CN101497612A - Novel carbostyrile compound, preparation and use - Google Patents

Novel carbostyrile compound, preparation and use Download PDF

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Publication number
CN101497612A
CN101497612A CNA2009100787711A CN200910078771A CN101497612A CN 101497612 A CN101497612 A CN 101497612A CN A2009100787711 A CNA2009100787711 A CN A2009100787711A CN 200910078771 A CN200910078771 A CN 200910078771A CN 101497612 A CN101497612 A CN 101497612A
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oxygen
carboxylic acid
fluoro
azatropylidene
alkyl
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毕华
冯泽旺
王建航
宋丽洁
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BEIJING HUAXI PHARM Co Ltd
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BEIJING HUAXI PHARM Co Ltd
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Abstract

The invention relates to a carbostyril derivative with excellent antimicrobial activity, which shows excellent antimicrobial activity, also has wide antimicrobial spectrum, and particularly has strong activity against Gram-positive bacteria. The invention also relates a method for preparing the carbostyril derivative, a pharmaceutical composition containing the carbostyril derivative or salt and ester thereof or a solvolyte thereof as an active ingredient, and application of the carbostyril derivative or the salt, the ester or the solvolyte thereof to preparation of medicines used as antimicrobial agents.

Description

Novel carbostyrile compound and preparation thereof and purposes
Technical field
The present invention relates to as medicine, veterinary drug, aquatic products medication and the useful quinolones synthetic antibacterial agents of germ resistance preservatives.That is to say, the present invention relates to the h limit (or g limit) of formula quinolone parent nucleus or be equivalent to its position thick and 6-, 7-, 8-, 9-or 10-unit's ring (shown in (I), (II)).With different to the known quinolones antiseptic-germicide a little less than the gram positive bacterial strain activity, it has shown excellent anti-microbial activity, the pharmacokinetics performance that also has very wide antimicrobial spectrum and improve greatly:
Figure A200910078771D00051
Or
Figure A200910078771D00052
Wherein
R 1Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkylamine, dialkylamine, aryl and the aralkyl that replaces arbitrarily;
R 2, R 3And R 4Each independently is hydrogen atom or Q-R 8Or R 4Be hydrogen atom or Q-R 8, R 2And R 3Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring; Or R 2Be hydrogen atom or Q-R 8, R 3And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
Q is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replaces arbitrarily;
R 8Be hydrogen atom, NR 9R 10Or the alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replace arbitrarily;
R 9And R 10Each independently is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl of hydrogen atom or replacement arbitrarily, or R 9And R 10Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
A is N or CR 6
R 6Alkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl for hydrogen atom or replacement arbitrarily;
B is N or CR 7
R 7Be hydrogen atom, halogen atom, hydroxyl or any alkoxyl group that replaces; Or R 7And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, the assorted naphthenic ring of 5-, 6-or 7-unit;
R 5Be hydrogen atom or any alkyl that replaces;
N is 1,2 or 3;
M is 1,2 or 3;
X is C, N, O or S.
The invention still further relates to the preparation method of formula (I) as defined above or compound or its salt (II), its solvate, with contain formula (I) or compound or its salt (II), its solvate pharmaceutical composition as activeconstituents, and formula (I) or compound or its salt (II), its solvate in preparation as the purposes in the antiseptic-germicide medicine.
Background technology
Gram positive organism is the main pathogenic bacterium that cause multiple disease.Along with antibiotics being extensive use of clinically, its resistance constantly increases, and has become at present one of most thorny issue clinically.Compare with gram-negative bacteria, gram positive organism lacks complicated infiltration mechanism and effluxes passage, thereby antimicrobial therapy is more effective to its infection usually.However, along with streptococcus pneumoniae and staphylococcus, especially methicillin-resistant gold Portugal bacterium (MRSA) is to beta-lactam and the chemical sproof continuous increase of macrolide antibiotics, and the treatment that the gram positive organism sexuality is dyed has become one of important topic that the clinicist need often face.In addition, although make the purulence suis at present to Penicillin antibiotics still sensitivity, to the general resistance of macrolide antibiotics.Enterococcus spp is to the intrinsic resistance of many microbiotic, and developed into drug resistance of vancomycin especially at present.
Quinolone has become and has tackled the most effectively one of antibacterials of many infectious diseases at present clinically.Be the main direction of year quinolone area research surplus in the of nearly ten how in the activity that keeps gram-negative bacteria is improved on the outstanding active basis anti-gram positive organism (particularly staphylococcus and streptococcus pneumoniae).In recent years, the Novel Quinolone kind is come out successively, makes the antimicrobial spectrum of such medicine expand to gram positive organism from traditional gram-negative bacteria thus.Meanwhile, the quinolone persister that is separated to clinically also shows a rising trend.Given this, the research work of developing the quinolones of the low again novel structure of existing anti-gram positive organism clinical efficacy and resistance selectivity extensively launches.
Before more than 40 year, people are surprised to find that at antimalarial drug---isolated a kind of by product has faint activity to some gram-negative bacteria in chloroquine (chloroquine) building-up process.By the structural modification to this by product, first Comprecin was born in 1962---Nalidixic Acid (nalidixic acid).These product have certain clinical efficacy to Grain-negative coccus property urinary tract infections.The seventies in 20th century, W-4565 (oxolinicacid) and pipemidic acid (pipemidic acid), first 7-piperazinyl quinolone) etc. come out one after another.These first-generation quinolones do not have activity to gram positive organism, only limit to treatment clinically by the microbial urinary tract infections of most of Grain-negatives.
To the gram positive organism early stage promise ketone medicine of non-activity almost
As first introduce in the C-6 position fluorine atom quinolone---the anti-microbial activity of flumequine (flumequine) obviously improves.This prompting: the suitable modification to mother nucleus structure perhaps can improve the activity of this class medicine to gram positive organism.Early 1980s, Koga etc. successfully develop the norfloxicin (norfloxacin) with 6-fluoro-7-piperazinyl structure in conjunction with the constitutional features of flumequine and pipemidic acid, and the fluoroquinolone New Times has been opened in the appearance of this medicine.In the period of after this surplus in the of short ten, Pefloxacin (pefloxacin, 6), enoxacin (enoxacin, 7), fleroxacin (fleroxacin, 8), Ciprofloxacin (ciprofloxacin, 9), lomefloxacin (1omefloxacin, 10), Ofloxacine USP 23 (ofloxacin, 11) and levofloxacin a large amount of outstanding kinds such as (levofloxacin, 12) constantly occur, and all inherited the constitutional features of 6-fluoro-7-piperazinyl, some drugs wherein is extensive use of so far clinically.The antimicrobial spectrum of these medicines obviously enlarges, and comprises gram-negative bacteria and gram positive organism, and the absorption in gi tract is good, and the Plasma Concentration height is used to the therapy system sexuality clinically and dyes.These early stage fluoroquinolones have outstanding anti-gram-negative bacteria activity, and streptococcus pneumoniae is only had medium activity, so be not enough to tackle respiratory tract infection; And the bacterial drug resistance that constantly occurs therebetween also makes its activity to golden Portugal bacterium weaken greatly.
Figure A200910078771D00072
Figure A200910078771D00073
Flumequine (4) norfloxicin (5) Pefloxacin (6)
Figure A200910078771D00075
Figure A200910078771D00076
Enoxacin (7) fleroxacin (8) Ciprofloxacin (9)
Figure A200910078771D00077
Figure A200910078771D00078
Figure A200910078771D00079
Enoxacin (10) Ofloxacine USP 23 (11) levofloxacin (12)
Gram positive organism had certain active early stage fluoroquinolones
Pharmaceutical Chemist is to fluoroquinolone parent nucleus C-5, and system has been carried out and structural modification widely in C-7 and C-8 position, and the anti-gram positive organism activity of such medicine is improved constantly.Introducing amino in the C-5 position then is one of structure of modification strategy the earliest.This measure makes that such antibiotic anti-gram positive organism activity is generally improved, as Sparfloxacin (sparfloxacin, 13).The C-5 bit substituent of grepafloxacin (grepafloxacin, 14) is a methyl, and its anti-gram positive organism activity is better than Ciprofloxacin.Said two devices significantly improves the activity of many gram positive organisms (especially streptococcus pneumoniae), and the activity to anerobe also has certain improvement simultaneously.Although it is better than Ciprofloxacin to staphylococcic activity, but still not satisfactory; Its raising to the activity against staphylococci of anti-the quinolones also only has learning value, also is not enough to produce significant clinical meaning.Regrettably, these 2 kinds are all former thereby used or withdraw from market by strict restriction because of toxicology soon after listing.After this Kai Fa 7-methylpiperazine base-8-BAY 128039---Gatifloxacin (gatifloxacin, 15) further improves the active of gram positive organism, simultaneously anti-anaerobic activity also be improved significantly.In recent years, introducing pyrrolidyl in the C-7 position makes such medicine significantly improve the activity of gram positive organism, as Clinafloxacin (clinafloxacin, 16), Tosulfloxacin (tosufloxacin, 17), Sitafloxacin (sitafloxacin, 18) and gemifloxacin (gemifloxacin, 19) demonstrated fully this constitutional features.In addition, introduce the dicyclo amido in the C-7 position, as Moxifloxacin (moxifloxacin, 20) and trovafloxacin (trovafloxacin, 21), its anti-gram positive organism activity is significantly improved, lipotropy obviously strengthens, and the transformation period obviously prolongs.
Other position substituting groups are optimized C-6 fluorine atom (it is relevant with genotoxicity that this fluorine atom is considered to) that makes on the removal fluoroquinolone parent nucleus become possibility, and the quinolones of new generation that has been born thus, be non-fluoroquinolones or go fluoroquinolones, its first representative is Jia Nuosha star (garenoxacin, BMS-284756, T-3811ME, 22).One of constructional feature of these product is that its C-8 bit substituent is a difluoro-methoxy, is not methoxyl group, and it is relevant with this substituent introducing that the improvement of its bacteriostatic activity and fungicidal activity is considered to.The Jia Nuosha star is effective especially to the gram positive coccus that comprises golden Portugal bacterium, is that its activity is better than Ciprofloxacin, Ofloxacine USP 23, levofloxacin and Moxifloxacin to the quinolone antibiotic of methicillin-sensitivity and resistance activity against staphylococci the best.
Figure A200910078771D00081
Husky star (13) grepafloxacin (14) Gatifloxacin (15) Clinafloxacin (16) of handkerchief
Figure A200910078771D00082
Figure A200910078771D00083
Figure A200910078771D00084
Tosulfloxacin (17) Sitafloxacin (18) Gu Misha star (19)
Figure A200910078771D00085
Figure A200910078771D00086
Figure A200910078771D00087
Moxifloxacin (20) trovafloxacin (21) Jia Nuosha star (22)
Gram positive organism had outstanding active Novel Quinolone class medicine
The basic structure of quinolone drug effect group is 1,4 dihydro-4-oxo pyridine-3-carboxylic acid, its C-5, the thick and aromatic ring in C-6 position.Has R on the nitrogen-atoms of 1-position 1, substituting group is essential by anti-microbial activity, and C-3 position carboxyl and C-4 position carbonyl are considered to most important with combining of DNA to the quinolone molecule, do not see as yet that so far these 2 positions connect other feasible substituent reports.So it also is that anti-microbial activity is necessary that C-3 position carboxyl and C-4 position carbonyl are considered to.Very approaching in view of C-2 position and combining site, this connects any substituting group all will hinder the quinolone molecule undoubtedly near target site and cause its active reduction.
In recent years, the Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly, by to N-1 on the parent nucleus, C-5, C-6, the structure of modification of C-7 and C-8 bit substituent and ingenious collocation have obtained the active quinolone antibiotic that obviously improves to gram positive organism, thereby improve the activity of its anti-gram positive organism.
To N-1 bit substituent structure of modification.Prior art studies show that the substituting group on the quinolone parent nucleus N-1 position is necessary for hydrophobic group, because it is not only controlling the overall activity of quinolone, and its pharmacokinetics character is also had certain influence.Cyclopropyl is one of best substituting group on this of generally acknowledging so far, N one 1 bit substituents of great majority quinolones that gone on the market and that researching and developing are cyclopropyl, as Ciprofloxacin, Sparfloxacin, grepafloxacin, Gatifloxacin, Clinafloxacin, gemifloxacin, Moxifloxacin and Jia Nuosha star.In addition, connect on the N-1 position cyclopropyl of Sitafloxacin a fluorine atom [suitable-(1R, 2s)-2-fluorine cyclopropyl], and also can improve its activity during this 2,4 difluorobenzene base, as Tosulfloxacin and trovafloxacin to gram positive organism and anerobe.The another kind that Ofloxacine USP 23 and levofloxacin have embodied on this position replaces form, promptly introduces a condensed ring by N-1 and C-8 position and forms the parent nucleus that three ring a pair of horses going side by sides are closed, and its oxygen heterocyclic 3-position connects methyl.This structure is that of cyclopropyl successfully substitutes group, but the activity of its S-isomer (levofloxacin) is 100 times of corresponding R-isomer.
To C-5 bit substituent structure of modification.Studies show that when the bigger substituting group (as halogen and methoxyl group) of volume was introduced in the C-5 position, the active of quinolone significantly reduced, may be such group with the active combining site of C-3 and C-4 position between have the event that interacts; And the substituting group of medium volume then can obviously improve its external activity to gram positive organism as the introducing of amino (Sparfloxacin), methyl (grepafloxacin) or hydroxyl etc.Though the substituting group on this position is believed to be helpful in the anti-gram positive organism activity of quinolones, but its influence also will be depended on N-1 to a great extent, substituting group on C-7 and the C-8 position, because its C-5 position of nearly all quinolone (as Ciprofloxacin, Ofloxacine USP 23, levofloxacin, Gatifloxacin, Clinafloxacin, Sitafloxacin, gemifloxacin, Moxifloxacin, trovafloxacin and Jia Nuosha magnitude) only connects a hydrogen atom, wherein a lot of N-1 bit substituents is a cyclopropyl, but the activity of their anti-gram positive organisms is far from each other.Wherein, the anti-microbial activity of Clinafloxacin, Sitafloxacin, gemifloxacin, Moxifloxacin and Jia Nuosha star obviously is better than other quinolones.This shows the result that the anti-gram positive organism activity of quinolones is substituting group comprehensive action on each position.
To C-6 bit substituent structure of modification.The anti-microbial activity that fluorine atom can obviously strengthen quinolone is introduced in the C-6 position.Obtained first fluoroquinolone one flumequine by introducing fluorine atom to parent nucleus C-6 position, the success of this research has disclosed the anti-gram positive organism activity that is expected to improve such medicine by the transformation to the basic structure of quinolone first.The introducing of C-6 position fluorine atom has significantly strengthened the quinolone molecule to the restraining effect of dna gyrase and to the perviousness of bacterial cell, therefore being considered to quinolone, to have an outstanding anti-microbial activity necessary, so, the most basic mother nucleus structure of such drug research during the 6-fluoroquinolone has just become subsequently surplus in the of 20 year.Simultaneously, the 6-that also occurs recent years goes fluoroquinolone to cause people's very big concern.Preliminary study result shows that compare with corresponding fluoroquinolone, 6-goes the genotoxicity level of fluoroquinolone to obtain reduction.It is reported that the outstanding representative one Jia Nuosha star of non-fluoroquinolone all is better than new fluoroquinolone Moxifloxacin to the activity of susceptibility and resistance gram positive organism.According to another report, 6-nitro and 6-aminoquinolone have better activity to gram positive coccus.For the 6-aminoquinolone, its overall active substituting group that depends on to a great extent on C-7 and the C-8 position.The active determination in vitro result shows that similar to fluoroquinolone, methyl or methoxy is introduced in the C-8 position of 6-nitro and 6-aminoquinolone can improve its anti-gram positive organism activity.
C-7 bit substituent structure of modification.The antimicrobial spectrum of C-7 bit substituent and quinolone, bioavailability and untoward reaction etc. are closely related.Cyclammonium base (as piperazinyl and pyrrolidyl) is that modal substituting group is gone up in this position.The piperazinyl quinolone of non-replacement (as norfloxicin, enoxacin or Ciprofloxacin) has outstanding activity to gram-negative bacteria, and can improve its oral absorption and anti-gram positive organism activity simultaneously when introducing methyl on the piperazine ring, but the active raising of anti-gram positive organism is accompanied by sometimes to the active reduction of Pseudomonas aeruginosa.C-7 bit substituent as Pefloxacin, fleroxacin, Ofloxacine USP 23 and levofloxacin is a 4-methylpiperazine base, the C-7 bit substituent of lomefloxacin, grepafloxacin and Gatifloxacin is a 3-methylpiperazine base, the C-7 bit substituent of Sparfloxacin is 3,5 lupetazin bases.Above-mentioned these 7-methylpiperazine base quinolones and other 7-piperazinyl quinolones compare gram positive organism and all have higher activity, and be sure of because it has the event of stronger perviousness to bacterial cell.
