IP Library › Granted Patent US 12,378,225
Granted Patent B2
US 12,378,225 · App. 17/597,102 · Granted Aug 5, 2025

Process for manufacturing (S)-3-hydroxy-1-(1H-indol-5-yl)-2-oxo-pyrrolidine-3-carboxylic acid 3,5-difluoro-benzylamide

Inventors: Timo Heinrich (Freigericht, DE); Jeyaprakashnarayanan Seenisamy (Bangalore, IN)
Assignee: Merck Patent GmbH
C07D403/04
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Quick Facts
Patent No.
US 12,378,225
App. No.
17/597,102
Granted
Aug 5, 2025
Kind
B2
Abstract

A process can be used for manufacturing (S)-3-hydroxy-1-(1H-indol-5-yl)-2-oxo-pyrrolidine-3-carboxylic acid 3,5-difluoro-benzylamide.

Claims (11)

1. A process for manufacturing (S)-3-hydroxy-1-(1H-indol-5-yl)-2-oxo-pyrrolidine-3-carboxylic acid 3,5-difluoro-benzylamide, the process comprising:

a) reacting 2-oxo-1-(1-(phenylsulfonyl)-H-indol-5-yl)pyrrolidine-3-carboxylic acid with 3,5-difluorobenzyl amine, to give 1-[1-(benzenesulfonyl)-1H-indol-5-yl]-N-[(3,5-difluorophenyl)methyl]-2-oxopyrrolidine-3-carboxamide,

b) enantioselectively oxidizing the 1-[1-(benzenesulfonyl)-1H-indol-5-yl]-N-[(3,5-difluorophenyl)methyl]-2-oxopyrrolidine-3-carboxamide, to give (3S)-1-[1-(benzenesulfonyl)-1H-indol-5-yl]-N-[(3,5-difiuorophenyl)methyl]-3-hydroxy-2-oxopyrrolidine-3-carboxamide, and

c) subsequently cleaving off a phenylsulfonyl group from the (3S)-1-[1-(benzenesulfonyl)-1H-indol-5-yl]-N-[3,5-difluorophenyl)methyl]-3-hydroxy-2-oxopyrrolidine-3-carboxamide, to give (S)-3-hydroxy-1-(1H-indol-5-yl)-2-oxo-pyrrolidine-3-carboxylic acid 3,5-difluoro-benzylamide.

2. The process according to claim 1 , wherein a) is carried out presence of a base selected from the group consisting of triethylamine, diazabicycloundecene (DBU), and di-isopropylethylamine.

3. The process according to claim 1 , wherein a) is carried out in dichloromethane.

4. The process according to claim 1 , wherein a) is carried out in the presence of propanephosphonic acid anhydride.

5. The process according to claim 1 , wherein b) is carried out in presence of an oxidizing reagent (+)-(2R,4aS,7S,8aR)-4H-4a, 7-methanooxazirino[3,2-i] [2,1] benzisothiazole, 8,8-dichlorotetrahydro-9,9-dimethyl-3,3-dioxide.

6. The process according to claim 1 , wherein b) is carried out in presence of tetrahydrofuran (THF) or diethylether.

7. The process according to claim 1 , wherein b) is carried out in presence of sodium-hexamethyldisilazane (NaHMDS).

8. The process according to claim 1 , wherein c) is carried out in presence of NaOH.

Priority Claims (1)
EP 19184056 · Jul 3, 2019 · regional
Continuity (1)
Related Publication 20220251072A1 · Aug 11, 2022
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