# US 12,006,291 B2 · Processes for the preparation of 4,6,7-trifluoro-1H-indole-2-carboxylic acid

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- Number: US 12,006,291 B2
- Document ID: US12006291B2
- Status: Granted
- Kind: B2
- Application number: 18/095,155
- Filed: 2023-01-10
- Published: 2023-07-27
- Granted: 2024-06-11
- Earliest claimed: 2022-01-11
- Assignees: Enanta Pharmaceuticals, Inc.
- Applicants: Enanta Pharmaceuticals, Inc.
- Inventors: Kaicheng Zhu; Tao Wang; Jiajun Zhang; Hui Cao; Ruichao Shen; Guoqiang Wang; George G. Wu; Yat Sun Or
- Web page: https://patentgrep.com/patent/US12006291B2

## CPC

- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to processes for preparing a Compound (1): or a pharmaceutically acceptable salt or solvate thereof. Compound (1) is useful as in many pharmaceutical agents, especially is useful as key intermediate in the synthesis of certain SARS-CoV-2 3CLpro inhibitors.

## Claims

### Claim 1

A process for producing Compound (1),
said process comprising the steps of:
(i) reacting Compound (a) with a bromination agent, to produce Compound (b):
(ii) reacting Compound (b) with N,O-dimethylhydroxylamine HCl, in the presence of an acid activation agent to produce Compound (c):
(iii) reducing Compound (c) with a reducing reagent to produce Compound (d):
(iv) reacting Compound (d) with Compound (d-1)
to produce Compound (e):
(v) reacting Compound (e) with a hydrogen source, to produce Compound (f):
and
(vi) hydrolyzing Compound (f) to produce Compound (1):

### Claim 2 (depends on 1)

The process of claim 1, wherein
in step (i), the bromination reagent is 1,3-dibromo-5,5-dimethylhydantoin;
in step (ii), the chlorination agent is oxalyl chloride;
in step (iii), the reducing reagent is diisobutylaluminium hydride;
in step (iv), the reaction is conducted in the presence of a catalyst selected from the group consisting of cuprous iodide, copper (I) oxide, and [1,1′-Bis(diphenylphosphino) ferrocene] palladium (II) dichloride, and an optional ligand;
in step (v), the reaction is conducted in the presence of a catalyst selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, and Raney nickel; and
in step (vi), the reaction is conducted in the presence of a base to remove the Boc group and methyl ester.

### Claim 3 (depends on 1)

The process of claim 1, wherein
in step (i), the reaction is conducted in a solvent, wherein the solvent is sulfuric acid;
in step (ii), the reaction is conducted in the presence of dimethyl formamide as a catalyst;
in step (iii), the reaction is conducted at a temperature from about −70° C. to about −60° C.;
in step (iv), the catalyst is cuprous iodide, the ligand is 2,2′-bipyridine, and the base is potassium phosphate tribasic;
in step (v), the hydrogen source is H2, the catalyst is palladium on carbon (5-10 mol %), and the hydrogen pressure is about 1 atm; and
in step (vi), the reaction is conducted in the presence of sodium hydroxide and the resulting reaction mixture is treated with hydrogen chloride to form Compound (1).

### Claim 4

A process for producing the Compound (1),
said process comprising the steps of:
(1) reacting Compound (a) with a bromination agent, to produce Compound (b):
(2) reacting Compound (b) with an acid activation reagent and a reducing agent to produce Compound (c-1):
(3) reacting Compound (c-1) with oxidizing agent to produce Compound (d):
(4) reacting Compound (d) with the compound of Formula (D-2)
to yield the compound of Formula (E):
wherein G6 is -Cbz, -Fmoc, -Moz, or -Pnz;
(5) hydrolyzing the compound of Formula (E) to produce Compound (g):
and
(6) reacting Compound (g) with a hydrogen source in the presence of a hydrogenation catalyst, to produce Compound (1):

### Claim 5 (depends on 4)

The process of claim 4, wherein
in step (1), the bromination reagent is 1,3-dibromo-5,5-dimethylhydantoin;
in step (2), the acid activation agent is oxalyl chloride and the reducing agent is lithium borohydride;
in step (3), the oxidizing agent is trichloroisocyanuric acid with TEMPO;
in step (4), G6 is -Cbz, and the reaction is conducted in the presence of cuprous iodide as a catalyst;
in step (5), the reaction is conducted in the presence of sodium hydroxide as a base; and
in step (6), the reaction is conducted in the presence of palladium on carbon as a catalyst.

### Claim 6 (depends on 2)

The method of claim 2, wherein in step (vi), the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, or a mixture of two or more thereof.

### Claim 7 (depends on 2)

The process of claim 2, wherein
in step (i), the reaction is conducted in a solvent, wherein the solvent is sulfuric acid;
in step (ii), the reaction is conducted in the presence of dimethyl formamide as a catalyst;
in step (iii), the reaction is conducted at a temperature from about −70 ° C. to about −60 ° C.;
in step (iv), the catalyst is cuprous iodide, the ligand is 2,2′-bipyridine, and the base is potassium phosphate tribasic;
in step (v), the hydrogen source is H2, the catalyst is palladium on carbon (5-10 mol%), and the hydrogen pressure is about 1 atm; and
in step (vi), the reaction is conducted in the presence of sodium hydroxide and the resulting reaction mixture is treated with hydrogen chloride to form Compound (1).