CN1246157A - Enzymatic resolution of benzodiazepine-acetic acid esters with lipase - Google Patents

Enzymatic resolution of benzodiazepine-acetic acid esters with lipase Download PDF

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CN1246157A
CN1246157A CN97181853A CN97181853A CN1246157A CN 1246157 A CN1246157 A CN 1246157A CN 97181853 A CN97181853 A CN 97181853A CN 97181853 A CN97181853 A CN 97181853A CN 1246157 A CN1246157 A CN 1246157A
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methyl
benzodiazepine
tetrahydrochysene
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A·S·维尔斯
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SmithKline Beecham Ltd
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    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
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    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
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Abstract

The present invention involves enantiomerically pure benzodiazepine * acetic acid esters and methods of preparing them by resolving a racemic mixture utilizing a lipase.

Description

The enzyme that carries out benzodiazepine -acetic ester with lipase splits
Invention field
The present invention relates to carry out the fractionation of the optically active isomer of compound with lipase.
Background of invention
People know can use the proteolytic ferment ester hydrolysis.In some cases, when the substrate ester had one or more chiral carbon atom, this proteolytic ferment can react than another kind of enantiomorph quickly with a kind of enantiomorph in the racemic mixture.For suitable substrate, this chemo-selective can be as the basis of this mixture fractionation.The product of this kind selective hydrolysis reaction is the carboxylic acid and the alcohol of the enantiomorph of reaction, and unreacted enantiomorph still is an ester.The easily separated property of described subsequently ester and acid becomes the basis of carboxylic acid or alcohol moiety stereochemistry purifying.
Generally speaking, when chirality and complicacy residue in the carboxylic moiety of molecule, then prepare corresponding chiral acid, and when complicacy and chirality residue in alcohol moiety, so then prepare chiral alcohol with lipase with esterase or proteolytic enzyme.Yet, the also known part example of people with the acid of lipase resolving chiral.
The stereochemistry purity of this method depends on the hydrolysis rate of every kind of isomer of racemoid usually, and is big more as relative rate difference, and the purity of final chiral product is then high more.Can no matter find suitable enzyme, the selection of the suitable enzyme of the compound that selective hydrolysis is given is decision by rule of thumb usually.Therefore, as useful enzyme, this enzyme must be substrate, the suitable enantiomorph of selective hydrolysis and produce acceptable enantiomeric excess (e.e.) only with the required compound.
WO 93/00095 (PCT/US/92/05463) and WO 94/14776 (PCT/US93/12436), WO 95/18619 (PCT/US95/00248) and PCT/US96/11108 disclose the benzodiazepine compound that partly has pharmaceutical use.This compounds is exactly this situation, and its pharmacologically active is mainly in a kind of enantiomorph of the racemoid of reporting therein.Therefore, people need prepare the method for non-racemic compound.Reported method is based on synthesizing enantiomer separation by chirality high performance liquid chromatography (HPLC) and homochiral therein.Yet the HPLC method has usually and is difficult to the shortcoming of carrying out on a large scale, the synthetic chiral synthon of chirality based on costliness, and may be in synthetic the generation partial racemization.Therefore, the Stereoselective method that needs new this compounds of preparation.
We have now found that by with the method for splitting of lipase stereo selective hydrolysis racemic mixture that derives from yeast Candida Antarctica, can prepare disclosed compound among WO93/00095 (PCT/US/92/05463), the WO 94/14776 (PCT/US93/12436) of non-racemic form and the WO95/18619 (PCT/US95/00248).This method for splitting carries out easily and has high selectivity, and has represented chirality 3-oxo-1, the important breakthrough of 4-benzodiazepine acetate chemical field.The fractionation of carrying out racemize benzodiazepine with enzymic hydrolysis had not before had report.
The present invention's summary
On the one hand, the present invention derives from one of lipase selective hydrolysis chirality enzyme of Candida Antarctica for using, thereby splits the 3-oxo-2,3,4 that some racemize replaces, 5-1H-tetrahydrochysene-1, the method for 4-benzodiazepine -2-acetic ester.
Another aspect of the invention is the 3-oxo-2,3,4 of enantiomer-pure replacement basically, 5-1H-tetrahydrochysene-1,4-benzodiazepine -2-acetic acid compound, the particularly a kind of like this compound that from racemic compound, prepares by the enzymic hydrolysis process.
In yet another aspect, the present invention is for improving 3-oxo-2,3,4,5-1H-tetrahydrochysene-1, the method for 4-benzodiazepine -2-acetate stereochemistry purity.
Aspect another, the present invention includes and be used for the specific midbody compound of pharmaceutical product synthetic.
At last, the present invention is the preparation of immobilised Candida Antarctica lipase B and produces the method for such preparation.
Detailed description of the present invention
The present invention is the method for preparation formula (I) compound: In formula (I), X is hydrogen, halogen, CO 2R 3, OR 4, COR 5Or Fibrinogen or vitronectin antagonists side chain; R 2Be C 1-6Alkyl, optional by Ar, Het or C 1-6Cycloalkyl substituted; R 3Be C 1-6Alkyl or benzyl; R 4Be C 1-6Alkyl, COR 3Or benzyl; R 5Be 4,4 '-Lian piperidines-1-base, (1 '-benzyloxycarbonyl)-4,4 '-Lian piperidines-1-base or (1 '-uncle-butoxy carbonyl)-4,4 '-Lian piperidines-1-base; Described method comprises: B handles formula (II) compound with Candida Antarctica lipase:
Figure A9718185300082
R wherein 1Be C 1-20Alkyl or C 3-20Alkenyl, optional by Ar, NR 2Or NR 3 +Replace, wherein R is C 1-4Alkyl, and make (S)-2,3,4 of generation, 5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-alphatic acid separates with corresponding (R)-ester.
