Description:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10; rule 13)

“A PROCESS FOR PREPARATION OF 5-(CHLOROMETHYL)-2,4-DIFLUOROPYRIDINE”

Hikal Limited, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I).

BACKGROUND OF THE INVENTION

5-(chloromethyl)-2, 4-difluoropyridine of formula (I) having CAS No. 1807230-91-6 is an important intermediate for preparation of various industrially acceptable advanced intermediate, APIs/AIs. The 5-(chloromethyl)-2, 4-difluoropyridine could also be used for preparation of PKC inhibitors, protein kinase pathway inhibitor, and immuno-inflammatory drugs. Many of these advanced intermediates are under investigation or under clinical studies. The prior art does not disclose any process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine, thus there is a need for a process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I)

which comprises the steps of:
a) reacting a compound of formula (V) where X is independently selected from Cl, Br, and I, with fluorinating agent, with or without phase transfer catalyst, in solvent to obtain corresponding compound of formula (VI);

b) reacting compound of formula (VI) with reducing agent in presence of solvent to obtain compound of formula (VII);

c) reacting compound of formula (VII) with chlorinating agent, with or without catalyst in solvent to obtain compound of formula (I).

The another aspect of the present invention is to provide a process for the preparation of 4,6-difluoronicotinate of formula (VI)

by reacting compound of formula (V) where X is independently selected from Cl, Br, and I with potassium fluoride, with or without phase transfer catalyst, in solvent.

The another aspect of the present invention is to provide a process for preparation of (4,6-difluoropyridin-3-yl) methanol of formula (VII),

by reacting methyl 4,6-difluoronicotinate of formula (VI) with reducing agent in presence of solvent.

The another aspect of the present invention is to provide a process for preparation 5-(chloromethyl)-2, 4-difluoropyridine of formula (I),

by reacting compound of formula (VII) with chlorinating agent in presence of catalyst in solvent.

In another aspect, the present invention provides a process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I),

which comprises the steps of:
a) reacting a compound of formula (V) where X is independently selected from Cl, Br, and I, with potassium fluoride, with or without phase transfer catalyst, in solvent to obtain corresponding compound of formula (VI);

b) reacting compound of formula (VI) with sodium borohydride or diisobutylaluminium hydride, in solvent to obtain compound of formula (VII);

c) reacting compound of formula (VII) with chlorinating agent in presence of catalyst in solvent to obtain compound of formula (I).

In another aspect, the present invention provides a use of 5-(chloromethyl)-2, 4-difluoropyridine (I) for the preparation of advanced intermediates of formula (VIII), (IX) using compound (I) which is prepared as per the process disclosed hereinabove.

The compound 5-(chloromethyl)-2, 4-difluoropyridine (I) is obtained by the present invention results with purity greater than 98%, preferably greater than 99%, more preferably 99.5% and impurities less than 1% as measured by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is now described in more detail hereinafter. The invention is embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In another embodiment of the present invention, wherein the said chlorinating agent, brominating agent or iodinating agent are well known in prior art.

In another embodiment of the present invention, wherein the said fluorinating agent is selected from a cesium fluoride, potassium fluoride, fluorides of xenon, Select Fluor, Tetrabutylammonium fluoride, Hydrogen fluoride, Tetramethylammonium Fluoride Tetrahydrate, Tetra butyl ammonium bifluoride, Tetrabutylammonium dihydrogen trifluoride, Triethylamine trihydrofluoride, Tetraethylammonium Fluoride, Trihydrofluoride, DMPU-HFIF5-Pyridine-HF, Diethylaminosulfur trifluoride (DAST), Ishikawa's Reagent, Perfluoro-1-butanesulfonyl Fluoride, Pyridine-2-sulfonyl Fluoride, AlkylFluor, PhenoFluor and the like .
In another embodiment of the present invention, wherein the said chlorinating agent is selected from a chlorine gas, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, trichloroisocyanuric acid, N-chlorosuccinimide, dichloro dimethyl hydantoin, trichloroisocyanuric acid, sodium dichloroisocyanurate, sodium hypochlorite, sulfuryl chloride, phosphoryl chloride and the like.

In another embodiment of the present invention, wherein the said phase transfer catalyst is selected from tetra butyl ammonium bromide, tetra butyl ammonium chloride, tetra butyl ammonium Iodide, crown ethers, 18-crown-6, dibenzo-18-crown-6, methyltrioctylammonium chloride, tetrabutylammonium fluoride, triethylbenzylammonium chloride, aliquat 336, and the like.