Another kind of common C-7 bit substituent is the amino-pyrroles alkyl, the introducing of this group often makes quinolone stronger than the anti-gram positive organism activity of corresponding 7-piperazinyl quinolone, and not only can improve its anti-gram positive organism activity when on pyrrolidine ring, introducing methyl, and help to overcome some physical properties of quinolones and the deficiency of pharmacokinetics properties.The C-7 bit substituent of Clinafloxacin and Tosulfloxacin is 3-amino-pyrroles alkyl, and the C-7 bit substituent of Sitafloxacin is spiral shell-amino-pyrroles alkyl, and the C-7 bit substituent of gemifloxacin is 3-aminomethyl-4-methoxy imino-1-pyrrolidyl.Wherein the anti-streptococcus pneumoniae activity of gemifloxacin is significantly improved.The C-7 bit substituent of DW286 (23, the gemifloxacin analogue) is 3-aminomethyl-3-methyl-4-methoxyimino-1-pyrrolidyl, and promptly at methyl of the extra introducing in the 3-position of gemifloxacin side chain, its anti-gram positive organism activity is better than gemifloxacin.The size of the alcoxyl imido grpup on the pyrrolidine ring of C-7 position and lipotropy have remarkably influenced to the anti-microbial activity and the pharmacokinetics character of fluoroquinolone.Along with the increase of alkyl, anti-gram positive organism activity also strengthens thereupon, but the activity of anti-gram-negative bacteria reduces.After macoradical (as benzyl etc.) substituted the alkyl in the alcoxyl imido grpup, though still can keep anti-microbial activity, its pharmacokinetics character and physics and chemistry flight of steps leading to a palace hall matter were then barely satisfactory.
Pyrrolidine ring thick again and or screw togather a ring and form 7-dicyclo amido fluoroquinolone, these Wyovins all can be regarded the derivative of tetramethyleneimine as.Wherein, the C-7 position side chain of Moxifloxacin is the diazabicyclo structure, the side chain of trovafloxacin and CFC-222 (24) is the azabicyclo structure that is connected with an amino, and the side chain of Sitafloxacin is the twin nuclei that screws togather a cyclopropyl in the 4-position of 3-amino-pyrrolidine.The C-7 position side chain that adds new fluoroquinolone such as Clinafloxacin, Tosulfloxacin and gemifloxacin in addition all contains a tetramethyleneimine skeleton, and they generally have very outstanding anti-microbial effect to gram positive organism.
Figure A200910078771D00101
Go in the fluoroquinolone at 6-, the C-7 position side chain of PGE9262932 (25) and PGE4175997 (26) is 3-aminoalkyl-1-pyrroles's cyclic group, the two is similar to trovafloxacin, all has broad spectrum antibiotic activity, its anti-gram positive organism activity is stronger than trovafloxacin, but to the activity of enterobacteriaceae a little less than trovafloxacin.The Jia Nuosha star is different with the structure of fluoroquinolones and above-mentioned 2 non-fluoroquinolones, its C-7 position side chain is not that cyclammonium base but one are contained the pulsating 5-isoindoline of aromatic structure base, this compound is keeping gram-negative bacteria on the outstanding active basis, to a lot of gram positive organisms, especially streptococcus pneumoniae had very outstanding anti-microbial activity.
Figure A200910078771D00111
PGE9262932(25) PGE4175997(26)
From the composition optimizes angle analysis, the 7-cyclammonium base of quinolone has very big modification space, and the position that allows in the quinolone molecule to connect macoradical also has only the C-7 position.For example, the 4-position N of 7-piperazine ring goes up the quinolone series that connects macoradical and has potential anti-microbial activity (particularly to gram positive organism), and some compound wherein is better than its parent compound 7-piperazinyl quinolone to staphylococcic activity.Think that in view of the above the macoradical that the C-7 position connects does not hinder the infiltration of quinolone molecule to bacterial cell.As everyone knows, the character of C-7 bit substituent is to influence the bioactive important factor of quinolone, this class N-substituted piperazinyl quinolone to the activity of gram positive organism why make moderate progress may be have the quinolone molecule of this structure easier in gram positive organism, accumulate so.
To C-8 bit substituent structure of modification.The naphthyridines ketone (as Tosulfloxacin, gemifloxacin and trovafloxacin) that the quinolone (as Ciprofloxacin and grepafloxacin) of many C-8 position unsubstituted and C-8 position are nitrogen-atoms has good anti-gram positive organism activity.The C-8 bit substituent has certain influence to the oral pharmacokinetics character that changes quinolone, the aspects such as selectivity that enlarge antimicrobial spectrum and reduction medicament-resistant mutation.Halogen atom is introduced in the C-8 position, methyl or methoxy can improve quinolones to the gram positive coccus external activity of (even comprising early stage fluoroquinolone persister), simultaneously anerobe is also demonstrated good antibacterial activity.Studies show that in early days, fluoro (as lomefloxacin and Sparfloxacin) and chloro (as Clinafloxacin and Sitafloxacin) are the best C-8 bit substituents that improves the quinolones anti-microbial activity, but also there are phototoxicity and some unacceptable untoward reaction simultaneously, so present people have abandoned the halogenated new drug layout strategy of 8-.Subsequently, not only strengthened activity, made phototoxicity and cytotoxicity reduce to bottom line again gram positive organism and anerobe by a large amount of 8-BAY 128039s of researching and developing out (Gatifloxacin and Moxifloxacin).
In recent years, the Novel Quinolone of succeeding in developing successively constantly improves to the activity of gram positive organism, and this might make the dream of " chemical sproof development is led in the exploitation of new drug " come true in the near future.Structure activity study shows, by structure of modification to quinolone, C-6 particularly, the modification of C-7 and C-8 bit substituent, can increase medicine action target spot number on the topoisomerase II in bacterial cell, weaken the effect of efflux protein (efflux pump) simultaneously, thereby reduce the frequency of occurrences of quinolone resistance gram-positive bacterial strain.
Though the Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly, in the hope of passing through to N-1 on the parent nucleus, C-5, C-6, the structure of modification of C-7 and C-8 bit substituent and ingenious collocation, thereby obtain the active quinolone antibiotic that obviously improves, to improve the activity of its anti-gram positive organism to gram positive organism.But on the h limit (or g limit) of quinolone parent nucleus or be equivalent to its position carbostyril compound thick and 6-, 7-, 8-, 9-or 10-unit ring and do not see any research and report as yet.
Therefore, under these backgrounds, based on above prior art, investigator of the present invention has carried out extensive studies, by on the h limit (or g limit) of quinolone parent nucleus or be equivalent to its position thick and 6-, 7-, 8-, 9-or 10-unit ring, and measure the pharmacologically active of formed compound, come the carbostyril compound of Development of New Generation, they comprise that to the wide spectrum pathogenic bacterium endurance strain demonstrates the intensive anti-microbial activity, also have further improved pharmacokinetics performance.The result, our early start works out and has found the h limit (or g limit) at the quinolone parent nucleus or is equivalent to general formula (I) or compound or its salt (II) or the solvate that its position is thick and 6-, 7-, 8-, 9-or 10-unit encircle, they demonstrate the intensive anti-microbial activity, and it is a compound as safe as a house, and has finished the present invention thus.
Summary of the invention
Infectious diseases is second the disease killer who threatens human health.Resistance still constantly occurs, and increases in hospital and community, has reduced patient's treatment and has selected, and has increased hospital stays and medical expense.As a result, need to substitute and improve antibacterials and treat the resistance pathogenic bacteria.
Quinolones is the synthetic drugs of a class wide spectrum, efficient, low toxicity.Early stage quinolones has stronger anti-microbial activity to Gram-negative bacteria, but lower to gram-positive bacteria activity.Though Shang Shi quinolones such as Gatifloxacin (Drug recently, 1999,683) and Moxifloxacin (external medicine-microbiotic fascicle 58 (4):, 2002,23 (6): anti-microbial activity 274) makes moderate progress, the activity of resisting gram-positive bacteria remains further to be strengthened, and needs to strengthen the anti-microbial activity to some specific bacteria such as streptococcus pneumoniae, faecalis etc. simultaneously but in general.Therefore, the higher medicine of validity appears in expectation clinically.In addition, known owing to take side effects such as the side effect of bringing out spasm or phototoxicity with non-steroidal anti-inflammatory drugs, also need to develop the higher quinolones synthetic antibacterial agents of security.
Have now found that the Carbostyril derivative of some replacement and its pharmaceutically acceptable salt and ester are as antimicrobial compounds, particularly resisting gram-positive and negative bacterium.
The invention provides formula (I) or compound (II), or its pharmaceutically acceptable salt or solvate
Figure A200910078771D00121
Or
Figure A200910078771D00122
Wherein:
R 1Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkylamine, dialkylamine, aryl and the aralkyl that replaces arbitrarily;
R 2, R 3And R 4Each independently is hydrogen atom or Q-R 8Or R 4Be hydrogen atom or Q-R 8, R 2And R 3Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring; Or R 2Be hydrogen atom or Q-R 8, R 3And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
Q is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replaces arbitrarily;
R 8Be hydrogen atom, NR 9R 10Or the alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replace arbitrarily;
R 9And R 10Each independently is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl of hydrogen atom or replacement arbitrarily, or R 9And R 10Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
A is N or CR 6
R 6Alkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl for hydrogen atom or replacement arbitrarily;
B is N or CR 7
R 7Be hydrogen atom, halogen atom, hydroxyl or any alkoxyl group that replaces; Or R 7And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, the assorted naphthenic ring of 5-, 6-or 7-unit;
R 5Be hydrogen atom or any alkyl that replaces;
N is 1,2 or 3;
M is 1,2 or 3;
X is C, N, O or S.
As defined above, have excellent anti-microbial activity, wide antimicrobial spectrum and superior pharmacokinetics performance, in formula (I) or the compound (II), alkyl (except as otherwise noted) both can be that linear alkyl also can be a branched-chain alkyl, can comprise 1～12 carbon atom, preferably contain 1～6 carbon atom, especially preferably contain 1～4 carbon atom.Most preferred alkyl is methyl, ethyl, propyl group and butyl, especially most preferable and ethyl.Thiazolinyl (except as otherwise noted) both can be that linear thiazolinyl also can be a branched-chain alkenyl, can comprise 2～12 carbon atoms, preferably contained 2～6 carbon atoms, especially preferably contained 2～4 carbon atoms.Most preferred thiazolinyl comprises vinyl, propenyl and butenyl.When alkyl is the part (as the moieties of aralkyl) of other group, preferably contain 1～6 carbon atom, especially preferably contain 1～4 carbon atom.Most preferred moieties is methyl and ethyl.
Aryl can be the hydrocarbon group of fragrance arbitrarily and comprise 6～24 carbon atoms, preferably contains 6～18 carbon atoms, more preferably contains 6～16 carbon atoms, especially preferably contains 6～14 carbon atoms, especially preferably contains 6～10 carbon atoms.Most preferred aryl comprises phenyl, naphthyl, anthryl, phenanthryl, pyrans, especially most preferably phenyl or naphthyl, especially most preferably phenyl.When aryl is the part (as the aryl moiety of aralkyl) of other group, preferred phenyl, naphthyl, phenanthryl or pyrans, preferred especially phenyl or naphthyl, especially preferred phenyl.
Aralkyl can be the alkyl that is replaced by aryl arbitrarily.Aralkyl preferably contains 7～30 carbon atoms, more preferably contains 7～24 carbon atoms, especially preferably contains 7～18 carbon atoms, especially preferably contains 7～11 carbon atoms, and most preferred aralkyl is a phenmethyl, menaphthyl, anthracene methyl, luxuriant and rich with fragrance methyl and pyrans methyl.Especially most preferably phenmethyl.
Cycloalkyl can be any saturated ring-type hydrocarbon group, contains 3～12 carbon atoms, preferably contains 3～8 carbon atoms, especially preferably contains 3～6 carbon atoms.Most preferred cycloalkyl is cyclopropyl, cyclopentyl and cyclohexyl, especially most preferably cyclopropyl.
Heteroaryl can be the monocycle or the polycyclic system of fragrance arbitrarily, contains at least one heteroatoms.Preferably, heteroaryl is 5-to a 18-unit aromatic nucleus system, the first aromatic nucleus system of preferred especially 5-to 14-, and the first aromatic nucleus system of especially preferred 5-to 10-contains at least one heteroatoms, is selected from oxygen, sulphur and nitrogen-atoms.Most preferred heteroaryl comprises pyridyl, pyranyl, mercapto pyranyl, pyrryl, furyl, thienyl, indyl, pseudoindoyl, indolizine base, imidazolyl, pyriconyl, pyrans ketone group, pyrimidyl, pyrazinyl, oxazolyl, thiazolyl, purine radicals, quinolyl, isoquinolyl, quinoxalinyl, pyridazinyl, benzofuryl, benzoxazolyl and acridyl.Most preferred especially heteroaryl comprises pyridyl, thienyl and furyl, especially most preferably 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 2-furyl.
Heterocyclic radical can be monocycle or polycyclic system arbitrarily, contains at least one heteroatoms, can unsaturated or fractional saturation or saturated fully.The term here " heterocycle " comprises above-mentioned heteroaryl and nonaromatic heterocycles base.Preferred heterocyclic radical is 3-to a 18-unit member ring systems, more preferably 3-to 14-unit member ring systems, especially preferably 3-to 10-unit member ring systems, the first member ring systems of more preferred 3-to 6-, especially the first member ring systems of preferred 5-to 6-contains at least one heteroatoms, is selected from oxygen, sulphur and nitrogen-atoms.Most preferred heterocyclic group comprises the heteroaryl of above-mentioned name, and pyranyl, piperidyl, pyrrolidyl, indolinyl, iso-dihydro-indole-group, alkyl dioxin, piperazinyl, morpholinyl, mercapto are for morpholinyl, morpholine sulfonic group, tetrahydro isoquinolyl and tetrahydrofuran base.
Heterocyclylalkyl can be the alkyl that is replaced by heterocyclic radical arbitrarily.Preferred heterocyclic moiety is the above-mentioned heterocyclic radical of 3-to 18-unit, more preferably the above-mentioned heterocyclic radical of 3-to 14-unit, the especially preferably above-mentioned heterocyclic radical of 3-to 10-unit, the especially preferably above-mentioned heterocyclic radical of 5-to 10-unit; Moieties is C 1-6Alkyl, preferred C 1-4Alkyl, especially preferable methyl.
Be optionally substituted when aforementioned substituting group is designated as, arbitrarily the substituting group that occurs can be arbitrary or a plurality of normally used substituting group in medicament research and development and/or for a change active, stability, bioavailability or other characteristic and in the modified compound structure.These substituting groups comprise halogen atom, nitro, cyano group, hydroxyl, cycloalkyl, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino radical, di alkylamino group, formyl radical, carbalkoxy, carboxyl, aldehyde radical, alkane sulfydryl, alkyl sulphinyl, alkyl sulphonyl, alkyl azochlorosulfonate, carbamyl, alkylamino radical, aryl and aralkyl.
When aforesaid any substituting group representative or comprise an alkyl substituent, this alkyl substituent can be line style or branched chain type and contain 1～12 carbon atom, preferred 1～6 carbon atom, most preferably 1～4 carbon atom.Cycloalkyl can comprise 3～8 carbon atoms, preferred 3～6 carbon atoms.Aryl or aryl moiety can contain 6～10 carbon atoms, preferred phenyl.Halogen atom can be fluorine, chlorine, bromine or iodine atom and any group that comprises halogen atom, as alkylhalide group, can comprise any or a plurality of halogen atom.
Preferred substituting group arbitrarily comprises halogen atom, nitro, cyano group, hydroxyl, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Halogenated alkoxy, amino, C 1-6Alkylamino radical, two (C 1-6Alkyl) amido, formyl radical, C 1-6Carbalkoxy, carboxyl, C 1-6Aldehyde radical, C 1-6Alkane sulfydryl, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, carbamyl, C 1-6Alkylamino radical.Preferred any substituting group comprises halogen atom, nitro, cyano group, hydroxyl, C 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl group, C 1-4Halogenated alkoxy.Halogen atom most preferably.
Formula of the present invention (I) or compound (II) can form pharmacy acceptable salt or solvate, these salt comprise the salt with inorganic salt example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc., salt with organic carboxyl acid such as acetate, trifluoroacetic acid, lemon calculation, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid, or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc., and with common known and conventional other sour salt that are used for the carbostyril compound technical field.These sour additive salt of conversion processes routinely.
Second aspect the invention still further relates to the preparation method of formula (I) or compound (II).
Formula (I) compound is according to preparation shown in following reaction scheme 1 or the reaction scheme 2.
Reaction scheme 1
Figure A200910078771D00151
(IV) (IV-a) (IV-b)
Figure A200910078771D00152
(II)
Reaction scheme 2
Figure A200910078771D00161
(VI) (VI-a) (VI-b)
Figure A200910078771D00162
(VI-c) (II)
Wherein: R 1, R 2, R 3, R 4, R 5, A, B, n, m respectively as defined above.
Shown in reaction scheme 1, be used for preparation formula (I) or (II) method of compound comprise the following steps:
1) formula (III) or (IV) compound and EMME carry out condensation, obtain formula (III-a) or (IV-a) compound, wherein R 11Represent methylidene or ethyl;
2) formula (III-a) or (IV-a) compound and X-R 1Condensation under alkaline condition obtains formula (III-b) or (IV-b) compound, and wherein X is a halogen atom, is preferably bromine atoms or iodine atom;
3) formula (III-b) or (IV-b) compound under alkaline condition through hydrolysis or HOR 5Alcoholysis obtains formula (I) or (II) compound.
