts.If the residue initial feed adds methyl alcohol (40ml) solubilizing reaction mixture, and then removes and desolvate.Repeating this step exhausts until initial feed.After initial feed exhausted, resistates obtained the 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-[(methoxymethoxy with silica gel (30g) chromatographic purification) methyl]-1,4-piperidines dicarboxylic ester (1.22g, quantitatively).
1H?NMR(300MHz，CDCl 3)δ1.45(9H，s)，1.63-1.74(2H，m)，2.44-2.56(1H，m)，2.61-2.79(1H，m)，3.34(3H，s)，3.53-3.76(3H，m)，4.10-4.36(1H，m)，4.41-4.67(5H，m)，5.18(1H，d，J＝10.3Hz)，5.28(1H，dd，J＝1.7，17.2Hz)，5.84-5.96(1H，m)。
G) at-30 ℃, in the 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-[(methoxymethoxy) methyl]-1,4-piperidines dicarboxylic ester (1.22g, 3.4mmol) methylene dichloride (9.4ml) solution in add methylsulfonyl chloride (0.4ml, 5.1mmol), triethylamine (0.95ml, 6.8mmol) and 4-dimethylaminopyridine (41.5mg, 0.34mmol), mixture stirred 40 minutes at 0 ℃.In reaction mixture impouring dilute hydrochloric acid, mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Organic solvent is removed in decompression, and resistates is dissolved in toluene (5ml) and methylene dichloride (10ml).Mixture is cooled to 0 ℃, and adding DBU (0.76ml, 5.1mmol).Mixture is risen to room temperature, stirred just in time 20 minutes.With reaction mixture impouring dilute hydrochloric acid, use ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively.The organic layer dried over mgso, organic solvent is removed in decompression.Resistates silica gel (30g) chromatography (hexane/ethyl acetate: 2/1) purification obtains the 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-the 5-[(methylsulfonyl) the oxygen base]-1; 4-piperidines dicarboxylic ester (0.24g; 15%) and the 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-3; 6-dihydro-1; 4 (2H)-pyridine dicarboxylates (0.79g, 68%).
The 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-the 5-[(methylsulfonyl) oxygen Base]-1,4-piperidines dicarboxylic ester
1H?NMR(300MHz，CDCl 3)δ1.43(9H，s)，1.79(1H，dt，J＝5.9，13.4Hz)，2.07-2.18(1H，m)，2.75-2.87(1H，m)，3.03(3H，s)，3.34(3H，s)，3.57-3.68(2H，m)，4.45-4.75(8H，m)，5.20(1H，dd，J＝0.9，10.3Hz)，5.29(1H，d，J＝16.9Hz)，5.84-5.96(1H，m)。
The 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-3,6-dihydro-1,4 (2H)-pyridine Dicarboxylic ester
1H?NMR(300MHz，CDCl 3)δ1.47(9H，s)，2.41-2.47(2H，m)，3.30(3H，s)，3.43(2H，d，J＝7.9Hz)，3.64-3.80(1H，m)，4.37-4.80(6H，m)，5.19(1H，dd，J＝1.3，10.4Hz)，5.29(1H，d，J＝17.2Hz)，5.87(1H，ddt，J＝5.3，10.4，17.2Hz)，6.77(1H，brs)。
H) the 1-allyl group 4-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-3, (1.15g adds hydrochloric acid/methyl alcohol (50ml) in methyl alcohol 3.4mmol) (15ml) solution to 6-dihydro-1,4 (2H)-pyridine dicarboxylate, stirs the mixture and spends the night.In mixture, add toluene, solvent removed in vacuo.Add methyl alcohol and toluene, solvent removed in vacuo once more in the resistates.Resistates is dissolved in methylene dichloride (20ml), in solution, adds 2 at 0-5 ℃, the 6-lutidine (3.6ml, 31mmol) and trifluoromethanesulfonic acid t-butyldimethylsilyl ester (4.2ml, 18mmol).After 1 hour, add saturated sodium-chloride water solution, use the separating funnel separating mixture.The organic layer dried over mgso, removal of solvent under reduced pressure.(hexane/ethyl acetate: 1/5) purification obtains 1-allyl group 4-methyl (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (1.09g, 81%) to resistates with silica gel (40g) chromatography.
1H?NMR(300MHz，CDCl 3)δ-0.01(6H，s)，0.83(9H，s)，2.33-2.46(1H，m)，2.47-2.62(1H，m)，3.40-3.53(2H，m)，3.63-3.92(1H，m)，3.73(3H，s)，4.33-4.65(4H，m)，5.20(1H，dd，J＝1.5，10.4Hz)，5.29(1H，d，J＝16.7Hz)，5.92(1H，ddt，J＝5.3，10.4，16.7Hz)，6.78-6.92(1H，m)。IR(KBr)n?2953，1715，1417，1251，1112cm -1
I) at-90 ℃～-80 ℃, in 20 minutes to 1-allyl group 4-methyl (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (0.52g, 1.39mmol) THF (10ml) solution in add the hexane solution (1.59M of n-Butyl Lithium, 1.31ml, 2.1mmol).Behind the restir 15 minutes, (pH7.0 is in mixture 10ml) with reaction mixture impouring ice (10g) and phosphate buffer soln.After adding ethyl acetate, use the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates obtains (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(chloro ethanoyl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid 1-allyl ester (244mg, 45%) with silica gel (30g) chromatographic purification.
1H?NMR(300MHz，CDCl 3)δ-0.02(6H，s)，0.82(9H，s)，2.23-2.43(1H，m)，2.57-2.68(1H，m)，3.40-3.53(2H，m)，3.63-3.92(2H，m)，4.33-4.65(5H，m)，5.20(1H，dd，J＝1.3，12.1Hz)，5.29(1H，dd，J＝1.5，17.2Hz)，5.92(1H，ddt，J＝5.3，12.1，17.2Hz)，6.73-6.85(1H，m)。
IR(KBr)n?2954，2858，1692，1650，1414，1113cm -1
J) at 0-5 ℃; at (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(chloro ethanoyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid 1-allyl ester (0.345g; 0.88mmol) methyl alcohol (5ml) solution in add thioisonicotinamide (5mg) and ammonium dithiocarbamate (149mg, 1.35mmol).Reaction mixture rises to room temperature.Mixture was stirred 15 minutes, stirred 1 hour at 55-60 ℃ then.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (170mg, 38%).
1H?NMR(300MHz，CDCl 3)δ0.00(3H，s)，0.02(3H，s)，0.84(9H，s)，2.40-2.57(2H，m)，3.45-3.85(3H，m)，3.38-3.65(4H，m)，5.18-5.35(2H，m)，5.88-6.01(1H，m)，6.07(1H，brs)，6.40(1H，s)。
Reference example 4
Figure S2008100051493D00691
(2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2-sulfydryl-1,3-thiazole-4-yl)-3, (539mg adds tosic acid monohydrate (50ml) to 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester in ethanol 1.30mmol) (40ml)/THF (3ml) solution.Four hours final vacuums remove and desolvate.Add the alkalization of 1N aqueous sodium hydroxide solution in the resistates.Add ethyl acetate and hexane in the mixture, mixture separates with separating funnel.Add 6N hydrochloric acid in the water layer, this mixture separates with separating funnel.The water layer ethyl acetate extraction.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso, and decompression is removed organic solvent and obtained (2S)-2-(hydroxymethyl)-4-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (218mg, 55%).
1H?NMR(300MHz，CDCl 3)δ2.40(1H，d，J＝17.4Hz)，2.52-2.64(1H，m)，3.54-3.93(3H，m)，4.38-4.69(2H，m)，4.62(2H，d，J＝5.5Hz)，5.22(1H，dd，J＝1.1，10.3Hz)，5.30(1H，dd，J＝1.5，17.2Hz)，5.93(1H，ddd，J＝5.7，10.3，17.2Hz)，6.12(1H，s)，6.41(1H，s)。
Reference example 5
Figure S2008100051493D00701
A) with (4S)-4-{[(benzyloxy) carbonyl] amino }-the 5-hydroxypentanoic acid tert-butyl ester (5.0g, methylene dichloride 15.5mmol) (50ml) solution is cooled to 0 ℃, the adding carbon tetrabromide (6.15g, 18.5mmol).(5.68g 21.7mmol) is divided into 5 parts, adds portion in per 2 minutes in mixture, stirs the mixture 30 minutes with triphenylphosphine at uniform temp.Solvent removed in vacuo.Add ether in the resistates, stir the mixture.After removing by filter the gained crystallization, vacuum concentrated filtrate, resistates are purified with silica gel chromatography and are obtained (4S)-4-{[(benzyloxy) carbonyl] amino }-the 5-bromo valeric acid tert-butyl ester (4.5g, 80%).
1H?NMR(300MHz，CDCl 3)δ1.43(9H，s)，1.84-1.92(2H，m)，2.23-2.41(2H，m)，3.50(1H，dd，J＝10.4，3.5Hz)，3.57(1H，dd，J＝10.4，4.4Hz)，3.86-3.97(1H，m)，5.04-5.16(3H，m)，7.27-7.40(5H，m)。
B) (4S)-and the 4-{[(benzyloxy) carbonyl] amino }-the 5-bromo valeric acid tert-butyl ester (4.5g, 11.7mmol) and tri-butyl tin hydride (6.3ml adds 2,2 '-Diisopropyl azodicarboxylate (0.19g in toluene 23.4mmol) (45ml) solution, 1.2mmol), mixture stirred 20 minutes at 80 ℃.Add entry in the reaction mixture, solution ethyl acetate extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying, and organic solvent is removed in decompression.Resistates is obtained (4R)-4-{[(benzyloxy with the silica gel chromatography purification) carbonyl] amino }-the valeric acid tert-butyl ester (3.5g, 98%).
1H?NMR(300MHz，CDCl 3)δ1.16(3H，d，J＝6.6Hz)，1.43(9H，s)，1.68-1.79(2H，m)，2.26-2.31(2H，m)，3.69-3.80(1H，m)，4.63-4.70(1H，m)，5.04-5.12(2H，m)，7.30-7.37(5H，m)。
C) (4R)-and the 4-{[(benzyloxy) carbonyl] amino }-(3.5g adds Pd-C (0.7g) in methyl alcohol 11.4mmol) (35ml) solution to the valeric acid tert-butyl ester, and mixture stirred 3 hours under nitrogen atmosphere.Remove by filter catalyzer, solvent removed in vacuo obtains (4R)-4-aminovaleric acid tert-butyl ester (2.1g).
1H?NMR(300MHz，CDCl 3)δ1.08(3H，d，J＝6.4Hz)，1.45(9H，s)，1.53-1.73(2H，m)，2.20-2.36(2H，m)，2.86-2.96(1H，m)。
(4R)-4-aminovaleric acid tert-butyl ester (2.1g) that d) will as above prepare, monobromo-acetic acid methyl esters (1.6ml, 16.9mmol) and diisopropylethylamine (3.0ml, methyl alcohol 17.2mmol) (60ml) solution stirred 1 hour at 60 ℃.Add again the monobromo-acetic acid methyl esters (0.3ml, 3.2mmol) and diisopropylethylamine (0.6ml 3.4mmol), stirs mixture 1 hour.Mixture is cooled to room temperature, solvent removed in vacuo.Resistates is dissolved in chloroform (40ml).Add in the solution carbonochloridic acid allyl ester (2.4ml, 22.6mmol), add then diisopropylethylamine (4.0ml, 23.0mmol).Mixture stirred 1 hour at uniform temp.Add entry in the reaction mixture, mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, removal of solvent under reduced pressure.Resistates is obtained (4R)-4-[[(allyloxy with the silica gel chromatography purification) carbonyl] (2-methoxyl group-2 oxoethyl) amino] the valeric acid tert-butyl ester (3.1g).
1H?NMR(300MHz，CDCl 3)δ1.13-1.17(3H，m)，1.43(9H，s)，1.64-1.74(2H，m)，2.25-2.39(2H，m)，3.69-3.94(5H，m)，4.18-4.37(1H，m)，4.56-4.64(2H，m)，5.15-5.35(2H，m)，5.81-6.00(1H，m)。
E) according to reference example 2.b) same procedure, with (4R)-4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino] the valeric acid tert-butyl ester obtains the 1-allyl group 4-tertiary butyl (2R)-2-methyl-5-oxo-1,4-piperidines dicarboxylic ester.
1H?NMR(300MHz，CDCl 3)δ1.15(3H，d，J＝6.8Hz)，1.51(9H，s)，2.13(1H，d，J＝15.8Hz)，2.43-2.52(1H，m)，3.68(1H，d，J＝18.7Hz)，4.38(1H，d，J＝18.7Hz)，4.57-4.62(3H，m)，5.19-5.35(2H，m)，5.86-6.00(1H，m)，12.2(1H，s)。
F) the 1-allyl group 4-tertiary butyl (2R)-2-methyl-5-oxo-1,4-piperidines dicarboxylic ester (1.93g, 6.5mmol) methyl alcohol (40ml) solution in add acetate (0.45ml, 7.9mmol) and sodium cyanoborohydride (0.49g, 7.8mmol), mixture at room temperature stirred 20 minutes, solvent removed in vacuo, resistates is purified with silica gel chromatography and is obtained the 1-allyl group 4-tertiary butyl (2R)-5-hydroxy-2-methyl-1,4-piperidines dicarboxylic ester (1.85g, 95%).
1H?NMR(300MHz，CDCl 3)δ1.20(3H，d，J＝6.9Hz)，1.47(9H，s)，1.69-1.87(2H，m)，2.47-2.56(1H，m)，2.70-2.80(1H，m)，3.23(1H，br?s)，3.70-3.87(1H，m)，4.12-4.28(1H，m)，4.51(1H，br?s)，4.57-4.60(2H，m)，5.17-5.33(2H，m)，5.87-6.00(1H，m)。
G) at-30 ℃, at the 1-allyl group 4-tertiary butyl (2R)-5-hydroxy-2-methyl-1, (1.85g adds methylsulfonyl chloride and triethylamine to 4-piperidines dicarboxylic ester in methylene dichloride 6.2mmol) (40ml) solution, mixture stirred 2 hours at 0 ℃.In reaction mixture impouring dilute hydrochloric acid, mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Removal of solvent under reduced pressure.Resistates is dissolved in the mixture of toluene (5ml) and methylene dichloride (10ml).Solution is cooled to 0 ℃, adds DBU.Mixture was stirred 1 hour.In reaction mixture impouring dilute hydrochloric acid, use ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses dried over mgso.Removal of solvent under reduced pressure.Resistates obtains the 1-allyl group 4-tertiary butyl (2R)-2-methyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (1.33g, 76%) with silica gel (30g) chromatographic purification.
1H?NMR(300MHz，CDCl 3)δ1.10(3H，d，J＝6.8Hz)，1.50(9H，s)，2.30(1H，d，J＝16.8Hz)，2.42-2.53(1H，m)，3.73(1H，d，J＝20.3Hz)，4.44(1H，d，J＝20.3Hz)，4.61-4.67(3H，m)，5.19-5.34(2H，m)，5.88-6.00(1H，m)，6.78(1H，s)。
H) the 1-allyl group 4-tertiary butyl (2R)-2-methyl-3, (0.64g adds hydrochloric acid/methyl alcohol (10ml) in methyl alcohol 2.3mmol) (10ml) solution to 6-dihydro-1,4 (2H)-pyridine dicarboxylate, stirs the mixture and spends the night.In mixture, add toluene, solvent removed in vacuo.Add methyl alcohol and toluene, solvent removed in vacuo once more in the resistates.Resistates is dissolved in THF (10ml), 0-5 ℃ of hexane solution that in solution, adds three silyls, two azomethanes (2M, 1.15ml, 2.3mmol).After 15 minutes, add 1N hydrochloric acid.Add ethyl acetate and saturated sodium-chloride water solution in the mixture.Mixture separates with separating funnel.Twice of ethyl acetate extraction of water layer.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso.Removal of solvent under reduced pressure, (hexane/ethyl acetate: 1/6 → 1/4) purification obtains 1-allyl group 4-methyl (2R)-2-methyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (0.31g) to resistates with silica gel (20g) chromatography.
