التفاصيل البيبلوغرافية
| العنوان: |
Stereoselective bioconversion of aliphatic dinitriles into cyano carboxylic acids |
| Document Number: |
20070196905 |
| تاريخ النشر: |
August 23, 2007 |
| Appl. No: |
10/599899 |
| Application Filed: |
April 01, 2005 |
| مستخلص: |
The present invention is directed to a regio- and stereoselective bioconversion of selected aliphatic dinitriles into corresponding cyanocarboxylic acids. More particularly, the present invention provides methods for the conversion of 2-isobutyl-succinonitrile into (S)-3 cyano-5-methylhexanoic acid, which is a useful intermediate in the synthesis of (S)-3(aminomethyl)-5-methylhexanoic acid (pregabalin). Pregabalin can be used for treating certain cerebral diseases, for example, in the treatment and prevention of seizure disorders, pain, and psychotic disorders. |
| Inventors: |
Burns, Michael P. (Mystic, CT, US); Weaver, Justin K. (Clinton, IN, US); Wong, John Wing (East Lyme, CT, US) |
| Claim: |
1. A method for preparing a compound of formula I: [chemical expression included] wherein C3 has an (S) configuration; R1 is hydrogen, (C1-6) alkyl or phenyl; and R2 is (C1-C8) alkyl, (C2-C8) alkenyl, (C3-C8) cycloalkyl, —O(C1-C6) alkyl, —CH2—CH2—O—(C1-C6)alkyl, (C1-C6)alkyl-OH, -phenyl-(C1-C6)alkyl-OH, -phenyl-O—(C1-C6)alkyl, phenyl or substituted phenyl; with the proviso that when R2 is methyl, R1 is hydrogen, (C1-C6) alkyl or phenyl. comprising the steps of: (a) contacting a compound of formula II: [chemical expression included] with an enzyme catalyst having nitrilase activity in a reaction medium; and (b) recovering the (3S) isomer of the compound of formula I from the reaction medium; and, optionally, recovering unchanged (3R) isomer of the compound of formula II. |
| Claim: |
2. The method of claim I wherein said recovered unchanged (3R) isomer of the compound of formula II of step (b) is racemized into a racemate of the compound of formula II by heating the (3R) isomer with a base in the presence of an organic solvent. |
| Claim: |
3. The method of claim 2 wherein step (a) is repeated using the racemate racemized from the recovered unchanged (3R) isomer of step (b). |
| Claim: |
4. A method according to claim 1 wherein said enzyme catalyst is selected from the group consisting of NIT-101, NIT-1 02, NIT-103 and nitrilase from Arabidopsis thaliana. |
| Claim: |
5. A method according to claim 1 wherein said reaction medium is comprised of distilled water or water buffered to a pH in the range of from about 5.0 to about 10.0. |
| Claim: |
6. The method according to claim 1 wherein the compound of formula I is (S)-3-cyano-5-methylhexanoic acid, the compound of formula II is racemic 2-isobutyl-succinonitrile and the recovered unchanged isomer of step (b) is (R)-2-isobutylsuccinonitrile. |
| Claim: |
7. The method of claim 6 wherein said recovered unchanged (R)-2-isobutyl-succinonitrile of step (b) is racemized into racemic 2-isobutyl-succinonitrile by heating with a base in a solvent. |
| Claim: |
8. The method of claim 7 wherein step (a) is repeated using the racemic 2-isobutyl-succinonitrile racemized from the recovered unchanged (R)-2-isobutyl-succinonitrile of step (b). |
| Claim: |
9. A process for preparing (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) comprising the steps of: (a) contacting 2-isobutyl-succinonitrile with an enzyme catalyst having nitrilase activity in a reaction medium; (b) recovering (S)-3-cyano-5-methylhexanoic acid from the reaction medium; (c) converting (S)-3-cyano-5-methylhexanoic acid into an acid salt; and (d) hydrogenating the acid salt to form (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin). |
| Claim: |
10. The process according to claim 9, wherein unchanged (R)-3-cyano-5-methylhexanoic acid is recovered from the reaction medium of step (a). |
| Claim: |
11. The process according to claim 9 wherein said unchanged (R)-3-cyano-5-methylhexanoic acid of step (a) is racemized by heating with base in the presence of an organic solvent to form racemic 2-isobutyl-succinonitrile and step (a) is repeated using said racemic 2-isobutyl-succinonitrile. |
| Claim: |
12. The method of claim 9 wherein said enzyme catalyst is a nitrilase in the form of whole microbial cells, permeabilized microbial cells, extracts of microbial cells, partially purified enzymes, purified enzymes or an enzyme catalyst immobilized on a support. |
| Claim: |
13. A method according to claim 9 wherein said enzyme catalyst is selected from the group consisting of NIT-101, NIT-102, NIT-103 and nitrilase from Arabidopsis thaliana. |
| Current U.S. Class: |
435128/000 |
| Current International Class: |
12; 07 |
| رقم الانضمام: |
edspap.20070196905 |
| قاعدة البيانات: |
USPTO Patent Applications |