Shown in reaction scheme 2, be used for preparation formula (I) or (II) method of compound comprise the following steps:
1) formula V or (VI) reaction of compound and barkite obtain formula (V-a) or (VI-a) compound, wherein R 12Represent methylidene or ethyl;
2) formula (V-a) or (VI-a) compound successively with ortho-formiate and NH 2R 1Reaction obtains formula (V-b) or (VI-b) compound;
3) with formula (V-b) or (VI-b) compound obtain formula (V-c) or (VI-c) compound at alkaline condition ShiShimonoseki ring;
4) with formula (V-c) or (VI-c) compound hydrolysis or HOR 5Alcoholysis obtains formula (I) or (II) compound.
In following preparation example, will more specifically explain above-mentioned synthetic method.
The third aspect, the present invention also provide contain as defined above formula (I) or (II) compound or its pharmaceutically acceptable salt or solvate as activeconstituents, and the antimicrobial compound of pharmaceutically acceptable carrier.When this combination is used for clinical purpose, but through type (I) or (II) compound or its pharmaceutically acceptable salt or solvate combine with pharmaceutically acceptable carrier and it be made into oral, non-stomach and intestine use or local solid, semisolid or the liquid pharmaceutical formulation that uses.
Specific embodiment
Synthetic
The invention compound comprises its salt, hydrate and solvate, can use known method or with process preparation like the known class, as use following reaction scheme.The professional and technical personnel will find to change or revise inessential parameter to reach equifinality.
For example
Following example only is used to illustrate the present invention, is not used in qualification the present invention.
Embodiment 1
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
A) under 0 ℃ to Diisopropylamine (86.4ml, splash in tetrahydrofuran (THF) 616.0mmol) (1.1L) solution n-Butyl Lithium hexane solution (2.5M, 246.4ml, 616.0mmol).Drip to finish, be cooled to-78 ℃, in 10min, add the 3-bromofluorobenzene (107.8g 616.0mmol), continues to stir 1h, in 5min, splash into DMF (53.5ml, 687.5mmol).Reaction mixture adds Glacial acetic acid (55ml) and distilled water (1.93L) after continuing to stir 10min, rises to room temperature, uses twice of ether extraction.Mixed extract is used distilled water, 0.2N hydrochloric acid soln, saturated common salt water washing respectively, anhydrous sodium sulfate drying, and vacuum is steamed and is desolventized.Residue through post separate 2-bromo-6-fluorobenzaldehyde (110.0g, 542.3mmol), yield 88.0%.
B) under nitrogen protection to 2-bromo-6-fluorobenzaldehyde (110.0g; 542.3mmol) and trimethyl silicane ethyl-acetylene (153.3ml; 1.08mol) DMF (2.75L) solution in add triethylamine (112.8ml; 813.5mmol), cuprous iodide (10.3g; 54.2mmol) and bi triphenyl phosphorus palladium chloride (19.0g, 27.2mmol).Reaction mixture stirs and spends the night, and pours distilled water (6.6L) into, extracts three times with ethyl acetate (2.2L).Mixed extract is used distilled water, saturated common salt water washing respectively, anhydrous sodium sulfate drying, and vacuum is steamed and is desolventized.Residue separates to such an extent that 2-fluoro-6-[(front three is silica-based through post) ethynyl] phenyl aldehyde (114.2g, 518.1mmol), yield 95.0%.
C) it is silica-based to add 2-fluoro-6-[(front three in autoclave) ethynyl] phenyl aldehyde (and 114.2g, 518.1mmol) and methyl alcohol (2.64L), stir down the feeding ammonia (114.3L, 5.18mol).Be heated to 80 ℃ of reaction 3h, be cooled to room temperature, vacuum is steamed and is desolventized.Residue through post separate 8-fluorine isoquinoline 99.9 (44.0g, 298.1mmol), yield 58.0%.
D) under-5～0 ℃ to 8-fluorine isoquinoline 99.9 (43.4g, 294.0mmol) the vitriol oil (350ml) solution in 10min, slowly add potassium nitrite (32.6g, 323.4mmol) the vitriol oil (175ml) solution, mixture stirs 30min down at 0 ℃, the TLC monitoring reaction is complete, pour in the ice (3.50kg), slowly add 33% ammoniacal liquor neutralization.Mixture uses methylene dichloride (5.25L) to extract three times, mixes organic layer saturated common salt water washing, and anhydrous sodium sulfate drying filters with the filter funnel that is covered with silica gel, silica gel ethyl acetate and isohexane mixing solutions (1:1,5.25L) washing.Mix the organic layer vacuum concentration get 8-fluoro-5-nitroisoquinoline (46.6g, 242.1mmol), yield 82.0%.
E) with 8-fluoro-5-nitroisoquinoline (46.2g, 240.0mmol) and NiCl 6H 2(10.0g 42.0mmol) is dissolved in the methyl alcohol (900ml) O, stirs in 30min with NaBH 4(108.9g, 2.88mol) gradation adds, and room temperature continues to stir 30min.Remove methyl alcohol under reduced pressure, the dissolving with hydrochloric acid black deposit with 10%, strong aqua neutralization, ether extraction.Extract anhydrous magnesium sulfate drying, vacuum steam and to desolventize, residue through post separate 8-fluoro-5-nitro-1,2,3, the 4-tetrahydroisoquinoline (40.5g, 206.5mmol), yield 86.0%.
F) under stirring at room to being dissolved with 8-fluoro-5-nitro-1,2,3,4-tetrahydroisoquinoline (40.4g, 206.0mmol) and triethylamine (105.2ml, the adding of Virahol 756.0mmol) (800ml) solution is dissolved with ethyl chloroacetate (73.6ml, Virahol 688.0mmol) (560ml) solution, continue to stir 3h, monitor to reacting completely with TLC.Remove solvent under reduced pressure, residue gets 8-fluoro-5-nitro-3 through the silicagel column purifying, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (48.0g, 179.0mmol), yield 87.0%.
G) under nitrogen protection to 8-fluoro-5-nitro-3; 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (37.0g, the Pd/C (10.0g) of adding 10% in methyl alcohol 138.0mmol) (2L) solution feeds hydrogen reaction 3.5h; the overanxious catalyzer of removing, filtrate is evaporated to dried.Residue through post separate 5-amino-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (13.6g, 57.3mmol), yield 41.4%.
H) with 5-amino-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (13.3g, 56.0mmol) and ethoxy methylene diethyl malonate (13.4g 62.0mmol) at 120～130 ℃ of following heating 2h, steams and removes the ethanol that reaction generates.Add n-Hexadecane (41.4g), slowly be warming up to 250 ℃, reaction 2h, cooling, overanxious, use the DMF recrystallization, get 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10-three hydrogen-1H-piperidines also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester (12.9g, 35.4mmol), yield 63.6%.
I) with 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester (7.0g also, 19.2mmol) be dissolved among the DMF (100ml), (5.3g 38.4mmol), stirs 10min at 60 ℃ to add salt of wormwood, add cyclopropane bromide (4.5g, 37.0mmol), continue down to stir 2h at 60～70 ℃, be evaporated to dried.In resistates, add distilled water, use chloroform extraction, extracting solution Anhydrous potassium carbonate drying, steam and remove chloroform, resistates must be with 1-cyclopropyl-8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9 with methylene dichloride and normal hexane mixed solvent recrystallization, 10-three hydrogen-1H-piperidines also [3,4-h] and quinoline-3 (4H)-carboxylic acid, ethyl ester (6.1g, 15.2mmol), yield 78.9%.
J) with 1-cyclopropyl-8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10-three hydrogen-1H-piperidines also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester (6.1g, 15.2mmol), 10% sodium hydroxide solution (60ml) and ethanol (20ml) reflux 3h, cooling, acetate accent pH to 7.0～7.5 with 10%, overanxious, the filter cake washing with alcohol gets 1-cyclopropyl-6-fluoro-4-oxygen-4,7 through DMF and alcohol mixed solvent recrystallization, 8,9,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-carboxylic acid 4.3g also, be faint yellow solid, yield 93.6%.
FAB-MS(m/z)：303(M+H) +。
Ultimate analysis: C 16H 15N 2O 3F
Calculated value (%) C63.57 H5.00 N9.27
Measured value (%) C63.46 H4.92 N9.29
Embodiment 2
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-IH-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
A) in the mixing solutions of concentrated hydrochloric acid (2.84L) and distilled water (1.58L), add in batches between monomethylaniline (1.44kg, 13.5mol), (2.54kg, distilled water 23.1mol) (2.25L) solution continue to stir 15min to drip Sodium tetrafluoroborate.(945.0g, distilled water 13.5mol) (1.35L) solution are bathed control reaction temperature at-5～-2 ℃ with cryosel, drip Bi Jixu and stir 30min, filter, and filter cake is successively with frozen water, methyl alcohol, ether washing, drying to splash into Sodium Nitrite.The solid of drying under reduced pressure gained is put into reaction flask, thermal degradation slowly in oil bath, after having decomposed, reaction product neutralizes with 5% sodium hydroxide earlier, be washed till pH=7～8 with saturated sodium bicarbonate again, extracted with diethyl ether, saturated common salt water washing organic layer, anhydrous sodium sulfate drying, after removing ether under reduced pressure, 115～116 ℃ cut is collected in distillation, gets target compound 679.5g, yield 46.1%.
B) stir down to sodium hydroxide (250.0g, 6.0mol) distilled water (320.0g) solution in add 1,3-dimethyl-2-imidazolone (6.0L), toluene fluoride (661.0g between in 1h, in mixture, dripping by dropping funnel, 6.0mol) 1,3-dimethyl-2-imidazolone (1.8L) solution.Then, in 3h by dropping funnel in mixture the dropwise addition of acrylic acid methyl esters (532.5g, 6.0mol) 1,3-dimethyl-2-imidazolone (1.8L) solution is kept temperature of reaction simultaneously at 0～4 ℃.Reaction solution is poured in the frozen water (25.0L).With ethyl acetate (1.5L) extraction, use the anhydrous sodium sulfate drying extraction liquid, remove solvent under reduced pressure, must 4-(3-fluorophenyl) methyl-butyrate (706.5g, 3.60mol), yield 60.0%.
C) (679.0g, (616.0g, 34.58mol) (70.0g, 4.79mol), back flow reaction 5h steams and removes acetate and water with the 3N hydrochloric acid soln to add distilled water in acetate 3.46mol) (2.8L) solution to 4-(3-fluorophenyl) methyl-butyrate.Resistates is dissolved in the ethyl acetate (4.2L), washes organic layer with water 3 times, anhydrous sodium sulfate drying removes the part ethyl acetate under reduced pressure, and faint yellow crystallization is separated out in cooling.Filter, drying under reduced pressure gets 4-(3-fluorophenyl) butyric acid (548.8g, 3.02mol), yield 87.0%.
D) under 40 ℃ to DMF (18.0g, 246.0mmol) and 4-(3-fluorophenyl) butyric acid (546.0g splashes into phosgene/dichloroethane solution (3.06kg) of 12% in ethylene dichloride 3.00mol) (15L) solution, continue to stir 30min, is cooled to room temperature.The adding aluminum chloride (438.0g, 3.30mol), temperature rises to 80 ℃ of reaction 1h, cooling, slowly splash into distilled water (15L), layering, organic layer removes solvent under reduced pressure after with anhydrous sodium sulfate drying, 8-fluoro-3,4-dihydro-1 (2H)-naphthalenone (453.0g, 2.76mol), yield 91.8%.
E) to 8-fluoro-3, (449.1g adds NaN in the ice-cold solution of concentrated hydrochloric acid 2.74mol) (5.4L) to 4-dihydro-1 (2H)-naphthalenone in batches 3(181.8g, 2.74mol), 0 ℃ is stirred 30min, rises to room temperature, and stirring is spent the night.Reaction solution is poured in the ice, pH is transferred to 10, divide 3 extractions with methylene dichloride with the 1N sodium hydroxide solution.Mix the organic layer anhydrous magnesium sulfate drying, filter, concentrate, silicagel column purifying (n-hexane/ethyl acetate) gets 9-fluoro-2,3,4, and 5-tetrahydrochysene-1H-benzo [c] azatropylidene-1-ketone (122.4g, 681.7mmol), yield 25%.
F) with 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene-1-ketone (109.6g 610.4mmol) is dissolved in the tetrahydrofuran (THF) (80ml), is cooled to 0 ℃, slowly add in batches Lithium Aluminium Hydride (71.2g, 1.84mol).Finish, back flow reaction 24h is cooled to room temperature, adds distilled water (71.2ml), 15% sodium hydroxide solution (71.2ml), distilled water (213.6ml) successively, filter, filtrate concentrate 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (61.6g, 373.2mmol), yield 61.0%.
G) under stirring at room to being dissolved with 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (59.5g, 360.5mmol) and triethylamine (184.1ml, the adding of Virahol 1.32mol) (1.4L) solution is dissolved with ethyl chloroacetate (128.8ml, Virahol 1.20mol) (980ml) solution, continue to stir 3h, monitor to reacting completely with TLC.Remove solvent under reduced pressure, residue gets 9-fluoro-4 through the silicagel column purifying, and 5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester (77.0g, 324.2mmol), yield 90.0%.
H) under cryosel is bathed to 78% sulfuric acid (111ml) and 9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester (67.7g, 285.0mmol) in splash into the mixing solutions of the concentrated nitric acid (36ml) and the vitriol oil (24ml), regulate rate of addition, control Nei Wen-5～-2 ℃ finish and continue to stir 1h.Reaction solution is poured in a large amount of frozen water, water layer extracts with toluene, merge organic layer, use 5% sodium hydroxide solution, saturated common salt water washing successively, anhydrous sodium sulfate drying removes solvent under reduced pressure, residue gets 9-fluoro-6-nitro-4 through the silicagel column purifying, 5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester (48.3g, 170.9mmol), yield 60.0%.
I) under nitrogen protection to 9-fluoro-6-nitro-4; 5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester (39.0g, the Pd/C (10.0g) of adding 10% in methyl alcohol 138.0mmol) (2L) solution feeds hydrogen reaction 3.5h; the overanxious catalyzer of removing, filtrate is evaporated to dried.Residue through post separate 9-fluoro-6-amino-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester (16g, 63.4mmol), yield 46.0%.
J) with 9-fluoro-6-amino-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester replaces 5-amino-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 1-cyclopropyl-6-fluoro-4-oxygen-4 according to the method for embodiment 1,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 47.2%.
FAB-MS(m/z)：317(M+H) +。
Ultimate analysis: C 17H 17N 2O 3F
Calculated value (%) C64.55 H5.42 N8.86
Measured value (%) C64.59 H5.43 N8.82
Embodiment 3
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
A) under-5～0 ℃ to 2-fluorobenzaldehyde (18.7g, 151.2mmol) the vitriol oil (180ml) solution in 10min, slowly add potassium nitrite (16.7g, 166.3mmol) the vitriol oil (90ml) solution, mixture stirs 30min down at 0 ℃, the TLC monitoring reaction is complete, pour in the ice (1.8kg), slowly add 33% ammoniacal liquor neutralization.Mixture uses methylene dichloride (2.7L) to extract three times, mixes organic layer saturated common salt water washing, and anhydrous sodium sulfate drying filters with the filter funnel that is covered with silica gel, silica gel ethyl acetate and isohexane mixing solutions (1:1,2.7L) washing.Mix the organic layer vacuum concentration get 2-fluoro-5-nitrobenzaldehyde (23.0g, 135.5mmol), yield 89.6%.
B) at room temperature to 2-fluoro-5-nitrobenzaldehyde (21.9g, 129.0mmol) and 8-ethyl-1,8-diazabicyclo [5,4,0]-and the middle adding of 7-undecylene trifluoromethyl sulfonic acid (43.4g) 2-amino-benzene methyl alcohol (13.3g, 129.0mmol), continue to stir 30min, add ether (4.3L), separate organic layer, use anhydrous sodium sulfate drying, remove solvent under reduced pressure, get 2-(2-fluoro-5-nitrophenyl)-2,4-dihydro-1H-benzo [d] [1,3] oxazine 33.5g, yield 95%.
C) to 2-(2-fluoro-5-nitrophenyl)-2,4-dihydro-1H-benzo [d] [1,3] oxazine (32.9g, 120.0mmol) ethanol (120ml) solution in add sodium borohydride (9.6g, 240.0mmol), back flow reaction 2h, be cooled to room temperature, add 10% hydrochloric acid soln, concentrating under reduced pressure.Residue with ethyl alcohol recrystallization get 2-(2-fluoro-5-nitrophenyl amino) phenylcarbinol (32.3g, 118.8mmol), yield 99.0%.
D) 2-(2-fluoro-5-nitrophenyl amino) phenylcarbinol (30.8g, 113.4mmol) and the mixing solutions of polyphosphoric acid (420ml) stir 1h at 80 ℃, add frozen water (2.08L), with the neutralization of 1N sodium hydroxide solution, filter, get 7-fluoro-10-nitro-6,11-dihydro-5H-dibenzo [b, e] and azatropylidene (26.6g, 103.0mmol), yield 90.8%.