1H?NMR(300MHz，CDCl 3)δ1.07(3H，d，J＝6.8Hz)，2.33(1H，d，J＝16.8Hz)，2.44-2.56(1H，m)，3.70-3.80(1H，m)，3.74(3H，s)，4.38-4.50(1H，m)，4.55-4.70(3H，m)，5.20(1H，ddd，J＝1.5，2.7，10.4Hz)，5.29(1H，ddd，J＝1.7，3.1，17.2Hz)，5.93(1H，ddd，J＝5.5，10.4，17.2Hz)，6.78(1H，brs)。
I) at-90 ℃～-80 ℃, in 15 minutes to 1-allyl group 4-methyl (2R)-2-methyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (0.30g, 1.25mmol) and THF (15ml) solution of bromochloromethane (125 μ l) in add n-Butyl Lithium hexane solution (1.59M, 1.15ml).Behind the restir 15 minutes, (pH7.0 is in mixture 10ml) with reaction mixture impouring ice (10g) and phosphate buffer soln.After adding ethyl acetate, use the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates obtains (2R)-4-(chloro ethanoyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (255mg, 80%) with silica gel (25g) chromatographic purification.
1H?NMR(300MHz，CDCl 3)δ1.06(3H，d，J＝6.8Hz)，2.43(2H，brs)，3.77-3.88(1H，m)，4.35-4.7(6H，m)，5.21(1H，ddd，J＝1.5，2.7，10.4Hz)，5.29(1H，ddd，J＝1.7，2.9，17.2Hz)，5.93(1H，ddd，J＝5.5，10.4，17.2Hz)，6.81(1H，brs)。
J) at 0-5 ℃; at (2R)-4-(chloro ethanoyl)-2-methyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (0.255g, add in methyl alcohol 1.0mmol) (5ml) solution thioisonicotinamide (5mg) and ammonium dithiocarbamate (0.22g, 2.0mmol).Reaction mixture rises to room temperature, and mixture was stirred 15 minutes, stirs 1.5 hours at 55-60 ℃ then.Solvent removed in vacuo adds the alkalization of 1N aqueous sodium hydroxide solution in the resistates.Add ethyl acetate and hexane in the solution, mixture separates with separating funnel.Water layer 6N hcl acidifying is used ethyl acetate extraction.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso.Solvent removed in vacuo obtains (2R)-4-(2-sulfydryl-1,3-thiazoles-4-yl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (170mg, 59%).
1H?NMR(300MHz，CDCl 3)δ1.14(3H，d，J＝6.9Hz)，2.05-2.14(1H，m)，2.59-2.70(1H，m)，3.72-3.84(1H，m)，4.43-4.74(4H，m)，5.21(1H，ddd，J＝1.5，2.7，10.4Hz)，5.29(1H，ddd，J＝1.5，2.9，17.2Hz)，5.93(1H，ddd，J＝5.7，10.4，17.2Hz)，6.19(1H，brs)，6.38(1H，s)。
Reference example 6
Figure S2008100051493D00751
A) carbonyl (4S)-4-{[(benzyloxy)] amino-the 5-hydroxypentanoic acid tert-butyl ester (4.0g, add in acetonitrile 12.4mmol) (80ml) solution silver suboxide (14.3g, 61.7mmol) and methyl-iodide (7.7ml 124mmol), stirs mixture 19 hours.After removing insolubles, solvent removed in vacuo, resistates is purified with silica gel chromatography and is obtained (4S)-4-{[(benzyloxy) carbonyl] amino }-the 5-methoxyl group valeric acid tert-butyl ester (2.98g, 71%).
1H?NMR(300MHz，CDCl 3)δ1.43(9H，s)，1.75-1.91(2H，m)，2.28-2.33(2H，m)，3.33(3H，s)，3.36-3.42(2H，m)，3.75-3.85(1H，m)，4.99-5.03(1H，m)，5.09(2H，s)，7.27-7.37(5H，m)。
B) according to reference example 2.b) same procedure with (4S)-4-{[(benzyloxy) carbonyl] amino-(2.98g 8.8mmol) obtains (4S)-4-amino-5-methoxyl group valeric acid tert-butyl ester (1.88g) to the 5-methoxyl group valeric acid tert-butyl ester.
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.84-1.91(2H，m)，2.40-2.45(2H，m)，3.22-3.30(1H，m)，3.37-3.55(5H，m)，4.41(2H，br?s)。
C) according to reference example 5.d) same procedure obtain (4S)-4-[[(allyloxy with (4S)-4-amino-5-methoxyl group valeric acid tert-butyl ester (1.88g)) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-methoxyl group valeric acid tert-butyl ester (2.48g).
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.74-1.92(2H，m)，2.27-2.33(2H，m)，3.24-3.25(3H，m)，3.38-3.53(2H，m)，3.68-3.73(3H，m)，3.91-4.07(2H，m)，4.20-4.36(1H，m)，4.54-4.65(2H，m)，5.16-5.34(2H，m)，5.81-5.59(1H，m)。
D) according to reference example 2.b) same procedure with (4S)-4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-methoxyl group valeric acid tert-butyl ester (1.66g, 4.6mmol and 0.82g, 2.3mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-2-(methoxymethyl)-5-oxo-1,4-piperidines dicarboxylic ester (1.24g, 55%).
1H?NMR(300MHz，CDCl 3)δ1.51(9H，s)，2.28(1H，d，J＝16.0Hz)，2.39-2.48(1H，m)，3.27-3.46(5H，m)，3.60-3.72(1H，m)，4.34-4.72(4H，m)，5.20-5.35(2H，m)，5.88-6.00(1H，m)，12.2(1H，s)。
E) according to reference example 5.f) same procedure with the 1-allyl group 4-tertiary butyl (2S)-2-(methoxymethyl)-5-oxo-1,4-piperidines dicarboxylic ester (1.24g, 3.8mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-5-hydroxyl-2-(methoxymethyl)-1,4-piperidines dicarboxylic ester (1.19g, 94%).
1H?NMR(300MHz，CDCl 3)δ1.47(9H，s)，1.63-1.74(1H，m)，2.02-2.12(1H，m)，2.47-2.57(1H，m)，2.69-2.84(1H，m)，3.08-3.52(5H，m)，3.70-3.81(1H，m)，4.20-4.63(4H，m)，5.17-5.35(2H，m)，5.86-6.00(1H，m)。
F) according to reference example 5.g) same procedure with the 1-allyl group 4-tertiary butyl (2S)-5-hydroxyl-2-(methoxymethyl)-1,4-piperidines dicarboxylic ester (1.19g, 3.6mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylates (0.74g, 66%).
1H?NMR(300MHz，CDCl 3)δ1.49(9H，s)，2.41-2.45(2H，m)，3.23-3.39(2H，m)，3.33(3H，s)，3.65-3.79(1H，m)，4.40-4.82(4H，m)，5.19-5.36(2H，m)，5.88-6.00(1H，m)，6.78(1H，s)。
G) at 0 ℃, (19ml, 470mmol) (12ml, 169mmol), mixture stirred 30 minutes at uniform temp middle adding Acetyl Chloride 98Min. methyl alcohol.This solution is joined the 1-allyl group 4-tertiary butyl (2S)-2-(methoxymethyl)-3, and (mixture was stirring at room 2 hours for 744mg, methyl alcohol 2.4mmol) (3ml) solution for 6-dihydro-1,4 (2H)-pyridine dicarboxylate.Remove and desolvate, resistates is dissolved in ethyl acetate.Solution is used dried over mgso with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing.Solvent removed in vacuo obtains 1-allyl group 4-methyl (2S)-2-(methoxymethyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (600mg, 93%).
1H?NMR(300MHz，CDCl 3)δ2.40-2.56(2H，m)，3.23-3.40(2H，m)，3.33(3H，s)，3.66-3.84(1H，m)，3.77(3H，s)，4.42-4.82(4H，m)，5.20-5.38(2H，m)，5.89-6.01(1H，m)，6.89(1H，s)。
H) according to reference example 2.d) same procedure with 1-allyl group 4-methyl (2S)-2-(methoxymethyl)-3; 6-dihydro-1; 4 (2H)-pyridine dicarboxylate (600mg; 2.2mmol) acquisition (2S)-4-(chloro ethanoyl)-2-(methoxymethyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (547mg, 71%).
1H?NMR(300MHz，CDCl 3)δ2.18-2.65(2H，m)，3.21-3.38(2H，m)，3.31(3H，s)，3.65-3.90(2H，m)，4.41(1H，d，J＝14.1Hz)，4.43(1H，d，J＝14.1Hz)，4.50-4.80(3H，m)，5.20-5.36(2H，m)，5.89-6.02(1H，m)，6.83(1H，s)。
I) according to reference example 2.e) same procedure with (2S)-4-(chloro ethanoyl)-2-(methoxymethyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (547mg; 1.9mmol) acquisition (2S)-2-(methoxymethyl)-4-(2-sulfenyl-1; 3-thiazole-4-yl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (286mg, 46%).
1H?NMR(300MHz，CDCl 3)δ2.42(2H，d，J＝16.8Hz)，2.52-2.63(1H，m)，3.21-3.43(2H，m)，3.34(3H，s)，3.65-3.86(1H，m)，4.43-4.82(4H，m)，5.21-5.36(2H，m)，5.89-6.02(1H，m)，6.10(1H，brs)，6.43(1H，s)。
Reference example 7
Figure S2008100051493D00781
A) at 0 ℃, (4S)-the 4-{[(benzyloxy) carbonyl] amino-the 5-hydroxypentanoic acid tert-butyl ester (8.09g, add in DMF 25mmol) (1 00ml) solution chlorination tertiary butyl dimethylsilane (4.90g, 32mmol) and imidazoles (2.21g, 32mmol), mixture was stirred 30 minutes.In reaction mixture impouring water, use ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses anhydrous sodium sulfate drying, removes and desolvates.Resistates is purified with silica gel chromatography and is obtained (4S)-4-{[(benzyloxy) carbonyl] amino }-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base } the valeric acid tert-butyl ester (10.4g, 95%).
1H?NMR(300MHz，CDCl 3)δ0.04(6H，s)，0.88(9H，s)，1.43(9H，s)，1.74-1.89(2H，m)，2.28-2.33(2H，m)，3.60-3.72(3H，m)，4.95(1H，d，J＝9.2Hz)，5.09(2H，s)，7.27-7.37(5H，m)。
B) according to reference example 2.b) same procedure with (4S)-4-{[(benzyloxy) carbonyl] amino-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base valeric acid tert-butyl ester (10.4g 24mmol) obtains (the 4S)-4-amino-5-{[tertiary butyl (dimethyl) silyl] the oxygen base valeric acid tert-butyl ester (7.39g).
1H?NMR(300MHz，CDCl 3)δ0.09(6H，s)，0.90(9H，s)，144(9H，s)，1.72-1.91(2H，m)，2.82-2.49(2H，m)，3.02-3.10(1H，m)，3.54(1H，dd，J＝10.1，6.5Hz)，3.71(1H，dd，J＝10.1，3.9Hz)，4.59(2H，br?s)。
C) according to reference example 5.d) same procedure with (the 4S)-4-amino-5-{[tertiary butyl (dimethyl) silyl] the oxygen base valeric acid tert-butyl ester (7.39g) obtains (4S)-4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base valeric acid tert-butyl ester (8.79g).
1H?NMR(300MHz，CDCl 3)δ0.05(6H，s)，0.87(9H，s)，1.44(9H，s)，1.75-1.89(2H，m)，2.28-2.36(2H，m)，3.59-3.82(5H，m)，3.98-4.01(2H，m)，4.09-4.23(1H，m)，4.54-4.63(2H，m)，5.14-5.33(2H，m)，5.80-5.59(1H，m)。
D) (4S)-and the 4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-{[tertiary butyl (dimethyl) silyl] the oxygen base } the valeric acid tert-butyl ester (5.29g, 1.2mmol) methyl alcohol (106ml) solution in add tosic acid monohydrate (0.22g, 1.2mmol), mixture was stirred 30 minutes.(0.22g 1.2mmol), stirs mixture 1 hour further to add the tosic acid monohydrate in the mixture.In reaction mixture impouring water, use ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses anhydrous sodium sulfate drying, removes and desolvates.Resistates is purified with silica gel chromatography and is obtained (4S)-4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-hydroxypentanoic acid tert-butyl ester (3.7g, 93%).
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.61-1.75(2H，m)，2.21-2.30(2H，m)，3.36-3.74(3H，m)，3.78，-3.80(3H，m)，4.01-4.13(1H，m)，4.24-4.36(1H，m)，4.52-4.66(2H，m)，5.17-5.37(2H，m)，5.80-6.00(1H，m)。
E) at 0 ℃, (4S)-and the 4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-hydroxypentanoic acid tert-butyl ester (2.38g, 6.9mmol) methylene dichloride (72ml) solution in add methylsulfonyl chloride (0.81ml, 10.4mmol) and triethylamine (1.45ml, 10.4mmol), mixture was stirred 10 minutes.In reaction mixture impouring water, use ethyl acetate extraction three times.Organic layer with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, is used anhydrous sodium sulfate drying, after the solvent removed in vacuo successively.Resistates is dissolved in acetonitrile (72ml), and the THF solution of adding tetrabutylammonium fluoride in solution (1M, 13.8ml, 13.8mmol).Mixture stirred 30 minutes at 80 ℃.In reaction mixture impouring water, use ethyl acetate extraction three times.Organic layer with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, is used anhydrous sodium sulfate drying, solvent removed in vacuo successively.Resistates is purified with silica gel chromatography and is obtained (4S)-4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-[(methylsulfonyl) the oxygen base] the valeric acid tert-butyl ester (1.1g; 38%) and (4S)-and the 4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-fluoro valeric acid tert-butyl ester (0.47g, 20%).
(4S)-and the 4-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-[(methylsulfonyl) oxygen Base] the valeric acid tert-butyl ester
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.75-1.99(2H，m)，2.32-2.37(2H，m)，3.01(3H，s)，3.74-3.75(3H，m)，3.88-4.03(2H，m)，4.20-4.42(3H，m)，4.55-4.71(2H，m)，5.19-5.35(2H，m)，5.80-5.99(1H，m)。
(4S)-and the 4-[[allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-5-fluoro valeric acid uncle fourth Ester
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，1.75-1.99(2H，m)，2.31-2.36(2H，m)，3.69-3.77(3H，m)，3.88-4.14(2H，m)，4.20-4.73(5H，m)，5.18-5.33(2H，m)，5.80-5.99(1H，m)。
F) according to reference example 2.b) same procedure with (4S)-4-{[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino-the 5-fluoro valeric acid tert-butyl ester (877mg, 2.5mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-5-oxo-1,4-piperidines dicarboxylic ester (460mg, 55%).
1H?NMR(300MHz，CDCl 3)δ1.51(9H，s)，2.34(1H，d，J＝15.7Hz)，2.45-2.55(1H，m)，3.64-3.80(1H，m)，4.28-4.81(6H，m)，5.20-5.35(2H，m)，5.88-6.00(1H，m)，12.2(1H，s)。
G) according to reference example 5.f) same procedure with the 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-5-oxo-1,4-piperidines dicarboxylic ester (460mg, 1.5mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-5-hydroxyl-1,4-piperidines dicarboxylic ester (400mg, 86%).
1H?NMR(300MHz，CDCl 3)δ1.48(9H，s)，1.67-1.84(1H，m)，2.09-2.30(1H，m)，2.42-2.60(1H，m)，2.70-2.88(1H，m)，3.11-3.32(1H，m)，3.70-3.83(1H，m)，3.96-4.67(6H，m)，5.21-5.34(2H，m)，5.88-6.00(1H，m)。
H) according to reference example 5.g) same procedure with the 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-5-hydroxyl-1,4-piperidines dicarboxylic ester (400mg, 1.3mmol) the acquisition 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylates (272mg, 72%).
