Method for Preparation of Carbamic Acid (R)-1-Aryl-2-Tetrazolyl-Ethyl Ester

• US 20110111467A1
• Filed: 10/14/2010
• Published: 05/12/2011
• Est. Priority Date: 10/15/2009
• Status: Active Grant

• Current Assignee: SK Biopharmaceuticals Co., Ltd. (SK Inc.)
• Original Assignee: SK Biopharmaceuticals Co., Ltd. (SK Inc.)
• Inventors: Lee, Dong Ho, Lee, Hyun Seok, Lee, Dae Won, Kim, Hui Ho, Uhm, Moo Yong, Lim, Sang Chul
• Granted Patent: US 8,404,461 B2
• Time in Patent Office: Days
• US Class Current: 435/121
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C12P 17/10 Nitrogen as only ring hetero atom

Abstract

Disclosed is a method for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters, comprising the enantioselective enzyme reduction of a 1-aryl-2-tetrazolyl-ethyl ketone to form a (R)-1-aryl-2-tetrazolyl-ethyl alcohol and the carbamation of said alcohol.

Claims

1. A method for preparing carbamic acid aryl-2-tetrazolyl ethyl ester, represented by Chemical Formula 1, comprising:

subjecting an arylketone, represented by Chemical Formula 2, to enantioselective enzymatic reduction to form an alcohol compound of (R)-configuration, represented by Chemical Formula 3; and

carbamating said alcohol

2. The method according to claim 1, wherein said enantioselective enzymatic reduction is carried out in a reaction mixture comprising said compound of formula 1, an oxidoreductase having at least 60% homology with amino acid sequences SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3 or SEQ ID NO;

4, NADH or NADPH as a cofactor that is oxidized during the reduction process and continuously regenerated, a cosubstrate comprising a secondary alcohol represented by the Formula R_xR_yCHOH, wherein R_x represents carbon with x being an integer from 1-10 and R_y represents hydrogen with y being an integer equal to two times the value of x plus two, and a suitable buffer.

3. The method according to claim 2, wherein the oxidoreductase is encoded, respectively, by nucleic acid sequence SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7 or SEQ ID NO;

8, or by a nucleic acid sequence that hybridizes to SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7 or SEQ ID NO;

8.

4. The method according to claim 3, wherein the oxidoreductase can be isolated from Candida magnolia, Candida vaccinii or Oryctolagus cuniculus.

5. The method according to claim 2, wherein the oxidoreductase is present in reaction mixture in a completely purified state, a partially purified state, or in the microbial cells that expressed it.

6. The method according to claim 5, wherein the oxidoreductase is present in the microbial cells that expressed it, which cells are in a native, permeabilized or lysed state.

7. The method according to claim 6, wherein the microbial cells are transformed Escherichia coli cells.

8. The method according to claim 2, wherein the regeneration of the oxidized cofactor results from the oxidation of said cosubstrate.

9. The method according to claim 2, wherein said cosubstrate is a secondary alcohol selected from the group consisting of 2-propanol, 2-butanol, 2-pentanol, 4-methyl-2-pentanol, 2-heptanol and 2-octanol.

10. The method according to claim 2, wherein said oxidoreductase affects both the reduction of the arylketone of Formula 2 and the oxidation of the cosubstrate.

11. The method according to claim 1, wherein the carbamating step is carried out by reacting the alcohol compound of (R)-configuration of Chemical Formula 3 with inorganic cyanate and an organic acid.

12. The method according to claim 1, wherein the carbamating step is carried out by hydrolyzing a product resulting from the reaction between the alcohol compound of (R)-configuration of Chemical Formula 3 and an isocyanate compound selected from the group consisting of chlorosulfonic isocyanate, trichloroacetyl isocyanate and trimethylsilyl isocyanate.

13. The method according to claim 1, wherein the carbamating step is carried out by introducing ammonia into a product resulting from the reaction between the alcohol compound of (R)-configuration of Chemical formula 3 and a carbonyl compound comprising 1,1′

-carbodiimidazole, carbamoylhalide, disuccinyl carbonate, phosgene, triphosgene or chloroformate.

14. The method according to claim 1, further comprising a crystallizing step after at least one of the enantioselective enzymatic reduction step and the carbamating step.

15. The method according to claim 14, wherein the crystallizing step comprises:

adding to a reaction product a solubilizing agent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, a lower alcohol of 1 to 4 carbon atoms and mixtures thereof; and

adding a precipitating agent thereto selected from the group consisting of water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane and mixtures thereof.

16. The method according to claim 1, additionally including the step of preparing the arylketone of Chemical Formula 2 by a substitution reaction between an arylketone of the following Chemical Formula 4 and a tetrazole of the following Chemical Formula 5:

17. A method according to claim 16, further comprising a crystallizing step comprising:

adding a solubilizing agent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, a lower alcohol of 1 to 4 carbon atoms and mixtures thereof to a product obtained by the substitution reaction; and

adding a precipitating agent selected from the group consisting of water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptanes and mixtures thereof.

18. A method for preparing an alcohol compound, represented by Chemical Formula 3, through the enantioselective enzymatic reduction of an arylketone, represented by Chemical Formula 2:

19. The method according to claim 18, wherein the oxidoreductase is encoded, respectively, by nucleic acid sequence SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7 or SEQ ID NO;

8, or by a nucleic acid sequence that hybridizes to SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7 or SEQ ID NO;

8, respectively.

20. The method according to claim 18, wherein the oxidoreductase can be isolated from Candida magnolia, Candida vaccinii or Oryctolagus cuniculus.