In another embodiment of the present invention, wherein a solvent used for preparation of compound (VI) is selected from polar aprotic solvent such as dimethyl sulfoxide, methyl cyanide, N,N-dimethyl formamide, N-methylpyrrolidone (NMP), dimethylpropyleneurea, hexamethylphosphoramide, sulfolane, tetrahydrofuran and the like and hydrocarbon solvent such as toluene, xylene, hexane, dodecane, durene, 1-Octadecene and the like and mixture thereof.

In another embodiment of the present invention, wherein the said reducing agent is selected from a group consisting of Sodium borohydride, Diisobutylaluminium hydride (DIBAL-H), Palladium on carbon, Raney Nickel, Lithium Aluminum Hydride, Lithium Borohydride, Borane-dimethyl sulfide, Vitride, Sodium triacetoxyborohydride, Platinum on carbon, Palladium (II) acetate, Palladium on carbon, nido boranes, thexyl borane and the like.

In another embodiment of the present invention, wherein a solvent used for preparation of compound (VII) is selected from water, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, t-butanol, n-butanol, amyl alcohol, ether solvent such as tetrahydrofuran, diethyl ether, tert-amyl ethyl ether, cyclopentyl methyl ether, di-tert-butyl ether, diisopropyl ether, 1,4-dioxane, ethyl tert-butyl ether, methyl tert-butyl ether, morpholine, halogenated solvents like dichloromethane, chloroform, hydrocarbon solvent such as toluene, xylene, hexane, dodecane, durene, 1-octadecene and the like and mixture thereof.

In another embodiment of the present invention, wherein the said catalyst used in chlorination reaction is selected from N, N-dimethyl formamide and the like.

In another embodiment of the present invention, wherein a solvent used for preparation of compound (I) is selected from selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl chloride, other solvents like cyclohexane, heptane, dimethyl carbonate, acetonitrile, methyl acetate, isopropyl acetate and the like.

In another embodiment of the present invention, wherein the said acid is selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.

In another embodiment of the present invention, the reaction temperature for preparation of compound (VI) is 20°C to 140°C; of compound (VII) is -40°C to 40°C; and of compound (I) is 0°C to 45°C.

In another embodiment of the present invention, wherein the reaction time for preparation of compound (VI) is 2 to 48 hours; of compound (VII) is 1 to 4 hours; and of compound (I) is 4 to 8 hours.

In another embodiment of the present invention, wherein the compound formula (I) is obtained with purity greater than 99.0% and assay greater than 99.5%.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The present invention relates to a process for preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I) where the by-product 4,6-difluoronicotinic acid obtained in reduction step is further treated with an alcohol in presence of an acid to prepare compound of formula (VI) which is further used for preparation of compound (VII) and compound of formula (I); hence the process is economical, and industrially feasible.

The present invention is illustrated in the following general synthetic schemes:
Scheme:

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1: Preparation of compound of formula (IV)
In an RBF, compound (II, 1.0 eq) and compound (III, 1-1.5 eq) was added at room temperature and heated at 65°C to 85°C for 2-4 hours with continuous distillation of methanol. The completion of reaction is monitored by TLC. After completion, the reaction mixture was cooled to 0°C to 5°C and ammonium hydroxide (1 - 2V) was added and stirred for 1 hour. The pH of reaction mixture was maintained to 1-2 using hydrochloric acid. The precipitated compound was filtered, washed with water, and dried to yield the product as white solid. (Yield: 60-70%).

Example 2: Preparation of compound of formula (V)
In an RBF, phosphorus trichloride (2-4 V) was added and cooled to 0°C to 5°C, and a compound (IV, 1.0 eq), triethyl amine (1-1.5 eq) were added. The reaction mixture was heated at 90°C to 110°C for 1-3 hours. The completion of reaction is monitored by TLC. After completion, the reaction mixture was cooled to 40°C to 50°C and excess phosphorus trichloride was removed under reduced pressure. To the reaction mixture water (2- 4 V) was added and cooled to 0°C to 5°C. The pH of reaction mixture was maintained to 7-9 using inorganic base. The precipitated compound was filtered, washed with water, and dried to yield the product light brown to white solid. (Yield: 60-85%).