E) under stirring at room to being dissolved with 7-fluoro-10-nitro-6,11-dihydro-5H-dibenzo [b, e] azatropylidene (26.6g, 103.0mmol) and triethylamine (52.6ml, 378.0mmol) Virahol (400ml) solution add and to be dissolved with ethyl chloroacetate (36.8ml, 344.0mmol) Virahol (280ml) solution, continue to stir 3h, with the TLC monitoring to reacting completely.Remove solvent under reduced pressure, residue gets 7-fluoro-10-nitro-6 through the silicagel column purifying, and 11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester (29.2g, 88.2mmol), yield 85.6%.
F) under nitrogen protection to 7-fluoro-10-nitro-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester (27.4g; 82.8mmol) methyl alcohol (1.2L) solution in add 10% Pd/C (6.0g); feed hydrogen reaction 3.5h, the overanxious catalyzer of removing, filtrate is evaporated to dried.Residue through post separate 7-fluoro-10-amino-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester (10.7g, 35.6mmol), yield 43.0%.
J) with 7-fluoro-10-amino-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester replaces 5-amino-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 1-cyclopropyl-6-fluoro-4-oxygen-4 according to the method for embodiment 1,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 45.0%.
FAB-MS(m/z)：365(M+H) +。
Ultimate analysis: C 21H 17N 2O 3F
Calculated value (%) C69.22 H4.70 N7.69
Measured value (%) C69.25 H4.76 N7.62
Embodiment 4
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
A) under nitrogen protection with the 2-fluorophenylacetic acid (663.5g 4.30mol) is dissolved in the methylene dichloride (8.2L), add DMF (6.1ml, 78.9mmol), in 6h, splash into oxalyl chloride (374.0ml, 4.30mol).Drip to finish, continue to stir 1.5h, reaction solution is cooled to 0 ℃, add in batches aluminum chloride (556.6g, 4.18mol).In reaction solution, feed ethylene gas,, add frozen water under the vigorous stirring, continue to stir 4h, rise to room temperature until reacting completely, layering, water layer washs with a small amount of ethylene dichloride.Washings is added in the organic layer, filters, concentrate 8-fluoro-3,4-dihydronaphthalene-2 (1H)-ketone (624.8g, 3.83mmol), yield 89.1%.
B) with 8-fluoro-3,4-dihydronaphthalene-2 (1H)-ketone (624.8g, 3.83mol) and sodiumazide (497.0g, acetate 7.67mol) (4.8L) solution is heated to 70 ℃, slowly drip sulfuric acid (1.2L, 21.58mol).Finish, reaction mixture is poured in the ice, with the solid sodium bicarbonate neutralization, use dichloromethane extraction, separate organic layer, use anhydrous sodium sulfate drying, concentrating under reduced pressure, resistates through the silicagel column purifying (methylene dichloride: methyl alcohol=95:5) 9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-3 (2H)-ketone (269.7g, 1.51mol), yield 39.4%.
C) to 9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-3 (2H)-ketone (269.7g, 1.51mol) methylene dichloride (1.2L) solution in add Tetrafluoroboric acid three second (580.0g, 3.05mol), back flow reaction 4h, under ice-water bath, reaction solution is neutralized with the 5N solution of potassium carbonate, separate organic layer, water layer washed with dichloromethane 2 times.Organic layer is mixed, use the Anhydrous potassium carbonate drying, remove solvent under reduced pressure, resistates gets 3-oxyethyl group-9-fluoro-4 through the silicagel column purifying, and 5-dihydro-1H-benzo [c] azatropylidene (249.4g, 1.20mol), yield 79.5%.
D) with 3-oxyethyl group-9-fluoro-4, and 5-dihydro-1H-benzo [c] azatropylidene (244.8g, 1.18mol) and Nitromethane 99Min. (72.0g, 1.18mol) reflux 24h, cooling, overanxious, wash with ether, the dry 9-fluoro-3-(Nitromethylene)-2 that gets, 3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (187.8g, 846.4mmol), yield 71.7%.
E) to 9-fluoro-3-(Nitromethylene)-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (170.4g, add in methyl alcohol 768.0mmol) (1.2L) solution platinum oxide (12.0g, 49.2mmol), logical H-H reaction to the system of room temperature no longer absorbs hydrogen, the overanxious catalyzer of removing, and filtrate decompression concentrates, resistates gets 9-fluoro-3-(amino methyl)-2 through the silicagel column purifying, 3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (103.2g, 532.6mmol), yield 69.3%.
F) in ethanol (1.6L), add 9-fluoro-3-(amino methyl)-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene (99.2g, 512.0mmol) and diethyl oxalate (75.2g, 512.0mmol), reflux 4h is cooled to room temperature, removes solvent under reduced pressure, residue gets 7-fluoro-1,2,12 with ethyl alcohol recrystallization, 12a-tetrahydro benzo [e] pyrazine is [1,2-a] azatropylidene-3,4 (6H also, 11H)-and diketone (89.6g, 361.8mmol), yield 70.7%.
G) with 7-fluoro-1,2,12,12a-tetrahydro benzo [e] pyrazine also [1,2-a] azatropylidene-3,4 (6H, 11H)-diketone (88.8g, 358.6mmo]) is dissolved in the tetrahydrofuran (THF) (470ml), is cooled to 0 ℃, slowly add in batches Lithium Aluminium Hydride (83.7g, 2.16mol).Finish, back flow reaction 24h is cooled to room temperature, add distilled water (41.8ml), 15% sodium hydroxide solution (41.8ml), distilled water (125.5ml) successively, filter, filtrate concentrate 7-fluoro-1,2,3,4,6,11,12,12a-octahydro benzo [e] pyrazine also [1,2-a] and azatropylidene (45.2g, 206.0mmol), yield 57.4%.
H) under stirring at room to being dissolved with 7-fluoro-1,2,3,4,6,11,12,12a-octahydro benzo [e] pyrazine also [1,2-a] azatropylidene (45.2g, 206.0mmol) and triethylamine (105.2ml, 756.0mmol) Virahol (800ml) solution add and to be dissolved with ethyl chloroacetate (73.6ml, 688.0mmol) Virahol (560ml) solution, continue to stir 3h, with the TLC monitoring to reacting completely.Remove solvent under reduced pressure, residue gets 7-fluoro-3,4,6,11,12 through the silicagel column purifying, the 12a-hexahydrobenzene also [e] pyrazine also [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester (53.6g, 182.8mmol), yield 88.7%.
I) vigorous stirring limit in limit is with 7-fluoro-3,4,6,11,12, the 12a-hexahydrobenzene is [e] pyrazine also [1 also, 2-a] (47.5g 162.0mmol) is dissolved in the vitriol oil (100ml) azatropylidene-2 (1H)-carboxylic acid, ethyl ester, is cooled to-10 ℃, slowly drip nitric acid (10.4ml, 69.3%, 162.0mmol) and the mixing solutions of sulfuric acid (10ml), continue to stir 15min, reaction solution is poured in the ice, and overanxious, vacuum-drying gets 7-fluoro-10-nitro-3,4,6,11,12, the 12a-hexahydrobenzene is [e] pyrazine also [1 also, 2-a] and azatropylidene-2 (1H)-carboxylic acid, ethyl ester (28.0g, 82.8mmol), yield 51.1%.
J) under nitrogen protection to 7-fluoro-10-nitro-3; 4; 6,11,12; the 12a-hexahydrobenzene is [e] pyrazine also [1 also; 2-a] and azatropylidene 2 (1H)-carboxylic acid, ethyl ester (28.0g, the Pd/C (6.0g) of adding 10% in methyl alcohol 82.8mmol) (1.2L) solution feeds hydrogen reaction 3.5h; the overanxious catalyzer of removing, filtrate is evaporated to dried.Residue through post separate 7-fluoro-10-amino-3,4,6,11,12, the 12a-hexahydrobenzene also [e] pyrazine also [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester (11.4g, 37.1mmol), yield 44.8%.
J) with 7-fluoro-10-amino-3,4,6,11,12, the 12a-hexahydrobenzene also [e] pyrazine also [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester replace 5-amino-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester, method according to embodiment 1 makes 1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.9%.
FAB-MS(m/z)：372(M+H) +。
Ultimate analysis: C 20H 22N 3O 3F
Calculated value (%) C64.68 H5.97 N11.31
Measured value (%) C64.72 H6.00 N11.28
Embodiment 5
1-cyclopropyl-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace 8-fluoro-5-nitroisoquinoline with the 5-nitroisoquinoline, make 1-cyclopropyl-4-oxygen-4,7,8,9 according to the method for embodiment 1,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 15.3%.
FAB-MS(m/z)：285(M+H) +
Ultimate analysis: C 16H 16N 2O 3
Calculated value (%) C67.59 H5.67 N9.85
Measured value (%) C67.62 H5.63 N9.81
Embodiment 6
1-cyclopropyl-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene be the preparation of [3,4-h] quinoline-3-carboxylic acid also
With 3,4-dihydro-1 (2H)-naphthalenone replaces 8-fluoro-3, and 4-dihydro-1 (2H)-naphthalenone makes 1-cyclopropyl-4-oxygen-4 according to the method for embodiment 2,7,8,9,10,11-six hydrogen-1H-azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 1.0%.
FAB-MS(m/z)：299(M+H) +。
Ultimate analysis: C 17H 18N 2O 3
Calculated value (%) C68.44 H6.08 N9.39
Measured value (%) C68.49 H6.11 N9.35
Embodiment 7
1-cyclopropyl-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace 2-fluoro-5-nitrobenzaldehyde with m-nitrobenzaldehyde, make 1-cyclopropyl-4-oxygen-4,7,8 according to the method for embodiment 3,13-tetrahydrochysene-1H-benzo [k] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 14.7%.
FAB-MS(m/z)：347(M+H) +。
Ultimate analysis: C 21H 18N 2O 3
Calculated value (%) C72.82 H5.24 N8.09
Measured value (%) C72.83 H5.25 N8.03
Embodiment 8
1-cyclopropyl-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace the 2-fluorophenylacetic acid with toluylic acid, make 1-cyclopropyl-4-oxygen-4,7,8,9,10,11 according to the method for embodiment 4,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 0.3%.
FAB-MS(m/z)：354(M+H) +。
Ultimate analysis: C 20H 23N 3O 3
Calculated value (%) C67.97 H6.56 N11.89
Measured value (%) C68.01 H6.55 N11.87
Embodiment 9
1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with iodoethane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 1 makes 1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 74.7%.
FAB-MS(m/z)：291(M+H) +。
Ultimate analysis: C 15H 15N 2O 3F
Calculated value (%) C62.06 H5.21 N9.65
Measured value (%) C62.09 H5.23 N9.62
Embodiment 10
1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10 with iodoethane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-ethyl-6-fluoro-4-oxygen-4 according to the method for embodiment 2,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 73.1%.
FAB-MS(m/z)：305(M+H) +。
Ultimate analysis: C 16H 17N 2O 3F
Calculated value (%) C63.15 H5.63 N9.21
Measured value (%) C63.17 H5.63 N9.18
Embodiment 11
1-ethyl-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with iodoethane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 3 makes 1-ethyl-6-fluoro-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 72.7%.
FAB-MS(m/z)：353(M+H) +。
Ultimate analysis: C 20H 17N 2O 3F
Calculated value (%) C68.17 H4.86 N7.95
Measured value (%) C68.20 H4.87 N7.93
Embodiment 12
1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10,11 with iodoethane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-ethyl-6-fluoro-4-oxygen-4,7,8 according to the method for embodiment 4,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 70.3%.
FAB-MS(m/z)：360(M+H) +。
Ultimate analysis: C 19H 22N 3O 3F
Calculated value (%) C63.50 H6.17 N11.69
Measured value (%) C63.51 H6.18 N11.65
Embodiment 13
1-ethyl-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with iodoethane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 5 makes 1-ethyl-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 69.7%.
FAB-MS(m/z)：273(M+H) +。
Ultimate analysis: C 15H 16N 2O 3
Calculated value (%) C66.16 H5.92 N10.29
Measured value (%) C66.18 H5.95 N10.25
Embodiment 14
1-ethyl-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10 with iodoethane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-ethyl-4-oxygen-4 according to the method for embodiment 6,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 72.7%.
FAB-MS(m/z)：287(M+H) +。
Ultimate analysis: C 16H 18N 2O 3
Calculated value (%) C67.12 H6.34 N9.78
Measured value (%) C67.14 H6.35 N9.76
Embodiment 15
1-ethyl-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with iodoethane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 7 makes 1-ethyl-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 73.3%.
FAB-MS(m/z)：335(M+H) +。
Ultimate analysis: C 20H 18N 2O 3
Calculated value (%) C71.84 H5.43 N8.38
Measured value (%) C71.85 H5.43 N8.35
Embodiment 16
1-ethyl-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10,11 with iodoethane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-ethyl-4-oxygen-4,7,8 according to the method for embodiment 8,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 69.5%.
FAB-MS(m/z)：342(M+H) +。
Ultimate analysis: C 19H 23N 3O 3
Calculated value (%) C66.84 H6.79 N12.31
Measured value (%) C66.85 H6.82 N12.28
Embodiment 17
1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 1 makes 1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.2%.
FAB-MS(m/z)：321(M+H) +。
Ultimate analysis: C 16H 14N 2O 3F 2
Calculated value (%) C60.00 H4.41 N8.75
Measured value (%) C60.04 H4.42 N8.73
Embodiment 18
1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10 with 1-bromo-2-fluorine cyclopropane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4 according to the method for embodiment 2,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 44.4%.
FAB-MS(m/z)：335(M+H) +。
Ultimate analysis: C 17H 16N 2O 3F
Calculated value (%) C61.07 H4.82 N8.38
Measured value (%) C61.10 H4.85 N8.36
Embodiment 19
1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 3 makes 1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 44.1%.
FAB-MS(m/z)：383(M+H) +。
Ultimate analysis: C 21H 16N 2O 3F
Calculated value (%) C65.97 H4.22 N7.33
Measured value (%) C65.98 H4.24 N7.31
Embodiment 20
1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10,11 with 1-bromo-2-fluorine cyclopropane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(2-fluorine) cyclopropyl-6-fluoro-4-oxygen-4,7,8 according to the method for embodiment 4,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 41.8%.
FAB-MS(m/z)：390(M+H) +。
Ultimate analysis: C 20H 21N 3O 3F
Calculated value (%) C61.69 H5.44 N10.79
Measured value (%) C66.71 H5.43 N10.76
Embodiment 21
1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 5 makes 1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.7%.
FAB-MS(m/z)：303(M+H) +。
Ultimate analysis: C 16H 15N 2O 3F
Calculated value (%) C63.57 H5.00 N9.27
Measured value (%) C63.59 H5.01 N9.25
Embodiment 22
1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10 with 1-bromo-2-fluorine cyclopropane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-(2-fluorine) cyclopropyl-4-oxygen-4 according to the method for embodiment 6,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 45.4%.
FAB-MS(m/z)：317(M+H) +。
Ultimate analysis: C 17H 17N 2O 3F
Calculated value (%) C64.55 H5.42 N8.86
Measured value (%) C64.58 H5.43 N8.83
Embodiment 23
1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 7 makes 1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 45.7%.
FAB-MS(m/z)：365(M+H) +。
Ultimate analysis: C 21H 17N 2O 3F
Calculated value (%) C69.22 H4.70 N7.69
Measured value (%) C69.24 H4.72 N7.67
Embodiment 24
1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10,11 with 1-bromo-2-fluorine cyclopropane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(2-fluorine) cyclopropyl-4-oxygen-4,7,8 according to the method for embodiment 8,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.0%.
FAB-MS(m/z)：372(M+H) +。
Ultimate analysis: C 20H 22N 3O 3F
Calculated value (%) C64.68 H5.97 N11.31
Measured value (%) C64.71 H5.99 N11.28
Embodiment 25
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluoroethane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 1 makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 54.0%.
FAB-MS(m/z)：309(M+H) +。
Ultimate analysis: C 15H 14N 2O 3F 2
Calculated value (%) C58.44 H4.58 N9.09
Measured value (%) C58.45 H4.60 N9.06
Embodiment 26
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10 with 1-bromo-2-fluoroethane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4 according to the method for embodiment 2,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 54.2%.
FAB-MS(m/z)：323(M+H) +。
Ultimate analysis: C 16H 16N 2O 3F 2
Calculated value (%) C59.62 H5.00 N8.69
Measured value (%) C59.63 H5.01 N8.67
Embodiment 27
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluoroethane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 3 makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 53.4%.
FAB-MS(m/z)：371(M+H) +。
Ultimate analysis: C 20H 16N 2O 3F
Calculated value (%) C64.86 H4.35 N7.56
Measured value (%) C64.89 H4.38 N7.52
Embodiment 28
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene is [3,4-h] quinoline-3-carboxylic also
The preparation of acid
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10,11 with 1-bromo-2-fluoroethane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8 according to the method for embodiment 4,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 51.9%.