1H?NMR(300MHz，CDCl 3)δ1.50(9H，s)，2.46-2.58(2H，m)，3.71-3.87(1H，m)，4.22-4.91(6H，m)，5.21-5.35(2H，m)，5.88-6.01(1H，m)，6.81(1H，br?s)。
I) according to reference example 6.g) same procedure with the 1-allyl group 4-tertiary butyl (2S)-2-(fluoro methyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (272mg, 0.91mmol) acquisition 1-allyl group 4-methyl (2S)-2-(fluoro methyl)-3,6-dihydro-1,4 (2H)-pyridine dicarboxylates (183mg, 78%).
1H?NMR(300MHz，CDCl 3)δ2.48-2.60(2H，m)，3.77(3H，s)，3.78-3.90(1H，m)，4.24-4.91(6H，m)，5.21-5.36(2H，m)，5.89-6.01(1H，m)，6.91(1H，br?s)。
J) according to reference example 2.d) same procedure with 1-allyl group 4-methyl (2S)-2-(fluoro methyl)-3; 6-dihydro-1; 4 (2H)-pyridine dicarboxylate (180mg; 0.70mmol) acquisition (2S)-4-(chloro ethanoyl)-2-(fluoro methyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (127mg, 66%).
1H?NMR(300MHz，CDCl 3)δ2.44-2.53(1H，m)，2.64(1H，d，J＝17.9Hz)，3.87-4.00(1H，m)，4.18-4.91(8H，m)，5.21-5.36(2H，m)，5.89-6.02(1H，m)，6.85(1H，br?s)。
K) according to reference example 2.e) same procedure with (2S)-4-(chloro ethanoyl)-2-(fluoro methyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (127mg; 0.46mmol) acquisition (2S)-2-(fluoro methyl)-4-(2-sulfenyl-1; 3-thiazole-4-yl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (120mg, 83%).
1H?NMR(300MHz，CDCl 3)δ2.37-2.46(1H，m)，2.52-2.63(1H，m)，3.79-3.84(1H，m)，4.24-4.91(6H，m)，5.22-5.37(2H，m)，5.89-6.02(1H，m)，6.13(1H，br?s)，6.45(1H，s)。
Reference example 8
A) at 0-5 ℃, (2S)-2-(hydroxymethyl)-4-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (218mg, 0.7mmol) THF (3ml) solution in add 4-methoxy-benzyl chlorine (95ml, 0.70mmol) and triethylamine (98ml, 0.7mmol).Mixture was stirred 3 hours, then stirring at room 45 minutes.Add sodium bicarbonate aqueous solution and ethyl acetate in the solution.Mixture separates with separating funnel.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and vacuum is removed organic layer.Resistates is purified with preparation type TLC and is obtained (2S)-2-(hydroxymethyl)-4-{2-[(4-methoxy-benzyl) sulfenyl]-1,3-thiazoles-4-yl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (150mg, 50%).
1H?NMR(300MHz，CDCl 3)δ2.40(1H，d，J＝16.7Hz)，2.53-2.65(1H，m)，3.50-3.80(3H，m)，3.69(3H，s)，4.29-4.67(2H，m)，4.30(2H，s)，4.56(2H，d，J＝5.5Hz)，5.13(1H，dd，J＝1.5，10.4Hz)，5.23(1H，dd，J＝1.5，17.2Hz)，5.87(1H，ddd，J＝5.5，10.4，17.2Hz)，6.56(1H，s)，6.75(2H，d，J＝8.6Hz)，6.81(1H，s)，7.21(2H，d，J＝8.6Hz)。
B) at 0-5 ℃, (2S)-and 2-(hydroxymethyl)-4-{2-[(4-methoxy-benzyl) sulfenyl]-1,3-thiazoles-4-yl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (75mg, 0.17mmol) chloroform (1ml) solution in add isocyanic acid chlorine sulfonyl ester (17ml, 0.20mmol).After three hours, add again isocyanic acid chlorine sulfonyl ester (10ml, 0.11mmol).After three hours, add entry in the mixture, stirred the mixture 10 minutes.Add ethyl acetate in the solution, use the separating funnel separation solution.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and vacuum is removed organic layer.Resistates is purified with preparation type TLC and is obtained (2S)-2-{[(aminocarboxyl) the oxygen base] methyl }-the 4-{2-[(4-methoxy-benzyl) sulfenyl]-1,3-thiazoles-4-yl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (74.5mg, 90%).
1H?NMR(300MHz，CDCl 3)δ2.37-2.45(1H，m)，2.61-2.78(1H，m)，3.72-4.95(9H，m)，3.77(3H，s)，4.38(2H，s)，5.21(1H，dd，J＝1.3，10.4Hz)，5.31(1H，d，J＝17.2Hz)，5.95(1H，ddd，J＝5.5，10.4，17.2Hz)，6.64(1H，br?s)，6.83(2H，d，J＝8.6Hz)，6.88(1H，s)，7.29(2H，d，J＝8.6Hz)。
C) with (2S)-2-{[(aminocarboxyl) the oxygen base] methyl }-the 4-{2-[(4-methoxy-benzyl) sulfenyl]-1,3-thiazole-4-yl }-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (74.5mg, 0.16mmol) and methyl-phenoxide (35ml 0.32mmol) is dissolved in trifluoroacetic acid (6ml).Then thioisonicotinamide (3ml) is added solution, mixture is 80-90 ℃ of backflow.Four hours final vacuums remove and desolvate.Add the alkalization of 1N aqueous sodium hydroxide solution in the resistates.Add ethyl acetate and hexane in the solution, solution separates with separating funnel.Add 6N hydrochloric acid in the water layer, add ethyl acetate in the solution and separate with separating funnel.The water layer ethyl acetate extraction.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso.Solvent removed in vacuo obtains (2S)-2-{[(aminocarboxyl) the oxygen base] methyl }-4-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (37.3mg, 67%).
1H?NMR(300MHz，CDCl 3)δ2.21-2.70(2H，m)，3.73-4.65(8H，m)，4.80(1H，brs)，5.18(1H，d，J＝10.3Hz)，5.26(1H，d，J＝17.2Hz)，5.88(1H，ddd，J＝5.1，10.3，17.2Hz)，6.22(1H，brs)，6.40(1H，s)。
Reference example 9
A) according to reference example 5.a) same procedure with (3R)-3-{[(benzyloxy) carbonyl] amino-the 4 hydroxybutyric acid tert-butyl ester (2.12g 6.9mmol) obtains (3R)-3-{[(benzyloxy) carbonyl] amino-4-bromo tert-butyl acetate (2.09g, 82%).
1H?NMR(300MHz，CDCl 3)δ1.44(9H，s)，2.55-2.70(2H，m)，3.47-3.64(2H，m)，4.21-4.32(1H，m)，5.03-5.18(2H，m)，5.40(1H，d，J＝8.6Hz)，7.27-7.43(5H，m)。
B) according to reference example 5.b) same procedure with (3R)-3-{[(benzyloxy) carbonyl] amino-4-bromo tert-butyl acetate (2.08g 5.6mmol) obtains (3S)-3-{[(benzyloxy) carbonyl] amino tert-butyl acetate (1.45g, 88%).
1H?NMR(300MHz，CDCl 3)δ1.22(3H，d，J＝6.8Hz)，1.44(9H，s)，2.34-2.51(2H，m)，4.01-4.14(1H，m)，5.01-5.17(2H，m)，5.22-5.33(1H，m)，7.28-7.36(5H，m)。
C) according to reference example 2.b) same procedure with (3S)-3-{[(benzyloxy) carbonyl] amino (1.45g 3.7mmol) obtains (3S)-3-aminobutyric acid tert-butyl ester (586mg, 75%) to tert-butyl acetate.
1H?NMR(300MHz，CDCl 3)δ1.11(3H，d，J＝6.4Hz)，1.46(9H，s)，2.22(1H，dd，J＝15.5，8.2Hz)，2.32(1H，dd，J＝15.5，4.7Hz)，3.28-3.39(1H，m)。
D) according to reference example 5.d) same procedure with (the 3S)-3-aminobutyric acid tert-butyl ester (586mg 4.9mmol) obtains (3S)-3-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino] tert-butyl acetate (917mg, 79%).
1H?NMR(300MHz，CDCl 3)δ1.22-1.28(3H，m)，1.43(9H，s)，2.09-2.64(2H，m)，3.68-3.73(5H，m)，4.42-4.55(1H，m)，4.55-4.66(2H，m)，5.15-5.38(2H，m)，5.80-6.02(1H，m)。
E) according to reference example 2.b) same procedure with (3S)-3-[[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino] tert-butyl acetate (917mg, 2.9mmol) the acquisition 1-allyl group 3-tertiary butyl (2S)-2-methyl-4-oxo-1,3-tetramethyleneimine dicarboxylic ester (166mg, 20%).
1H?NMR(300MHz，CDCl 3)δ1.31-1.51(12H，m)，4.10-4.33(2H，m)，4.55-4.72(3H，m)，5.20-5.38(2H，m)，5.86-6.03(1H，m)，10.39(1H，brs)。
F) according to reference example 5.f) same procedure with the 1-allyl group 3-tertiary butyl (2S)-2-methyl-4-oxo-1,3-tetramethyleneimine dicarboxylic ester (166mg, 0.59mmol) the acquisition 1-allyl group 3-tertiary butyl (2S)-4-hydroxy-2-methyl-1,3-tetramethyleneimine dicarboxylic ester (127mg, 76%).
1H NMR (300MHz, CDCl 3) δ 1.43-1.50 (12H, m), 2.38-2.62 (2H, m), 3.27 (1H, dd, J=11.2,7.0Hz), 3.95 (1H, br s), 4.04 (1H, quintet, J=6.4Hz), 4.39-4.46 (1H, m), and 4.55-4.64 (2H, m), 5.18-5.35 (2H, m), 5.87-6.00 (1H, m).
G) according to reference example 5.g) same procedure with the 1-allyl group 3-tertiary butyl (2S)-4-hydroxy-2-methyl-1,3-tetramethyleneimine dicarboxylic ester (127mg, 0.45mmol) the acquisition 1-allyl group 3-tertiary butyl (2S)-2-methyl-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (120mg, 100%).
1H?NMR(300MHz，CDCl 3)δ1.40-1.45(3H，m)，1.50(9H，s)，4.18-4.41(2H，m)，4.60-4.70(2H，m)，4.73-4.86(1H，m)，5.20-5.38(2H，m)，5.89-6.03(1H，m)，6.60-6.67(1H，m)。
H) according to reference example 6.g) same procedure with the 1-allyl group 3-tertiary butyl (2S)-2-methyl-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (120mg, 0.45mmol) acquisition 1-allyl group 3-methyl (2S)-2-methyl-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (62mg, 61%).
1H?NMR(300MHz，CDCl 3)δ1.41-1.47(3H，m)，3.78(3H，s)，4.21-4.45(2H，m)，4.60-4.71(2H，m)，4.80-4.90(1H，m)，5.20-5.38(2H，m)，5.89-6.02(1H，m)，6.69-6.77(1H，m)。
I) according to reference example 2.d) same procedure with 1-allyl group 3-methyl (2S)-2-methyl-2; 5-dihydro-1H-pyrroles-1; 3-dicarboxylic ester (62mg; 0.28mmol) acquisition (2S)-3-(chloro ethanoyl)-2-methyl-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (37mg, 55%).
1H?NMR(300MHz，CDCl 3)δ1.39-1.44(3H，m)，4.31-4.58(4H，m)，4.60-4.71(2H，m)，4.89-5.00(1H，m)，5.21-5.38(2H，m)，5.89-6.02(1H，m)，6.67-6.87(1H，m)。
J) according to reference example 2.e) same procedure with (2S)-3-(chloro ethanoyl)-2-methyl-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (37mg; 0.15mmol) acquisition (2S)-2-methyl-3-(sulfenyl-1; 3-thiazole-4-yl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (36mg, 84%).
1H?NMR(300MHz，CDCl 3)δ1.42-1.46(3H，m)，4.26-4.50(2H，m)，4.56-4.72(2H，m)，4.87-5.00(1H，m)，5.21-5.38(2H，m)，5.88-6.03(1H，m)，6.25-6.45(2H，m)。
Reference example 10
Figure S2008100051493D00871
A) at-30 ℃, (35g adds triethylamine (18ml in THF 108mmol) (500ml) solution to N-(benzyloxy) the cbz l aspartic acid 4-tert-butyl ester, 130mmol), (12.5ml 130mmol), stirs mixture at uniform temp then to add chloro ethyl formate.(12.3g, aqueous solution 324mmol) stir mixture 30 minutes to add sodium borohydride at-30 ℃ in mixture then.Mixture is risen to 0 ℃, stirred then 30 minutes.Add entry in the reaction mixture, mixture ethyl acetate extraction three times, organic layer with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, is used anhydrous sodium sulfate drying successively.Solvent removed in vacuo, resistates are purified with silica gel (210g) chromatography (hexane/ethyl acetate=3/2 → 1/1) and are obtained (3S)-3-{[(benzyloxy) carbonyl] amino }-the 4 hydroxybutyric acid tert-butyl ester (27.1g, 81%).
1H?NMR(300MHz，CDCl 3)δ1.41(9H，s)，2.40-2.62(3H，m)，3.69(2H，d，J＝4.6Hz)，3.97-4.07(1H，m)，5.08(2H，s)，5.48(1H，brs)，7.27-7.37(5H，m)。
B) ice-cooled following, (3S)-and the 3-{[(benzyloxy) carbonyl] amino }-the 4 hydroxybutyric acid tert-butyl ester (14.26g, 46.1mmol) methylene dichloride (190ml) solution in add 4-dimethylaminopyridine (0.28g, 2.3mmol), diisopropylethylamine (24ml, 138mmol) and the chloro dimethyl cellosolve (105ml, 138mmol).Mixture is risen to room temperature.After 12 hours, under ice bath cooling, add in the mixture frozen water and 1N hydrochloric acid with pH regulator to about 3.Add saturated sodium-chloride water solution in the mixture, use the separating funnel separation solution.Organic layer washes with water once, uses the saturated sodium-chloride water solution washed twice, uses dried over mgso.Solvent removed in vacuo obtains (3S)-3-{[(benzyloxy) carbonyl] amino }-4-(methoxymethoxy) tert-butyl acetate (16.4g, 100%).
1H?NMR(300MHz，CDCl 3)δ1.41(9H，s)，2.53(2H，d，J＝6.1Hz)，3.32(3H，s)，3.54(1H，dd，J＝5.0，9.5Hz)，3.63(1H，dd，J＝3.8，9.5Hz)，4.12-4.23(1H，m)，4.58(2H，s)，5.08(2H，s)，5.41(1H，d，J＝8.6Hz)，7.27-7.38(5H，m)。
C) (3S)-and the 3-{[(benzyloxy) carbonyl] amino }-(16.3g adds 10%Pd-C (3.3g) in methyl alcohol 53mmol) (150ml) solution to 4-(methoxymethoxy) tert-butyl acetate, and mixture was stirred 6 hours under nitrogen atmosphere.Add 10%Pd-C (0.75g) again, mixture was stirred 1.5 hours.After removing by filter catalyzer, solvent removed in vacuo obtains (3S)-3-amino-4-(methoxymethoxy) tert-butyl acetate (9.7g, 84%).
1H?NMR(300MHz，CDCl 3)δ1.43(9H，s)，2.42-2.57(2H，m)，3.28-3.65(5H，m)，3.35(3H，s)，4.63(2H，s)。
D) at room temperature, to (3S)-3-amino-4-(methoxymethoxy) tert-butyl acetate (9.7g, 44mmol) and diisopropylethylamine (11.5ml, in methyl alcohol 66mmol) (300ml) solution dripping bromine for methyl acetate (6.2ml, 66mmol).Solution stirred 1 hour at 60 ℃.In solution, add again the monobromo-acetic acid methyl esters (2.1ml, 22mmol) and diisopropylethylamine (3.8ml 22mmol), stirs mixture 1 hour, is cooled to room temperature, except that desolvating.Resistates is dissolved in chloroform (100ml), 0 ℃ in solution, drip the carbonochloridic acid allyl ester (94ml, 88mmol), drip then diisopropylethylamine (15.5ml, 88mmol).Mixture was stirred 1 hour at uniform temp, again stirring at room 13 hours.Under the ice bath cooling, in reaction mixture, add entry, mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Resistates silica gel (230g) chromatography (hexane/ethyl acetate: 2/1 → 1/1) purification obtains (3S)-3-{[(allyloxy) carbonyl] (2-methoxyl group-2-oxoethyl) amino }-4-(methoxymethoxy) tert-butyl acetate (11.7g, 71%).
