Description:FIELD OF THE INVENTION:
The present invention generally relates to the field of process chemistry, and more particularly related to a process for preparation of 1-(2,3,6-trihalophenyl) alkan-2-one such as 1-(2,3,6-trifluorophenyl) propan-2-one.

BACKGROUND OF THE INVENTION:
Compounds 1-(2,3,6-trihalophenyl) alkan-2-one, particularly 1-(2,3,6-Trifluorophenyl) acetone (I) is a key starting material of Atogepant.

Atogepant is a potent, selective and oral antagonist of calcitonin gene-related peptide (CGRP) receptors (CGRP) and is sold under the brand name Qulipta. It is indicated for the prevention of episodic migraine headaches.
PCT application WO2013169348 discloses the process for preparation of 1-(2,3,6-trifluorophenyl) acetone by reacting 2,3,6-trifluorophenylacetic acid with POCl3 under ice cooling in dimethyl formamide and isopropyl acetate. The solution was added in the mixture of potassium carbonate and N, O-dimethylhydroxylamine hydrochloride in water below 8°C to form N-Methoxy-N-methyl-2-(2,3,6-trifluorophenyl) acetamide as an oil.
The solution of CeCl3 in THF was prepared and cooled to 5°C. Methyl magnesium chloride in tetrahydrofuran was added to the solution of CeCl3 at 5-9°C and warmed up to 16°C and maintained for 1 hour. The mixture was cooled to -10 to -15°C.
N-Methoxy-N-methyl-2-(2,3,6-trifluorophenyl) acetamide was charged to the reaction mixture over 15 minutes at -10 to -15°C. 1-(2,3,6-Trifluorophenyl) acetone was isolated and purified by silica gel column. The reaction can be represented as shown below in scheme 1.

Scheme 1
The starting material 2,3,6-trifluorophenylacetic acid is commercially available however it is costly and hence contributes to the cost of 1-(2,3,6-Trifluorophenyl) acetone. Thus, the process is not economically feasible.
The application CN115894198 claims preparation of 1-(2,3,6-Trifluorophenyl) acetone by reacting 2,2-dimethyl-5-(2,3,6-trifluorophenyl) acetyl)-1,3-dioxane-4,6-diketone with an appropriate acid such as acetic acid, trifluoroacetic acid. The reaction can be represented as shown below in scheme 2.

Scheme 2
For synthesis of 2,2-dimethyl-5-(2,3,6-trifluorophenyl) acetyl)-1,3-dioxane-4,6-diketone. 2,3,6-trifluorophenylacetic acid is used as starting material which has greater cost impact.
Indian application IN202111060969 claims formylating 1,2,4-trihalobenzene in presence of base to form 2,3,6-trihalobenzaldehyde. The aldehyde is further reacted with a nucleophile in presence of a base to form trihalobenzyl alkyl ketone.

Scheme 3
The present invention aims to provide a cost effective process for preparation of 1-(2,3,6-trifluorophenyl) acetone from easily available and less expensive reagents at commercial scale.
SUMMARY OF THE INVENTION:
The present invention relates to a process of preparation of 1-(2,3,6-trifluorophenyl) propan-2-one of formula (I) including
a) C-alkylation of 1,2,4-trifluorobenzene of formula (V) by reacting with epichlorohydrin of formula (VI) to form 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV);

b) epoxidation of 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV) in presence of suitable base to form 2-(2,3,6-trifluorobenzyl) oxirane of formula (III);

c) ring opening of 2-(2,3,6-trifluorobenzyl) oxirane of formula (III) in presence of a suitable reducing agent to form 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II); and

d) oxidation of 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II). The process as claimed in claim 1. wherein stage (a) is carried out in presence of alkyl lithium selected from n-BuLi and n-hexyllithium and in a solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran and Toluene.

The step (a) is carried out in presence of alkyl lithium selected from n-BuLi and n-hexyllithium and in a predefined solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran and toluene The predefined solvent in step (a) is preferably tetrahydrofuran. The step (a) is carried out at a predefined temperature of -30 to -70°C preferably -50 to -60°C.
The base in step (b) is alkali hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide. The predefined solvent in step (b) is selected form tetrahydrofuran, methanol, ethanol and isopropanol, water and/or mixtures thereof preferably mixture of tetrahydrofuran and water. The step (b) is carried out at a predefined temperature of 35-55°C, preferably 40-45°C.
The reducing agent in step (c) is selected from sodium borohydride, Lithium aluminium hydride, (LAH) preferably sodium borohydride; a metal catalyst is selected from palladium on carbon, platinum supported on carbon, platinum supported on copper and nickel. The step (c) is carried out in a predefined solvent selected from THF, alcoholic solvents such as methanol, ethanol or isopropyl alcohol, preferably ethanol, at a predefined temperature of 35-50°C, preferably 40-45°C.
The oxidizing agent in step (d) is selected from sodium hypochlorite, periodic acid, pyridinium chlorochromate, Dess-martin reagent, chromic acid, iodoxybenzene and oxalyl chloride-DMSO preferably sodium hypochlorite in presence of a catalyst selected from TEMPO and Sodium bromide. The step (d) is carried out in a predefined solvent selected from methylene dichloride and acetonitrile, preferably methylene dichloride. The step (d) is carried out at a predefined temperature of -5 to 15°C, preferably 0 to -5°C.

