Processes for the preparation of 4,6,7-trifluoro-1H-indole-2-carboxylic acid

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):

2. 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.

3. 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 H 2 , 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).

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 G 6 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):

5. 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), G 6 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.

6. 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.

7. 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 H 2 , 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).