1H?NMR(300MHz，CDCl 3)δ1.43(9H，s)，2.54-2.75(2H，m)，3.33(3H，s)，3.54-3.82(5H，m)，4.04-4.09(2H，m)，4.50-4.71(5H，m)，5.15-5.38(2H，m)，5.80-6.02(1H，m)。
E) at the potassium tert.-butoxide (3.14g of 60 ℃ of heating, add (3S)-3-{[(allyloxy in THF 28mmol) (130ml) suspension) carbonyl] (2-methoxyl group-2-oxoethyl) amino }-4-(methoxymethoxy) tert-butyl acetate (5.24g, THF 14mmol) (50ml) solution stirs mixture 5 minutes.After being cooled to 0 ℃, with reaction mixture impouring dilute hydrochloric acid (judging that pH is about 3 backs), behind the adding saturated sodium-chloride water solution, mixture ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses dried over mgso.Solvent removed in vacuo.Add in methyl alcohol (100ml) solution of resistates (4.17g) acetate (1.45ml, 25mmol) and sodium cyanoborohydride (1.06g, 17mmol), mixture was stirring at room 30 minutes.Solvent removed in vacuo.Resistates is purified with silica gel (60g) chromatography (hexane/ethyl acetate=2/1 → 1/1) and is obtained the 1-allyl group 3-tertiary butyl (2S)-4-hydroxyl-2-[(methoxymethoxy) methyl]-1,3-tetramethyleneimine dicarboxylic ester (1.47g, 30%).
1H?NMR(300MHz，CDCl 3)δ1.46(9H，s)，2.98(0.6H，brs)，3.02(0.4H，brs)，3.33(3H，s)，3.36(3H，s)，3.46-3.80(3H，m)，4.02-4.70(8H，m)，5.22(1H，d，J＝10.4Hz)，5.31(1H，d，J＝17.2Hz)，5.94(1H，ddd，J＝5.5，10.4，17.2Hz)。
F) at-30 ℃, the 1-allyl group 3-tertiary butyl (2S)-4-hydroxyl-2-[(methoxymethoxy) methyl]-1,3-tetramethyleneimine dicarboxylic ester (1.47g, 4.26mmol) methylene dichloride (20ml) solution in add methylsulfonyl chloride (0.50ml, 6.5mmol), triethylamine (1.2ml, 8.6mmol) and 4-dimethylaminopyridine (52mg, 0.43mmol), mixture stirred 75 minutes at 0 ℃.In reaction mixture impouring dilute hydrochloric acid, mixture chloroform extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.Solvent removed in vacuo.Resistates is dissolved in methylene dichloride (10ml), and solution is cooled to 0 ℃, and adding DBU (0.95ml, 6.4mmol).Mixture is risen to room temperature, stirred just in time 30 minutes.With reaction mixture impouring dilute hydrochloric acid, solution ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses anhydrous sodium sulfate drying.Solvent removed in vacuo.Resistates is purified with silica gel (30g) chromatography (hexane/ethyl acetate=4/1 → 2/1) and is obtained the 1-allyl group 3-tertiary butyl (2S)-2-[(methoxyl group) methyl]-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (0.92g, 66%).
1H?NMR(300MHz，CDCl 3)δ1.48(9H，s)，3.25(3H，s)，3.91-4.42(4H，m)，4.50-4.65(4H，m)，4.79-4.87(1H，m)，5.20(1H，d，J＝10.4Hz)，5.29(1H，d，J＝17.2Hz)，5.93(1H，ddd，J＝5.5，10.4，17.2Hz)，6.72-6.78(1H，，m)。
G) the 1-allyl group 3-tertiary butyl (2S)-2-[(methoxymethoxy) methyl]-2,5-dihydro-1H-pyrroles-1, (296mg adds hydrochloric acid/methyl alcohol (5ml) in methyl alcohol 0.90mmol) (2ml) solution to the 3-dicarboxylic ester, stirs the mixture and spends the night.In solution, add toluene, solvent removed in vacuo.Add methyl alcohol and toluene, solvent removed in vacuo once more in the resistates.Resistates is dissolved in THF (8ml), in solution, adds 2 at 0-5 ℃, the 6-lutidine (0.84ml, 7.2mmol) and trifluoromethanesulfonic acid tertiary butyl dimethyl silanyl ester (0.83ml, 3.6mmol).Mixture is stirring at room 1 hour, 0-5 ℃ of hexane solution that in mixture, adds three silyls, two azomethanes (2M, 0.45ml, 0.90mmol).After 30 minutes, mixture temperature is risen to room temperature, stirred 30 minutes.After 30 minutes, add 1N hydrochloric acid and saturated sodium-chloride water solution in the mixture, mixture separates with separating funnel.The organic layer dried over mgso, solvent removed in vacuo.Resistates is purified with silica gel (26g) chromatography (hexane/ethyl acetate=1/5) and is obtained 1-allyl group 3-methyl (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (71mg, 22%).
1H?NMR(300MHz，CDCl 3)δ-0.08(3H，s)，-0.07(3H，s)，0.78(9H，s)，3.75(3H，s)，3.84-4.42(4H，m)，4.58-4.64(2H，m)，4.77-4.84(1H，m)，5.18-5.23(1H，m)，5.29(1H，dt，J＝1.7，17.2Hz)，5.92(1H，ddd，J＝5.5，10.4，17.2Hz)，6.77-6.84(1H，m)。
H) at-90 ℃～-80 ℃, in 10 minutes to 1-allyl group 3-methyl (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (0.20g, 0.55mmol) and bromochloromethane (54ml, 0.83mmol) THF (6ml) solution in add n-Butyl Lithium hexane solution (1.59M, 0.52ml, 0.83mmol).Behind the restir 30 minutes, (pH7.0 is in mixture 10ml) with reaction mixture impouring ice (10g) and phosphate buffer soln.After adding ethyl acetate, use the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates obtains (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(chloro ethanoyl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (163mg, 79%) with silica gel (27g) chromatographic purification.
1H?NMR(300MHz，CDCl 3)δ-0.08(3H，s)，-0.06(3H，s)，0.78(9H，s)，3.86-4.13(2H，m)，4.23-4.63(6H，m)，4.87-4.96(1H，m)，5.21(1H，dd，J＝2.9，10.4Hz)，5.29(1H，d，J＝17.0Hz)，5.92(1H，ddd，J＝5.7，10.4，17.0Hz)，6.79(0.5H，brs)，6.85(0.5H，brs)。
I) at 0-5 ℃; at (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(chloro ethanoyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (163mg; 0.44mmol) methyl alcohol (2ml) solution in add thioisonicotinamide (2mg) and ammonium dithiocarbamate (72mg, 0.65mmol).Reaction mixture rises to room temperature, stirs 40 minutes.Mixture was stirred 30 minutes at 65-70 ℃, stirred 1 hour at 75-85 ℃ then.Solvent removed in vacuo.Add ethyl acetate in the solution, separate with separating funnel.The water layer ethyl acetate extraction.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso.Solvent removed in vacuo, resistates obtains (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(2-sulfydryl-1 with the ethyl acetate/hexane recrystallization, 3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (70.5mg, 39%).
1H?NMR(300MHz，DMSO-d 6)δ-0.15(3H，s)，-0.12(3H，s)，0.76(9H，s)，3.90-4.13(3H，m)，4.23-4.34(1H，m)，4.49-4.70(2H，m)，4.88-4.95(1H，m)，5.16-5.34(2H，m)，5.86-5.99(1H，m)，6.56(0.6H，brs)，6.59(0.4H，brs)，7.06(1H，s)。
Reference example 11
A) according to reference example 6.g) same procedure with the 1-allyl group 3-tertiary butyl (2R)-2-[(methoxymethoxy) methyl]-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (470mg, 1.4mmol) acquisition 1-allyl group 3-methyl (2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (234mg, 68%).
1H?NMR(300MHz，CDCl 3)δ3.70-4.59(7H，m)，4.62-4.67(2H，m)，4.82-5.01(1H，m)，5.22-5.38(2H，m)，5.89-6.02(1H，m)，6.82-6.92(1H，m)。
B) at 0 ℃, (60% is suspended in the oil 39mg with sodium hydride, 0.98mmol) adding 1-allyl group 3-methyl (2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (234mg, 0.97mmol) DMF (4.7ml) solution, mixture was stirred 30 minutes.(0.95ml, 9.7mmol), mixture at room temperature stirred 1 hour to add methyl-iodide at 0 ℃ in solution then.After being cooled to 0 ℃, in reaction mixture impouring frozen water, use ethyl acetate extraction three times.Organic layer is water, saturated sodium-chloride water solution washing successively, uses anhydrous sodium sulfate drying then.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained 1-allyl group 3-methyl (2R)-2-(methoxymethyl)-2,5-dihydro-1H-pyrroles-1,3-dicarboxylic ester (55mg, 15%).
1H?NMR(300MHz，CDCl 3)δ3.29-3.30(3H，m)，3.70-3.97(4H，m)，4.22-4.49(2H，m)，4.52-4.72(3H，m)，4.86-4.91(1H，m)，5.21-5.38(2H，m)，5.89-6.02(1H，m)，6.82-6.94(1H，m)。
C) according to reference example 2.d) same procedure with 1-allyl group 3-methyl (2R)-2-(methoxymethyl)-2; 5-dihydro-1H-pyrroles-1; 3-dicarboxylic ester (55mg; 0.22mmol) acquisition (2R)-3-(chloro ethanoyl)-2-(methoxymethyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (38mg, 64%).
1H?NMR(300MHz，CDCl 3)δ3.25-3.26(3H，m)，3.70-3.90(2H，m)，4.31-4.71(6H，m)，4.95-5.01(1H，m)，5.21-5.36(2H，m)，5.89-6.02(1H，m)，6.81-6.88(1H，m)。
D) according to reference example 2.e) same procedure with (2R)-3-(chloro ethanoyl)-2-(methoxymethyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (38mg; 0.22mmol) acquisition (2R)-2-(methoxymethyl)-3-(2-sulfenyl-1; 3-thiazole-4-yl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (37mg, 85%).
1H?NMR(300MHz，CDCl 3)δ3.44-3.45(3H，m)，3.53-3.71(1H，m)，3.87-3.95(1H，m)，4.20-4.46(2H，m)，4.63-4.70(2H，m)，4.86-4.96(1H，m)，5.22-5.39(2H，m)，5.89-6.03(1H，m)，6.29-6.34(1H，m)，6.62(1H，s)。
Reference example 12
Figure S2008100051493D00931
With (2S)-4-(chloro ethanoyl)-2-methyl-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (331mg; 1.36mmol) according to reference example 2.e) and same procedure preparation (2S)-2-methyl-4-(2-sulfenyl-1; 3-thiazole-4-yl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate is dissolved in THF (3ml) with it.(103mg, in THF 2.71mmol) (3ml) suspension, mixture at room temperature stirred 10 minutes at 0 ℃ drips of solution to be added to lithium aluminum hydride.Add methyl alcohol in the solution, mixture is filtered with silicagel pad.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained 4-[(5S)-1,5-dimethyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-mercaptan (224mg, 77%).
1H?NMR(300MHz，CDCl 3)δ1.24(3H，d，J＝6.4Hz)，2.49(3H，s)，3.43-3.59(2H，m)，3.97-4.03(1H，m)，5.89(1H，br?s)，6.30(1H，s)。
Reference example 13
Figure S2008100051493D00941
With (2R)-3-(chloro ethanoyl)-2-methyl-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (243mg; 1.00mmol) obtain 4-[(2R according to the same procedure of reference example 12)-1; 2-dimethyl-2; 5-dihydro-1H-pyrroles-3-yl]-1; 3-thiazol-2-thiol (103mg, 49%).
1H?NMR(300MHz，CDCl 3-CD 3OD)δ1.33(3H，d，J＝6.4Hz)，2.57(3H，s)，6.20-6.22(1H，m)，6.43(1H，s)。
Reference example 14
Figure S2008100051493D00942
With (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-3-(chloro ethanoyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (270mg; 0.72mmol) obtain 4-[(2R according to the same procedure of reference example 12)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-methyl-2; 5-dihydro-1H-pyrroles-3-yl]-1; 3-thiazol-2-thiol (97mg, 39%).
1H?NMR(300MHz，CDCl 3)δ0.24(3H，s)，0.25(3H，s)，0.97(9H，s)，，2.51(3H，s)，3.29-3.37(1H，m)，3.55-3.61(1H，m)，3.67-3.73(1H，m)，3.80-3.96(2H，m)，6.18-6.20(1H，m)，6.61(1H，s)。
Reference example 15
Figure S2008100051493D00951
A) (10g, (9.5ml 80mmol), stirs mixture 3 hours at 60-70 ℃ 6-methylnicotinic acid methyl esters to add bromotoluene in ethyl acetate 66mmol) (70ml) solution.Mixture is cooled to room temperature, filters.Resistates ethyl acetate/hexane washed twice, vacuum-drying obtains bromination 1-benzyl-5-(methoxycarbonyl)-2-picoline (1.59g, 7%).
1H?NMR(300MHz，CDCl 3)δ3.12(3H，s)，3.98(3H，s)，6.28(2H，s)，7.30-7.42(5H，m)，8.13(1H，d，J＝8.3Hz)，8.78(1H，dd，J＝1.8，8.3Hz)，9.44(1H，d，J＝1.8Hz)。
B) at-70 ℃, (3.2g adds sodium borohydride (0.75g, water 20mmol) (10ml) solution to bromination 1-benzyl-5-(methoxycarbonyl)-2-picoline in methyl alcohol 9.9mmol) (50ml) suspension.Mixture is risen to 0 ℃, stirred 20 minutes.Add ethyl acetate/salt solution in the reaction mixture, mixture separates with separating funnel.Twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, solvent removed in vacuo.Resistates (2.34g) is purified with silica gel (60g) chromatography (hexane/ethyl acetate=4/1) and is obtained 1-benzyl-6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridine carboxylic acid methyl esters (2.05g, 84%).
1H?NMR(300MHz，CDCl 3)δ1.03(3H，d，J＝6.6Hz)，1.97-2.08(1H，m)，2.42-2.54(1H，m)，2.87-2.97(1H，m)，3.21-3.24(2H，m)，3.53(1H，d，J＝13.4Hz)，3.68(3H，s)，3.75(1H，d，J＝13.4Hz)，6.94-6.98(1H，m)，7.18-7.35(5H，m)。
C) at 0-5 ℃, 1-benzyl-6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridine carboxylic acid methyl esters (2.05g, and adding carbonochloridic acid allyl ester in THF 8.36mmol) (15ml) solution (1.1ml, 10.4mmol).Immediately mixture is risen to room temperature, stirred 18 hours.After being cooled to 0-5 ℃, add saturated sodium bicarbonate aqueous solution and ethyl acetate, mixture separates with separating funnel.Twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, solvent removed in vacuo.Resistates is purified with silica gel (55g) chromatography (hexane/ethyl acetate=6/1 → 4/1) and is obtained 1-allyl group 3-methyl 6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (1.42g, 71%).
