Method for producing pyrrole derivative, and intermediate thereof

Patent metadata

Field	Value
Publication number	US-10005725-B2
Application number	US-201715699954-A
Country	US
Kind code	B2
Filing date	Sep 8, 2017
Priority date	Aug 27, 2013
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

The present invention provides a method for producing an atropisomer of a pyrrole derivative having excellent mineralocorticoid receptor antagonistic activity, and an intermediate thereof. A method for producing an atropisomer of a pyrrole derivative using a compound represented by (B) [wherein R 1 represents a C1-C4 alkyl group, and R 2 represents a 2-hydroxyethyl group or a carboxymethyl group] as a production intermediate.

First claim

The invention claimed is:

1. A method for producing compound (A):

comprising reacting ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate represented by formula (Ia):

with 4-(methylsulfonyl)aniline in a reaction solvent in the presence of one reagent selected from a metal alkoxide and a Grignard reagent.

2. The method according to claim 1 , wherein the reagent is a Grignard reagent.

3. The method according to claim 1 , wherein the Grignard reagent is selected from ethylmagnesium bromide, ethylmagnesium chloride, isopropylmagnesium chloride, methylmagnesium bromide, and phenylmagnesium bromide.

4. The method according to claim 1 , wherein the Grignard reagent is ethylmagnesium bromide.

5. The method according to claim 2 , wherein the reaction solvent is tetrahydrofuran.

6. The method according to claim 2 , wherein reacting ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate with the Grignard reagent is carried out at a reaction temperature from room temperature to 150° C.

7. The method according to claim 6 , wherein the reaction temperature is from 60° C. to 100° C.

8. The method according to claim 2 , wherein reacting ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate with the Grignard reagent is carried at a reaction time from 0.5 to 5 hours.

9. The method according to claim 8 , wherein the reaction time is from 0.5 to 2 hours.

10. The method according to claim 1 , wherein the reagent is a metal alkoxide.

11. The method according to claim 1 , wherein the metal alkoxide is selected from potassium t-butoxide, sodium t-butoxide, sodium methoxide, and potassium ethoxide.

12. The method according to claim 10 , wherein the reaction solvent is selected from tetrahydrofuran, toluene, dimethylsulfoxide, and N,N-dimethylacetamide.

13. The method according to claim 10 , wherein reacting ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate with the metal alkoxide is carried out at a reaction temperature from room temperature to 70° C.

14. The method according to claim 13 , wherein the reaction temperature is from 40° C. to 70° C.

15. The method according to claim 10 , wherein reacting ethyl (S)-1-(2-hydroxyethyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate with the metal oxide is carried at a reaction time from 0.5 to 5 hours.

16. The method according to claim 15 , wherein the reaction time is from 1 to 2 hours.

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Watanabe Masashi
• Nagasawa Hiroshi
• Sato Noritada

Classifications

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07D207/34 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C12P17/10

  Nitrogen as only ring hetero atom · CPC title

• C07D207/456 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms · CPC title

• C12P41/005

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