The 3-oxo-2,3,4 of formula (I), 5-1H-tetrahydrochysene-1,4-benzodiazepine acetic ester are important pharmaceutical products or are the intermediate in the pharmaceutical product preparation.As described in the WO 95/18619 (PCT/US95/00248), (S) steric isomer of these compounds has pharmacologically active.Therefore, need carry out that homochiral is synthetic, physical sepn or chemistry split.Although reported that the physics of this compounds splits and homochiral is synthetic, but do not obtained chemistry and split.
We have now found that Candida Antarctica lipase B can highly-solid selectively ground and the 3-oxo-2,3,4 that replaces of optional 7-, 5-tetrahydrochysene-1, and 4-benzodiazepine -acetic ester reaction obtains (S)-acid.And (R)-enantiomorph is not effective hydrolysis substrate of this enzyme, so hydrolysis spontaneous stopping when about 50% transforms.This enzyme also is extremely sensitive for the specific replacement of (S)-substrate.For example, methylene radical replaces 1, loss of activity during the 1-nitrogen of 4-benzodiazepine .Equally, when the X substituting group be CO 2R 3The time, the X substituting group is moved to the forfeiture that the 8-position causes hydrolytic activity by 7-.Yet the diversity that benzodiazepine ring is 7 but allows.In formula (II), R 1Be suitably for C 1-12Alkyl or C 1-12Alkenyl optional is replaced by phenyl.R 1Be more suitable for being C 1-4Alkyl or benzyl.R 2Be suitably for H or C 1-4Alkyl optional is replaced by phenyl.In formula (II), R 1Be preferably methyl, R 2Be methyl.X is suitably for H, bromo, iodo, tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, hydroxyl, methoxyl group, (4,4 '-Lian piperidines-1-yl) carbonyl or [1 '-tert-butoxycarbonyl-(4,4 '-Lian piperidines-1-yl)] carbonyl.R 3Be preferably the tertiary butyl.
Used enzyme can be full cell culture, enzyme extract, isolating enzyme or the isolating enzyme part that is connected with solid carrier such as macroporous acrylic resin.The load preparation of Candida Antarctica lipase B can be from Novo Nordisk, and Badsvaerd, Denmark are obtained by commerce with Novozym 435 and from Boehringer Mannheim Gmbh, Mannheim, and Germany is obtained by commerce with L-2 lipase.This enzyme is generally heat-staple, and can tolerate the organic solvent of multiple high density.Because the easy property handled, so the preferred load preparation of this enzyme.
Yet, when using the load preparation of this enzyme, may produce some problem, particularly when this enzyme and resin be that non covalent bond is when combining.For example, we find that the operable number of times of resin-carried enzyme may be somewhat limited owing to proteic leaching.In addition, we find when reaction is carried out on a large scale, because albumen drip washing may form emulsion.
We find these problems can by with linking agent as glutaraldehyde to as described in resin carry out pre-treatment and overcome.Other linking agent also is useful as dimethyl suberimidate and glutaraldehyde oligomer.Generally speaking, this pre-treatment only be included in organic solvent as in the trimethyl carbinol and the water mixture with glutaraldehyde with as described in plastic resin treatment a few hours.This processing can make stable resin, so that the enzyme of losing on by this resin when each the use still less, therefore can increase the number of times that this resin re-uses.
Described hydrolysis is generally carried out in water and ORGANIC SOLVENT MIXTURES.Multiple organic solvent is useful, as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), uncle-butanols, benzene and toluene, uses solution or two-phase system also to be fit to.Yet, when selecting appropriate solvent, can need to carry out some tests, so that the solubility property of Substrate conforms to.For example, when selecting acetone-water mixture to make solvent, Substrate (R, S)-and methyl 7-[(1 '-tert-butoxycarbonyl-(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetic ester reactive relatively poor.If use uncle-butanol/water mixture, then reaction is carried out steadily.Ketone and secondary alcohol and tertiary alcohols are especially suitable for use as the organic solvent of a phase system.The increase of speed of reaction can obtain by the mixture that uses two-phase system such as water and aromatic solvent mixture such as water and benzene,toluene,xylene or trimethylbenzene sometimes.Particularly suitable is water/toluene.
Can cushion or keep constant pH by adding alkali and carry out reaction mixture.Yet between pH6.0-8.0, the general variation of the speed of reaction or stereoselectivity is very little.
Reaction is adapted at more than 20 ℃ temperature and carries out.Generally speaking, if be reflected at room temperature according to appointment 28-45 ℃ carry out, can reduce the consumption and the reaction times of solvent so.For example, if react at about 36 ℃, the solvent of 200 parts of volumes can be reduced to the solvent of about 40 parts of volumes so, and the reaction times also can be reduced to about 24 hours by 4 days.
Described reaction generally proceeds to 50% starting ester consumption.This can pass through HPLC (preferred chirality HPLC) monitoring.Since (R)-ester is the relatively poor substrate of this enzyme, so the reaction times is not crucial.Generally speaking, according to the temperature of reaction, used solvent and substrate, the reaction times can range from hours to a couple of days.Generally be fit in 10-24 hour.
