CA2064248A1 - Process for producing lower alkyl esters of r-(+)-3-oxocycloalkane carboxylic acids - Google Patents
Process for producing lower alkyl esters of r-(+)-3-oxocycloalkane carboxylic acidsInfo
- Publication number
- CA2064248A1 CA2064248A1 CA002064248A CA2064248A CA2064248A1 CA 2064248 A1 CA2064248 A1 CA 2064248A1 CA 002064248 A CA002064248 A CA 002064248A CA 2064248 A CA2064248 A CA 2064248A CA 2064248 A1 CA2064248 A1 CA 2064248A1
- Authority
- CA
- Canada
- Prior art keywords
- lower alkyl
- carboxylic acids
- alkyl esters
- acid
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- 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
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Abstract In a process for obtaining lower alkyl esters of R-(+)3-oxocycloalkane carboxylic acids, the corresponding racemate undergoes hydrolysis at a pH between 7 and 8 in order to hydrolyse the unwanted enantiomer. The ester of interest can then be isolated from the reaction medium.
Description
2~6~2~
Process for the preparation of lower alkylestars of R~ 3-oxocycloalkanecarboxylic acid The invention relates to a process for preparing lower alkytesters of R-(+)-3-oxocycloalkanecarboxylic acid (where '7cycloalkane" represents cyclopentane and cyclohexane and "lower alkyl" represents C1-4-alkyl) by enzymatic resolution of the corresponding racemates.
The enantiomeres which may be prepared according to the invention ar~ important starting product~ for the preparation of certain known hetrazepines which oan beused as pharmaceutical substances. When synthasisin~3 enantio-merically pure cornpounds of this category ~ substance it is advant~geous to use 3-oxocycloalkanecarboxylic acid esters which have the same connguration at the optica~ly active centre as the active substance itself.
It is known to separate 3-~xocyclopentanecarboxylic acid using the optically active base brucine (Bull. Chem. Soc. Jap. 31, 333-335 (1958)). In or~sr to prepare theestsr required for the he~razepine synthesis, the R-(+)-3-oxocyclo-pentanecarbo~ylic acid released c~n then be converted into the ester by conventional methods.
However, this process is not really suitable for application on an industrial scale because brucine is highly toxic and difficult to obtain.
Aocording to the invention, the R-(+~-3-oxocycloalkanecarboxylic acid esters can now be obtained in good yields and of suitable purity even on an industrial scale by treating racemic 3-oxocycloalkanecarboxylic acid esters with hydrolaseswhish cleave the unwanted ester, so that the resulting acid oan readily been separated from the desired ester and the latter can then be isolated. The new process is appropriately carried out in a mixture o~ water and water-miscible cosolvents such as methanol, dimethylformamide or dimethylsulfoxide at temperatures between about 0 and ~0, prefer~bly between 5 and 30C, the pll being malntained at betYveen about 7 and 8 by means of conventional phosphate buffer and the addition of alkali.
Particularly suitab~e hydrolases ar~ carboxyl ester hydrolases such as porcine pancreas lipase (PPL) or lipase from Candida cylinderaos (CCL). Porcine liver esterase (PLE) is particularly suitable. The enzymes may ~Iso be used after being immobilised in a manner known per se, e. 9. bound to the comrnercial product Eupergit C (made by Rohrn Phanna of Darmstadt).
Th0 quarrffly of enzyme required is about 20 to 200 ~Jg of substrate. The substra~e may be, in particular, the lower alkyl ester$, particularly the methyl or ethyl ester of 3-2 ~ 4 8 oxocyclopentanecarboxylic acid and 3-oxocyclohexanacarboxylic acid.
An example of the canying out of the process, which rnay be medified if desired, will now be given.
Preparation of methyl R-(~)-3-oxocyclopentanecarboxylate 20,000 uni~s of porcine liver esterase are added at 20C to a stirred suspension of 142.2 ~ (1 mol) of racemic methyl 3-oxocyclopentanecarboxylate in 1,~00 ml of 0.1 rnolar phosphate buffer, pH 7.5 ~potassium dihydrogen phosphate, disodiumhydrogen phosphate). The proton concentration ~pH 7.5) is kept const~nt by adding m~tered amounts o~ 1 N sodium hydroxide solution using an au~o~itrator. After 700 ml of 1 N sodiurn hydroxide sohution have bean consumed the hydrolysis is stopped by extraction*. The unreacted ester is ex~ract~d by st~rring three times wi~h 500 ml of m~thylene chloride. The methylene chloride phase is dried o~er sodium sulphate and filtered and the solvent is distilled off in vacuo. The residue is further processed without distillation.