FAB-MS(m/z)：378(M+H) +。
Ultimate analysis: C 19H 21N 3O 3F 2
Calculated value (%) C60.47 H5.61 N11.13
Measured value (%) C60.49 H5.62 N11.10
Embodiment 29
1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluoroethane, 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, method according to embodiment 5 makes 1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 52.8%.
FAB-MS(m/z)：291(M+H) +。
Ultimate analysis: C 15H 15N 2O 3F
Calculated value (%) C62.06 H5.21 N9.65
Measured value (%) C62.08 H5.23 N9.62
Embodiment 30
1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10 with 1-bromo-2-fluoroethane, 11-tetrahydrochysene-1H-azatropylidene is [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation also, makes 1-(2-fluoro ethyl)-4-oxygen-4 according to the method for embodiment 6,7,8,9,10,11-six hydrogen-1H-azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 54.0%.
FAB-MS(m/z)：305(M+H) +。
Ultimate analysis: C 16H 17N 2O 3F
Calculated value (%) C63.15 H5.63 N9.21
Measured value (%) C63.15 H5.65 N9.18
Embodiment 31
1-(2-fluoro ethyl)-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluoroethane, 13-dihydro-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 7 makes 1-(2-fluoro ethyl)-4-oxygen-4,7,8,13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 53.9%.
FAB-MS(m/z)：353(M+H) +。
Ultimate analysis: C 20H 17N 2O 3F
Calculated value (%) C68.17 H4.86 N7.95
Measured value (%) C68.19 H4.86 N7.93
Embodiment 32
1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7,9,10,11 with 1-bromo-2-fluoroethane, 11a, 12,13-seven hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(2-fluoro ethyl)-4-oxygen-4,7,8 according to the method for embodiment 8,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene also [3,4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 52.9%.
FAB-MS(m/z)：360(M+H) +。
Ultimate analysis: C 19H 22N 3O 3F
Calculated value (%) C63.50 H6.17 N11.69
Measured value (%) C63.51 H6.19 N11.67
Embodiment 33
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
A) replace the 3-bromofluorobenzene with 2-bromo-1-chloro-4-fluorobenzene, make 5-chloro-8-fluorine isoquinoline 99.9, yield 35.6% according to the method for embodiment 1.
B) replace 8-fluoro-5-nitroisoquinoline with 5-chloro-8-fluorine isoquinoline 99.9, make 5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester, 73.1% according to the method for embodiment 1.
C) under the vigorous stirring to the 5-chloro-8-fluoro-3 in water-bath; 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (32.5g; 126.0mol) and aluminum chloride (48.0g; slowly add Acetyl Chloride 98Min. (17.0g 360mmol); 216.0mmol); reaction mixture continues vigorous stirring 1h; pour in the mixing solutions of ice (100g) and concentrated hydrochloric acid (60ml), layering, organic layer is used saturated sodium bicarbonate solution and distilled water wash successively; dry; remove solvent under reduced pressure, resistates gets 6-ethanoyl-5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (20.4g through the silicagel column purifying; 68.0mmol), yield 54.0%.
D) to ethanolic soln (the 150ml ethanol of sodium ethylate; 1.5g add oxalic acid diethyl ester (18.5ml sodium Metal 99.5); 137.5mmol); be heated with stirring to 50 ℃; in 30min, drip 6-ethanoyl-5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (15.0g, ethanol 50.0mmol) (30ml) solution; continue reaction 3h; remove solvent under reduced pressure, resistates is transferred pH to 1.0 with dilute hydrochloric acid, filters; washing and drying; get 5-chloro-6-(4-oxyethyl group-3,4-dioxy butyryl radicals)-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (19.0g with re-crystallizing in ethyl acetate; 47.5mmol), yield 95.0%.
E) with 5-chloro-6-(4-oxyethyl group-3,4-dioxy butyryl radicals)-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (18.0g; 45.0mmol), triethyl orthoformate (11.3ml, 67.5mmol) and aceticanhydride (17.3ml) be heated to 90 ℃, treat solid dissolving after; insulation reaction 1h, underpressure distillation, resistates is cooled to 50 ℃; add ethanol (150ml); frozen water is cooled to 5～10 ℃, slowly adds 2,4 difluorobenzene amine (8.1g; 63.0mmol), a large amount of solids appear.Continue to be stirred to tlc analysis detection reaction terminal point; freezing suction filtration; use washing with alcohol; get 5-chloro-6-{2-[(2; 4-difluorophenyl amino) methylene radical]-4-oxyethyl group-3,4-dioxy butyryl radicals }-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (19.2g; 35.6mmol), yield 79.1%.
F) with 5-chloro-6-{2-[(2; 4-difluorophenyl amino) methylene radical]-4-oxyethyl group-3; 4-dioxy butyryl radicals }-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester (16.2g, 30.0mmol); Anhydrous potassium carbonate (6.0g; 43.0mmol) and DMF (60ml) be heated with stirring to 70 ℃; continue stirring reaction to 1.5h, reduce to room temperature, heating cold water (130ml); separate out a large amount of solids; suction filtration, washing gets 1-(2 with chloroform and ethanol mixed solvent recrystallization; the 4-difluorophenyl)-8-ethoxycarbonyl-6-fluoro-4-oxygen-7; 9,10-three hydrogen-1H-piperidines is [3,4-h] quinoline-3 (4H)-formyl ethyl formate (11.6g also; 23.0mmol), yield 76.7%.
G) with 1-(2,4 difluorobenzene base)-8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10-three hydrogen-1H-piperidines also [3,4-h] quinoline-3 (4H)-formyl ethyl formate (9.9g, 19.6mmol) and 7% aqueous sodium hydroxide solution (91ml, 161.0mmol) heated and stirred is warming up to 70 ℃, continue to be stirred to tlc analysis detection reaction terminal point, transfer pH to 1.0 with concentrated hydrochloric acid, continue to stir 20min, be cooled to room temperature, filter, dry 1-(2,4 difluorobenzene the base)-6-fluoro-4-oxygen-4,7 that gets, 8,9,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-formyl formic acid (7.3g also, 18.1mmol), yield 92.3%.
H) under frozen water cooling to 1-(2 ,-difluorophenyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-formyl formic acid (5.3g, 13.2mmol) and drip in the 30min in 15% the aqueous sodium hydroxide solution (30ml) 7.5% aqueous hydrogen peroxide solution (15ml, 33.1mmol), continue insulation reaction 2h, transfer pH to 1.0, separate out a large amount of solids with dilute hydrochloric acid, filter, drying gets 1-(2 ,-difluorophenyl)-6-fluoro-4-oxygen-4 with the chloroform recrystallization, 7,8,9,10-pentahydro--1H-piperidines also [3,4-h] quinoline-3-carboxylic acid (4.3g, 11.5mmol), be faint yellow solid, yield 87.1%.
FAB-MS(m/z)：375(M+H) +。
Ultimate analysis: C 19H 13N 2O 3F 3
Calculated value (%) C60.97 H3.50 N7.48
Measured value (%) C61.01 H3.51 N7.46
Embodiment 34
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
A) replace with 1-chloro-4-fluoro-2-toluene between toluene fluoride, make 6-chloro-9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester, yield 4.9% according to the method for embodiment 2.
B) with 6-chloro-9-fluoro-4; 5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester replaces 5-chloro-8-fluoro-3; 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester; method according to embodiment 33 makes 7-ethanoyl-6-chloro-9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester yield 58.7%.
C) with 7-ethanoyl-6-chloro-9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester replaces 6-ethanoyl-5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester; method according to embodiment 33 makes 1-(2; the 4-difluorophenyl)-and 6-fluoro-4-oxygen-4,7,8; 9; 10,11-six hydrogen-1H-azatropylidene is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 47.2%.
FAB-MS(m/z)：389(M+H) +。
Ultimate analysis: C 20H 15N 2O 3F 3
Calculated value (%) C61.86 H3.89 N7.21
Measured value (%) C61.87 H3.91 N7.19
Embodiment 35
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
A) replace 3-bromofluorobenzene among the embodiment 1 with 1-chloro-4-fluorobenzene, make 5-chloro-2-fluorobenzaldehyde, yield 58.2% according to the method for embodiment 1.
B) replace 2-fluoro-5-nitrobenzaldehyde with 5-chloro-2-fluorobenzaldehyde, make 7-fluoro-10-chloro-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester, yield 73.2% according to the method for embodiment 3.
C) with 7-fluoro-10-chloro-6; 11-dihydro-5H-dibenzo [b; e] azatropylidene-5-carboxylic acid, ethyl ester replacement 5-chloro-8-fluoro-3; 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester; method according to embodiment 33 makes 7-fluoro-10-chloro-9-ethanoyl-6; 11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester, yield 54.5%.
D) with 7-fluoro-10-chloro-9-ethanoyl-6; 11-dihydro-5H-dibenzo [b, e] azatropylidene-5-carboxylic acid, ethyl ester replaces 6-ethanoyl-5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester; method according to embodiment 33 makes 1-(2; the 4-difluorophenyl)-and 6-fluoro-4-oxygen-4,7,8; 13-tetrahydrochysene-1H-benzo [k] azatropylidene also [3; 4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 45.0%.
FAB-MS(m/z)：437(M+H) +。
Ultimate analysis: C 24H 15N 2O 3F 3
Calculated value (%) C66.06 H3.46 N6.42
Measured value (%) C66.07 H3.45 N6.40
Embodiment 36
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
A) replace the 2-fluorophenylacetic acid with 5-chloro-2-fluorophenylacetic acid, make 10-chloro-7-fluoro-3,4,6,11,12 according to the method for embodiment 4, the 12a-hexahydrobenzene is [e] pyrazine [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester also also, yield 4.9%.
B) with 10-chloro-7-fluoro-3,4,6; 11,12, the 12a-hexahydrobenzene is [e] pyrazine also [1 also; 2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester replaces 5-chloro-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 9-ethanoyl-10-chloro-7-fluoro-3 according to the method for embodiment 33; 4,6,11; 12; the 12a-hexahydrobenzene is [e] pyrazine [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester also also, yield 53.5%.
C) with 9-ethanoyl-10-chloro-7-fluoro-3,4,6,11; 12, the 12a-hexahydrobenzene also [e] pyrazine also [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester replace 6-ethanoyl-5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester; method according to embodiment 33 makes 1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8; 9,10,11,11a; 12,13-nine hydrogen-1H-pyrazine is [1,2-j] azatropylidene also [3 also; 4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 44.4%.
FAB-MS(m/z)：444(M+H) +。
Ultimate analysis: C 23H 20N 3O 3F 3
Calculated value (%) C62.30 H4.55 N9.48
Measured value (%) C62.31 H4.56 N9.45
Embodiment 37
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace 2-bromo-1-chloro-4-fluorobenzene with 2-bromo-1-chlorobenzene, make 1-(2 ,-difluorophenyl)-4-oxygen-4,7,8,9 according to the method for embodiment 33,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 7.1%.
FAB-MS(m/z)：357(M+H) +。
Ultimate analysis: C 19H 14N 2O 3F 2
Calculated value (%) C64.04 H3.96 N7.86
Measured value (%) C64.05 H3.99 N7.83
Embodiment 38
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene be the preparation of [3,4-h] quinoline-3-carboxylic acid also
Replace 1-chloro-4-fluoro-2-toluene with ortho-chlorotolu'ene, make 1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10 according to the method for embodiment 34,11-six hydrogen-1H-azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 1.5%.
FAB-MS(m/z)：371(M+H) +。
Ultimate analysis: C 20H 16N 2O 3F 2
Calculated value (%) C64.86 H4.35 N7.56
Measured value (%) C64.87 H4.37 N7.54
Embodiment 39
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
Replace 5-chloro-2-fluorobenzaldehyde with the 3-chlorobenzaldehyde, make 1-(2 ,-difluorophenyl)-4-oxygen-4,7,8 according to the method for embodiment 35,13-tetrahydrochysene-1H-benzo [k] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also, is faint yellow solid, total recovery 9.8%.
FAB-MS(m/z)：419(M+H) +。
Ultimate analysis: C 24H 16N 2O 3F 2
Calculated value (%) C68.90 H3.85 N6.70
Measured value (%) C68.92 H3.86 N6.68
Embodiment 40
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10,11,11a, 12, the also also preparation of [3,4-h] quinoline-3-carboxylic acid of [1,2-j] azatropylidene of 13-nine hydrogen-1H-pyrazine
Replace 5-chloro-2-fluorophenylacetic acid with the 3-chlorobenzene acetic acid, make 1-(2,4 difluorobenzene base)-4-oxygen-4,7,8 according to the method for embodiment 36,9,10,11,11a, 12,13-nine hydrogen-1H-pyrazine is [1,2-j] azatropylidene [3,4-h] quinoline-3-carboxylic acid also also, is faint yellow solid, total recovery 0.7%.
FAB-MS(m/z)：426(M+H) +。
Ultimate analysis: C 23H 21N 3O 3F 2
Calculated value (%) C64.93 H4.98 N9.88
Measured value (%) C64.95 H5.00 N9.85
Embodiment 41
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 5-chloro-6-(4-oxyethyl group-3,4-dioxy butyryl radicals)-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester condensation; method according to embodiment 33 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7; 8; 9,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 25.9%.
FAB-MS(m/z)：391(M+H) +。
Ultimate analysis: C 18H 13N 4O 3F 3
Calculated value (%) C55.39 H3.36 N14.35
Measured value (%) C55.41 H3.37 N14.32
Embodiment 42
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline-3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 6-chloro-7-(4-oxyethyl group-3,4-dioxy butyryl radicals)-9-fluoro-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester condensation; method according to embodiment 34 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7; 8,9,10; 11-six hydrogen-1H-azatropylidene also [3; 4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 28.4%.
FAB-MS(m/z)：405(M+H) +。
Ultimate analysis: C 19H 15N 4O 3F 3
Calculated value (%) C56.44 H3.74 N13.86
Measured value (%) C56.45 H3.76 N13.82
Embodiment 43
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 10-chloro-9-(4-oxyethyl group-3,4-dioxy butyryl radicals)-7-fluoro-6,11-dihydro-5H-dibenzo [b; e] azatropylidene-5-carboxylic acid, ethyl ester condensation, make 1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4 according to the method for embodiment 35; 7; 8,13-tetrahydrochysene-1H-benzo [k] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 27.8%.
FAB-MS(m/z)：453(M+H) +。
Ultimate analysis: C 23H 15N 4O 3F 3
Calculated value (%) C61.06 H3.34 N12.38
Measured value (%) C61.08 H3.37 N12.35
Embodiment 44
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 9-(4-oxyethyl group-3,4-dioxy butyryl radicals)-10-chloro-7-fluoro-3,4; 6,11,12; also also [1,2-a] azatropylidene-2 (the 1H)-carboxylic acid, ethyl ester condensation of [e] pyrazine of 12a-hexahydrobenzene makes 1-(6-amino-3 according to the method for embodiment 36; 5-difluoro pyridine-2-yl)-and 6-fluoro-4-oxygen-4,7,8; 9; 10,11,11a; 12; 13-nine hydrogen-1H-pyrazine [1,2-j] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 25.5%.
FAB-MS(m/z)：460(M+H) +。
Ultimate analysis: C 22H 20N 5O 3F 3
Calculated value (%) C57.51 H4.39 N15.24
Measured value (%) C57.53 H4.42 N15.23
Embodiment 45
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8,9,10-pentahydro--1H-piperidines is the preparation of [3,4-h] quinoline-3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 5-chloro-6-(4-oxyethyl group-3,4-dioxy butyryl radicals)-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester condensation; method according to embodiment 37 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7; 8; 9,10-pentahydro--1H-piperidines is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 26.4%.
FAB-MS(m/z)：373(M+H) +。
Ultimate analysis: C 18H 14N 4O 3F 2
Calculated value (%) C58.07 H3.79 N15.05
Measured value (%) C58.10 H3.81 N15.03
Embodiment 46
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8,9,10,11-six hydrogen-1H-azatropylidene is the preparation of [3,4-h] quinoline 3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 6-chloro-7-(4-oxyethyl group-3,4-dioxy butyryl radicals)-4,5-dihydro-1H-benzo [c] azatropylidene-2 (3H)-carboxylic acid, ethyl ester condensation; method according to embodiment 38 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7; 8,9,10; 11-six hydrogen-1H-azatropylidene also [3; 4-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 29.0%.
FAB-MS(m/z)：387(M+H) +。
Ultimate analysis: C 19H 16N 4O 3F 2
Calculated value (%) C59.07 H4.17 N14.50
Measured value (%) C59.09 H4.18 N14.48
Embodiment 47
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8, the also preparation of [3,4-h] quinoline-3-carboxylic acid of 13-tetrahydrochysene-1H-benzo [k] azatropylidene
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2; 4-difluoroaniline and 10-chloro-9-(4-oxyethyl group-3,4-dioxy butyryl radicals)-6,11-dihydro-5H-dibenzo [b; e] azatropylidene-5-carboxylic acid, ethyl ester condensation, make 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4 according to the method for embodiment 39; 7; 8,13-tetrahydrochysene-1H-benzo [k] azatropylidene is [3,4-h] quinoline-3-carboxylic acid also; be faint yellow solid, yield 23.9%.