Although many other lipase also be selectively acting in 3-oxo-2,3,4 of the present invention, 5-tetrahydrochysene-1, the effective enzyme of 4-benzodiazepine compound, this ring system is only accepted CandidaAntarctica lipase B can the selective hydrolysis substrate.For example, this reaction can't be carried out when testing the lipase in following source: porcine pancreatic lipase, Candida lipolytica, Candida Cylindracea, melon Mucor, fluorescent pseudomonas, Aspergillus usamii, geotrichum candidum, aspergillus niger, Humicola Lanuginosa, Ammano SAM2, rhizopus arrhizus, Penicilliumcycopum, snow-white head mold, melon head mold, Ammano lipase A, RhizopusDelewar, Lou ground poison mould and Boehringer lipase-L-1, L-3, L-4, L-5, L6 and L-8.Derive from the also reactionless activity of second kind of lipase-lipase A of Candida Antarctica.
The methyl ester of the unsubstituted benzodiazepine of the equal hydrolyzable 7-of other lytic enzyme such as Carlsberg subtilisin and pork liver lipase, but stereoselectivity is very little.
Use the routine techniques that separates ester and acid to separate carboxylic acid product and unreacted ester.Generally speaking, reaction mixture is transferred to the pH (as＞7) and the high salt concn of alkalescence, and with suitable organic solvent extraction.The unreacted ester that makes like this is dissolved in the organic solvent, and carboxylic acid product is present in water layer.Dry and evaporate organic solvent and obtain chiral ester; And acidifying water layer, extraction, drying and evaporate organic solvent and obtain required chiral acid.Other technology is as using crystallization or all can be used to separate acid and ester through silica-gel carrier or ion-exchange or other suitable resin chromatography, and is included in the scope of the present invention.
Can use other correlation technique of the carboxylic acid product of separating specific ester substrate and generation.For example, (R)-7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine -solvability of 2-methyl acetate in water is very high, extracts from water layer even therefore also be difficult under alkaline pH.In such cases, can be beneficial to separate with the acid of the agent treated reaction of the reaction words property of preferential and a kind of substrate reactions and the mixture of ester products.For example; we find to use carbonyl benzyloxy chlorine, tert-butoxycarbonyl chlorine or corresponding acid anhydrides to handle (S)-7-[(4 at about 7.0 o'clock at pH; 4 '-Lian piperidines-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate and its be (R) methyl esters isomer accordingly, can produce the preferential acidylate of the piperidines basic ring of described ester.In case after the piperidine ring acidylate, this ester can preferentially be dissolved in the organic solvent so, therefore can pass through extracting and separating.
Being fit to the prepared according to the methods of the invention product is enantiomer-pure basically.Generally speaking greater than 80% (e.e), be preferably greater than 90%, more preferably greater than 95%, most preferably greater than 99%.
Although the present invention is mainly the non-racemic 3-oxo-2 of preparation formula (I), 3,4,5-tetrahydrochysene-1, the method of 4-benzodiazepine product, but be appreciated that also can wherein there be (the R)-enantiomorph of significant quantity in the present invention as the method for the stereochemistry purity of the chipal compounds of increase formula (I).For example, when chemistry buffering or physical method such as chromatography can not produce the product of gratifying enantiomeric purity, so can be with the e.e. of method increase product of the present invention.
In specific embodiment, the present invention is the method for preparation formula (III) compound:
Figure A9718185300121
Wherein X ' is H, halogen, CO 2R 3Or OR 4R 2Be C 1-6Alkyl, optional by Ar, Het or C 1-6Cycloalkyl substituted; R 3Be C 1-6Alkyl or benzyl; R 4Be C 1-6Alkyl, COR 3Or benzyl; Described method comprises: (a) by handle the compound of formula (IV) with the lipase B of Candida Antarctica: R wherein 1Be C 1-20Alkyl or C 3-20Alkenyl, optional by Ar, NR 2Or NR 3 +Replace, wherein R is C 1-4Alkyl; And R 2And X ' is suc as formula definition in (III); (b) make (S) 2,3,4 of generation, 5-tetrahydrochysene-4-methyl-3-oxo-1 H-1,4-benzodiazepine -2-alphatic acid separates with corresponding (R)-ester.
In another preferred embodiment, the present invention is preparation (S)-7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method of 4-benzodiazepine -2-acetate, this method comprises with the lipase B that derives from Candida Antarctica handles (R, S) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And with (S) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate and (R) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate separates.Other mutation of this embodiment preferred comprises that wherein said substrate is (R, S) 7-[(1 '-benzyloxycarbonyl-(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1 H-1,4-benzodiazepine -2-methyl acetate, and further be included in the step of removing tert-butoxycarbonyl or benzyloxycarbonyl after the Chiral Separation.This type of blocking group generally can be by ordinary method such as acid treatment or catalytic hydrogenation removal.
In another preferred embodiment, the present invention is preparation (S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method of 4-benzodiazepine -2-acetate, this method comprise with the lipase B that derives from Candida Antartica handles (R, S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And with (S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate and (R) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate separates.
In another embodiment preferred, the present invention is preparation (S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method of 4-benzodiazepine -2-acetate, this method comprise with the lipase B that derives from Candida Antartica handles (R, S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And with (S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate and (R) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate separates.