1H?NMR(300MHz，CDCl 3)δ1.09(3H，d，J＝7.0Hz)，2.02-2.12(1H，m)，2.50-2.63(1H，m)，3.65-3.78(1H，m)，3.75(1H，s)，4.50-4.65(4H，m)，5.20(1H，d，J＝10.3Hz)，5.29(1H，d，J＝17.0Hz)，5.93(1H，ddd，J＝5.0，10.3，17.0Hz)，6.97-7.03(1H，m)。
D) at-90 ℃～-80 ℃, in 15 minutes to 1-allyl group 3-methyl 6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (0.44g, 1.85mmol) and bromochloromethane (0.18ml, 2.8mmol) THF (15ml) solution in add n-Butyl Lithium hexane solution (1.59M, 1.75ml, 2.8mmol).Behind the restir 40 minutes, (pH7.0 is in mixture 10ml) with reaction mixture impouring ice (10g) and phosphate buffer soln.After adding ethyl acetate, use the separating funnel separating mixture, twice of ethyl acetate extraction of water layer.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates obtains 5-(chloro ethanoyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (253mg, 53%) with silica gel (25g) chromatographic purification.
1H?NMR(300MHz，CDCl 3)δ1.09(3H，d，J＝7.0Hz)，2.10-2.22(1H，m)，2.60-2.74(1H，m)，3.67-3.78(1H，m)，4.40(2H，s)，4.55-4.70(4H，m)，5.20(1H，d，J＝10.4Hz)，5.28(1H，d，J＝17.0Hz)，5.92(1H，ddd，J＝5.0，10.4，17.0Hz)，6.92-6.98(1H，m)。
E) at 0-5 ℃, at 5-(chloro ethanoyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (0.50g, add in methyl alcohol 1.94mmol) (10ml) solution thioisonicotinamide (5mg) and ammonium dithiocarbamate (0.32g, 2.9mmol).Reaction mixture is risen to room temperature, stirred 10 minutes, stirred 50 minutes at 60-70 ℃ then.Solvent removed in vacuo.Add the alkalization of 1N aqueous sodium hydroxide solution in the resistates.Add ethyl acetate and hexane in the solution, use the separating funnel separation solution.Add ethyl acetate after adding 6N hydrochloric acid in the water layer, mixture is separated with separating funnel once more.The water layer ethyl acetate extraction.Organic layer saturated sodium-chloride water solution washed twice is used dried over mgso, and solvent removed in vacuo obtains 2-methyl-5-(2-sulfydryl-1,3-thiazoles-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (368mg, 64%).
1H?NMR(300MHz，CDCl 3)δ1.14(3H，d，J＝6.8Hz)，2.00-2.20(1H，m)，2.56-2.73(1H，m)，3.68-3.78(1H，m)，4.46-4.67(4H，m)，5.17-5.32(2H，m)，5.86-6.00(1H，m)，6.22(0.5H，brs)，6.24(0.5H，brs)，6.41(1H，s)。
Reference example 16
Figure S2008100051493D00971
A) according to reference example 3.a) same procedure with (2R)-2-{[(benzyloxy) carbonyl] aminobutyric acid obtains (1R)-1-(hydroxymethyl) propyl carbamic acid benzyl ester.
1H?NMR(300MHz，CDCl 3)δ0.94(3H，t，J＝7.3Hz)，1.41-1.64(2H，m)，2.12(1H，brs)，3.52(3H，m)，4.82(1H，brs)，5.09(2H，s)，7.27-7.37(5H，m)。
B) to (1R)-1-(hydroxymethyl) propyl carbamic acid benzyl ester (9.46g, 42.4mmol), 2,2,6,6-tetramethyl--piperidino oxygen base (0.143g, 0.85mmol) and Sodium Bromide (4.36g, 42mmol) adding of the suspension in mixture toluene (125ml), water (21ml) and ethyl acetate (125ml) sodium bicarbonate (10.3g).At 0-5 ℃, in 1 hour, in mixture, add aqueous sodium hypochlorite solution.Solution is used the extracted with diethyl ether water layer after separating with separating funnel.Organic layer washs with 10% aqueous potassium hydrogen sulfate that contains potassiumiodide, 10% sodium thiosulfate solution and saturated sodium-chloride water solution.Mixture concentrates with vaporizer, and resistates is dissolved in THF (60ml) at 0-5 ℃.Immediately solution is risen to room temperature, stirred 1.5 hours at uniform temp.After concentrating with vaporizer, resistates (2E, 4R)-4-{[(benzyloxy) carbonyl of purifying with silica gel (200g) chromatography (ethyl acetate/hexane=1/3) and obtain] amino }-2-hecanoic acid t-butyl ester (9.73g).
1H?NMR(300MHz，CDCl 3)δ0.93(3H，t，J＝7.5Hz)，1.46(9H，s)，1.42-1.68(2H，m)，4.20-4.32(1H，m)，3.65-3.73(1H，m)，5.07(1H，d，J＝15.8Hz)，5.11(1H，d，J＝15.8Hz)，5.82(1H，d，J＝15.6Hz)，6.71(1H，dd，J＝5.7，15.6Hz)，7.28-7.37(5H，m)。
C) (2E, 4R)-the 4-{[(benzyloxy) carbonyl] amino }-(9.73g, (3.5ml is 61mmol) with 10% palladium carbon (3.2g) to add acetate in methyl alcohol 30.5mmol) (200ml) solution for the 2-hecanoic acid t-butyl ester.Mixture stirred 7 hours under nitrogen atmosphere.Filtration catalizer under nitrogen atmosphere obtains (4R)-4-hexosamine tert-butyl ester acetate (7.5g, quantitative) with the vaporizer concentrated filtrate
1H?NMR(300MHz，CDCl 3)δ0.95(3H，t，J＝7.5Hz)，1.46(9H，s)，1.53-1.63(2H，m)，1.68-1.92(2H，m)，2.35(2H，t，J＝7.5Hz)，2.90-2.98(1H，m)。
D) according to reference example 3.d) same procedure obtain (4R)-4-[[(allyloxy with (the 4R)-4-hexosamine tert-butyl ester) carbonyl] (2-methoxyl group-2-oxoethyl) amino] hecanoic acid t-butyl ester.
1H?NMR(300MHz，CDCl 3)δ0.88(3H，t，J＝7.3Hz)，1.41(9H，s)，1.37-1.49(4H，m)，2.21-2.42(2H，m)，3.66-3.77(5H，m)，3.90-4.20(1H，m)，4.50-4.63(2H，m)，5.13-5.32(2H，m)，5.78-5.97(1H，m)。
E) according to reference example 3.e) and (the 4R)-4-[[(allyloxy of same procedure f)) carbonyl] (2-methoxyl group-2-oxoethyl) amino] the hecanoic acid t-butyl ester acquisition 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-ethyl-1,4-piperidines dicarboxylic ester.
1H?NMR(300MHz，CDCl 3)δ0.86(3H，t，J＝7.3Hz)，1.44(9H，s)，1.36-1.47(1H，m)，1.58-1.73(2H，m)，1.83-1.93(1H，m)，2.39-2.48(1H，m)，2.54-2.73(1H，m)，3.65-3.77(1H，m)，4.04-4.34(2H，m)，4.55(2H，d，J＝5.5Hz)，5.18(1H，dd，J＝1.3，10.4Hz)，5.26(1H，dd，J＝1.3，17.0Hz)，5.90(1H，ddt，J＝5.5，10.4，17.0Hz)。
F) according to reference example 3.g) same procedure with the 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-ethyl-1,4-piperidines dicarboxylic ester obtains the 1-allyl group 4-tertiary butyl (2R)-2-ethyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate.
1H?NMR(300MHz，CDCl 3)δ0.85(3H，t，J＝7.5Hz)，1.32-1.59(2H，m)，1.47(9H，s)，2.35-2.42(2H，m)，3.55-3.73(1H，m)，4.29-4.63(4H，m)，5.19(1H，dd，J＝1.5，10.4Hz)，5.28(1H，dd，J＝1.5，17.0Hz)，5.92(1H，ddt，J＝5.5，10.4，17.0Hz)，6.74(1H，brs)。
Reference example 17
A) according to reference example 16.a) same procedure N-[(benzyloxy) carbonyl]-the D-Xie Ansuan obtains (1R)-1-(hydroxymethyl)-2-methyl-propyl benzyl carbamate.
1H?NMR(300MHz，CDCl 3)δ0.91(3H，d，J＝7.0Hz)，0.94(3H，d，J＝7.9Hz)，1.78-1.90(1H，m)，2.03-2.12(1H，m)，3.44-3.75(3H，m)，4.84(1H，br?s)，5.09(2H，s)，7.28-7.37(5H，m)。
B) according to reference example 16.b) same procedure obtain (2E, 4R)-4-{[(benzyloxy) carbonyl with (1R)-1-(hydroxymethyl)-2-methyl-propyl benzyl carbamate] amino-5-methyl-2-hecanoic acid t-butyl ester.
1H?NMR(300MHz，CDCl 3)δ0.89(3H，d，J＝7.0Hz)，0.92(3H，d，J＝6.8Hz)，1.46(9H，s)，1.78-1.92(1H，m)，4.16-4.26(1H，m)，4.76(1H，d，J＝9.7Hz)，5.07(1H，d，J＝13.9Hz)，5.11(1H，d，J＝12.1Hz)，5.83(1H，dd，J＝1.3，15.5Hz)，6.73(1H，dd，J＝5.5，15.5Hz)，7.28-7.37(5H，m)。
C) according to reference example 16.c) same procedure with (2E, 4R)-4-{[(benzyloxy) carbonyl] amino-5-methyl-2-hecanoic acid t-butyl ester obtains (4S)-4-amino-5-methylhexanoic acid tert-butyl ester acetate.
1H?NMR(300MHz，CDCl 3)δ0.94(3H，d，J＝7.0Hz)，0.95(3H，d，J＝6.8Hz)，1.41(9H，s)，1.63-1.91(3H，m)，2.28-2.47(2H，m)，2.83(1H，dt，J＝4.4，8.8Hz)。
D) according to reference example 3.d) same procedure obtain (4S)-4-[[(allyloxy with (4S)-4-amino-5-methylhexanoic acid tert-butyl ester acetate) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-methylhexanoic acid tert-butyl ester.
1H?NMR(300MHz，CDCl 3)δ0.87(3H，d，J＝6.6Hz)，0.97(3H，d，J＝6.6Hz)，1.35-1.65(2H，m)，1.42(9H，s)，1.88-2.02(1H，m)，2.26-2.52(2H，m)，3.59-3.93(5H，m)，4.51-4.68(2H，m)，5.18-5.31(2H，m)，5.78-5.96(1H，m)。
E) according to reference example 3.e) and (the 4S)-4-[[(allyloxy of same procedure f)) carbonyl] (2-methoxyl group-2-oxoethyl) amino]-the 5-methylhexanoic acid tert-butyl ester acquisition 1-allyl group 4-tertiary butyl (2S)-5-hydroxyl-2-sec.-propyl-1,4-piperidines dicarboxylic ester.
1H?NMR(300MHz，CDCl 3)δ0.84-0.97(6H，m)，1.45(9H，s)，1.50-1.70(1H，m)，1.74-2.13(2H，m)，2.33-3.09(2H，m)，3.64-4.38(3H，m)，4.50-4.65(2H，m)，5.15-5.34(2H，m)，5.85-5.98(1H，m)。
F) according to reference example 3.g) same procedure with the 1-allyl group 4-tertiary butyl (2S)-5-hydroxyl-2-sec.-propyl-1,4-piperidines dicarboxylic ester obtains the 1-allyl group 4-tertiary butyl (2S)-2-sec.-propyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate.
1H?NMR(300MHz，CDCl 3)δ0.84(3H，d，J＝6.8Hz)，0.91(3H，d，J＝6.6Hz)，1.47(9H，s)，1.63-1.73(1H，m)，2.23-2.36(1H，m)，2.62(1H，d，J＝17.4Hz)，3.53-3.72(1H，m)，3.90-4.14(1H，m)，4.40-4.65(4H，m)，5.19(1H，dd，J＝1.3，10.4Hz)，5.28(1H，d，J＝17.4Hz)，5.92(1H，ddt，J＝5.5，10.4，17.4Hz)，6.75(1H，brs)。
G) according to reference example 6.g) same procedure with the 1-allyl group 4-tertiary butyl (2S)-2-sec.-propyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate obtains 1-allyl group 4-methyl (2S)-2-sec.-propyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate.
1H?NMR(300MHz，CDCl 3)δ0.84(3H，d，J＝6.6Hz)，0.90(3H，d，J＝6.4Hz)，1.60-1.72(1H，m)，2.28-2.40(1H，m)，2.67(1H，d，J＝17.6Hz)，3.55-3.77(1H，m)，3.74(3H，s)，3.93-4.13(1H，m)，4.41-4.65(3H，m)，5.19(1H，ddd，J＝1.5，2.8，10.4Hz)，5.28(1H，d，J＝17.2Hz)，5.92(1H，ddt，J＝5.5，10.4，17.2Hz)，6.86(1H，brs)。
H) according to reference example 2.d) same procedure with 1-allyl group 4-methyl (2S)-2-sec.-propyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate obtains (2R)-4-(chloro ethanoyl)-2-sec.-propyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.
1H?NMR(300MHz，CDCl 3)δ0.85(3H，d，J＝6.8Hz)，0.89(3H，d，J＝6.6Hz)，1.50-1.64(1H，m)，2.21-2.34(1H，m)，2.78(1H，d，J＝17.4Hz)，3.64-3.75(2H，m)，4.33-4.44(2H，m)，4.50-4.70(3H，m)，5.17-5.32(2H，m)，5.85-5.99(1H，m)，6.80(1H，brs)。
I) according to reference example 2.e) same procedure with (2S)-4-(chloro ethanoyl)-2-sec.-propyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester obtains (2S)-4-(2-sulfydryl-1; 3-thiazole-4-yl)-and 2-sec.-propyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.
1H?NMR(300MHz，CDCl 3)δ0.87(3H，d，J＝6.6Hz)，0.92(3H，d，J＝6.6Hz)，1.67-1.83(1H，m)，2.38-2.58(2H，m)，3.57-3.80(1H，m)，3.97-4.18(1H，m)，4.44-4.68(3H，m)，5.21(1H，dd，J＝1.3，10.4Hz)，5.29(1H，dd，J＝1.4，17.2Hz)，5.93(1H，ddt，J＝5.5，10.4，17.2Hz)，6.03(1H，brs)，6.38(1H，brs)。
Reference example 18
Figure S2008100051493D01021
With (2R)-5-(chloro ethanoyl)-2-methyl-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester obtains 4-[(6R according to the same procedure of reference example 12)-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-mercaptan.
1H?NMR(300MHz，CD 3OD)δ1.23(3H，brs)，2.10-2.29(1H，m)，2.54(3H，brs)，2.80(2H，brs)，3.50-3.70(2H，m)，6.38(1H，brs)，6.71(1H，brs)。
Reference example 19
A) according to reference example 6.g) same procedure with (3S)-3-{[(benzyloxy) carbonyl] amino tert-butyl acetate (5.63g 19.2mmol) obtains (3S)-3-{[(benzyloxy) carbonyl] amino methyl-butyrate (3.61g, 75%).
1H?NMR(300MHz，CDCl 3)δ1.24(3H，d，J＝6.8Hz)，2.54(2H，d，J＝5.5Hz)，3.67(3H，s)，4.05-4.18(1H，m)，5.06-5.13(2H，m)，5.15-5.24(1H，m)，7.28-7.39(5H，m)。
B) according to reference example 3.c) same procedure with (3S)-3-{[(benzyloxy) carbonyl] amino (3.61g 14.4mmol) obtains (3S)-3-aminobutyric acid methyl esters (1.47g, 87%) to methyl-butyrate. 1H?NMR(300MHz，CDCl 3)δ1.14(3H，d，J＝6.4Hz)，2.33(1H，dd，J＝15.7，8.2Hz)，2.43(1H，dd，J＝15.7，4.6Hz)，3.34-3.45(1H，m)，3.69(3H，s)。
C) at 0 ℃, (3S)-3-aminobutyric acid methyl esters (1.47g, add in THF 12.5mmol) (30ml) solution carbonochloridic acid allyl ester (1.60ml, 15.1mmol) and diisopropylethylamine (2.62ml, 15.0mmol), mixture stirred 30 minutes at uniform temp.In reaction mixture impouring water, use twice of ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and organic solvent is removed in decompression.Resistates obtains (3S)-3-{[(allyloxy with silica gel (25g) chromatographic purification) carbonyl] amino } methyl-butyrate (2.06g, 81%).