FAB-MS(m/z)：435(M+H) +。
Ultimate analysis: C 23H 16N 4O 3F 2
Calculated value (%) C63.59 H3.71 N12.90
Measured value (%) C63.61 H3.72 N12.89
Embodiment 48
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8,9,10,11,11a, 12, the also also preparation of [3,4-h] quinoline-3-carboxylic acid of [1,2-j] azatropylidene of 13-nine hydrogen-1H-pyrazine
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2,4 difluorobenzene amine and 9-(4-oxyethyl group-3,4-dioxy butyryl radicals)-10-chloro-3; 4,6,11,12; also also [1,2-a] azatropylidene-2 (the 1H)-carboxylic acid, ethyl ester condensation of [e] pyrazine of 12a-hexahydrobenzene makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4 according to the method for embodiment 40; 7,8,9,10; 11,11a, 12,13-nine hydrogen-1H-pyrazine also [1; 2-j] azatropylidene [3,4-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 11.5%.
FAB-MS(m/z)：442(M+H) +。
Ultimate analysis: C 22H 21N 5O 3F 2
Calculated value (%) C59.86 H4.80 N15.87
Measured value (%) C59.87 H4.82 N15.87
Embodiment 49
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
A) with the 3-fluorophenol (949.0g, 8.45mol), benzyltrimethylammonium hydroxide (136.5ml, 773.5mmol) and vinyl cyanide (2.86L, 43.55mol) mixing solutions reflux 20h, be cooled to room temperature, add ether, use HCl and the distilled water wash of NaOH, the 1N of 1N successively.The organic layer anhydrous magnesium sulfate drying, concentrate 3-(3-fluorophenoxy) propionitrile (825.5g, 4.99mol), yield 59.0%.
B) (780.0g 4.74mol) and the mixing solutions reflux 16h of concentrated hydrochloric acid (3.6L), is cooled to room temperature with 3-(3-fluorophenoxy) propionitrile, filter, the filter cake distilled water wash, NaOH (18L) dissolving with 1N removes by filter insolubles, filtrate is used the concentrated hydrochloric acid acidifying, solid collected by filtration is used distilled water wash, and anhydrous magnesium sulfate drying gets 3-(3-fluorophenoxy) propionic acid (744.0g, 4.03mol), yield 85.1%.
C) to 3-(3-fluorophenoxy) propionic acid (720.0g, add in toluene 3.96mol) (9L) solution sulfur oxychloride (1.44L, 19.44mol).Reaction mixture reflux 1.5h, reduced vacuum concentrates, and resistates is dissolved in chloroform (9L), is cooled to-65 ℃, splash into trifluoromethanesulfonic acid (540.0ml, 6.12mol).Reaction mixture is risen to room temperature, stir 2h, add distilled water, layering, organic layer washs with the NaOH of 1N.Mix the organic layer anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure gets 5-fluoro-2 through the silicagel column purifying, and 3-dihydrobenzopyrans-4-ketone (345.6g, 2.09mol), yield 52.7%.
D) to ice-cold 5-fluoro-2, (342.0g adds NaN in sulfuric acid 2.05mol) (2.9L) solution to 3-dihydrobenzopyrans-4-ketone in batches 3(198.0g, 3.06mol), reaction mixture stirs 30min at 0 ℃, rises to room temperature, and stirring is spent the night.Reaction mixture is poured in the ice, NaOH with 1N is neutralized to pH=10, with dichloromethane extraction 3 times, mix the organic layer anhydrous magnesium sulfate drying, filtration, concentrate, get 6-fluoro-3 through the silicagel column purifying, 4-dihydrobenzo [f] [1,4] oxygen azatropylidene-5 (2H)-ketone (122.4g, 0.68mol), yield 33.3%.
E) with 6-fluoro-3,4-dihydrobenzo [f] [1,4] oxygen azatropylidene-5 (2H)-ketone replaces 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene-1-ketone, method according to embodiment 2 makes 1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 7.2%.
FAB-MS(m/z)：319(M+H) +。
Ultimate analysis: C 16H 15N 2O 4F
Calculated value (%) C60.37 H4.75 N8.80
Measured value (%) C60.38 H4.78 N8.76
Embodiment 50
1-cyclopropyl-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline 3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
A) with 1-chloro-2-oil of mirbane (315.1g 2.0mol) is heated to 160 ℃, stir in 30min, add down 2-fluoro-6-hydroxy benzaldehyde (224.2g, 1.6mol).Finish, continue to stir 1h, be cooled to room temperature, add frozen water, use ether extraction.Extract is removed insolubles after filtration, uses anhydrous sodium sulfate drying, vacuum concentration, resistates through the mixed solvent recrystallization of normal hexane and benzene get 2-fluoro-6-(2-nitro-phenoxy) phenyl aldehyde (365.7g, 1.4mol), yield 87.5%.
B) (143.7g adds Raney's nickel (7.2g) in dehydrated alcohol 0.55mol) (500ml) solution, and room temperature is led to H-H reaction 4.5h, removes by filter catalyzer, and filtrate is evaporated to dried to 2-fluoro-6-(2-nitro-phenoxy) phenyl aldehyde.Resistates gets 1-fluoro-10 with the normal hexane recrystallization, and 11-dihydro-dibenzo [b, f] [1,4] oxygen azatropylidene (90.4g, 0.42mol), yield 76.4%.
C) with 1-fluoro-10,11-dihydro-dibenzo [b, f] [1,4] the oxygen azatropylidene replaces 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene makes 1-cyclopropyl-6-fluoro-4-oxygen-4,7 according to the method for embodiment 2,8,9,10-pentahydro--1H-oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 10.0%.
FAB-MS(m/z)：367(M+H) +。
Ultimate analysis: C 20H 15N 2O 4F
Calculated value (%) C65.57 H4.13 N7.65
Measured value (%) C65.59 H4.14 N7.62
Embodiment 51
1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
A) under ice-water bath to piperazine-2-carboxylic acid's dihydrochloride (175.0g, 861.0mmol), dioxane (1.26L) and aqueous sodium hydroxide solution (5N, 630ml) splash into tert-Butyl dicarbonate (438.9g in the mixing solutions of Zu Chenging, 2.02mol), stirring at room 4h, remove solvent under reduced pressure, resistates washs with ether, under ice-water bath, transfer pH to 2～3, use ethyl acetate extraction, the extracting solution anhydrous magnesium sulfate drying with concentrated hydrochloric acid, remove solvent under reduced pressure and get 1,4-two tert-butoxycarbonyl-piperazines-2-carboxylic acid (220.5g, 667.1mmol), yield 77.5%.
B) under-10 ℃ to 1,4-two tert-butoxycarbonyl-piperazines-2-carboxylic acid (191.9g, 581.4mmol) tetrahydrofuran (THF) (1.9L) solution in 1h, add triethylamine (70.5g, 697.3mmol) and chloromethane tetryl formate (87.4g, 640.3mmol), reacting liquid filtering splashes into sodium borohydride (89.7g in filtrate under-10 ℃, 2.38mol) the aqueous solution (228ml), stir 1h.Add ethyl acetate (4.75L) and water (1.9L), (1N) decomposes unreacted sodium borohydride with hydrochloric acid, layering, ethyl acetate layer washes with water, anhydrous magnesium sulfate drying removes solvent under reduced pressure and gets 2-methylol piperazine-1,4-di-tert-butyl dicarboxylate (150.5g, 475.7mmol), yield 81.8%.
C) to 2-methylol piperazine-1, the 4-di-tert-butyl dicarboxylate (144.0g, add in methyl alcohol 453.6mmol) (3.96L) solution sodium hydroxide (71.6g, 1.79mol), reflux 16h, remove solvent under reduced pressure, in resistates, add distilled water, use ethyl acetate extraction, the extracting solution anhydrous magnesium sulfate drying, remove under reduced pressure solvent get 3-methylol piperazine-1-carboxylic acid tert-butyl ester (97.6g, 450.0mmol), yield 99.2%.
D) get 2, (101.1g 640.0mmol), is dissolved in a certain amount of anhydrous chlorides of rase sulfoxide the 6-difluoro-benzoic acid, adds amount of ethyl acetate, heating reflux reaction.After reaction finishes, boil off sulfur oxychloride, underpressure distillation gets 2, and (96.0g 544.0mmol), is colourless liquid, yield 85.0% to the 6-difluoro benzoyl chloride.
E) at room temperature to 3-methylol piperazine-1-carboxylic acid tert-butyl ester (95.0g; 438.9mmol) and triethylamine (91.8ml; 659.3mmol) tetrahydrofuran (THF) (1.9L) solution add 2; 6-difluoro benzoyl chloride (93.1g; 526.3mmol); stirring at room 1h; in reaction solution, add distilled water; use ethyl acetate extraction, the extracting solution anhydrous magnesium sulfate drying removes solvent under reduced pressure; resistates gets 4-(2 through the silicagel column purifying; the 6-difluoro benzoyl)-and 3-methylol piperazine-1-carboxylic acid tert-butyl ester (117.8g, 330.6mmol), yield 75.3%.
F) 4-(2 under the room temperature; the 6-difluoro benzoyl)-3-methylol piperazine-1-carboxylic acid tert-butyl ester (112.8g; 319.2mmol) DMF (2.4L) solution in add sodium hydride (60%, 38.4g, 957.6mmol); stirring at room 2h; in reaction solution, add frozen water, use ethyl acetate extraction, the extracting solution distilled water wash; anhydrous magnesium sulfate drying; remove solvent under reduced pressure, resistates gets 7-fluoro-6-oxygen-3,4 through the silicagel column purifying; 12; 12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester (88.8g also; 261.6mmol), yield 82.0%.
G) to 7-fluoro-6-oxygen-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester (87.5g also, 260.1mmol) tetrahydrofuran (THF) (450ml) solution in add borine tetrahydrofuran solution (1N, 1.04L, 1.04mol), stir 12h down at 65 ℃, be cooled to room temperature, and adding methyl alcohol (2.7L) and sodium hydroxide (225.0g, 5.63mol), stirring at room 1h, remove solvent under reduced pressure, in resistates, add distilled water, use ethyl acetate extraction, the extract anhydrous magnesium sulfate drying, remove solvent under reduced pressure, resistates gets 7-fluoro-3,4 through the silicagel column purifying, 12,12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester (54.4g also, 168.8mmol), yield 64.8%.
H) with 7-fluoro-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester replacement 7-fluoro-3,4,6,11,12, the 12a-hexahydrobenzene is [e] pyrazine [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester also also, method according to embodiment 4 makes 1-cyclopropyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 10.1%.
FAB-MS(m/z)：374(M+H) +。
Ultimate analysis: C 19H 20N 3O 4F
Calculated value (%) C61.12 H5.40 N11.25
Measured value (%) C61.15 H5.42 N11.23
Embodiment 52
1-cyclopropyl-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline 3-carboxylic acid also
A) replace the 3-fluorophenol with the 2-nitrophenols, make 9-nitro-3,4-dihydrobenzo [f] [1,4] oxygen azatropylidene-5 (2H)-ketone, yield 8.8% according to the method for embodiment 49.
B) with 9-nitro-3,4-dihydrobenzo [f] [1,4] oxygen azatropylidene-5 (2H)-ketone replaces 7-fluoro-6-oxygen-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester makes 9-nitro-2,3 according to the method for embodiment 51,4,5-tetrahydro benzo [f] [1,4] oxygen azatropylidene, yield 65.2%.
C) with 9-nitro-2,3,4,5-tetrahydro benzo [f] [1,4] oxygen azatropylidene replaces 8-fluoro-5-nitro-1,2,3, the 4-tetrahydroisoquinoline makes 1-cyclopropyl-4-oxygen-4 according to the method for embodiment 1,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 20.5%.
FAB-MS(m/z)：301(M+H) +。
Ultimate analysis: C 16H 16N 2O 4
Calculated value (%) C63.99 H5.37 N9.33
Measured value (%) C63.41 H5.38 N9.31
Embodiment 53
1-cyclopropyl-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
A) replace 2-fluoro-6-hydroxy benzaldehyde with the 2-hydroxy benzaldehyde, make 10,11-dihydro-dibenzo [b, f] [1,4] oxygen azatropylidene, yield 66.9% according to the method for embodiment 50.
B) with 10,11-dihydro-dibenzo [b, f] [1,4] the oxygen azatropylidene replaces 9-fluoro-2,3,4,5-tetrahydrochysene-1H-benzo [c] azatropylidene, method according to embodiment 2 makes 1-cyclopropyl-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 5.1%.
FAB-MS(m/z)：349(M+H) +。
Ultimate analysis: C 20H 16N 2O 4
Calculated value (%) C68.96 H4.63 N8.04
Measured value (%) C68.97 H4.65 N8.01
Embodiment 54
1-cyclopropyl-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] azatropylidene
A) with 2-fluoro-3-nitrotoluene (155.2g, 1.0mol) and potassium hydroxide (72.0g, distilled water 1.0mol) (500ml) solution is heated to and boils, and stirs to add potassium permanganate down in batches (316.0g 2.0mol), continues stirring reaction 4h.Filter, filtrate is acidified to pH=1～2 with concentrated hydrochloric acid, filters, and filtrate is poured in an amount of frozen water, and cooling crystallization filters, filter cake distilled water recrystallization, must 2-fluoro-3-nitrobenzoic acid (114.8g, 0.62mol), yield 62.0%.
B) with 2-fluoro-3-nitrobenzoyl acid substitution 2, the 6-difluoro-benzoic acid makes 10-nitro-3,4,12 according to the method for embodiment 51, and 12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester also, yield 34.0%.
C) with 10-nitro-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester replacement 7-fluoro-10-nitro-3,4,6,11,12, the 12a-hexahydrobenzene is [e] pyrazine [1,2-a] azatropylidene-2 (1H)-carboxylic acid, ethyl ester also also, method according to embodiment 4 makes 1-cyclopropyl-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] azatropylidene [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 20.9%.
FAB-MS(m/z)：356(M+H) +。
Ultimate analysis: C 19H 21N 3O 4
Calculated value (%) C64.21 H5.96 N11.82
Measured value (%) C64.23 H5.98 N11.79
Embodiment 55
1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with iodoethane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 49 makes 1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 73.2%.
FAB-MS(m/z)：307(M+H) +。
Ultimate analysis: C 15H 15N 2O 4F
Calculated value (%) C58.82 H4.94 N9.15
Measured value (%) C58.83 H4.96 N9.13
Embodiment 56
1-ethyl-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with iodoethane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 50 makes 1-ethyl-6-fluoro-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 72.6%.
FAB-MS(m/z)：355(M+H) +。
Ultimate analysis: C 19H 15N 2O 4F
Calculated value (%) C64.40 H4.27 N7.91
Measured value (%) C64.42 H4.28 N7.88
Embodiment 57
1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-6-fluoro-4-oxygen-7,8,9,11 with iodoethane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 51 makes 1-ethyl-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 70.1%.
FAB-MS(m/z)：362(M+H) +。
Ultimate analysis: C 18H 20N 3O 4F
Calculated value (%) C59.83 H5.58 N11.63
Measured value (%) C59.85 H5.57 N11.61
Embodiment 58
1-ethyl-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with iodoethane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 52 makes 1-ethyl-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 72.8%.
FAB-MS(m/z)：289(M+H) +。
Ultimate analysis: C 15H 16N 2O 4
Calculated value (%) C62.49 H5.59 N9.72
Measured value (%) C62.52 H5.60 N9.70
Embodiment 59
1-ethyl-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with iodoethane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 53 makes 1-ethyl-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 73.1%.
FAB-MS(m/z)：337(M+H) +。
Ultimate analysis: C 22H 21N 5O 3F 2
Calculated value (%) C67.85 H4.79 N8.33
Measured value (%) C67.85 H4.82 N8.32
Embodiment 60
1-ethyl-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-4-oxygen-7,8,9,11 with iodoethane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 54 makes 1-ethyl-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 69.8%.
FAB-MS(m/z)：344(M+H) +。
Ultimate analysis: C 18H 21N 3O 4
Calculated value (%) C62.96 H6.16 N12.24
Measured value (%) C62.97 H6.18 N12.21
Embodiment 61
1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 49 makes 1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 44.6%.
FAB-MS(m/z)：337(M+H) +。
Ultimate analysis: C 16H 14N 2O 4F 2
Calculated value (%) C57.14 H4.20 N8.33
Measured value (%) C57.16 H4.21 N8.32
Embodiment 62
1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with 1-bromo-2-fluorine cyclopropane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 50 makes 1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.9%.
FAB-MS(m/z)：385(M+H) +。
Ultimate analysis: C 20H 14N 2O 4F 2
Calculated value (%) C62.50 H3.67 N7.29
Measured value (%) C62.50 H3.68 N7.26
Embodiment 63
1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-6-fluoro-4-oxygen-7,8,9,11 with 1-bromo-2-fluorine cyclopropane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 51 makes 1-(2-fluorine cyclopropyl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 41.6%.