DESCRIPTION OF THE INVENTION:
References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed and obviously many modifications and variations are possible in light of the above teaching.
The inventors of the present invention have developed a a novel process for preparation of 1-(2,3,6-trifluorophenyl) propan-2-one of formula (I).

In one aspect the present invention relates to preparation of 1-(2,3,6-trifluorophenyl) propan-2-one of formula (I).

The process of the present invention includes the steps of:
(a) C-alkylation of 1,2,4-trifluorobenzene of formula (V) by reacting with epichlorohydrin of formula (VI) at a predefined temperature in a predefined solvent in presence of an organolithium reagent to form 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV);

(b) epoxidation of 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV) at a predefined temperature in a predefined solvent in presence of a suitable base to form 2-(2,3,6-trifluorobenzyl) oxirane of formula (III);

c) ring opening of 2-(2,3,6-trifluorobenzyl) oxirane of formula (III) at a predefined temperature in a predefined solvent in presence of a suitable reducing agent and a metal catalyst to form 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II); and

d) oxidation of 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II) at a predefined temperature in a predefined solvent in presence of suitable oxidizing reagent and a catalyst to form 1-(2,3,6-trifluorophenyl) acetone of formula (I).

The reaction can be schematically represented as shown below in scheme 4.

Scheme 4
In this embodiment of the present invention, the predefined solvent used for C-alkylation in step (a) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran and Toluene. The reaction is carried out preferably in tetrahydrofuran. The organolithium reagent used for C-alkylation in step (a) is a suitable alkyl lithium selected from N-BuLi and n-hexyllithium. The C-alkylation is carried out at predefined temperature of -30 to -70°C, preferably at -50 to -60°C.
The suitable base employed in step (b) selected from alkali hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably sodium hydroxide. The predefined solvent used in step (b) is selected form tetrahydrofuran, alcoholic solvents such as methanol, ethanol and isopropanol, water and/or mixtures thereof. Preferably the solvent used is the mixture of tetrahydrofuran and water. The reaction is carried out at a predefined temperature of 35-55°C, preferably at 40-45°C.
The reducing agent employed for ring opening step (c) is selected from sodium borohydride, Lithium aluminium hydride (LAH) and the metal catalyst is selected from Palladium on carbon, platinum supported on carbon, platinum supported on Copper and Nickel. The predefined solvent used in step (c) is selected from tetrahydrofuran, alcoholic solvents such as methanol, ethanol and isopropyl alcohol. The reaction is carried out at a predefined temperature of 35-50°C, preferably 40-45°C.
Suitable oxidizing reagents for step (d) oxidation in stage (d) is selected from sodium hypochlorite, periodic acid, pyridinium chlorochromate, Dess-martin reagent, chromic acid, iodoxybenzene and oxalyl chloride-DMSO. In a preferred embodiment the reaction proceeds using sodium hypochlorite. The catalyst is selected from TEMPO and Sodium bromide. The predefined solvent is selected from methylene dichloride, acetonitrile and THF. The reaction is carried out at a predefined temperature of -5°C to 15°C, preferably at 0 to -5°C.
These and other embodiments will be apparent to those of skill in the art and others in view of the following detailed description of some embodiments. It should be understood, however, that this summary and the detailed description illustrate only some examples of various embodiments and are not intended to be limiting to the invention as claimed. The following examples illustrate the invention but are not limiting thereof.