1H?NMR(300MHz，CDCl 3)δ1.25(3H，d，J＝6.8Hz)，2.24(3H，d，J＝5.5Hz)，3.69(3H，s)，4.03-4.16(1H，m)，4.54-4.58(2H，m)，5.15-5.34(3H，m)，5.85-5.98(1H，m)。
D) at 40 ℃, with sodium hydride (60% is suspended in the oil, and 0.41g 10.2mmol) adds (3S)-3-{[(allyloxy) carbonyl] amino } methyl-butyrate (2.06g, 10.2mmol) and ethyl propenoate (1.11ml, toluene 10.2mmol) (25ml) solution.Mixture was stirred 2 hours, then in the impouring dilute hydrochloric acid.Twice of ethyl acetate extraction of solution.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso.Vacuum is removed organic solvent.Add in the resistates methyl alcohol (40ml), acetate (0.70ml, 12.2mmol) and sodium cyanoborohydride (0.77g, 12.2mmol), mixture was stirring at room 20 minutes.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained 1-allyl group 3-ethyl (6S)-4-hydroxyl-6-methyl isophthalic acid, 3-piperidines dicarboxylic ester and 1-allyl group 3-methyl (6S)-4-hydroxyl-6-methyl isophthalic acid, the mixture (1.21g) of 3-piperidines dicarboxylic ester.
According to reference example 3.g) same procedure handle said mixture and obtain 1-allyl group 3-ethyl (6S)-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate (127mg, 5%) and 1-allyl group 3-methyl (6S)-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylates (252mg, 10%).
1-allyl group 3-methyl (6S)-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate
1H?NMR(300MHz，CDCl 3)δ1.12(3H，d，J＝7.0Hz)，2.04-2.13(1H，m)，2.54-2.63(1H，m)，3.70-3.79(1H，m)，4.23(2H，q，J＝7.1Hz)，4.55-4.68(4H，m)，5.19-5.34(2H，m)，5.89-6.02(1H，m)，7.00-7.04(1H，m)。
1-allyl group 3-methyl (6S)-6-methyl-5,6-dihydro-1,3 (2H)-pyridine dicarboxylate
1H?NMR(300MHz，CDCl 3)δ1.12(3H，d，J＝6.8Hz)，1.31(3H，t，J＝7.1Hz)，2.04-2.13(1H，m)，2.53-2.64(1H，m)，3.70-3.79(1H，m)，3.77(3H，s)，4.55-4.68(4H，m)，5.19-5.34(2H，m)，5.89-6.02(1H，m)，7.00-7.04(1H，m)。
E) according to reference example 1.b) same procedure with 1-allyl group 3-ethyl (6S)-6-methyl-5; 6-dihydro-1; 3 (2H)-pyridine dicarboxylate (126mg; 0.50mmol) acquisition (2S)-5-(chloro ethanoyl)-2-methyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (62mg, 48%).
1H?NMR(300MHz，CDCl 3)δ1.12(3H，d，J＝7.0Hz)，2.13-2.24(1H，m)，2.66-2.75(1H，m)，3.71-3.79(1H，m)，4.36-4.46(2H，m)，4.60-4.71(4H，m)，5.20-5.34(2H，m)，5.88-6.01(1H，m)，6.96-6.99(1H，m)。
F) according to reference example 1.c) same procedure with (2S)-5-(chloro ethanoyl)-2-methyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (141mg; 0.55mmol) acquisition (2S)-2-methyl-5-(2-sulfenyl-1; 3-thiazole-4-yl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (160mg, 99%).
1H?NMR(300MHz，CDCl 3)δ1.16(3H，d，J＝7.0Hz)，2.08-2.18(1H，m)，2.60-2.70(1H，m)，3.71-3.79(1H，m)，4.52-4.65(4H，m)，5.22-5.34(2H，m)，5.89-6.01(1H，m)，6.18-6.20(1H，m)，6.42(1H，s)，10.66(1H，br?s)。
Reference example 20
A) at 0 ℃, ethanol (188ml, add in 3.24mol) Acetyl Chloride 98Min. (46ml, 0.65mol).Mixture stirred 30 minutes at uniform temp, it was joined (3S)-3-{[(benzyloxy) carbonyl] amino }-the 4 hydroxybutyric acid tert-butyl ester (10.0g, ethanol 32.3mmol) (20ml) solution.The mixture stirring is spent the night.Except that after desolvating, resistates is dissolved in ethyl acetate, solution with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, is used anhydrous sodium sulfate drying successively.Organic solvent is removed in decompression, resistates is purified with silica gel chromatography and is obtained (3S)-3-{[(benzyloxy) carbonyl] amino }-4 hydroxybutyric acid ethyl ester (2.92g, 32%) and by product lactone compound (3S)-5-oxo tetrahydrochysene-3-furyl benzyl carbamate (4.24g, 56%).
(3S)-and the 3-{[(benzyloxy) carbonyl] amino }-the 4 hydroxybutyric acid ethyl ester
1H?NMR(300MHz，CDCl 3)δ1.24(3H，t，J＝7.1Hz)，2.61-2.65(2H，m)，2.78(1H，br?s)，3.68-3.73(2H，m)，4.07-4.17(3H，m)，5.07-5.10(2H，m)，5.50-5.58(1H，m)，7.28-7.39(5H，m)。
(3S)-5-oxo tetrahydrochysene-3-furyl benzyl carbamate
1H?NMR(300MHz，CDCl 3)δ1.24(3H，t，J＝7.1Hz)，2.46(1H，dd，J＝3.5，17.9Hz)，2.81(1H，dd，J＝7.5，17.9Hz)，4.17-4.24(1H，m)，4.44-4.53(2H，m)，5.10(2H，s)，5.40-5.45(1H，m)，7.28-7.39(5H，m)。
B) according to reference example 3.c) same procedure with (3S)-3-{[(benzyloxy) carbonyl] amino-(2.92g 10.4mmol) obtains (3S)-3-amino-4-hydroxybutyric acid ethyl ester to the 4 hydroxybutyric acid ethyl ester.
Above-claimed cpd need not to purify, with it according to reference example 19.c) the same procedure allyloxy carbonyl turn into obtaining (3S)-3-{[(allyloxy) carbonyl] amino-4 hydroxybutyric acid ethyl ester (0.96g, 40%).
1H?NMR(300MHz，CDCl 3)δ1.27(3H，t，J＝7.1Hz)，2.42(1H，br，s)，2.64-2.68(2H，m)，3.71-3.76(2H，m)，4.01-4.11(1H，m)，4.16(2H，q，J＝7.1Hz)，4.54-4.58(2H，m)，5.19-5.34(2H，m)，5.47(1H，br?s)，5.85-5.98(1H，m)。
C) according to reference example 7.a) same procedure with (3S)-3-{[(allyloxy) carbonyl] amino-4 hydroxybutyric acid ethyl ester (0.96g, 4.2mmol) acquisition (3S)-3-{[(allyloxy) carbonyl] amino-the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl butyrate (1.25g, 87%).
1H?NMR(300MHz，CDCl 3)δ0.04(6H，s)，0.89(9H，s)，1.25(3H，t，J＝7.1Hz)，2.58-2.62(2H，m)，3.64(1H，dd，J＝5.1，9.9Hz)，3.70(1H，dd，J＝3.8，9.9Hz)，4.04-4.16(1H，m)，4.13(2H，q，J＝7.1Hz)，4.54-4.58(2H，m)，5.19-5.34(3H，m)，5.85-5.98(1H，m)。
D) at 40 ℃, (60% is suspended in the oil with sodium hydride, 145mg, 3.6mmol) adding (3S)-3-{[(allyloxy) carbonyl] amino-the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl butyrate (1.25g, 3.6mmol) and ethyl propenoate (0.39ml, toluene 3.6mmol) (10ml) solution.Mixture was stirred 1 hour at 60 ℃, then in the impouring dilute hydrochloric acid.Solution ethyl acetate extraction three times.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.Solvent removed in vacuo.Resistates is dissolved in methyl alcohol (25ml), add in the solution acetate (0.25ml, 4.4mmol) and sodium cyanoborohydride (0.27g, 4.3mmol), mixture was stirring at room 30 minutes.Solvent removed in vacuo, resistates are purified with silica gel chromatography and are obtained 1-allyl group 3-ethyl (6S)-6-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-hydroxyl-1,3-piperidines dicarboxylic ester (0.48g, 33%).
1H?NMR(300MHz，CDCl 3)δ0.04(6H，s)，0.89(9H，s)，1.26(3H，t，J＝7.1Hz)，2.48-2.66(3H，m)，3.60-3.73(3H，m)，4.04-4.23(4H，m)，4.14(2H，q，J＝7.1)，4.54-4.62(2H，m)，5.19-5.34(2H，m)，5.85-5.98(1H，m)。
E) according to reference example 5.g) same procedure with 1-allyl group 3-ethyl (6S)-6-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-hydroxyl-1,3-piperidines dicarboxylic ester (484mg, 1.2mmol) acquisition 1-allyl group 3-ethyl (6S)-6-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5,6-dihydro-1,3 (2H)-pyridine dicarboxylates (151mg, 33%).
1H?NMR(300MHz，CDCl 3)δ0.01-0.04(6H，m)，0.84-0.89(9H，m)，1.23-1.33(3H，m)，2.18-2.65(2H，m)，3.45-3.92(3H，m)，4.07-4.26(2H，m)，4.45-4.68(3H，m)，5.19-5.35(2H，m)，5.86-6.02(1H，m)，7.01(1H，br?s)。
F) according to reference example 1.b) same procedure with 1-allyl group 3-ethyl (6S)-6-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5; 6-dihydro-1; 3 (2H)-pyridine dicarboxylate (151mg; 0.39mmol) acquisition (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5-(chloro ethanoyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (79mg, 52%).
1H?NMR(300MHz，CDCl 3)δ0.02(3H，s)，0.03(3H，s)，0.86(9H，s)，2.42-2.65(2H，m)，3.45-3.57(3H，m)，3.67-3.78(1H，m)，4.40(2H，s)，4.50-4.65(4H，m)，5.19-5.34(2H，m)，5.88-6.01(1H，m)，6.98(1H，br?s)。
G) according to reference example 1.c) same procedure with (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5-(chloro ethanoyl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (79mg; 0.20mmol) acquisition (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5-(2-sulfenyl-1; 3-thiazole-4-yl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (90mg, quantitatively).
1H?NMR(300MHz，CDCl 3)δ0.03(6H，s)，0.86(9H，s)，2.27-2.38(1H，m)，2.50-2.61(1H，m)，3.48-3.82(3H，m)，4.40-4.66(4H，m)，5.19-5.34(2H，m)，5.88-6.01(1H，m)，6.29(1H，br?s)，6.44(1H，br?s)，11.49(1H，br?s)。
Reference example 21
A) according to reference example 3.a) same procedure obtain (1R)-1-(hydroxymethyl) propyl carbamic acid benzyl ester with (2R)-N-benzyloxycarbonyl-2-aminopropane carboxylic acid.
1H?NMR(300MHz，CDCl 3)δ0.94(3H，t，J＝7.3Hz)，1.41-1.64(2H，m)，2.12(1H，brs)，3.52(3H，m)，4.82(1H，brs)，5.09(2H，s)，7.27-7.37(5H，m)。
B) to (1R)-1-(hydroxymethyl) propyl carbamic acid benzyl ester (9.46g, 42.4mmol), 2,2,6,6-tetramethyl--piperidino oxygen base (0.143g, 0.85mmol) and Sodium Bromide (4.36g, 42mmol) adding of the suspension in mixture toluene (125ml), water (21ml) and ethyl acetate (125ml) sodium bicarbonate (10.3g).At 0-5 ℃, in 1 hour, in mixture, add aqueous sodium hypochlorite solution.Solution is used the extracted with diethyl ether water layer after separating with separating funnel.Organic layer washs with 10% aqueous potassium hydrogen sulfate that contains potassiumiodide, 10% hypo solution and saturated sodium-chloride water solution.Mixture concentrates with vaporizer, and resistates is dissolved in THF (60ml) at 0-5 ℃.Immediately solution is risen to room temperature, stirred 1.5 hours at uniform temp.After concentrating with vaporizer, resistates (2E, 4R)-4-{[(benzyloxy) carbonyl of purifying with silica gel (200g) chromatography (ethyl acetate/hexane=1/3) and obtain] amino }-2-hecanoic acid t-butyl ester (9.73g).
1H?NMR(300MHz，CDCl 3)δ0.93(3H，t，J＝7.5Hz)，1.46(9H，s)，1.42-1.68(2H，m)，4.20-4.32(1H，m)，3.65-3.73(1H，m)，5.07(1H，d，J＝15.8Hz)，5.11(1H，d，J＝15.8Hz)，5.82(1H，d，J＝15.6Hz)，6.71(1H，dd，J＝5.7，15.6Hz)，7.28-7.37(5H，m)。
C) (2E, 4R)-the 4-{[(benzyloxy) carbonyl] amino }-(9.73g, (3.5ml is 61mmol) with 10% palladium carbon (3.2g) to add acetate in methyl alcohol 30.5mmol) (200ml) solution for the 2-hecanoic acid t-butyl ester.Mixture stirred 7 hours under nitrogen atmosphere.Filtration catalizer under nitrogen atmosphere obtains (4R)-4-hexosamine tert-butyl ester acetate (7.5g, quantitative) with the vaporizer concentrated filtrate
1H?NMR(300MHz，CDCl 3)δ0.95(3H，t，J＝7.5Hz)，1.46(9H，s)，1.53-1.63(2H，m)，1.68-1.92(2H，m)，2.35(2H，t，J＝7.5Hz)，2.90-2.98(1H，m)。
D) according to reference example 3.d) same procedure obtain (4R)-4-[[(allyloxy with (the 4R)-4-hexosamine tert-butyl ester) carbonyl] (2-methoxyl group-2-oxoethyl) amino] hecanoic acid t-butyl ester.
1H?NMR(300MHz，CDCl 3)δ0.88(3H，t，J＝7.3Hz)，1.41(9H，s)，1.37-1.79(4H，m)，2.21-2.42(2H，m)，3.66-3.77(5H，m)，3.90-4.20(1H，m)，4.50-4.63(2H，m)，5.13-5.32(2H，m)，5.78-5.97(1H，m)。
E) according to reference example 3.e) and (the 4R)-4-[[(allyloxy of same procedure f)) carbonyl] (2-methoxyl group-2-oxoethyl) amino] the hecanoic acid t-butyl ester acquisition 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-ethyl-1,4-piperidines dicarboxylic ester.
1H?NMR(300MHz，CDCl 3)δ0.86(3H，t，J＝7.3Hz)，1.44(9H，s)，1.36-1.47(1H，m)，1.58-1.73(2H，m)，1.83-1.93(1H，m)，2.39-2.48(1H，m)，2.54-2.73(1H，m)，3.65-3.77(1H，m)，4.04-4.34(2H，m)，4.55(2H，d，J＝5.5Hz)，5.18(1H，dd，J＝1.3，10.4Hz)，5.26(1H，dd，J＝1.3，17.0Hz)，5.90(1H，ddt，J＝5.5，10.4，17.0Hz)。
F) according to reference example 3.g) same procedure with the 1-allyl group 4-tertiary butyl (2R)-5-hydroxyl-2-ethyl-1,4-piperidines dicarboxylic ester obtains the 1-allyl group 4-tertiary butyl (2R)-2-ethyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate.
1H?NMR(300MHz，CDCl 3)δ0.85(3H，t，J＝7.5Hz)，1.32-1.59(2H，m)，1.47(9H，s)，2.35-2.42(2H，m)，3.55-3.73(1H，m)，4.29-4.63(4H，m)，5.19(1H，dd，J＝1.5，10.4Hz)，5.28(1H，dd，J＝1.5，17.0Hz)，5.92(1H，ddt，J＝5.5，10.4，17.0Hz)，6.74(1H，brs)。
G) according to reference example 6.g) same procedure with the 1-allyl group 4-tertiary butyl (2R)-2-ethyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylate (1.40g, 4.72mmol) acquisition 1-allyl group 4-methyl (2R)-2-ethyl-3,6-dihydro-1,4 (2H)-pyridine dicarboxylates (1.09g, 91%).