Example 3.0: Preparation of compound of formula (VI) using potassium fluoride.
In an RBF, Toluene (4-8 V), potassium fluoride (3-5 eq), and TBAB (1-2 eq) was added. The reaction mixture was heated at 110°C to 120°C for 1-2 hours. The toluene was removed using vacuum distillation, and DMSO (6-8 V) was added. The reaction mixture was cooled to 70°C to 90°C and compound (V, 1.0 eq) was added and maintained at a temperature for 10-24 hours. The completion of reaction is monitored by TLC. After completion, the reaction mixture was filtered, and the bed was washed with MTBE (4- 6V). To the filtrate water (15-20 V) was added and the layer was separated. The organic layer was washed with aq. sodium bicarbonate solution, and solvent was removed by distillation. The crude compound was purified by high vacuum distillation to obtain pure colorless compound (VI, yield 40 to 50 %).

Example 3.1: Preparation of compound of formula (VI) using spray dried potassium fluoride.
In an RBF, Compound (V, 1.0 eq), potassium fluoride (Spray dried) (3-5 eq), TBAB (1-2 eq) and DMSO (6-8 V) were added. The reaction mixture was heated at 70°C to 80°C and maintained at a temperature for 10-15 hours. The completion of reaction is monitored by TLC. After completion, the reaction mixture was filtered, and the bed was washed with MTBE (4- 6V). To the filtrate water (15-20 V) was added and the layer was separated. The organic layer was washed with aq. sodium bicarbonate solution, and solvent was removed by distillation. The crude compound was purified by high vacuum distillation to obtain pure yellow color compound (VI, yield 60 to 70 %).

Example 3.2: Preparation of compound of formula (VI) Cesium fluoride.
In an RBF, Compound (V, 1.0 eq), Cesium fluoride (3-5 eq), TBAB (1-2 eq) and DMSO (6-8 V) were added. The reaction mixture was warmed at 25°C to 40°C and maintained at a temperature for 30-48 hours. The completion of reaction is monitored by TLC. After completion, the reaction mixture was filtered, and the bed was washed with MTBE (4- 6V). To the filtrate water (15-20 V) was added and the layer was separated. The organic layer was washed with aq. sodium bicarbonate solution, and solvent was removed by distillation. The crude compound was purified by high vacuum distillation to obtain pure yellow color compound (VI, yield 55 to 65%).

Example 4.0: Preparation of compound of formula (VII) using DIBAL-H.
In an RBF, Compound (VI, 1.0 eq.) and THF (10 V) are added under nitrogen atmosphere. The reaction mixture was cooled to - 25°C ± 5°C and slowly DIBAL-H (1.0 M solution in Toluene, 1.5 eq) was added and maintained for 1-2 h. The completion of reaction is monitored by TLC. After reaction completion RM cooled to 0-5°C and quenched by Methanol (0.75 V) and water (1.5 V). The quenched mass was filtered, and the bed washed with MTBE (3- 4V). In filtrate mass water added and layer was separated. Aq. layer extracted in MTBE. The combined organic layer was washed with brine solution and distilled under reduced pressure (less than 50 torr) below 45°C. The crude compound is obtained (VII, yield 80-90 %). The crude compound was used as such without further purification.

Example 4.1: Preparation of compound of formula (VII) using sodium borohydride.
In an RBF compound (VI, 1.0 eq), water (8-10V) was added and cooled to 0°C to 10°C. To the above reaction mixture slowly sodium borohydride was added and stirred for 1-3 hours. The completion of reaction is monitored by TLC. After completion, the reaction mixture MTBE (4- 6V) was added. The organic layer was separated, washed with brine solution and solvent was removed by distillation. The crude compound is obtained (VII, yield 40-60 %). Aq. Layer pH adjusted acidic using 1N HCl and extracted in MTBE the organic layer was separated, washed with brine solution and solvent was removed by distillation. The crude 4,6-difluoronicotinic acid compound is obtained with yield 30-40 %) and this acid further converted into compound of formula (VI).

Example 5: Preparation of compound of formula (I)
In an RBF, Compound (VII, 1.0 eq), N, N-dimethylformamide (0.01-0.03V), dichloromethane (8-10V) was added and cooled to 0°C to 10°C. To the above reaction mixture slowly thionyl chloride (2-2.5eq) was slowly added. The reaction mixture was stirred at 10°C to 25°C for 1-3 hours. The completion of reaction is monitored by TLC. After completion, to the reaction mixture water (3-6V) was added. The organic layer was separated, washed with aq. sodium bicarbonate solution and solvent was removed by distillation. The crude compound is obtained (I, yield 85-95 %) and purified by vacuum distillation to obtain pure colorless liquid (I, 75-85 %, with HPLC purity > 99.5 %).
, Claims:We Claim:

1) A process for the preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I) which comprises the steps of:

a) reacting a compound of formula (V) where X is independently selected from Cl, Br, and I, with fluorinating agent, with or without phase transfer catalyst, in solvent to obtain compound of formula (VI);

b) reacting compound of formula (VI) with reducing agent in presence of solvent to obtain compound of formula (VII);

c) reacting compound of formula (VII) with chlorinating agent, with or without catalyst, in solvent to obtain compound of formula (I).