In yet another aspect, the present invention is the method for the non-racemic compound of preparation formula (I), and wherein X is-COR 5Or Parenogen or vitronectin antagonists side chain, described method comprises conversion type (I) compound, wherein X is H, halogen, CO 2R 3Or OR 4
X is-COR formula (III) compound preparing wherein 5Or be useful especially intermediate during formula (I) compound of Fibrinogen or vitronectin antagonists side chain.The preferred part of X ' is H, Br, I, CO 2CH 3, CO 2-t-Bu and OH.Preferred R 1Part is C 1-4Alkyl and benzyl.
Useful especially compound according to method preparation disclosed herein is:
(S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate;
(S)-and 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate;
(S)-and 7-bromo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate;
(S)-and 7-tert-butoxycarbonyl-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate and their simple ester.General ester is C 1-4Alkyl ester, phenylester and benzyl ester and derivative thereof, and these esters can be prepared by corresponding carboxylic acid by conventional esterification.
Therefore, the present invention also is the method for preparation formula (I) compound on the other hand, and X is COR in formula (I) 5Or Fibrinogen or vitronectin antagonists side chain, described method comprises by method for preparing formula (III) compound, and formula (III) compound is converted into formula (I) compound, wherein X is COR 5Or Parenogen or vitronectin antagonists side chain.By popular response and method, as in those methods described in WO 93/00095 (PCT/US 92/05463), WO 94/14776 (PCT/US93/12436), WO 95/18619 (PCT/US 95/00248), WO 96/00730 (PCT/US95/08306), WO 96/00574 (PCT/US 95/08146), PCT/US 97/18001 and the WO 97/24336 (it is for referencial use to be incorporated herein these disclosures), midbody compound of the present invention can be converted into formula (I) compound, wherein X is COR 5Or Parenogen or vitronectin antagonists side chain.
In a more preferred embodiment, the present invention is the method for preparation formula (I) compound, and these compounds are as (S)-7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate, this method comprises (S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate, (S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate, (S) 7-bromo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate; Or (S) 7-tert-butoxycarbonyl-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate is converted into (S)-7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate.
The illustrative methods that can be used for above-mentioned intermediate is converted into formula (I) compound provides at flow process I
Flow process I
Figure A9718185300151
A) pyridine ICl or CBr 4/ Ph 3P; B) CO, Pd (OAc) 4, Ph 3P and (4,4 '-Lian piperidines or 1 '-Boc-4,4 '-Lian piperidines or 1 '-Cbz-4,4 '-Lian piperidines)
Yet, it is contemplated that many other conventional synthetic methods of independent chiral intermediate preparation formula (I) compound that can use formula (III).
Use useful compound among the normally used abbreviation of chemical field and denotational description the present invention at this.In addition, the part term has following meaning:
As used in this, Parenogen or vitronectin antagonists side chain can provide with following formula usually: W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) s-V-or W '-(CR ' 2) q-U-(CR ' 2) s-, wherein
R '-be H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R " be R ' ,-C (O) R ' or C (O) OR ';
R 1Be H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R 5Be H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R 7For H, halo ,-OR 12,-SR 12,-CN ,-NR ' R 12,-NO 2,-CF 3, CF 3S (O) r-,-CO 2R ' ,-CONR ' 2, R 14-C 0-6Alkyl-, R 14-C 0-6Oxoalkyl group-, R 14-C 2-6Alkenyl ,-R 14-C 2-6Alkynyl-, R 14-C 0-6Alkoxyl group-, R 14-C 0-6Alkylamino or R 14-C 0-6Alkyl-S (O) r-;
R 8For H ,-COR ', CN, NO 2, SO 2R ' or C (O) OR 5
R 9For R ' ,-CF 3,-SR ' or-OR ';
R 10Be H, C 1-4Alkyl or-NR ' R ";
R 12For R ' ,-COR ', ,-C (O) NR ' 2,-C (O) OR 5,-S (O) mR ' or S (O) 2NR ' 2
R 14Be H, C 3-6Cycloalkyl, Het or Ar;
R 15Be H, C 1-10Alkyl, C 3-7Cycloalkyl-C 0-8Alkyl or Ar-C 0-8Alkyl;
U and V do not exist, or are CO, CR ' 2, C (=CR 15 2), S (O) n, O, NR 15, CR 15' OR 15, CR ' (OR ") CR ' 2, CR ' 2CR ' (OR ") ,-C (O) CR ' 2, CR 15 2C (O), CONR 15, NR 15CO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR 15, NR 15C (S), SO 2NR 15, NR 15SO 2, N=N, NR 15NR 15, NR 15CR 15 2, NR 15CR 15 2, CR 15 2O, OCR 15 2, C ≡ C, CR 15=CR 15, Het or Ar, prerequisite is that U and V do not exist simultaneously;
W is R ' R " N-, R ' R " NR ' N-, R ' R " NR ' NCO-, R ' 2NR ' NC (=NR ')-, R ' ONR ' C (=NR ')-,
Figure A9718185300161
Q is NR ', O or S;
R aBe H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, OR 1, SR 1, COR 1, OH, NO 2, N (R 1) 2, CO (NR 1) 2, CH 2N (R 1) 2
R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, OR 1, SR 1, COR 1, OH, NO 2, N (R 1) 2, COCNR 1) 2, CH 2N (R 1) 2, perhaps R bAnd R cForm 5 yuan or 6 yuan of aromatic rings or non-aromatic ring together, optional by halogen, C 1-4Alkyl, OR 1, SR 1, COR 1, OH, NO 2, N (R 1) 2, CO (NR 1) 2, CH 2N (R 1) 2, CN or R " R ' NC (=NR ')-replace;
X is N=CR ', C (O) or O;
Y does not exist, or is S or O;
Z is (CH 2) t, Het, Ar or C 3-7Cycloalkyl;
M is 1 or 2;
N is 0,1,2 or 3;
Q is 0,1,2 or 3;
R is 0,1 or 2;
S is 0,1 or 2;
T is 0,1 or 2;
V is 0 or 1; And
W is 0 or 1; Q is 0,1,2 or 3.
This type of side chain is having description (it is for referencial use to be incorporated herein its disclosure) as WO 93/00095 (PCT/US 92/05463), WO 94/14776 (PCT/US 93/12436), WO 95/18619 (PCT/US 95/00248), WO 96/00730 (PCT/US 95/08306), WO 96/00574 (PCT/US 95/08146) and PCT/US96/11108.The basic group nitrogen that is appreciated that W and W ' is optional protected when carrying out method of the present invention.Nitrogen-protecting group group is well known in the art, and comprises as ethanoyl, formyl radical, trifluoroacetyl group, benzoyl, benzyloxycarbonyl and alkoxy carbonyl.
Typical fibrinogen receptor or Vitronectic receptor antagonist side chain are:
Figure A9718185300181
At this used C 1-4Alkyl is intended to comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.C 1-6Alkyl comprises amyl group, n-pentyl, isopentyl, neo-pentyl and hexyl and simple aliphatic isomer thereof in addition.Same C 1-20Alkyl comprises the simple aliphatic hydrocrbon of the carbon atom that specifies number.Any alkyl can be chosen wantonly by R 7Replace, except that specializing.C in addition 0-4Alkyl and C 0-6Alkyl shows does not need alkyl to have (as there being covalent linkage).
At this used C 2-6Alkenyl refers to the alkyl of 2-6 carbon atom, and wherein carbon-carbon single bond is replaced by carbon-carbon double bond.C 2-6Alkenyl comprises several isomer of ethene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, iso-butylene and amylene and hexene.Same C 3-20Alkenyl comprises the simple aliphatic hydrocrbon of the carbon atom that specifies number, and wherein one or more carbon-carbon single bonds are replaced by carbon-carbon double bond.Comprise cis and trans two kinds of isomer.Except that specializing, any alkenyl can be chosen wantonly by R 7Replace.
C 2-6Alkynyl refers to the alkyl of 2-6 carbon atom, and one of them carbon-carbon single bond is replaced by carbon carbon triple bond.C 2-6Alkynyl comprises the simple isomer of acetylene, 1-propine, 2-propine, ethyl acetylene, 2-butyne, 3-butine and pentyne and hexin.C 2-6Any sp in the alkynyl 3Carbon atom can be chosen wantonly by R 7Replace.
C 1-4Oxoalkyl group refers to the alkyl of 4 carbon atoms of as many as, wherein CH 2Group is by C (O) or carbonyl substituted.The formyl radical, ethanoyl, 1-propionic aldehyde, 2-acetone, 3-propionic aldehyde, 2-butanone, 3-butanone, 1-and the 4-butyraldehyde that replace are representative example.C 1-6Oxoalkyl group comprises in addition by the more senior analogue and the isomer of 5 and 6 carbon atoms of carbonyl substituted.
C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl or C 1-6Substituting group on the oxoalkyl group such as R 7Can produce on any carbon atom of rock steady structure, and can be by conventional synthetic technology acquisition.
Halogen atom refers to fluorine, chlorine, bromine or iodine.
Refer to phenyl or naphthyl at this used Ar or aryl, or by 1-3 R 7The phenyl or naphthyl that part replaces.R particularly 7Can be C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkylthio, trifluoroalkyl, OH, F, Cl, Br or I.
Het or heterocycle refer to optional 5 yuan or 6 yuan of monocycles that replace, or 9 yuan or 10 yuan of dicyclos, wherein contain 1-3 heteroatoms that is selected from nitrogen, oxygen and sulphur, and these rings are stable and can obtain by conventional chemical is synthetic.Illustrative heterocycle is cumarone, benzoglyoxaline, chromene, thionaphthene, furans, imidazoles, indoles, indoline, morpholine, piperidines, piperazine, pyrroles, tetramethyleneimine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, different quinoline woods, tetrahydrochysene and perhydro quinoline and different quinoline woods.The 6 yuan of heterocycles such as piperidines, piperazine, tetrahydropyridine and the pyridine that contain 1 or 2 nitrogen-atoms are the preferred heterocycle of part Z.On the Het ring can by chemosynthesis obtain and stable 3 substituent any possible combinations of as many as being selected from R 7Substituent combination all within the scope of the present invention.
C 3-7Cycloalkyl refers to the ring system of the optional replacement of 3-7 carbon atom, can contain two unsaturated carbon carbon bonds of as many as.C 3-7Cycloalkyl is generally cyclopropyl, cyclobutyl, cycloalkyl, cyclopentenyl, cyclohexyl, cyclohexenyl and suberyl.On the cycloalkyl ring can by chemosynthesis obtain and stable 3 substituent any possible combinations of as many as being selected from R 7Substituent combination all within the scope of the present invention.
Used at this
Figure A9718185300191
Refer to nitrogen heterocyclic, can be saturated or undersaturated stable 5 yuan, 6 yuan or 7 yuan of monocycles, perhaps be 7-10 unit dicyclo, can contain 3 nitrogen-atoms of as many as, perhaps contain 1 nitrogen-atoms and the heteroatoms that is selected from oxygen and sulphur, and can on any atom that produces rock steady structure, be substituted.This ring nitrogen can be substituted, and produces quaternary nitrogen.Nitrogen heterocyclic ring can be in any stable position by R 20Replace, as H, C 1-4Alkoxyl group, F, Cl, Br, I, NO 2, NR ' 2, OH, CO 2R ', CONHR ', CF 3, R 14-C 0-4Alkyl, R 14-C 1-4Alkyl-S (O) u(is 0,1 or 2 as u wherein) or the C that is replaced by any above-mentioned substituting group 1-4Alkyl.Representational
Figure A9718185300201
Example be pyrroline, tetramethyleneimine, imidazoles, tetrahydroglyoxaline, imidazolidine, pyrazoles, pyrazoline, pyrazolidine, piperidines, piperazine, morpholine, pyridine, pyridine, tetrahydropyridine, tetrahydrochysene and six hydrogen azatropylidenes, quinoline is peaceful, quinoline is peaceful, quinoline, different quinoline woods, and tetrahydrochysene and perhydro quinoline and different quinoline woods.Particularly
Figure A9718185300202
Can be pyridyl, pyrrolidyl, piperidyl, piperazinyl, azetidinyl, the peaceful base of quinoline or tetrahydro pyridyl.Preferably
Figure A9718185300203
Be 4-pyridyl, 4-(2-amino-pyridine base), 4-tetrahydro pyridyl, 4-piperidyl or 4-piperazinyl.
Work as R bAnd R cIn conjunction with forming and R bAnd R cWhen 5 yuan or 6 yuan aromatic rings of ring condensed that connect or non-aromatic ring, the ring of formation is generally and is selected from 5 yuan of above-mentioned heterocyclic or 6 yuan of heterocycles, perhaps is phenyl, cyclohexyl or cyclopentyl ring.The derivative of the preferred benzimidazolyl-of W ' part, 4-azepine benzimidazolyl-, 5-azepine benzimidazolyl-and replacement thereof.
Being used for formula of the present invention (II) and ester (IV) can be according to preparing in the method described in the following patent: WO 93/00095 (PCT/US 92/05463), WO 94/14776 (PCT/US93/12436), WO 95/18619 (PCT/US 95/00248), WO 96/00730 (PCT/US95/08306), WO 96/00574 (PCT/US 95/08146), WO 97/24336 and PCT/US 96/11108 (it is for referencial use to be incorporated herein these disclosures).
Also be clearly to those skilled in the art: method of the present invention can be used to prepare the formula V compound:
Figure A9718185300211
R wherein 1, R 2With X with identical described in the formula (II), these compounds of hydrolysis obtain non-racemize (R) carboxylic acid isomer of formula (II), wherein R according to conventional methods 1Be H.
The following examples are not used in and limit the scope of the invention, and provide these embodiment how to prepare and use compound of the present invention in order to illustrate.Many for a person skilled in the art other embodiments be clearly and utilizable.
Embodiment
Embodiment 1
Universal method with Candida Antartica lipase B hydrolysis
With 3-oxo-2,3,4,5-tetrahydrochysene-1,4-benzodiazepine -2-methyl acetate (0.5g) or its derivative that suitably replaces are dissolved in acetone (30ml) or the trimethyl carbinol and the damping fluid (70ml, pH7.0,0.1N phosphoric acid salt).The Candida Antarctica lipase that adds macroporous acrylic ester resin (200mg ,/700PLU/g put on market with the Novozym435 trade(brand)name) load stirs this reactant 4.0 days under room temperature.Monitor this reaction through HPLC, this reaction is spontaneous during hydrolysis 47% stops.With sodium hydroxide solution pH is transferred to 8.0, add ethyl acetate (75ml).Filter this mixture and remove enzyme catalyst, separating ethyl acetate layer.With ethyl acetate (2 * 75ml) aqueous layer extracted.The acetic acid ethyl ester extract that dry (sodium sulfate) merges, the vacuum-evaporation ethyl acetate obtains (R)-ester (0.28g).By relatively determining stereochemistry (chirality HPLC), e.e.＞99% with real (R)-ester.
With concentrated hydrochloric acid the pH of water is transferred to 5, with ethyl acetate (5 * 75ml) extractions.The acetic acid ethyl ester extract that dry (sodium sulfate) merges, evaporation obtains (S) acid (0.23g).E.e. be 99% (calculating) by chirality HPLC.
Split following 3-oxo-2,3,4 with aforesaid method, 5-tetrahydrochysene-1,4-benzodiazepine -2-acetate.
Figure A9718185300221
X R 1E.e.H CH 3(S) 99% (R) 99%Br CH 3(S) 99.4% (R) 99.4%I CH 3(S) 98% (R) 95%CO 2-t-Bu CH 3(S) 99.8% (R) 99.1%[1 '-Cbz-(4,4 '-bi-CH 3(S) carbonyl 98.3% piperidines-1-yl)]
Embodiment 2
(S)-and 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the preparation of 4-benzodiazepine -2-acetate
(R, S) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, (34g 0.077mol) makes slurry to 4-benzodiazepine -2-methyl acetate in water (580ml) and 1.0N hydrochloric acid (34ml).In 30 ℃ this mixture was stirred 0.5 hour, add 1.0N hydrochloric acid and keep pH to be about 6.2.(Boehringer L-2 lipase, 8.2g), in 30 ℃ of these mixtures of stirring, adding 1.5M ammonia solution maintenance pH is 6.2 to add immobilised lipase resin.When no longer needing titrating solution, leach enzyme resin, and water (50ml) washing.
With benzyl chloroformate (7.8g, methylene dichloride 0.046mol) (130ml) solution-treated filtrate.Stirred these mixtures 1 hour in 30 ℃, adding the 1.5M ammonia solution, to keep pH be 7.0.Separate each phase, with methylene dichloride (130ml) aqueous phase extracted.
Keeping pH is 6.8, under vacuum, 55 ℃ of heating waters.When the volume of solution is about 150ml, this solution is cooled to 5 ℃, placed 12 hours and adjusted frequently pH.Leach solid then, use cold water washing, and drying obtains target compound (16g, 80%); Analyzing through chirality HPLC is 99.9% (S)-isomer.
The evaporation dichloromethane extract obtains target compound (R) 7-[1 '-benzyloxycarbonyl-(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate, be faint yellow crystalline solid (23g, 100%); Analyzing through chirality HPLC is＞98% (R)-isomer.
Embodiment 3
(S)-and 7-[[(N '-benzyloxycarbonyl)-4,4 '-Lian piperidyl] carbonyl]-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the preparation of 4-benzodiazepine -2-acetate
A) 7-[[(N '-benzyloxycarbonyl)-4,4 '-Lian piperidyl] carbonyl]-3-oxo-2,3,4,5-tetrahydrochysene-1,4-benzodiazepine -2-methyl acetate
Under 95 ℃, the carbon monoxide pressure of 8-14psi, with 7-iodo-3-oxo-2,3,4,5-tetrahydrochysene-1,4-benzodiazepine -2-methyl acetate (50g, 134mmol), 1 '-benzyloxycarbonyl-4,4 '-Lian piperidine hydrochlorate (52.12g, 154mmol), Hunigs alkali (67.9ml, 402mmol), NMP (200ml), water (5.2ml, 289mmol) and the two triphenyl phosphines of Palladous chloride (II) (1.88g, the jolting on the Parr vibrator of mixture 2.68mmol).After 4 hours, carbon monoxide absorbs and stops, and makes this reaction mixture be cooled to room temperature.Add methylene dichloride (400ml) then, filter this solution, wash with water.Organic layer is concentrated into dried, residue is made slurry in methyl alcohol (770ml).Filtration product is used methanol wash, drains to obtain target compound (54g, 70%).
B) (S)-7-(4,4 '-Lian piperidyl) carbonyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1,4-benzodiazepine -2-acetate
The compound of embodiment 3 (a) is dissolved in the trimethyl carbinol and the damping fluid (70ml, pH7.0,0.1N phosphoric acid salt).The Candida Antartica lipase B that adds macroporous acrylic ester resin (200mg ,/700PLU/g put on market with Novozym 435 trade(brand)names) load stirs this reactant 4.0 days under room temperature.With sodium hydroxide solution pH is transferred to 8.0, add ethyl acetate (75ml).Filter this mixture, the separating ethyl acetate layer.With ethyl acetate aqueous layer extracted again.The acetic acid ethyl ester extract that dry (sodium sulfate) merges, the vacuum-evaporation ethyl acetate obtains (R)-ester.
With hydrochloric acid the pH of water is transferred to 5, use ethyl acetate extraction.The acetic acid ethyl ester extract that dry (sodium sulfate) merges, evaporation obtain (S)-acid (e.e. is 99%).
Under hydrogen environment (45psi), with (S) acid methyl alcohol (40ml) of (0.15mmol) and acetate (8) solution with 10%Pd/C (20mg) jolting 30 minutes.Filter this mixture by CELITE , vacuum concentrated filtrate obtains target compound.
Embodiment 4
(S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the preparation of 4-benzodiazepine -2-acetate
Will (R, S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, (20g 0.081mol) makes slurry to 4-benzodiazepine -2-methyl acetate in toluene (200ml), be heated to reflux 5 minutes.This solution is cooled to 40 ℃, adds entry (200ml) and Novozym 435 (20g).In 40 ℃ of these reactants of stirring, keeping pH with ammonia solution (1.5mol) is 7.0.After 16 hours, the reaction of HPLC analysis revealed is finished.Leach enzyme resin, with warm water (45ml) and warm toluene (75ml) washing.
The separation of methylbenzene layer, (2 * 100ml) aqueous layer extracted, keeping pH with ammonia solution (1.5M) is 8.0 with ethyl acetate.The organic extract (toluene and acetic acid ethyl ester extract) that merges is evaporated to dried, makes residue recrystallization from methylene dichloride-hexane, obtain (the R)-isomer (8g, 80%) of starting ester.
Make the water layer layering with ethyl acetate, with hcl acidifying to pH be 4.0, be evaporated to driedly, recrystallization obtains target compound.