1H?NMR(300MHz，CDCl 3)δ0.88(3H，t，J＝7.4Hz)，1.32-1.57(2H，m)，2.44-2.47(2H，m)，3.63-3.79(1H，m)，3.76(3H，s)，4.35-4.65(4H，m)，5.19-5.34(2H，m)，5.88-6.01(1H，m)，6.88(1H，brs)。
H) according to reference example 1.b) same procedure with 1-allyl group 4-methyl (2R)-2-ethyl-3; 6-dihydro-1; 4 (2H)-pyridine dicarboxylate (435mg; 1.72mmol) acquisition (2R)-4-(chloro ethanoyl)-2-ethyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (177mg, 38%).
1H?NMR(300MHz，CDCl 3)δ0.88(3H，t，J＝7.3Hz)，1.32-1.57(2H，m)，2.34-2.46(1H，m)，2.50-2.57(1H，m)，3.70-3.82(1H，m)，4.34-4.48(1H，m)，4.39(1H，d，J＝14.1)，4.43(1H，d，J＝14.1)，4.60-4.65(1H，m)，5.19-5.34(2H，m)，5.88-6.01(1H，m)，6.81(1H，br?s)。
I) according to reference example 1.c) same procedure with (2R)-4-(chloro ethanoyl)-2-ethyl-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (167mg; 0.61mmol) acquisition (2R)-2-ethyl-4-(2-sulfenyl-1; 3-thiazole-4-yl)-3; 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (105mg, 55%).
1H?NMR(300MHz，CDCl 3)δ0.90(3H，t，J＝7.4Hz)，1.37-1.66(2H，m)，2.17-2.24(1H，m)，2.58-2.68(1H，m)，3.65-3.79(1H，m)，4.43-4.67(4H，m)，5.21-5.34(2H，m)，5.89-6.01(1H，m)，6.08(1H，br?s)，6.39(1H，s)，10.94(1H，br?s)。
Embodiment 27
A) at 0-5 ℃, THF solution (1M with two (trimethyl silane) lithium amides, 0.25ml, 0.25mmol) adding (2S)-4-(2-sulfydryl-1,3-thiazole-4-yl)-2-sec.-propyl-3, (80mg, THF 0.25mmol) (4.3ml) solution stir mixture 10 minutes 6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.In reaction soln, add (4R at 0 ℃; 5R; 6S)-(3-[(two phenoxy group phosphonos) oxygen base]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-acetonitrile solution (30% of 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate; 0.94g; 0.50mmol), solution was left standstill 12 hours at refrigerator.In reaction soln, add frozen water, the reaction mixture ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying.After the solvent removed in vacuo, resistates is dissolved in THF (5.65ml), adds entry at 0 ℃ in solution, with 1N hydrochloric acid with pH regulator to about 3.With about 1 hour of solution stirring.Add sodium bicarbonate aqueous solution in the reaction mixture, twice of ethyl acetate extraction of solution.Organic layer washs with saturated sodium-chloride water solution, uses anhydrous sodium sulfate drying, solvent removed in vacuo.Resistates is dissolved in methylene dichloride (5ml).0 ℃ in solution, add acetate (36 μ l, 0.63mmol) and tri-butyl tin hydride (0.67ml, 2.5mmol), at room temperature add then two (triphenylphosphine) Palladous chlorides (II) (17.5mg, 0.025mmol).Mixture was stirred 10 minutes at uniform temp.With reaction mixture impouring ice (5g) and phosphate buffered saline buffer (pH7.0, mixture 5ml).After the separating funnel separation, organic layer water extracting twice.Vacuum is removed the organic solvent of water layer, and resistates is purified with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6S)-6-sec.-propyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (29.9mg, 17%).
1H?NMR(300MHz，D 2O)δ0.95(6H，d，J＝6.8Hz)，0.97(3H，d，J＝6.8Hz)，1.12(3H，d，J＝6.4Hz)，1.95-2.07(1H，m)，2.47-2.76(2H，m)，3.16-3.36(3H，m)，3.82(2H，brs)，4.08-4.15(2H，m)，6.38(1H，brs)，7.48(1H，s)。
IR(KBr)3434，2969，1753，1598cm -1
Embodiment 28
Figure S2008100051493D01121
A) according to embodiment 27.a) same procedure with (6R)-6-sec.-propyl-4-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester obtains (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6R)-6-sec.-propyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.92-0.98(9H，s)，1.12(3H，d，J＝6.4Hz)，1.90-2.03(1H，m)，2.62-2.73(2H，m)，3.09-3.38(3H，m)，3.48-3.65(1H，m)，3.77-3.83(1H，m)，4.04-4.16(2H，m)，6.42(1H，s)，7.48(1H，m)。
IR(KBr)3412，2968，1755，1599，1393cm -1
Embodiment 29
Figure S2008100051493D01122
A) according to embodiment 27.a) same procedure with (6S)-6-isobutyl--4-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester obtains (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6R)-6-isobutyl--1,2,3,6-tetrahydrochysene-4-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.86(6H，d，J＝6.2Hz)，0.95(3H，d，J＝7.7Hz)，1.12(3H，d，J＝6.2Hz)，1.50-1.79(3H，m)，2.63-2.70(2H，m)，3.13-3.37(3H，m)，3.47-3.65(2H，m)，3.98-4.15(2H，m)，6.39(1H，brs)，7.47(1H，s)。
IR(KBr)3386，2966，1756，1600，1388cm -1
Embodiment 30
Figure S2008100051493D01131
A) according to embodiment 2.a) same procedure with (2R)-2-methyl-5-(2-sulfydryl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester obtains (4R, 5S, 6S)-and 3-[4-{ (6R)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1,3-thiazoles-2-yl] sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ0.10(9H，s)，1.11(3H，d，J＝7.3Hz)，1.17(3H，d，J＝6.8Hz)，1.21(3H，d，J＝6.1Hz)，2.04-2.15(1H，m)，2.58-2.71(1H，m)，3.18-3.24(1H，m)，3.37-3.48(1H，m)，3.82-3.93(1H，m)，4.06-4.21(2H，m)，4.62-4.86(6H，m)，5.15-5.48(4H，m)，5.87-6.03(2H，m)，6.71(1H，brs)，7.11(1H，s)。
B) according to embodiment 2.b) same procedure with (4R, 5S, 6S)-and 3-[(4-{ (6R)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate acquisition (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(6R)-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.0Hz)，1.31(3H，d，J＝6.4Hz)，2.18-2.33(1H，m)，2.50-2.64(1H，m)，3.10-3.49(3H，m)，3.95-4.16(4H，m)，6.54(1H，s)，7.41(1H，s)。
IR(KBr)3428，2970，1759，1599，1392cm -1
Embodiment 31
Figure S2008100051493D01141
A) according to embodiment 1.a) and same procedure 4-[(6R 1.b))-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-acquisition of 2-mercaptan (4R, 5S, 6S)-and 3-(4-[(6R)-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ1.06(3H，d，J＝7.3Hz)，1.16(3H，d，J＝6.4Hz)，1.29(3H，d，J＝6.4Hz)，2.17-2.30(2H，m)，2.46(3H，s)，2.64-2.76(1H，m)，3.21-3.25(1H，m)，3.32-3.43(1H，m)，3.48-3.61(2H，m)，4.15-4.27(2H，m)，4.71(1H，dd，J＝5.7，13.4Hz)，4.83(1H，dd，J＝5.3，13.4Hz)，5.26(1H，d，J＝10.4Hz)，5.44(1H，d，J＝17.2Hz)，5.96(1H，dddd，J＝5.3，5.7，10.4，17.2Hz)，6.60(1H，s)，7.07(1H，s)。
B) according to embodiment 1.c) same procedure with (4R, 5S, 6S)-and 3-(4-[(6R)-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-acquisition of 2-allyl carboxylate (4R, 5S, 6S)-and 3-(4-[(6R)-1, the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.4Hz)，1.28(3H，d，J＝6.6Hz)，2.27-2.40(1H，m)，2.58-2.72(1H，m)，2.83(3H，s)，3.13-3.38(4H，m)，3.90-4.14(3H，m)，6.52(1H，s)，7.40(1H，s)。
IR(KBr)3400，2968，1764，1602，1386cm -1
Embodiment 32
Figure S2008100051493D01151
A) according to embodiment 1.a) and same procedure 4-[(6S 1.b))-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-acquisition of 2-mercaptan (4R, 5S, 6S)-and 3-(4-[(6S)-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate.
1H?NMR(300MHz，CDCl 3)δ1.04-1.31(9H，m)，2.07-2.20(2H，m)，2.43(3H，s)，2.54-2.64(1H，m)，3.21-3.24(1H，m)，3.48-3.99(3H，m)，4.14-4.26(2H，m)，4.62-4.86(2H，m)，5.14-5.47(2H，m)，5.89-6.03(1H，m)，6.59(1H，s)，7.05(1H，s)。
B) according to embodiment 1.c) same procedure with (4R, 5S, 6S)-and 3-(4-[(6S)-1,6-dimethyl-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-acquisition of 2-allyl carboxylate (4R, 5S, 6S)-and 3-(4-[(6S)-1, the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.1Hz)，1.12(3H，d，J＝6.2Hz)，1.27(3H，d，J＝7.0Hz)，2.27-2.40(1H，m)，2.58-2.72(1H，m)，2.81(3H，s)，3.13-3.38(4H，m)，3.90-4.14(3H，m)，6.51(1H，s)，7.40(1H，s)。
IR(KBr)3280，2965，1788，1602，1384cm -1
Embodiment 33
Figure S2008100051493D01161
A) according to embodiment 27.a) same procedure with (2S)-2-sec.-propyl-4-(2-sulfenyl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate obtains (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(5S)-5-sec.-propyl-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
1H?NMR(300MHz，D 2O)δ0.91-0.96(9H，m)，1.11(3H，d，J＝6.4Hz)，1.93-2.05(1H，m)，3.11-3.22(1H，m)，3.34(1H，dd，J＝2.7，6.0Hz)，4.05-4.13(2H，m)，4.25-4.42(3H，m)，6.35(1H，s)，7.51(1H，s)。
Embodiment 34
Figure S2008100051493D01171
At 0 ℃, (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2S)-2-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (7.3mg, add in phosphate buffer soln 0.018mmol) the salt acid imide by benzyl formate (22.3mg, 0.13mmol).Solution is regulated pH to 8.5 with the 1N aqueous sodium hydroxide solution, stirs 1.5 hours at uniform temp.Regulate pH to 7.0 with 1N hydrochloric acid then, purify with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(5S)-1-(iminomethyl)-5-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (5.9mg, 75%).
1H?NMR(300MHz，D 2O)δ0.96(3H，d，J＝7.3Hz)，1.11(3H，d，J＝6.4Hz)，1.40(3H，d，J＝6.6Hz)，3.05-3.16(1H，m)，3.34(1H，dd，J＝2.7，5.9Hz)，4.05-4.14(2H，m)，4.30-4.37(1H，m)，5.03-5.20(1H，m)，6.27(1H，s)，7.55(1H，s)，8.04(1H，s)。
IR(KBr)3402，2974，1758，1710，1597，1391cm -1
Embodiment 35
Figure S2008100051493D01181
At 0 ℃, (4R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(2S)-2-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (7.6mg, add in phosphate buffer soln 0.019mmol) the salt acid imide by ethyl acetate (18.4mg, 0.15mmol).Solution is regulated pH to 8.5 with the 1N aqueous sodium hydroxide solution, stirs 6 hours.Regulate pH to 7.0 with 1N hydrochloric acid then, purify with polymkeric substance chromatography (CHP-20P).Merge part with the elution of the 3-8%THF aqueous solution, lyophilize obtains the unbodied (4R of white, 5S, 6S)-3-(4-[[(5S)-1-imino-ethyl-5-methyl-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (7.9mg, 93%).
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.3Hz)，1.10(3H，d，J＝6.4Hz)，1.31(1.65H，d，J＝6.2Hz)，1.34(1.35H，d，J＝6.4Hz)，2.18(1.65H，s)，2.30(1.35H，s)，3.05-3.15(1H，m)，3.33(1H，dd，J＝2.6，6.0Hz)，4.03-4.13(2H，m)，4.27-4.33(0.45H，m)，4.43-4.48(0.55H，m)，4.97-5.07(0.55H，m)，5.16-5.25(0.45H，m)，6.26(1H，s)，7.53(0.45H，s)，7.54(0.55H，s)。
IR(KBr)3406，1760，1682，1605，1385cm -1
Embodiment 36
Figure S2008100051493D01191
A) according to embodiment 1.a) same procedure with (2S)-2-methyl-5-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (160mg, 054mmol) obtain (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (175mg, 52%).
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.10(3H，d，J＝7.1Hz)，1.19(3H，d，J＝6.8Hz)，1.24(3H，d，J＝6.2Hz)，2.09-2.17(1H，m)，2.62-2.70(1H，m)，3.25(1H，dd，J＝3.5，6.2Hz)，3.51-3.61(1H，m)，3.88-3.94(1H，m)，4.17-4.25(2H，m)，4.64-4.88(6H，m)，5.21-5.51(4H，m)，5.91-6.04(2H，m)，6.73-6.76(1H，m)，7.12(1H，s)。
B) according to embodiment 2.b) same procedure with (4R, 5S, 6S)-and 3-[(4-{ (6S)-1-[(allyloxy) carbonyl]-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-(175mg 0.28mmol) obtains (4R, 5S to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-3-(4-[(6S)-the 6-methyl isophthalic acid, 2,5,6-tetrahydrochysene-3-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (70mg, 59%).
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.7Hz)，1.13(3H，d，J＝6.2Hz)，1.31(3H，d，J＝6.4Hz)，2.20-2.31(1H，m)，2.52-2.62(1H，m)，3.14-3.20(1H，m)，3.33-3.37(1H，m)，3.41-3.51(1H，m)，3.96-4.01(2H，m)，4.09-4.15(2H，m)，6.53-6.65(1H，m)，7.41(1H，s)。
IR(KBr)3404，2971，1758，1597，1456，1389，1265，1148，1028，767cm -1
Embodiment 37
Figure S2008100051493D01201
A) according to embodiment 6.a) same procedure with (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (90mg, 0.20mmol) acquisition (4R, 5S, 6S)-3-(4-[(6S)-the 1-[(allyloxy) carbonyl]-6-(hydroxymethyl)-1,2,5,6-tetrahydrochysene-3-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (40mg, 34%).
1H?NMR(300MHz，CDCl 3)δ1.12(3H，d，J＝7.4Hz)，1.33(3H，d，J＝6.2Hz)，2.24-2.33(1H，m)，2.57-2.65(1H，m)，3.27(1H，dd，J＝2.9，6.0Hz)，3.50-3.73(3H，m)，3.89-4.06(1H，m)，4.18-4.31(2H，m)，4.56-4.88(6H，m)，5.22-5.50(4H，m)，5.90-6.05(2H，m)，6.68-6072(1H，m)，7.15(1H，s)。
B) according to embodiment 1.c) same procedure with (4R, 5S, 6S)-3-(4-[(6S)-the 1-[(allyloxy) carbonyl]-6-(hydroxymethyl)-1,2,5,6-tetrahydrochysene-3-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-(40mg 0.053mmol) obtains (4R, 5S to 4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6S)-6-(hydroxymethyl)-1,2,5,6-tetrahydrochysene-3-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (16.9mg, 54%).