2) A process for the preparation of 4,6-difluoronicotinate of formula (VI)

by reacting compound of formula (V) where X is independently selected from Cl, Br, and I

with potassium fluoride, with or without phase transfer catalyst, in solvent.

3) A process for the preparation of (4,6-difluoropyridin-3-yl) methanol of formula (VII) by reacting methyl 4,6-difluoronicotinate of formula (VI) with reducing agent in presence of solvent, where the compound (VI) is obtained by a process as claimed in claim 2.

4) A process for the preparation of 5-(chloromethyl)-2, 4-difluoropyridine of formula (I) by reacting (4,6-difluoropyridin-3-yl) methanol of formula (VII) with chlorinating agent in presence of catalyst in solvent, where the compound (VII) is obtained by a process as claimed in claim 3.

5) The process as claimed in claim 1, wherein the said fluorinating agent is selected from a cesium fluoride, potassium fluoride, fluorides of xenon, Select Fluor, TBAF, HF, Tetramethylammonium Fluoride Tetrahydrate, Tetrabutyl ammonium bifluoride, Tetrabutylammonium dihydrogen trifluoride, Triethylamine trihydrofluoride, Tetraethylammonium Fluoride, Trihydrofluoride, DMPU-HFIF5-Pyridine-HF, DAST, Ishikawa's Reagent, Perfluoro-1-butanesulfonyl Fluoride, Pyridine-2-sulfonyl Fluoride, AlkylFluor, and PhenoFluor; said chlorinating agent is selected from a chlorine gas, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, trichloroisocyanuric acid, N-chlorosuccinimide, dichloro dimethyl hydantoin, trichloroisocyanuric acid, sodium dichloroisocyanurate, sodium hypochlorite, sulfuryl chloride, and phosphoryl chloride.

6) The process as claimed in claim 1, wherein the said phase transfer catalyst is selected from tetra butyl ammonium bromide, tetra butyl ammonium chloride, tetra butyl ammonium Iodide, crown ethers, 18-crown-6, dibenzo-18-crown-6, methyltrioctylammonium chloride, tetrabutylammonium fluoride, triethylbenzylammonium chloride, and aliquat 336; and said catalyst used in chlorinating reaction is N, N-dimethyl formamide.

7) The process as claimed in claim 1, wherein the said reducing agent is selected from a group consisting of Sodium borohydride, Diisobutylaluminium hydride (DIBAL-H), Palladium on carbon, Raney Nickel, Lithium Aluminum Hydride, Lithium Borohydride, Borane-dimethyl sulfide, Vitride, Sodium triacetoxyborohydride, Platinum on carbon, Palladium (II) acetate, Palladium on carbon, nido boranes, and thexyl borane.

8) The process as claimed in claim 1, wherein the said solvent used for the preparation of used for preparation of compound (VI) is selected from polar aprotic solvent such as dimethyl sulfoxide, methyl cyanide, N,N-dimethyl formamide, N-methylpyrrolidone (NMP), dimethylpropyleneurea, hexamethylphosphoramide, sulfolane, tetrahydrofuran and the like and hydrocarbon solvent such as toluene, xylene, hexane, dodecane, durene, 1-Octadecene; said solvent used for compound (VII) is selected from water, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, t-butanol, n-butanol, amyl alcohol, ether solvent such as tetrahydrofuran, diethyl ether, tert-amyl ethyl ether, cyclopentyl methyl ether, di-tert-butyl ether, diisopropyl ether, 1,4-dioxane, ethyl tert-butyl ether, methyl tert-butyl ether, morpholine, halogenated solvents like dichloromethane, chloroform, hydrocarbon solvent such as toluene, xylene, hexane, dodecane, durene, 1-octadecene; and the said solvents used for the preparation of compound (I) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl chloride, other solvents like cyclohexane, heptane, dimethyl carbonate, acetonitrile, methyl acetate, and isopropyl acetate.