EXAMPLES:
Example 1
Preparation of (2-Chloro-1-(2,3,6-trifluorophenyl) ethanol (Formula IV)
In an inert atmosphere, 1,2,4-Trifluorobenzene (100 gm) was charged in tetrahydrofuran (500 ml) at 25-30°C. The reaction mixture was cooled to -50°C to -60°C and stirred for 30 minutes. N-butyl lithium (1.6 M in THF) (500 ml) was slowly added to the reaction mixture at -50 to -60°C over the period of 6 hours. The mixture was stirred for 60 minutes. Epichlorohydrin (77.5 gm) was charged slowly to the reaction mass at -50 to -60°C over the period of 90 minutes. The temperature of the reaction mass was raised to -45 to -50°C and maintained for 2-3 hours. After completion of the reaction 20% ammonium chloride (500 ml) was charged slowly to the reaction mass at -45 to -50°C. The temperature was further raised to 25 to 30°C and maintained for 30 minutes.
MDC (200 ml) was charged to the reaction mass at 25 to 30°C and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted again using MDC (200 ml x 2). The layers were separated and sodium sulphate (20 gm) was charged to the organic layer and stirred. The organic layer was filtered and distilled under vacuum at 40°C. The oil 2-Chloro-1-(2,3,6-trifluorophenyl) ethanol (150 gm, 88%) was obtained that serves as the starting material for the next step.
HPLC Purity: 98.45%
1 HNMR: (300 Mz) CDCl3, 7.08-7.17 (m, 1H), 6.82-6.89 (m, 1H), 4.07-
4.10 (d, J=11.1Hz, 1H), 3.76-3.80 (m,1H), 3.50-3.54 (m, 1.0 H),1.79-1.80 (m, 1H)

Example 2
Preparation of 2-(2,3,6-Trifluorobenzyl) oxirane (Formula III)
2-Chloro-1-(2,3,6-trifluorophenyl) ethanol (100 gm) obtained in step I was charged to THF (500 ml) at 25 to 30°C and stirred for 15 minutes. The solution was cooled to 15 to 20°C. 1.2M sodium hydroxide (500 ml) was charged to the above solution at 15-20°C. The mixture was heated to 40-45°C and maintained for 2 hours. After completion of reaction the mass was cooled to 25-30°C and the organic layer was distilled under vacuum at 40°C
MDC (200 ml) was charged to the mass at 25 to 30°C and stirred for 30 minutes. The layers were separated and the aqueous layer was back extracted with MDC (200 ml x 2). All the organic layers were combined and sodium sulphate (20 gm) was added. The mixture was filtered and the organic layer was distilled under vacuum. The oil 2-(2,3,6-Trifluorobenzyl) oxirane (75.23 gm, 90%) obtained serves as the starting material for the next step.
HPLC Purity: 98.0%
Example 3
Preparation of 1-(2,3,6-Trifluorophenyl)-2-propanol (Formula II)
(2,3,6-Trifluorobenzyl) oxirane (100 gm) was charged to ethanol (400 ml) at 25-30°C and the solution was stirred for 15 minutes at 25-30°C. The mixture was cooled to 15 to 20°C. Sodium borohydride (31.93 gm) was added lot wise over 120 minutes at 15-20°C. The reaction mass was heated to 35-40°C and maintained at 35-40°C for 2 hours. After completion of the reaction, the mass was cooled gradually to 10-15°C. Water (500 ml) was added to the reaction mass at 10-15°C. The temperature was raised to 25-30°C and stirred for 30 minutes. The organic layer was distilled under vacuum at 40°C. Ethyl acetate (200 ml) was charged to the mass at 25-30°C and stirred for 30 minutes. The layers were separated and the aqueous layer was back extracted with ethyl acetate (200 ml x 2). The organic layers were collected. 30% brine solution (200 ml) was charged to the mass at 25-30°C and stirred for 30 minutes. The organic layer was separated and Sodium sulphate (20 gm) was charged and stirred at 25-30°C. The organic layer was filtered and distilled under vacuum at 40°C. 1-(2,3,6-Trifluorophenyl)-2-propanol (90 gm, 89%) was obtained as oil.
HPLC purity: 97.6%
LCMS:96.91 (Na+ 214.17), 1 HNMR: (300 Mz) CDCl 3, 7.00-7.06 (m, 1H), 6.78-6.96 (m,
1H), 4.08-4.12 (m, 1H), 2.78-2.92 (m,2H), 1.25-1.27 (m, 2.0H),
Example 4
Preparation of 1-(2,3,6-Trifluorophenyl) acetone (Formula I)
Sodium bromide (32.4 gm) was charged to the separately prepared 1M sodium hydroxide solution (400 ml) at 25-30°C and stirred for 10 minutes. MDC (700 ml) was charged to the above solution and stirred for 10 minutes. 1-(2,3,6-Trifluorophenyl)-2-propanol (100 gm) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was chilled to 0 to -5°C and TEMPO (0.6 gm) was charged and the mixture was stirred for 15 minutes. 10% Sodium hypochlorite solution (450 ml) was charged slowly in around 3 hours to the mixture at 0 to -5°C. The mixture was stirred for 2-3 hours.
After the reaction completion, water (300 ml) was charged at 0 to -5°C and stirred. The layers were separated and MDC (200 ml) was charged to the aqueous layer. The organic layers were combined and 10% NaHSO4 solution (200 ml) was added and stirred for 30 minutes. The layers were separated and 5% NaOH (200 ml) was charged to the organic layer. The layers were separated and 10% activated charcoal (10gm) was charged to the organic layer followed by stirring for 30 minutes. The mass was filtered and the organic layer was distilled under vacuum at 40°C. 1-(2,3,6-Trifluorophenyl) acetone (90 gm, 90%) was obtained as oil.
HPLC Purity: 98.5%
1 HNMR: (300 Mz) CDCl 3, 7.03-7.28(m, 1H), 6.81-6.86 (m, 1H), 3.83 (S, 2H), 2.3 (S,3H)
In the context of the present invention, the process of the present invention is cost effective. The process of the present invention employs reagents that are easily available and less expensive. The process of the present invention is feasible for higher scale production.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the scope of the present invention.
, Claims:We claim:
1) A process for preparation of 1-(2,3,6-trifluorophenyl) propan-2-one of formula (I) comprising,
a) C-alkylation of 1,2,4-trifluorobenzene of formula (V) by reacting with epichlorohydrin of formula (VI) to form 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV);
z
b) epoxidation of 2-chloro-1-(2,3,6-trifluorophenyl) ethanol of formula (IV) in presence of suitable base to form 2-(2,3,6-trifluorobenzyl) oxirane of formula (III);