FAB-MS(m/z)：392(M+H) +。
Ultimate analysis: C 19H 19N 3O 4F 2
Calculated value (%) C58.31 H4.89 N10.74
Measured value (%) C58.33 H4.88 N10.72
Embodiment 64
1-(2-fluorine cyclopropyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluorine cyclopropane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 52 makes 1-(2-fluorine cyclopropyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 43.5%.
FAB-MS(m/z)：319(M+H) +。
Ultimate analysis: C 16H 15N 2O 4F
Calculated value (%) C60.37 H4.75 N8.80
Measured value (%) C60.39 H4.78 N8.76
Embodiment 65
1-(2-fluorine cyclopropyl)-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with 1-bromo-2-fluorine cyclopropane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 53 makes 1-(2-fluorine cyclopropyl)-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 45.1%.
FAB-MS(m/z)：367(M+H) +。
Ultimate analysis: C 20H 15N 2O 4F
Calculated value (%) C65.57 H4.13 N7.65
Measured value (%) C65.59 H4.14 N7.63
Embodiment 66
1-(2-fluorine cyclopropyl)-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-4-oxygen-7,8,9,11 with 1-bromo-2-fluorine cyclopropane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 54 makes 1-(2-fluorine cyclopropyl)-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 42.9%.
FAB-MS(m/z)：374(M+H) +。
Ultimate analysis: C 19H 20N 3O 4F
Calculated value (%) C61.12 H5.40 N11.25
Measured value (%) C61.15 H5.41 N11.23
Embodiment 67
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7 with 1-bromo-2-fluoroethane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 49 makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 54.2%.
FAB-MS(m/z)：325(M+H) +。
Ultimate analysis: C 15H 14N 2O 4F 2
Calculated value (%) C55.56 H4.35 N8.64
Measured value (%) C55.58 H4.37 N8.62
Embodiment 68
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with 1-bromo-2-fluoroethane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 50 makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 52.8%.
FAB-MS(m/z)：373(M+H) +。
Ultimate analysis: C 19H 14N 2O 4F 2
Calculated value (%) C61.29 H3.79 N7.52
Measured value (%) C61.31 H3.81 N7.50
Embodiment 69
1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-6-fluoro-4-oxygen-7,8,9,11 with 1-bromo-2-fluoroethane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 51 makes 1-(2-fluoro ethyl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 50.4%.
FAB-MS(m/z)：380(M+H) +。
Ultimate analysis: C 18H 19N 3O 4F 2
Calculated value (%) C56.99 H5.05 N11.08
Measured value (%) C57.01 H5.06 N11.08
Embodiment 70
1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7 with 1-bromo-2-fluoroethane, 9, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 10-three hydrogen-1H-oxygen azatropylidene, method according to embodiment 52 makes 1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 52.4%.
FAB-MS(m/z)：307(M+H) +。
Ultimate analysis: C 15H 15N 2O 4F
Calculated value (%) C58.82 H4.94 N9.15
Measured value (%) C58.83 H4.95 N9.15
Embodiment 71
1-(2-fluoro ethyl)-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace cyclopropane bromide and 8-ethoxycarbonyl-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6 with 1-bromo-2-fluoroethane, 7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 53 makes 1-(2-fluoro ethyl)-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 53.9%.
FAB-MS(m/z)：355(M+H) +。
Ultimate analysis: C 19H 15N 2O 4F
Calculated value (%) C64.40 H4.27 N7.91
Measured value (%) C64.42 H4.27 N7.89
Embodiment 72
1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline 3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
Replace cyclopropane bromide and 10-tertbutyloxycarbonyl-4-oxygen-7,8,9,11 with 1-bromo-2-fluoroethane, 11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene, method according to embodiment 54 makes 1-(2-fluoro ethyl)-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 51.7%.
FAB-MS(m/z)：362(M+H) +。
Ultimate analysis: C 18H 20N 3O 4F
Calculated value (%) C59.83 H5.58 N11.63
Measured value (%) C59.84 H5.57 N11.64
Embodiment 73
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
A) replace the 3-fluorophenol with 2-chloro-5-fluorophenol, make 9-chloro-6-fluoro-2,3-dihydrobenzo [f] [1,4] oxygen azatropylidene-4 (5H)-carboxylic acid, ethyl ester, yield 4.8% according to the method for embodiment 49.
B) 9-chloro-6-fluoro-2, and 3-dihydrobenzo [f] [1,4] oxygen azatropylidene-4 (5H)-carboxylic acid, ethyl ester replaces 5-chloro-8-fluoro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester, method according to embodiment 33 makes 1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 27.3%.
FAB-MS(m/z)：391(M+H) +。
Ultimate analysis: C 19H 13N 2O 4F 3
Calculated value (%) C58.47 H3.36 N7.18
Measured value (%) C58.49 H3.37 N7.18
Embodiment 74
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
A) to 2-chloro-5-fluorophenol (293.0g, 2.00mol), anhydrous magnesium dichloride (286.0g, 3.00mol) and triethylamine (759.0g, 7.50mol) acetonitrile (10L) solution in add Paraformaldehyde 96 (405.0g, 13.50mol), reaction mixture reflux 3.5h, be cooled to room temperature, the aqueous hydrochloric acid of adding 5% is used ether extraction, anhydrous magnesium sulfate drying, remove solvent under reduced pressure, resistates through the silicagel column purifying get 3-chloro-6-fluoro-2-hydroxy benzaldehyde (304.0g, 1.74mmol), yield 87.0%.
B) replace 2-fluoro-6-hydroxy benzaldehyde with 3-chloro-6-fluoro-2-hydroxy benzaldehyde, make 4-chloro-1-fluoro-10,11-dihydro-dibenzo [b, f] [1,4] oxygen azatropylidene, yield 66.9% according to the method for embodiment 50.
C) 4-chloro-1-fluoro-10, and 11-dihydro-dibenzo [b, f] [1,4] oxygen azatropylidene replaces 7-fluoro-10-nitro-6,11-dihydro-5H-dibenzo [b, e] azatropylidene makes 4-chloro-1-fluorine dibenzo [b according to the method for embodiment 3, f] [1,4] oxygen azatropylidene-10 (11H)-carboxylic acid, ethyl ester, yield 84.6%.
D) with 4-chloro-1-fluorine dibenzo [b, f] [1,4] oxygen azatropylidene-10 (11H)-carboxylic acid, ethyl ester replaces 5-chloro-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 1-(2 according to the method for embodiment 33,-difluorophenyl)-6-fluoro-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 24.2%.
FAB-MS(m/z)：439(M+H) +。
Ultimate analysis: C 23H 13N 2O 4F 3
Calculated value (%) C63.02 H2.99 N6.39
Measured value (%) C63.05 H3.01 N6.38
Embodiment 75
1-(2,4 difluorobenzene base)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene is [6,7-h] quinoline-3-also
The preparation of carboxylic acid
A) replace 8-fluorine isoquinoline 99.9 with 3-chloro-2-toluene fluoride, make 3-chloro-2-fluoro-6-nitrotoluene, yield 42.6% according to the method for embodiment 1.
B) replace 2-fluoro-3-nitrotoluene with 3-chloro-2-fluoro-6-nitrotoluene, make 3-chloro-2-fluoro-6-nitrobenzoic acid, yield 62.0% according to the method for embodiment 54.
C) with 3-chloro-2-fluoro-6-nitrobenzoyl acid substitution 2, the 6-difluoro-benzoic acid makes 10-chloro-7-nitro-6-oxygen-3 according to the method for embodiment 51,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester, yield 34.0%.
D) with 10-chloro-7-nitro-6-oxygen-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester replaces 8-fluoro-5-nitro-3,4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester, method according to embodiment 1 makes 10-chloro-7-amino-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester, yield 42.0%.
E) stir down to the anhydrous hydrogen fluoride (97.6g that is cooled to-15 ℃, 4.88mol) in slowly add 10-chloro-7-amino-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] and [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester (270.9g, 765.5mmol), slowly dropping is cooled to-15 ℃ Sodium Nitrite (55.4g in advance, 803.0mmol) hydrogen fluoride (temperature that keeps reaction system in the dropping process is a little less than 10 ℃ for 185.6g, 9.28mol) solution.With hydrazine hydrate (85%, 3.1g, 82.5mmol) with deionized water (3.1g) dilution after, under dry ice-methyl alcohol cryostat, add anhydrous hydrogen fluoride (29.5g, 1.48mol) in, join rapidly in the diazotization reaction system after mixing.In reaction system, add ethyl acetate, layering, organic layer concentrates to remove and desolvates, and resistates gets 10-chloro-7-fluoro-3,4 through the silicagel column purifying, 12,12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester (229.4g also, 643.0mmol), yield 84.0%.
F) 10-chloro-7-fluoro-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester replaces 5-chloro-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 1-(2 according to the method for embodiment 33, the 4-difluorophenyl)-and 6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 23.5%.
FAB-MS(m/z)：446(M+H) +。
Ultimate analysis: C 22H 18N 3O 4F 3
Calculated value (%) C59.33 H4.07 N943
Measured value (%) C59.34 H4.09 N9.42
Embodiment 76
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
Replace 2-chloro-5-fluorophenol with the 2-chlorophenol, make 1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9 according to the method for embodiment 73,10-pentahydro--1H-oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, is faint yellow solid, yield 1.5%.
FAB-MS(m/z)：373(M+H) +。
Ultimate analysis: C 19H 14N 2O 4F 2
Calculated value (%) C61.29 H3.79 N7.52
Measured value (%) C61.30 H3.81 N7.50
Embodiment 77
1-(2,4 difluorobenzene base)-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
Replace 2-chloro-5-fluorophenol with the 2-chlorophenol, make 1-(2,4 difluorobenzene base)-4-oxygen-4,7 according to the method for embodiment 74,8-three hydrogen-1H-benzo [k] oxygen azatropylidene is [6,7-h] quinoline-3-carboxylic acid also, is faint yellow solid, yield 14.8%.
FAB-MS(m/z)：421(M+H) +。
Ultimate analysis: C 23H 14N 2O 4F 2
Calculated value (%) C65.72 H3.36 N6.66
Measured value (%) C65.73 H3.38 N6.65
Embodiment 78
1-(2,4 difluorobenzene base)-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
A) replace 2 with 3-chloro-2-fluorobenzoic acid, the 6-difluoro-benzoic acid makes 10-chloro-3,4,12 according to the method for embodiment 51, and 12a-tetrahydrochysene-1H-benzo [f] pyrazine is [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester also, yield 33.6%.
B) the 10-chloro-3,4,12,12a-tetrahydrochysene-1H-benzo [f] pyrazine also [2,1-c] [1,4] oxygen azatropylidene-2 (6H)-carboxylic acid tert-butyl ester replaces 5-chloro-8-fluoro-3, and 4-dihydro-isoquinoline-2 (1H)-carboxylic acid, ethyl ester makes 1-(2 according to the method for embodiment 33, the 4-difluorophenyl)-and 4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 22.7%.
FAB-MS(m/z)：428(M+H) +。
Ultimate analysis: C 22H 19N 3O 4F 2
Calculated value (%) C61.82 H4.48 N9.83
Measured value (%) C61.83 H4.49 N9.83
Embodiment 79
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline 3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2,4-difluoroaniline and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7,9,10-three hydrogen-1H-oxygen azatropylidene also [6,7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4 according to the method for embodiment 73,7,8,9,10-pentahydro--1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 28.1%.
FAB-MS(m/z)：407(M+H) +。
Ultimate analysis: C 18H 13N 4O 4F 3
Calculated value (%) C53.21 H3.22 N13.79
Measured value (%) C53.23 H3.24 N13.76
Embodiment 80
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
With 2,6-diamino-3,5-difluoro pyridine replace 2,4 difluorobenzene amine and 8-ethoxycarbonyl-6-fluoro-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 74 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 27.5%.
FAB-MS(m/z)：455(M+H) +。
Ultimate analysis: C 22H 13N 4O 4F 3
Calculated value (%) C58.16 H2.88 N12.33
Measured value (%) C58.18 H2.89 N12.32
Embodiment 81
1-(6-amino-3,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline 3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2,4-difluoroaniline and 10-tertbutyloxycarbonyl-6-fluoro-4-oxygen-7,8,9,11,11a, 12-six hydrogen-1H-pyrazine [1,2-j] also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of oxygen azatropylidene, make 1-(6-amino-3 according to the method for embodiment 75,5-difluoro pyridine-2-yl)-6-fluoro-4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 24.8%.
FAB-MS(m/z)：462(M+H) +。
Ultimate analysis: C 21H 18N 5O 4F 3
Calculated value (%) C54.67 H3.93 N15.18
Measured value (%) C54.68 H3.95 N15.16
Embodiment 82
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8,9,10-pentahydro--1H-oxygen azatropylidene is the preparation of [6,7-h] quinoline-3-carboxylic acid also
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2,4-difluoroaniline and 8-ethoxycarbonyl-4-oxygen-7,9,10-three hydrogen-1H-oxygen azatropylidene also [6,7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, make 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4 according to the method for embodiment 76,7,8,9,10-pentahydro-1H-oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 28.7%.
FAB-MS(m/z)：389(M+H) +。
Ultimate analysis: C 18H 14N 4O 4F 2
Calculated value (%) C55.67 H3.63 N14.43
Measured value (%) C55.69 H3.65 N14.42
Embodiment 83
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7, the 8-three hydrogen-also preparation of [6,7-h] quinoline-3-carboxylic acid of 1H-benzo [k] oxygen azatropylidene
With 2,6-diamino-3,5-difluoro pyridine replace 2,4 difluorobenzene amine and 8-ethoxycarbonyl-4-oxygen-7-hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3 (4H)-carboxylic acid, ethyl ester condensation, method according to embodiment 77 makes 1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8-three hydrogen-1H-benzo [k] oxygen azatropylidene also [6,7-h] quinoline-3-carboxylic acid, be faint yellow solid, yield 23.4%.
FAB-MS(m/z)：436(M+H) +。
Ultimate analysis: C 23H 15N 3O 4F 2
Calculated value (%) C63.45 H3.47 N9.65
Measured value (%) C63.47 H3.48 N9.64
Embodiment 84
1-(6-amino-3,5-difluoro pyridine-2-yl)-4-oxygen-4,7,8,9,10,11,11a, the also preparation of [6,7-h] quinoline-3-carboxylic acid of 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene
With 2,6-diamino-3, the 5-difluoro pyridine replaces 2,4 difluorobenzene amine and 10-tertbutyloxycarbonyl-4-oxygen-7,8,9,11,11a, also [6,7-h] quinoline-3 (the 4H)-carboxylic acid, ethyl ester condensation of 12-six hydrogen-1H-pyrazine [1,2-j] oxygen azatropylidene makes 1-(6-amino-3 according to the method for embodiment 78,5-difluoro pyridine-2-yl)-and 4-oxygen-4,7,8,9,10,11,11a, 12-octahydro-1H-pyrazine [1,2-j] oxygen azatropylidene [6,7-h] quinoline-3-carboxylic acid also, be faint yellow solid, yield 10.9%.
FAB-MS(m/z)：444(M+H) +。
Ultimate analysis: C 21H 19N 5O 4F 2
Calculated value (%) C56.88 H4.32 N15.79
Measured value (%) C56.89 H4.34 N15.81
The structural formula of synthetic target compound sees Table 1～2 in embodiment 1～84.
[table 1]
Figure A200910078771D00591
Figure A200910078771D00601
[table 2]
Figure A200910078771D00611
Biological assay
The antibacterial activity in vitro test
The agar dilution of use standard is measured formula (I) ﹠amp; The ability of formula (II) and its pharmaceutically acceptable salt, solvate and derivative resisting gram-positive and negative Pseudomonas.
The following mensuration of minimal inhibitory concentration: the agar plate that a series of pastille concentration gradients of (1) preparation are successively decreased.(2) after the bacteria suspension dilution with 0.5 Maxwell standard opacity tube, draw the bacterium liquid for preparing with the multiple spot inoculator and be inoculated in agar plate surface, each bacterial plaque Chinese bacterium number is about 104CFU.Inoculation is that the no medicine contrast of inoculation earlier is dull and stereotyped in proper order, then from hanging down drug level to high drug level flat board.(3) after agar plate has been inoculated bacterium liquid, agar plate is inverted into 35 ℃ ± 2 ℃ incubators hatches 24h, observed and recorded MIC result.
MIC is interpretation standard as a result: according to the CLSI/NCCLS standard, be judged to be the minimum inhibitory concentration (MIC) of this medicine to this strain bacterium with the minimum concentration of asepsis growth plate.Experiment is the Quality Control bacterial strain with escherichia coli ATCC25922, streptococcus aureus ATCC29213, hemophilus influenzae ATCC49247, and all experiment all judges whether to meet the CLSI/NCCLS quality control standard with the MIC of Quality Control bacterial strain.
Test compound of the present invention is selected in the test medication for use, and numbering is as table 2; The contrast medicine Ciprofloxacin of selecting for use in the test (CPFX), levofloxacin (LVFX), Moxifloxacin (MFLX) are fastened city's sales item.
Following table is listed the MICs (μ g/mL) of part of compounds of the present invention and contrast medicine:
Table 3 in-vitro antibacterial test-results (MIC, μ g/mL)
CPFX LVFX MFLX No.5 No.6 No.7 No.8 No.9 No.11
MSSA 2 1 0.0626 0.0626 0.1252 0.5 1 2 2
Methicillin-resistant staphylococcus aureus 8 2 0.5 0.2504 0.5 2 4 4 8
Staphylococcus epidermidis 1 1 0.5 0.5 0.5 2 2 2 2
Streptococcus pneumoniae 4 1 0.1252 0.2504 0.2504 2 2 2 2
Faecalis 2 2 0.2504 0.1252 0.2504 2 1 1 1
Bacillus coli 0.1252 0.0626 0.1252 0.1252 0.0626 0.2504 0.5 0.5 0.2504
Klebsiella pneumonia 0.2504 0.2504 0.0626 0.2504 0.1252 0.2504 0.2504 0.2504 0.5
Emplastic serratia 0.0313 0.0313 0.0313 0.0313 0.0626 0.5 0.1252 0.2504 0.2504
Pseudomonas aeruginosa 0.2504 0.5 0.5 0.5 0.5 1 1 1 1
Hemophilus influenzae 0.1252 0.1252 ≤0.0313 0.0626 0.1252 0.1252 0.2504 0.5 0.2504
Proteus vulgaris ≤0.0313 0.0626 0.0626 0.0626 0.1252 0.2504 0.5 0.5 0.5
Bacteroides fragilis 2 1 0.5 0.5 0.5 1 0.5 1 1
Legionella pneumophilia 0.1252 0.0626 ≤0.0313 0.0626 ≤0.0313 0.2504 0.5 0.2504 0.5
Mycoplasma pneumoniae 0.5 0.5 0.0626 ≤0.0313 0.0626 0.5 0.5 1 1
Chlamydia pneumoniae 1 1 0.1252 0.1252 0.0626 1 1 1 1
Tubercule bacillus 2 1 0.1252 0.0626 0.1252 1 2 1 1
Continuous table 3 in-vitro antibacterial test-results (MIC, μ g/mL)
No.13 No.15 No.17 No.19 No.20 No.21 No.25 No.27 No.29
MSSA 0.0626 0.0313 0.0626 ≤0.0313 ≤0.0313 0.0313 0.0626 0.0626 0.0313
Methicillin-resistant staphylococcus aureus 0.2504 0.5 0.2504 0.2504 0.2504 0.1252 0.1252 0.2504 0.2504
Staphylococcus epidermidis 0.5 0.5 1 1 0.2504 0.5 1 1 0.2504
Streptococcus pneumoniae 0.1252 0.2504 0.2504 0.1252 0.2504 0.0626 0.2504 0.5 0.5
Faecalis 0.2504 0.2504 0.1252 0.2504 0.2504 0.5 0.1252 0.2504 0.2504
Bacillus coli 0.0626 0.0626 0.1252 0.0626 0.1252 0.1252 0.0626 0.1252 0.1252
Klebsiella pneumonia 0.0626 0.0626 0.0626 0.0626 0.1252 0.0626 0.0626 ≤0.0313 ≤0.0313
Emplastic serratia 0.0313 ≤0.0313 0.0313 0.0313 ≤0.0313 0.0313 0.0313 0.0313 ≤0.0313
Pseudomonas aeruginosa 0.2504 0.5 0.5 0.5 0.2504 0.2504 0.5 0.2504 0.2504
Hemophilus influenzae ≤0.0313 ≤0.0313 0.0626 ≤0.0313 0.0626 ≤0.0313 0.1252 0.0626 0.0626
Proteus vulgaris 0.0626 0.1252 0.0626 0.0626 0.0626 0.0626 0.0626 ≤0.0313 ≤0.0313
Bacteroides fragilis 0.5 0.5 0.2504 0.5 0.2504 0.2504 0.5 0.5 0.5
Legionella pneumophilia 0.0626 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313
Mycoplasma pneumoniae ≤0.0313 0.0626 0.0626 ≤0.0313 0.0626 0.0626 0.0626 ≤0.0313 0.0626
Chlamydia pneumoniae 0.1252 0.0626 0.1252 0.1252 0.0626 0.0626 0.1252 0.1252 0.1252
Tubercule bacillus 0.0626 ≤0.0313 ≤0.0313 0.0626 0.1252 0.1252 0.0626 0.1252 0.1252
Continuous table 3 in-vitro antibacterial test-results (MIC, μ g/mL)
No.31 No.34 No.35 No.37 No.39 No.41 No.42 No.45 No.49
MSSA ≤0.0313 0.0313 ≤0.0313 ≤0.0313 ≤0.0313 0.0313 0.0626 0.0626 0.0313
Methicillin-resistant staphylococcus aureus 0.2504 0.5 0.2504 0.2504 0.2504 0.1252 0.2504 0.5 0.2504
Staphylococcus epidermidis 0.2504 1 1 1 0.5 0.5 1 1 0.2504
Streptococcus pneumoniae 0.0626 0.0626 0.1252 0.0626 0.2504 0.0626 0.2504 0.1252 0.2504
Faecalis 0.1252 0.2504 0.1252 0.1252 0.2504 0.2504 0.1252 0.2504 0.2504
Bacillus coli 0.1252 0.0626 0.1252 0.1252 0.1252 0.1252 0.1252 0.1252 0.1252
Klebsiella pneumonia 0.0626 0.0626 0.0626 0.0626 0.1252 0.0626 0.0626 ≤0.0313 ≤0.0313
Emplastic serratia 0.0313 ≤0.0313 0.0313 0.0313 ≤0.0313 0.0313 0.0313 0.0313 ≤0.0313
Pseudomonas aeruginosa 0.2504 0.5 0.1252 0.5 0.2504 0.5 0.5 0.2504 0.5
Hemophilus influenzae 0.0626 ≤0.0313 0.0626 0.0626 0.0626 ≤0.0313 0.0626 ≤0.0313 ≤0.0313
Proteus vulgaris 0.0626 0.1252 ≤0.0313 0.0626 ≤0.0313 0.0626 0.0626 ≤0.0313 0.0626
Bacteroides fragilis 0.5 0.2504 0.2504 0.5 0.2504 0.5 0.5 0.2504 0.5
Legionella pneumophilia 0.0626 0.0626 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313
Mycoplasma pneumoniae ≤0.0313 0.0626 ≤0.0313 0.0626 ≤0.0313 ≤0.0313 ≤0.0313 0.0626 ≤0.0313
Chlamydia pneumoniae 0.1252 0.1252 0.0626 0.1252 0.1252 0.0626 0.1252 0.0626 0.0626
Tubercule bacillus 0.0626 0.0626 ≤0.0313 0.1252 0.0626 ≤0.0313 0.1252 0.1252 0.1252
Continuous table 3 in-vitro antibacterial test-results (MIC, μ g/mL)
No.50 No.51 No.52 No.55 No.56 No.58 No.61 No.62 No.63
MSSA ≤0.0313 0.0313 ≤0.0313 0.0626 ≤0.0313 0.0313 0.0626 0.0313 0.0313
Methicillin-resistant staphylococcus aureus 0.2504 0.5 0.1252 0.5 0.1252 0.5 0.5 0.2504 0.1252
Staphylococcus epidermidis 0.2504 0.5 0.2504 0.5 0.5 0.2504 0.1252 0.2504 0.1252
Streptococcus pneumoniae 0.0626 0.1252 0.0626 0.1252 0.0626 0.1252 0.1252 0.1252 0.1252
Faecalis 0.1252 0.2504 0.1252 0.2504 0.1252 0.1252 0.1252 0.2504 0.2504
Bacillus coli 0.0626 0.0626 0.0626 0.1252 0.0626 0.0626 0.1252 0.1252 0.0626
Klebsiella pneumonia 0.0626 ≤0.0313 0.0626 0.0626 ≤0.0313 ≤0.0313 0.0626 0.0626 0.0626
Emplastic serratia ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313
Pseudomonas aeruginosa 0.5 0.2504 0.5 0.5 0.2504 0.5 0.2504 1 0.2504
Hemophilus influenzae ≤0.0313 0.0626 0.0313 0.0626 ≤0.0313 ≤0.0313 ≤0.0313 0.0313 0.0626
Proteus vulgaris 0.0626 ≤0.0313 ≤0.0313 0.0626 ≤0.0313 0.0626 0.0626 0.0626 0.1252
Bacteroides fragilis 0.2504 0.5 0.2504 0.5 0.2504 0.2504 0.2504 0.5 0.5
Legionella pneumophilia ≤0.0313 0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313
Mycoplasma pneumoniae ≤0.0313 0.0626 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 ≤0.0313 0.0626 ≤0.0313
Chlamydia pneumoniae 0.0626 0.0626 0.1252 0.1252 0.1252 0.0626 0.0626 0.0626 0.1252
Tubercule bacillus ≤0.0313 0.0626 ≤0.0313 0.1252 ≤0.0313 0.0626 0.1252 0.0626 0.1252
Continuous table 3 in-vitro antibacterial test-results (MIC, μ g/mL)
No.65 No.68 No.70 No.71 No.73 No.77 No.79
MSSA ≤0.0313 0.0626 0.0626 0.1252 0.0626 0.0626 0.0313
Methicillin-resistant staphylococcus aureus 0.2504 0.5 0.5 1 0.2504 0.5 0.2504
Staphylococcus epidermidis 0.1252 0.1252 0.2504 0.5 0.2504 0.2504 0.2504
Streptococcus pneumoniae 0.2504 0.0626 0.1252 0.2504 0.2504 0.2504 0.1252
Faecalis 0.2504 0.2504 0.1252 0.5 0.2504 0.5 0.1252
Bacillus coli 0.1252 0.2504 0.0626 0.1252 0.2504 0.2504 0.1252
Klebsiella pneumonia 0.0626 0.0626 0.0626 0.0313 0.1252 0.0626 0.0626
Emplastic serratia ≤0.0313 ≤0.0313 ≤0.0313 0.0313 0.0313 ≤0.0313 0.0313
Pseudomonas aeruginosa 0.5 1 0.5 1 0.2504 0.2504 0.5
Hemophilus influenzae ≤0.0313 0.0626 ≤0.0313 0.0313 ≤0.0313 ≤0.0313 ≤0.0313
Proteus vulgaris 0.0626 0.1252 0.1252 0.0626 0.0626 0.1252 0.0626
Bacteroides fragilis 0.2504 1 0.5 1 0.5 0.2504 0.5
Legionella pneumophilia ≤0.0313 0.0313 0.0626 0.0626 ≤0.0313 0.0313 0.0313
Mycoplasma pneumoniae 0.0313 0.0626 0.0313 0.0313 0.0313 0.0626 ≤0.0313
Chlamydia pneumoniae 0.0626 0.0626 0.0626 0.1252 0.1252 0.0626 0.1252
Tubercule bacillus 0.1252 0.1252 0.0626 0.0626 0.1252 0.0626 0.1252

Claims (15)

1. formula (I) or compound (II), its salt or its solvate:
Figure A200910078771C00021
Or
Figure A200910078771C00022
Wherein
R 1Be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkylamine, dialkylamine, aryl and the aralkyl that replaces arbitrarily;
R 2, R 3And R 4Each independently is hydrogen atom or Q-R 8Or R 4Be hydrogen atom or Q-R 8, R 2And R 3Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring; Or R 2Be hydrogen atom or Q-R 8, R 3And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
Q is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replaces arbitrarily;
R 8Be hydrogen atom, NR 9R 10Or the alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replace arbitrarily;
R 9And R 10Each independently is alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl of hydrogen atom or replacement arbitrarily, or R 9And R 10Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring;
A is N or CR 6
R 6Alkyl, aryl, aralkyl, heterocyclic radical and Heterocyclylalkyl for hydrogen atom or replacement arbitrarily;
B is N or CR 7
R 7Be hydrogen atom, halogen atom, hydroxyl or any alkoxyl group that replaces; Or R 7And R 4Together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with 3-, 4-, the assorted naphthenic ring of 5-, 6-or 7-unit;
R 5Be hydrogen atom or any alkyl that replaces;
N is 1,2 or 3;
M is 1,2 or 3;
X is C, N, O or S.
2. compound as claimed in claim 1, its salt or its solvate, wherein
Substituting group is halogen atom, nitro, cyano group, hydroxyl, C arbitrarily 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Halogenated alkoxy, amino, C 1-6Alkylamino radical, two (C 1-6Alkyl) amido, formyl radical, C 1-6Carbalkoxy, carboxyl, C 1-6Aldehyde radical, C 1-6Alkane sulfydryl, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, carbamyl, C 1-6Alkylamino radical.
3. as the described compound of claim 1-2, its salt or its solvate, wherein
Substituting group is halogen atom, nitro, cyano group, hydroxyl, C arbitrarily 1-4Alkyl, C 1-4Haloalkyl, C 1-4Alkoxyl group, C 1-4Halogenated alkoxy.
4. as the described compound of claim 1-3, its salt or its solvate, wherein
R 1Be the C that replaces arbitrarily 1-6Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, amino, C 1-6Alkylamine, C 1-6Dialkylamine, C 6-10Aryl and C 7-11Aralkyl;
A is CR 6
R 6Be hydrogen atom or any C that replaces 1-6Alkyl, C 6-10Aryl, C 7-11(its heterocyclic radical is the C of 5 yuan or 6 yuan rings for aralkyl, heterocyclic radical (this heterocyclic radical is 5 yuan or 6 yuan of rings) and Heterocyclylalkyl 1-6Alkyl);
R 5Be hydrogen atom or any C that replaces 1-6Alkyl.
5. as the described compound of claim 1-4, its salt or its solvate, wherein
B is CR 7
R 7Be hydrogen atom, halogen atom, hydroxyl or any C that replaces 1-6Alkoxyl group.
6. as the described compound of claim 1-5, its salt or its solvate, wherein
R 2, R 3And R 4Each independently is hydrogen atom or Q-R 8Or R 4Be hydrogen atom or Q-R 8, R 2And R 3Be the C that replaces arbitrarily together 2-6Thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring (its heterocyclic radical is the C of 5 yuan or 6 yuan rings 1-6Alkyl); Or R 2Be hydrogen atom or Q-R 8, R 3And R 4Be the C that replaces arbitrarily together 2-6Thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring (its heterocyclic radical is the C of 5 yuan or 6 yuan rings 1-6Alkyl);
Q is the C that replaces arbitrarily 1-6Alkyl, C 6-10Aryl, C 7-11(its heterocyclic radical is the C of 5 yuan or 6 yuan rings for aralkyl, heterocyclic radical (this heterocyclic radical is 5 yuan or 6 yuan of rings) or Heterocyclylalkyl 1-6Alkyl);
R 8Be hydrogen atom, NR 9R 10Or the C that replaces arbitrarily 1-6Alkyl, C 6-10Aryl, C 7-11(its heterocyclic radical is the C of 5 yuan or 6 yuan rings for aralkyl, heterocyclic radical (this heterocyclic radical is 5 yuan or 6 yuan of rings) or Heterocyclylalkyl 1-6Alkyl);
R 9And R 10Each independently is hydrogen atom or any C that replaces 1-6Alkyl, C 6-10Aryl, C 7-11(its heterocyclic radical is the C of 5 yuan or 6 yuan rings for aralkyl, heterocyclic radical (this heterocyclic radical is 5 yuan or 6 yuan of rings) or Heterocyclylalkyl 1-6Or R alkyl), 9And R 10Be the C that replaces arbitrarily together 2-6Thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring (its heterocyclic radical is the C of 5 yuan or 6 yuan rings 1-6Alkyl).
7. as the described compound of claim 1-6, its salt or its solvate, wherein
R 2, R 3And R 4Each independently is a hydrogen atom; Or R 4Be hydrogen atom, R 2And R 3Be the C that replaces arbitrarily together 2-6Thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring (its heterocyclic radical is the C of 5 yuan or 6 yuan rings 1-6Alkyl); Or R 2Be hydrogen atom, R 3And R 4Be the C that replaces arbitrarily together 2-6Thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or 7-unit heterocycloalkyl ring (its heterocyclic radical is the C of 5 yuan or 6 yuan rings 1-6Alkyl).
8. as the described compound of claim 1-7, its salt or its solvate, wherein
R 1Be the C that replaces arbitrarily 1-6Alkyl, C 3-6Cycloalkyl, C 6-10Aryl;
A is CR 6R 6Be hydrogen atom;
R 5Be hydrogen atom.
9. as the described compound of claim 1-8, its salt or its solvate, wherein
B is CR 7R 7Be hydrogen atom, halogen atom.
10. medicine is characterized in that containing among the claim 1-9 any described compound, its salt or its solvated compounds as effective constituent.
11. an antimicrobial drug is characterized in that containing among the claim 1-9 any described compound, its salt or its solvate as effective constituent.
12. a curative that infects disease is characterized in that containing among the claim 1-9 any described compound, its salt or its solvate as effective constituent.
13. a treatment of diseases method is characterized in that giving any described compound, its salt or its solvate among the claim 1-9.
14. a methods of treatment that infects disease is characterized in that giving any described compound, its salt or its solvate among the claim 1-9.
15. any described compound, its salt or its solvate application in antimicrobial drug is produced among the claim 1-9.
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