Enzymatic processes for the preparation of (±)-2-(difluoromethyl)-1-(alkoxycarbonyl)-cyclopropanecarboxylic acid and (±)-2-(vinyl)-1-(alkoxycarbonyl)-cyclopropanecarboxylic acid

Patent metadata

Field	Value
Publication number	US-10689675-B2
Application number	US-201815886318-A
Country	US
Kind code	B2
Filing date	Feb 1, 2018
Priority date	Feb 1, 2017
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Disclosed are methods of synthesizing racemic 2-(difluoromethyl)-1-(alkoxycarbonyl)-cyclopropanecarboxylic acids and 2-(vinyl)-1-(alkoxycarbonyl)-cyclopropanecarboxylic acids and their salts, such as the dicyclohexylamine salt. Also disclosed are methods for preparing enantioenriched (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-(difluoromethyl)cyclopropane-1-carboxylic acid and esters of the same. These compounds are useful intermediates in the synthesis of viral protease inhibitors.

First claim

We claim:

1. A method of conversion of starting material 1 to reaction product 2 according to reaction Scheme A:

wherein R 1 is (C 1 -C 6 )alkyl;
R 2 is —CF 2 H or —CH═CH 2 ; and
the first enzyme is a mutant of BsteE esterase;
wherein BsteE esterase has the sequence:
AKIVPPKPFFFEAGERAVLLLHGFTGNSADVRMLGRFLESKGYTCHAPIYKGHGVPP EELVHTGPDDWWQDVMNGYEFLKNKGYEKIAVAGLSLGGVFSLKLGYTVPIEGIVTMCAP MYIKSEETMYEGVLEYAREYKKREGKSEEQIEQEMEKFKQTPMKTLKALQELIADVRDHL DLIYAPTFVVQARHDEMINPDSANIIYNEIESPVKQIKWYEQSGHVITLDQEKDQLHEDIYAF LESLDW (SEQ ID NO:10); and
wherein the mutant of BsteE esterase comprise the sequence ID NO: 10 having a first mutation of T25H, a second mutation of L92H, and a third mutation selected from the group consisting of C115S, C115A, K121R, K121Y, K121H, K121D, K121L, K121T, K121A, K121N, E123T, M126F, M126V, M126I, M126Q, M126N, K164S, L166N, L166M, L166I, L166T, L166A, I170N, I170Q, I170V, I170T, I170A, D172N, M194A, M194L, I195G, I195A, I195V, and K215N.

2. The method of claim 1 , wherein the amount of the first enzyme is about 50 wt % to about 200 wt % as compared to the starting material in Scheme A.

3. The method of claim 1 , wherein the first solvent comprises one or more organic solvents.

4. The method of claim 1 , wherein the first solvent further comprises an aqueous buffer.

5. The method of claim 1 , wherein the first solvent further comprises a base.

6. The method of claim 5 , wherein the base is a di(alkyl)amine.

7. The method of claim 1 , further comprising contacting the reaction product of reaction Scheme A with a base to obtain a salt of the reaction product.

8. The method of claim 7 , wherein the base is a di(alkyl)amine.

9. The method of claim 1 , wherein the diastereomeric excess of the reaction product is greater than about 90%.

10. The method of claim 6 , wherein the base is a di(cycloalkyl)amine or a di(aralkyl)amine.

11. The method of claim 8 , wherein the base is a di(cycloalkyl)amine or a di(aralkyl)amine.

Assignees

• Abbvie Inc

Inventors

• Abrahamson Michael J
• Chemburkar Sanjay R
• Kielbus Angelica B
• Cink Russell D

Classifications

• C12P41/005

  by esterification of carboxylic acid groups in the enantiomers or the inverse reaction · CPC title

• C12P7/62 Primary

  Carboxylic acid esters · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title

• C12Y301/01001

  Carboxylesterase (3.1.1.1) · CPC title

• C12N9/18 Primary

  Carboxylic ester hydrolases {(3.1.1)} · CPC title