c) ring opening of 2-(2,3,6-trifluorobenzyl) oxirane of formula (III) in presence of a suitable reducing agent to form 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II); and

d) oxidation of 1-(2,3,6-trifluorophenyl)-2-propanol of formula (II). The process as claimed in claim 1. wherein stage (a) is carried out in presence of alkyl lithium selected from n-BuLi and n-hexyllithium and in a solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran and Toluene.

2) The process as claimed in claim 1, wherein step (a) is carried out in presence of alkyl lithium selected from n-BuLi and n-hexyllithium and in a predefined solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran and Toluene.
3) The process as claimed in claim 1, wherein the predefined solvent in step (a) is tetrahydrofuran.
4) The process as claimed in claim 1, wherein step (a) is carried out at a predefined temperature of -30 to -70°C.
5) The process as claimed in claim 1, wherein step (a) is carried out at a predefined temperature of -50 to -60°C.
6) The process as claimed in claim 1, wherein base in step (b) is alkali hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.
7) The process as claimed in claims 1 and 6, wherein base in step (b) is sodium hydroxide.
8) The process as claimed in claim 1, wherein the predefined solvent in step (b) is selected form tetrahydrofuran, methanol, ethanol and isopropanol, water and/or mixtures thereof.
9) The process as claimed in claims 1 and 9, wherein the predefined solvent in step (b) is mixture of tetrahydrofuran and water.
10) The process as claimed in claim 1, wherein step (b) is carried out at a predefined temperature of 35-55°C.
11) The process as claimed in claim 1, wherein step (b) is carried out at a predefined temperature of 40-45°C.
12) The process as claimed in claim 1, wherein the reducing agent in step (c) is selected from sodium borohydride, Lithium aluminium hydride (LAH); a metal catalyst is selected from palladium on carbon, platinum supported on carbon, platinum supported on copper and nickel.
13) The process as claimed in claims 1 and 13, wherein the reducing agent in step (c) is sodium borohydride.
14) The process as claimed in claim 1, wherein step (c) is carried out in a predefined solvent selected from THF, alcoholic solvents such as methanol, ethanol or isopropyl alcohol.
15) The process as claimed in claim 1, wherein the predefined solvent in step (c) is ethanol.
16) The process as claimed in claim 1, wherein step (c) is carried out at a predefined temperature of 35-50°C.
17) The process as claimed in claim 1, wherein step (c) is carried out at a predefined temperature of 40-45°C.
18) The process as claimed in claim 1, wherein the oxidizing agent in step (d) is selected from sodium hypochlorite, periodic acid, pyridinium chlorochromate, Dess-martin reagent, chromic acid, iodoxybenzene and oxalyl chloride-DMSO.
19) The process as claimed in claim 1, wherein theoxidizing agent in step (d) is sodium hypochlorite.
20) The process as claimed in claim 1, wherein oxidation in step (d) is carried out using sodium hypochlorite in presence of a catalyst selected from TEMPO and Sodium bromide.
21) The process as claimed in claim 1, wherein step (d) is carried out in a predefined solvent selected from methylene dichloride and acetonitrile.
22) The process as claimed in claim 1, wherein the predefined solvent in step (d) is methylene dichloride.
23) The process as claimed in claim 1, wherein step (d) is carried out at a predefined temperature of -5 to 15°C.
24) The process as claimed in claim 1, wherein step (d) is carried out at a predefined temperature of 0 to -5°C.

Dated this 21st day of March 2024.

For AARTI PHARMALABS LIMITED

Mahurkar Anand Gopalkrishna
IN/PA-1862
(Agent for Applicant)