Yield: 40 ~ (56.3% of theo~ a l~ ~ + 27.44, c ~ 1.618 (methanol).
The product is sufliciently isomerically pure for hJrther processing.
~ If immobilised enzyme is used the process can be ended by flltenng off.
Process for the preparation of lower alkylestars of R~ 3-oxocycloalkanecarboxylic acid The invention relates to a process for preparing lower alkytesters of R-(+)-3-oxocycloalkanecarboxylic acid (where '7cycloalkane" represents cyclopentane and cyclohexane and "lower alkyl" represents C1-4-alkyl) by enzymatic resolution of the corresponding racemates.
The enantiomeres which may be prepared according to the invention ar~ important starting product~ for the preparation of certain known hetrazepines which oan beused as pharmaceutical substances. When synthasisin~3 enantio-merically pure cornpounds of this category ~ substance it is advant~geous to use 3-oxocycloalkanecarboxylic acid esters which have the same connguration at the optica~ly active centre as the active substance itself.
It is known to separate 3-~xocyclopentanecarboxylic acid using the optically active base brucine (Bull. Chem. Soc. Jap. 31, 333-335 (1958)). In or~sr to prepare theestsr required for the he~razepine synthesis, the R-(+)-3-oxocyclo-pentanecarbo~ylic acid released c~n then be converted into the ester by conventional methods.
However, this process is not really suitable for application on an industrial scale because brucine is highly toxic and difficult to obtain.
Aocording to the invention, the R-(+~-3-oxocycloalkanecarboxylic acid esters can now be obtained in good yields and of suitable purity even on an industrial scale by treating racemic 3-oxocycloalkanecarboxylic acid esters with hydrolaseswhish cleave the unwanted ester, so that the resulting acid oan readily been separated from the desired ester and the latter can then be isolated. The new process is appropriately carried out in a mixture o~ water and water-miscible cosolvents such as methanol, dimethylformamide or dimethylsulfoxide at temperatures between about 0 and ~0, prefer~bly between 5 and 30C, the pll being malntained at betYveen about 7 and 8 by means of conventional phosphate buffer and the addition of alkali.
Particularly suitab~e hydrolases ar~ carboxyl ester hydrolases such as porcine pancreas lipase (PPL) or lipase from Candida cylinderaos (CCL). Porcine liver esterase (PLE) is particularly suitable. The enzymes may ~Iso be used after being immobilised in a manner known per se, e. 9. bound to the comrnercial product Eupergit C (made by Rohrn Phanna of Darmstadt).
Th0 quarrffly of enzyme required is about 20 to 200 ~Jg of substrate. The substra~e may be, in particular, the lower alkyl ester$, particularly the methyl or ethyl ester of 3-2 ~ 4 8 oxocyclopentanecarboxylic acid and 3-oxocyclohexanacarboxylic acid.
An example of the canying out of the process, which rnay be medified if desired, will now be given.
Preparation of methyl R-(~)-3-oxocyclopentanecarboxylate 20,000 uni~s of porcine liver esterase are added at 20C to a stirred suspension of 142.2 ~ (1 mol) of racemic methyl 3-oxocyclopentanecarboxylate in 1,~00 ml of 0.1 rnolar phosphate buffer, pH 7.5 ~potassium dihydrogen phosphate, disodiumhydrogen phosphate). The proton concentration ~pH 7.5) is kept const~nt by adding m~tered amounts o~ 1 N sodium hydroxide solution using an au~o~itrator. After 700 ml of 1 N sodiurn hydroxide sohution have bean consumed the hydrolysis is stopped by extraction*. The unreacted ester is ex~ract~d by st~rring three times wi~h 500 ml of m~thylene chloride. The methylene chloride phase is dried o~er sodium sulphate and filtered and the solvent is distilled off in vacuo. The residue is further processed without distillation.
Yield: 40 ~ (56.3% of theo~ a l~ ~ + 27.44, c ~ 1.618 (methanol).