1H?NMR(300MHz，D 2O)δ0.94(3H，d，J＝7.5Hz)，1.11(3H，d，J＝6.4Hz)，2.26-2.53(2H，m)，3.09-3.21(1H，m)，3.32-3.35(1H，m)，3.38-3.49(1H，m)，3.57-3.64(1H，m)，3.77-3.83(1H，m)，3.98-4.13(4H，m)，6.52-6.56(1H，m)，7.41(1H，s)。
IR(KBr)3380，2969，1760，1596，1389，1263，1056cm -1
Embodiment 38
A) according to embodiment 1.a) same procedure with (2R)-2-ethyl-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (105mg, 0.34mmol) acquisition (4R, 5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-2-ethyl-1,2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (108mg, 51%).
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，0.91(3H，t，J＝6.7Hz)，1.09(3H，d，J＝7.1Hz)，1.24(3H，d，J＝6.2Hz)，1.41-1.69(2H，m)，2.35-2.42(1H，m)，2.67-2.76(1H，m)，3.24(1H，dd，J＝2.9，6.2Hz)，3.51-3.63(1H，m)，3.70-3.81(1H，m)，4.17-4.24(2H，m)，4.45-4.68(4H，m)，4.70-4.87(2H，m)，5.18-5.50(4H，m)，5.90-6.05(2H，m)，6.64(1H，brs)，7.09(1H，s)。
B) according to embodiment 2.b) same procedure with (4R, 5S, 6S)-and 3-[(4-{ (2R)-1-[(allyloxy) carbonyl]-2-ethyl-1,2,3,6-tetrahydrochysene-4-pyridyl }-1, the 3-thiazol-2-yl) sulfenyl]-4-methyl-7-oxo-6-[(1R)-1-[(three silyls) the oxygen base] ethyl]-(108mg 0.17mmol) obtains (4R, 5S to 1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate, 6S)-3-(4-[(2R)-2-ethyl-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (35mg, 47%).
1H?NMR(300MHz，D 2O)δ0.94(3H，t，J＝7.5Hz)，0.95(3H，d，J＝6.1Hz)，1.12(3H，d，J＝6.2Hz)，1.59-1.81(2H，m)，2.35-2.46(1H，m)，2.72-2.81(1H，m)，3.13-3.22(1H，m)，3.25-3.37(2H，m)，3.76-3.80(2H，m)，4.08-4.14(2H，m)，6.37-6.40(1H，m)，7.46(1H，s)。
IR(KBr)3248，2969，1760，1599，1392，1264，1028cm -1
Embodiment 39
A) according to embodiment 1.a) same procedure with (2R)-2-(chloro methyl)-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (150mg, 0.45mmol) acquisition (4R, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (140mg, 47%).
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.13(3H，d，J＝7.1Hz)，1.23(3H，d，J＝6.2Hz)，2.71-2.76(2H，m)，3.25(1H，dd，J＝2.9，6.0Hz)，3.45-3.63(3H，m)，3.76-3.91(1H，m)，4.18-4.26(2H，m)，4.45-4.88(6H，m)，5.22-5.50(4H，m)，5.90-6.04(2H，m)，6.68(1H，br?s)，7.15(1H，s)。
B) according to embodiment 2.b) same procedure with (4R, 5S, 6S)-3-(4-[(2R)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-[(1R)-1-[(three silyls) the oxygen base] ethyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (140mg, 0.21mmol) acquisition (4R, 5S, 6S)-3 (4-[(2R)-2-(chloro methyl)-1,2,3,6-tetrahydrochysene-4-pyridyl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (51mg, 52%).
1H?NMR(300MHz，D 2O)δ1.02(3H，d，J＝7.1Hz)，1.19(3H，d，J＝6.4Hz)，2.64-2.82(2H，m)，3.19-3.28(1H，m)，3.40-3.43(1H，m)，3.69-4.00(5H，m)，4.13-4.20(2H，m)，6.47-6.50(1H，m)，7.51(1H，s)。
IR(KBr)3412，2968，1758，1600，1393，1264，1028cm -1
Embodiment 40
Figure S2008100051493D01241
A) according to the same procedure of embodiment 14, with (2R)-2-{[(2-aminocarboxyl) the oxygen base] methyl }-4-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester (503mg, 1.42mmol) acquisition (4R, 5S, 6S)-and 3-{[4-((2R)-2-{[(aminocarboxyl) oxygen base] methyl }-1,2,3,6-tetrahydrochysene-4-pyridyl)-and 1,3-thiazoles-2-yl] sulfenyl }-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (19mg, 3%).
1H?NMR(300MHz，D 2O)δ0.95(3H，d，J＝7.3Hz)，1.12(3H，d，J＝6.0Hz)，2.49-2.92(2H，m)，3.14-3.20(1H，m)，3.33-3.35(1H，m)，3.82-3.85(2H，m)，4.08-4.23(2H，m)，4.30-4.37(1H，m)，6.39-6.42(1H，m)，7.46(1H，s)。
IR(KBr)3406，2969，1759，1728，1602，1391，1264，1087cm -1
Reference example 22
Figure S2008100051493D01251
A) at room temperature, 1-allyl group 3-methyl (2S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-1, (1.29g adds triphenylphosphine (1.35g) in tetracol phenixin 4.28mmol) (16ml) solution to the 3-dicarboxylic ester, and mixture heating up was refluxed 6 hours.Insolubles is dissolved in chloroform, solvent removed in vacuo.Resistates is purified with silica gel (150g) column chromatography (hexane/ethyl acetate 4/1 → 2/1) and is obtained 1-allyl group 3-methyl (2S)-2-(chloro methyl)-2, the 5-dihydro-] H-pyrroles-1,3-dicarboxylic ester (268mg, 24%).
1H?NMR(300MHz，CDCl 3)δ3.70(3H，s)，3.92-4.06(2H，m)，4.17-4.38(2H，m)，4.52-4.58(2H，m)，5.00-5.07(1H，m)，5.11-5.17(1H，m)，5.18-5.25(1H，m)，5.76-5.92(1H，m)，6.81-6.88(1H，m)。
B) according to reference example 2.d) same procedure with 1-allyl group 3-methyl (2S)-2-(chloro methyl)-2; 5-dihydro-1H-pyrroles-1; 3-dicarboxylic ester (268mg; 1.03mmol) acquisition (2S)-3-(chloro ethanoyl)-2-(chloro methyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (86mg, 30%).
1H?NMR(300MHz，CDCl 3)δ3.98-4.03(1H，m)，4.09-4.34(1H，m)，4.37-4.61(4H，m)，4.63-4.68(2H，m)，5.22-5.36(3H，m)，5.88-6.02(1H，m)，6.95-7.03(1H，m)。
C) according to reference example 2.e) same procedure with (2S)-3-(chloro ethanoyl)-2-(chloro methyl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (86mg; 0.31mmol) acquisition (2S)-2-(chloro methyl)-3-(2-sulfydryl-1; 3-thiazole-4-yl)-2; 5-dihydro-1H-pyrroles-1-allyl carboxylate (87mg, 89%).
1H?NMR(300MHz，CDCl 3)δ3.73-3.80(1H，m)，4.26-4.43(1H，m)，4.62-4.68(4H，m)，5.24-5.38(4H，m)，5.89-6.02(1H，m)，6.48-6.54(2H，m)。
Embodiment 41
Figure S2008100051493D01261
A) according to embodiment 1.a) same procedure with (2S)-2-(chloro methyl)-3-(2-sulfydryl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate (87mg, 0.27mmol) acquisition (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (30mg, 17%).
1H?NMR(300MHz，CDCl 3)δ0.12(9H，s)，1.08(3H，d，J＝7.1Hz)，1.24(3H，d，J＝6.1Hz)，3.24(1H，dd，J＝2.9，6.6Hz)，3.42-3.51(1H，m)，4.07-4.24(4H，m)，4.35-4.44(2H，m)，4.66-4.88(4H，m)，5.23-5.38(4H，m)，5.47(1H，qd，J＝1.5，17.2Hz)，5.91-6.05(2H，m)，6.45(1H，br)，7.38(1H，s)。
B) according to embodiment 2.b) same procedure with (4R, 5S, 6S)-3-(4-[(2S)-the 1-[(allyloxy) carbonyl]-2-(chloro methyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-4-methyl-7-oxo-6-{ (1R)-1-[(three silyls) the oxygen base] ethyl }-1-azabicyclo [3.2.0] hept-2-ene"-2-allyl carboxylate (30mg, 0.047mmol) acquisition (4R, 5S, 6S)-3-(4-[(2S)-2-(chloro methyl)-2,5-dihydro-1H-pyrroles-3-yl]-1, the 3-thiazol-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (3.0mg, 14%).
1H?NMR(300MHz，D 2O)δ0.92(3H，d，J＝7.5Hz)，1.11(3H，d，J＝6.4Hz)，3.12-3.19(1H，m)，3.32-3.36(1H，m)，3.94-4.11(6H，m)，5.18(1H，br)，6.41(1H，br)，7.64(1H，br)。
IR(KBr)3418，2968，1758，1602，1394，1280，1029cm -1
Embodiment 42
Figure S2008100051493D01271
A) according to the same procedure of embodiment 22 with 1-allyl group 3-methyl (2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrroles-1, the 3-dicarboxylic ester obtains (2R)-2-(chloro methyl)-3-(2-sulfydryl-1,3-thiazoles-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate.Same procedure according to embodiment 41 obtains (4R then, 5S, 6S)-3-(4-[(2R)-2-(chloro methyl)-2,5-dihydro-1H-pyrroles-3-yl]-1,3-thiazoles-2-yl } sulfenyl)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
Embodiment 43
Figure S2008100051493D01281
A) according to the same procedure of reference example 8 with (2R)-2-(hydroxymethyl)-3-(2-sulfydryl-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate obtains (2R)-2-{[(aminocarboxyl) the oxygen base] methyl }-3-(2-sulfydryl)-1,3-thiazole-4-yl)-2,5-dihydro-1H-pyrroles-1-allyl carboxylate.Same procedure according to embodiment 14 obtains (4R then, 5S, 6S)-and 3-{[4-((2R)-2-{[(aminocarboxyl) oxygen base] methyl }-2,5-dihydro-1H-pyrroles-3-yl)-and 1,3-thiazoles-2-yl] sulfenyl }-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
Embodiment 44
Figure S2008100051493D01282
A) according to the same procedure of reference example 20 with (3R)-3-{[(benzyloxy) carbonyl] amino-the 4 hydroxybutyric acid tert-butyl ester obtains (2R)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-5-(2-sulfenyl-1,3-thiazole-4-yl)-3,6-dihydro-1 (2H)-pyridine carboxylic acid allyl ester.Same procedure according to embodiment 37 obtains (4R then, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-3-(4-[(6R)-6-(hydroxymethyl)-1,2,5,6-tetrahydrochysene-3-pyridyl]-1,3-thiazoles-2-yl } sulfenyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
Industrial applicability
The present invention can provide gram-positive bacterium, especially MRSA and MRCNS be had The beta-Lactam antibiotic of excellent antibacterial activity.

Claims (22)

1. the 'beta '-lactam compounds of a following formula [1] or its pharmacy acceptable salt or non-toxic ester:
Figure S2008100051493C00011
R wherein 1Low alkyl group for low alkyl group or hydroxyl replacement; R 2Be hydrogen atom or low alkyl group; X is Sauerstoffatom, sulphur atom or imino-; M and n independently are that integer 0-4 and m and n sum are 0-4; Y 1Amino, lower alkoxy, low-grade alkyl amino, the carboxyl of optional protection, the optional formamyl that replaces or the optional low alkyl group that replaces for the hydroxyl of halogen atom, cyano group, optional protection, optional protection; Y 2Be hydrogen atom, condition is 1-4 Y 1May reside on the same ring 2 Y 1May reside on the same carbon atom.
2. the 'beta '-lactam compounds of claim 1 or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 2.
3. the 'beta '-lactam compounds of claim 1 or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 3.
4. the 'beta '-lactam compounds of claim 1 or its pharmacy acceptable salt or non-toxic ester, wherein said 'beta '-lactam compounds is the 'beta '-lactam compounds of following formula [1a];
Figure S2008100051493C00012
R wherein 1, R 2, X, m, n, Y 1And Y 2Define as claim 1.
5. the 'beta '-lactam compounds of claim 4 or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 2.
6. the 'beta '-lactam compounds of claim 4 or its pharmacy acceptable salt or non-toxic ester, wherein m and n sum are 3.
7. each 'beta '-lactam compounds or its pharmacy acceptable salt or non-toxic ester of claim 1-6, wherein X is a sulphur atom.
8. each 'beta '-lactam compounds or its pharmacy acceptable salt or non-toxic ester, wherein R of claim 1-6 1Be 1-(R)-hydroxyethyl.
9. the 'beta '-lactam compounds of claim 7 or its pharmacy acceptable salt or non-toxic ester, wherein R 1Be 1-(R)-hydroxyethyl.
10. the 'beta '-lactam compounds of claim 1 or its pharmacy acceptable salt or non-toxic ester, this compound is a following formula: compound:
Figure S2008100051493C00021
11. the 'beta '-lactam compounds of a preparation formula [1] or the method for its salt:
Figure S2008100051493C00022
R wherein 1Low alkyl group for low alkyl group or hydroxyl replacement; R 2Be hydrogen atom or low alkyl group; X is Sauerstoffatom, sulphur atom or imino-; M and n independently are that integer 0-4 and m and n sum are 0-4; Y 1Amino, lower alkoxy, low-grade alkyl amino, the carboxyl of optional protection, the optional formamyl that replaces or the optional low alkyl group that replaces for the hydroxyl of halogen atom, cyano group, optional protection, optional protection; Y 2Be hydrogen atom, condition is 1-4 Y 1May reside on the same ring 2 Y 1May reside on the same carbon atom,
Described method is included in alkali and exists down, makes formula [2] compound:
R wherein 1aThe low alkyl group that the low alkyl group that replaces for low alkyl group, hydroxyl or the hydroxyl of protected radical protection replace, R 2Define the same, R 5Be the blocking group of carboxyl, L is the active ester of hydroxyl,
React with formula [3] compound:
Figure S2008100051493C00032
Wherein m, n, X and Y 1Define the same, Y 3Be hydrogen atom;
Perhaps make thiolate reaction acquisition formula [4] compound of formula [2] compound and formula [3] compound:
Figure S2008100051493C00033
R wherein 1a, R 2, R 5, m, n, X, Y 1And Y 3Define the same,
Appropriate combination is selected from following suitable reactions then: remove R 1aAnd Y 1Hydroxy-protective group, remove Y 1The amido protecting group, remove Y 3The amido protecting group and remove R 5And Y 1Carboxy protective group.
12. a medicinal compositions, described medicinal compositions comprise each 'beta '-lactam compounds or its pharmacy acceptable salt or non-toxic ester of claim 1-10.
13. the medicinal compositions of claim 12, this pharmaceutical composition are antibacterials.
14. the compound of following formula
Y wherein 3Be hydrogen atom, optional low alkyl group or the protecting group that replaces, Y 1, X, m and n such as above-mentioned definition.
15. the compound of following formula
Figure S2008100051493C00042
R wherein aBe the optional low alkyl group that replaces, R bIt for amino protecting group and p 0 or 1 integer.
16. the compound of claim 15, wherein p is 0.
17. the compound of claim 15, wherein p is 0 and R aBe methyl.
18. each compound of claim 15-17, wherein R bBe allyl group oxygen base carbonyl.
19. the compound of following formula
Wherein ALOC is an allyl group oxygen base carbonyl.
20. the compound of following formula
Wherein ALOC is an allyl group oxygen base carbonyl.
21. the compound of following formula
X wherein aFor halogen atom and ALOC are allyl group oxygen base carbonyl.
22. the compound of following formula
Figure S2008100051493C00052
Wherein ALOC is an allyl group oxygen base carbonyl.
CNA2008100051493A 2000-11-08 2001-11-06 Novel beta-lactam compounds and process for producing the same Pending CN101215288A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104546856B (en) * 2013-10-18 2016-11-23 北京北科德源生物医药科技有限公司 A kind of antibacterial application of beta-lactam

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104546856B (en) * 2013-10-18 2016-11-23 北京北科德源生物医药科技有限公司 A kind of antibacterial application of beta-lactam

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