Embodiment 5
(S)-and 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1 H-1, the preparation of 4-benzodiazepine -2-acetate
The method that repeats embodiment 3 is extremely from containing (S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the step of aqueous phase extraction (the R)-ester of 4-benzodiazepine -2-acetate.PH with the aqueous solution transfers to 7.0 then, and adding pyridine ICl title complex (10.2g, 0.042mol).Keeping pH with ammonia solution (1.5M) is 6.0, and this mixture was stirred 1 hour.With concentrated hydrochloric acid pH is transferred to 4.0 then, stirred 16 hours.Leaching product, is the washing of 4 damping fluid with cold pH, and drying obtains target compound (11.2g, 84%).Through chirality HPLC analysis revealed is 99.82% (S)-isomer.
Embodiment 6
The preparation of solid supported enzyme
Under room temperature, (Novo Nordisk 3g) water (4ml), the trimethyl carbinol (45ml) and glutaraldehyde (1ml, the 50%w/w aqueous solution) stir about 3-4 hour, does not regulate pH with Novozym 435.Leach resin, wash with water, it is used without further drying.

Claims (14)

1. the method for preparation formula (I) compound:
Figure A9718185300021
In formula (I), X is hydrogen, halogen, CO 2R 3, OR 4, COR 5Or Fibrinogen or vitronectin antagonists side chain; R 2Be C 1-6Alkyl, optional by Ar, Het or C 1-6Cycloalkyl substituted; R 3Be C1-6 alkyl or benzyl; R 4Be C 1-6Alkyl, COR 3Or benzyl; R 5Be 4,4 '-Lian piperidines-1-base, (1 '-uncle-benzyloxycarbonyl)-4,4 '-Lian piperidines-1-base or (1 '-uncle-butoxy carbonyl)-4,4 '-Lian piperidines-1-base; Described method comprises: (a) handle formula (II) compound with Candida Antartica lipase B:
Figure A9718185300022
R 1Be C 1-20Alkyl or C 3-20Alkenyl, optional by Ar, NR 2Or NR 3 +Replace, wherein R is C 1-4Alkyl, and (b) separate 2,3,4 of corresponding ester and generation, 5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-alphatic acid.
2. the process of claim 1 wherein described Candida Antartica lipase B is fixed on the solid carrier.
3. the method for claim 2 is wherein fixed described CandidaAntarctica lipase B by handling with linking agent.
4. the process of claim 1 wherein by separate (S)-isomer and (R)-isomer with the not miscible organic solvent extraction aqueous solution.
5. the process of claim 1 wherein R 1Be methyl.
6. the process of claim 1 wherein R 2Be methyl.
7. the process of claim 1 wherein that temperature of reaction is higher than room temperature.
8. prepare (S)-7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method for 4-benzodiazepine -2-acetate, this method comprises: (a) handle (R with the lipase B that derives from Candida Antartica, S) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And (b) separate (R) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate and (S) 7-[(4,4 '-Lian piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate.
9. prepare (S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method for 4-benzodiazepine -2-acetate, this method comprises: (a) handle (R with the lipase B that derives from Candida Antartica, S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And (b) separate (R) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate and (S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate.
10. prepare (S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the method for 4-benzodiazepine -2-acetate, this method comprises: (a) handle (R with the lipase B that derives from Candida Antartica, S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate; And (b) separate (R) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate and (S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate.
11. compound is:
(S) 2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate;
(S) 7-iodo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate;
(S) 7-bromo-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate; Or
(S) 7-tert-butoxycarbonyl-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-acetate.
12. prepare the method for the described formula of claim 1 (I) compound, X is-COR in formula (I) 5Or Fibrinogen or vitronectin antagonists side chain, described method comprises that the compound with claim 11 is converted into described formula (I) compound.
13. the method for preparation formula (I) compound:
Figure A9718185300041
In formula (I), X is COR 5Or Fibrinogen or vitronectin antagonists side chain; R 2Be C 1-6Alkyl, optional by Ar, Het or C 1-6Cycloalkyl substituted; R 3Be C 1-6Alkyl or benzyl; R 4Be C 1-6Alkyl, COR 3Or benzyl; R 5Be 4,4 '-Lian piperidines-1-base, (1 '-benzyloxycarbonyl)-4,4 '-Lian piperidines-1-base or (1 '-uncle-butoxy carbonyl) 4,4 '-Lian piperidines-1-base; Described method comprises: (a) by handle the compound of formula (IV) with the lipase B of Candida Antarctica:
Figure A9718185300051
R wherein 1Be C 1-20Alkyl or C 3-20Alkenyl, optional by Ar, NR 2Or NR 3 +Replace, wherein R is C 1-4Alkyl, preparation formula (III) compound:
Figure A9718185300052
Wherein X ' is H, halogen, CO 2R 3Or OR 4R 2Be C 1-6Alkyl, optional by Ar, Het or C 1-6Cycloalkyl substituted; R 3Be C 1-6Alkyl or benzyl; R 4Be C 1-6Alkyl, COR 3Or benzyl; Reach and (b) separate (the R)-ester of corresponding formula (III) and (S)-2,3,4 of generation, 5-tetrahydrochysene-4-methyl-3-oxo-1H-1,4-benzodiazepine -2-alphatic acid; And (c) formula (III) compound is converted into formula (I) compound, wherein X is COR 5Or Fibrinogen or vitronectin antagonists side chain.
14. the method for claim 14, wherein R 1Be C 1-4Alkyl or benzyl; X ' is H, Br, I, CO 2CH 3, CO 2-t-Bu or OH.
CN97181853A 1996-12-27 1997-12-23 Enzymatic resolution of benzodiazepine-acetic acid esters with lipase Pending CN1246157A (en)

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