The product is sufliciently isomerically pure for hJrther processing.
~ If immobilised enzyme is used the process can be ended by flltenng off.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of R-(+)3-oxocyclopenlane - or -hexanecarboxylic acid from racemic methyl 3-oxocyclopenlane- or -hexanecarboxylate, characterized in that the racemate is treated in an aqueous medium with porcine liver esterase (PLE), the acid formed by the hydrolysis of the unwanted enantiomer or the salt of the acid is separated off and the methyl R-(+)-3-oxocycloalkanecarboxylate is isolated.
2. Process according to claim 1, characterized in that it is carried out at a pH between about 7 and 8.
3. Process according to claim 1 or 2, characterized in that the reaction medium used is water in admixture with cosolvents, preferably methanol, dimethylformamide or dimethylsulphoxide.
4. Process according to claim 1, 2 or 3, characterized in that the reaction temperature is 0 to 40°C.
5. Methyl R-(+)-3-oxocyclopentanecarboxylate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3922752.9 | 1989-07-11 | ||
| DE3922752A DE3922752A1 (en) | 1989-07-11 | 1989-07-11 | METHOD FOR THE PRODUCTION OF R - (+) -3-OXOCYCLOALKANCARBONESEURENEDERALKYLESTERS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2064248A1 true CA2064248A1 (en) | 1991-01-12 |
Family
ID=6384722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002064248A Abandoned CA2064248A1 (en) | 1989-07-11 | 1990-07-06 | Process for producing lower alkyl esters of r-(+)-3-oxocycloalkane carboxylic acids |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0407909B1 (en) |
| JP (1) | JPH05501049A (en) |
| AT (1) | ATE113662T1 (en) |
| CA (1) | CA2064248A1 (en) |
| DD (1) | DD298429A5 (en) |
| DE (2) | DE3922752A1 (en) |
| DK (1) | DK0407909T3 (en) |
| ES (1) | ES2064544T3 (en) |
| GR (1) | GR3014935T3 (en) |
| WO (1) | WO1991000922A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19844876A1 (en) * | 1998-09-30 | 2000-04-06 | Basf Ag | Optical resolution of arylalkanoic acid vinyl or isopropenyl ester, useful in rapid preparation of optically pure chiral carboxylic acids, by enantio-selective transesterification in presence of lipase or esterase |
| FR2796641B1 (en) * | 1999-07-22 | 2001-09-21 | Aventis Pharma Sa | NOVEL PROCESS FOR THE PREPARATION OF BENZOPERHYDROISOINDOLE COMPOUNDS |
-
1989
- 1989-07-11 DE DE3922752A patent/DE3922752A1/en not_active Withdrawn
-
1990
- 1990-07-06 ES ES90112919T patent/ES2064544T3/en not_active Expired - Lifetime
- 1990-07-06 EP EP90112919A patent/EP0407909B1/en not_active Expired - Lifetime
- 1990-07-06 WO PCT/EP1990/001089 patent/WO1991000922A1/en active Application Filing
- 1990-07-06 CA CA002064248A patent/CA2064248A1/en not_active Abandoned
- 1990-07-06 AT AT90112919T patent/ATE113662T1/en not_active IP Right Cessation
- 1990-07-06 JP JP2510289A patent/JPH05501049A/en active Pending
- 1990-07-06 DK DK90112919.7T patent/DK0407909T3/en active
- 1990-07-06 DE DE59007604T patent/DE59007604D1/en not_active Expired - Fee Related
- 1990-07-10 DD DD90342664A patent/DD298429A5/en not_active IP Right Cessation
-
1995
- 1995-02-01 GR GR950400199T patent/GR3014935T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0407909B1 (en) | 1994-11-02 |
| GR3014935T3 (en) | 1995-05-31 |
| DE3922752A1 (en) | 1991-01-17 |
| ATE113662T1 (en) | 1994-11-15 |
| WO1991000922A1 (en) | 1991-01-24 |
| DD298429A5 (en) | 1992-02-20 |
| JPH05501049A (en) | 1993-03-04 |
| DE59007604D1 (en) | 1994-12-08 |
| EP0407909A1 (en) | 1991-01-16 |
| ES2064544T3 (en) | 1995-02-01 |
| DK0407909T3 (en) | 1995-01-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |