Field of the invention
The present invention relates to a process for preparation of pyridinone derivative having formula I.

FORMULA I

Background of the invention
Pyridinone derivatives are the key intermediates for the agrochemical and pharmaceutical products.
The PCT Publication No. WO2006/12320 provides a process for preparation of pyridinone derivative comprising the steps of condensation of 4-alkoxy-1,1,1-trifluorobut-3-en-2-one with a trialkylphosphono acetate in the presence of a base followed by cyclization to give pyran-2-one derivative which upon treatment with ammonium hydroxide in the presence of glacial acetic acid gives pyridinone derivative as an oil, in yield of 32%.
The said process suffers from several drawbacks such as poor yield; use of acetic acid at industrial scale is not safe and may corrode the reaction vessel. The pyridinone derivative is isolated as an oil, therefore isolated product is impure and further, no method is disclosed to purify pyridinone derivative.
Therefore, there is a need to develop an efficient and industrially advantageous process for preparing a pyridinone derivative of formula I, having comparative high yield, by avoiding use of an acid.

Summary of the invention
The present invention provides a process for preparation of pyridinone derivative of formula I,

FORMULA I
comprises:
a) contacting a compound of formula II,

FORMULA II
with ammonia in the absence of an acid to obtain the compound of formula I.
The present invention provides a process for preparation of pyridinone derivative of formula I having purity at least 90%,

FORMULA I
comprises;
a) contacting the compound of formula I having purity less than 80% with solvent to obtain a reaction mixture; and
b) isolating the compound formula I, having purity at least 90%, from the reaction mixture of the step a).
The present invention provides a process for preparation of pyridinone derivative of formula I,

FORMULA I
comprises:
a) protecting a compound of formula III,

FORMULA III
to obtain a compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
c) cyclizing the compound of formula VI to obtain a compound formula II;

FORMULA II
d) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I.
The present invention provides a process for preparation of a pyridinone derivative of I,

FORMULA I
comprises:
a) contacting a compound of formula IV

FORMULA IV
wherein P1 is an amino protecting group;

wherein P1 is an amino protecting group;
with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
b) cyclizing the compound of formula VI to obtain a compound formula II;

FORMULA II
c) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I.
The present invention provides a process for preparation of a pyridinone derivative of formula I,

FORMULA I
comprises:
a) cyclizing a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
to obtain a compound formula II;

FORMULA II
b) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I.
The present invention provides a process for preparation of a compound formula II,

FORMULA II
comprises:
a) protecting a compound of formula III,

FORMULA III
to obtain compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
c) cyclizing the compound of formula VI to obtain a compound formula II.

The present invention provides a process for preparation of a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group
comprises:
a) protecting a compound of formula III,

FORMULA III
to obtain a compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain the compound of formula VI.

The present invention provides a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group.

Detailed description of the invention
As used herein, the term “protecting group” refers to an amino protecting groups selected from the group consisting of di-tert-butyl dicarbonate (Boc), acetyl, tosyl carboxybenzyl and fluorenylmethyloxycarbonyl or the like.
As used herein, the term “halogenating agent” refers to an agent selected from a group consisting of thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus pentabromide, phosphorus pentabromide, triphenylphosphine/carbon tetrachloride, or the like.
The present invention relates to a process for preparation of a pyridinone derivative of formula I,

FORMULA I
by contacting the compound of formula II,

FORMULA II
with ammonia in the absence of an acid to obtain a reaction mixture.
The ammonia used in the reaction may be anhydrous or in solution with a solvent such as water and methanol.
The reaction is carried out at a temperature in the range of 5°C to 80°C.
The compound of formula I is isolated from the reaction mixture by using any separation technique known in the art such as extraction, filtration, and vaporization/concentration of reaction solvent.
According to one embodiment, the present invention provides a process for preparation of a pyridinone derivative of formula I, having purity atleast 90%, by contacting a pyridinone derivative of of formula I, having purity less than 80%, with solvent(s) at a temperature in the range of 15°C to 50°C.
The solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, and ethyl acetate, hexanes, pentane, toluene and/or mixture thereof.
The reaction mixture is stirred for 10 to 40 minutes. Then, the reaction mixture is cooled to a temperature in the range of -5°C to 10°C and compound formula I, having purity atleast 90%, is isolated from the reaction mixture.
In a specific embodiment, the present invention provides a process for preparation of 4-(trifluoromethyl)-2(1H)-pyridinone by reacting 4-(trifluoromethyl)-2H-pyran-2-one with ammonia and isolating 4-(trifluoromethyl)-2(1H)-pyridinone in a solvent.
In another specific embodiment, 4-(trifluoromethyl)-2(1H)-pyridinone prepared by the method of the present invention is converted to 2-halo-4-trifluoromethyl)pyridine using a halogenating agent, wherein halo is selected from Cl, Br, I or the like.
In another specific embodiment, 4-(trifluoromethyl)-2(1H)-pyridinone prepared by the method of the present invention is converted to 2-chloro-4-trifluoromethyl)pyridine using a chlorinating agent.
The compound of formula II can be prepared by using a compound of formula III as starting material.
The compound of formula III is protected with protected groups to obtained compound of formula IV.
The step of protection is optionally carried out in the presence of catalyst selected from dimethylaminopyridine (DMAP), diisopropylethylamine, triethylamine, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate and alike or mixture thereof in a solvent.
The step of protection of amino group is done at a temperature in the range -10°C to 25°C.
The solvent used in the step of protection is selected from a dichloromethane, dichloroethane, dioxane, dimethoxyethane, tetrahydrofuran, acetonitrile, alcohol selected from methanol, ethanol and alike or mixture thereof.
The compound of formula IV is reacted with a compound of formula V to obtain a reaction mixture.
The reaction of a compound of formula IV with a compound of formula V is carried out in a solvent selected from a group consisting of a hydrocarbon solvent such as toluene, hexane, heptane, dichloromethane, dichloroethane, ether solvent such as tetrahydrofuran, diethylether, diisopropylether, methyl tert-butyl ether at a temperature of 25°C to 130°C.
In a specific embodiment, the compound of formula V is selected from methyl (triphenylphosphoranylidene)acetate, ethyl (triphenylphosphoranylidene) acetate, ethyl 2-(triphenylphosphoranylidene)propionate, (tert-butoxy carbonyl methylene)triphenylphosphorane, benzyl(triphenylphosphoranylidene)acetate or the like.
Optionally, a salt of a compound of formula V may be used for the reaction.
After completion of the reaction, the reaction mixture is cooled to a temperature 20°C to 35°C and reaction mixture is concentrated to obtain crude compound of formula VI. The resulting crude compound is dissolved in hydrocarbon solvent and followed by filtration through silica bed to eliminate triphenylphosphine oxide (TPPO). The hydrocarbon solvent is selected from hexane, heptane and pentane and or mixture thereof. Then the resulting filtrate is concentrated to obtain compound of formula VI.
In a specific embodiment, tert-butyl [(1E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl]carbamate is reacted with ethyl (triphenylphosphoranylidene)acetate in toluene to give ethyl (2E,4E)-5-[(tert-butoxycarbonyl)amino]-3-(trifluoromethyl)penta-2,4-dienoate.
The step of cyclization is carried out in the presence of an acid selected from a group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, p-toluenesulphuric acid or the like.
The cyclization of compound of formula VI may be carried out at a temperature in the range of 25°C to 80°C.
In a specific embodiment, ethyl (2E,4E)-5-[(tert-butoxycarbonyl)amino]-3-(trifluoromethyl) penta-2,4-dienoate is cyclized to 4-(trifluoromethyl)-2H-pyran-2-one in the presence of hydrochloric acid.
The compound of formula III may be prepared by any method known the art or can be purchased from the market.
The compound of formula II, III, formula IV and formula VI may not be isolated from the reaction mixture and may be utilized as such for further reaction, or these said compounds can be isolated from the reaction mixture by using any separation technique known in the art such as extraction, filtration, and vaporization/concentration of reaction solvent.
It is well known that 4-(trifluoromethyl)-2H-pyridinone exists in an equilibrium with 4-(trifluoromethyl)-2-pyridino1.
The purity of compound of formula I, II, formula III, formula IV and formula VI is measured by any analytical techniques known in the art like high pressure liquid chromatography (HPLC), thin layer chromatography (TLC) and gas chromatography (GC).
The completion of reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), High pressure liquid chromatography (HPLC), Ultra-pressure liquid chromatography (UPLC) and the like.
The scope of the present invention is to provide novel compounds of formula III, formula IV and formula VI; which may exist as E-isomer or Z-isomer or E/Z isomer mixture.

EXAMPLES
Example 1: Process for preparation of (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one
Solution of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (200g, 2.08 mol) in dichloromethane (266g, 1.56 mol) was cooled to 0°C and then ammonia gas (100g, 6.24 mol) was purged into the solution with maintaining the temperature below 10°C. The resulting solution was stirred at room temperature for 2.5 hours and then dichloromethane was evaporated from the reaction mass. The crude product was boiled off below 55°C under vacuum to get pure 158g (91%) of title compound having purity 94%, checked by Gas Chromatography.

Example 2: Process for preparation of tert-butyl [(1E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl]carbamate
Boc anhydride (31.3g, 0.14 mol) was added dropwise through addition funnel at 0°C to a mixture of (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one (22g, 0.15 mol) and DMAP (0.76g, 0.04 mol) in dichloromethane. Reaction was stirred at room temperature for one and half hour. After the completion of reaction, reaction mass was washed with water (3x100ml) followed by layer separation. The organic layer was dried over sodium sulphate and concentrated to get crude product. Crude product was diluted with ethyl acetate (5%) in hexanes and then passed through silica gel. Filtrate was concentrated to get 28g (71.1%) of title compound having purity 91.28%.

Example 3: Process for preparation of ethyl (2E,4E)-5-[(tert-butoxycarbonyl)amino]-3-(trifluoromethyl)penta-2,4-dienoate
Tert-butyl [(1E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl]carbamate (28g, 0.11mol) and ethyl (triphenylphosphoranylidene)acetate (40.8g, 0.11 mol) were taken in toluene in a clean and dry 3-necked round bottom flask equipped with thermometer pocket, condenser and allowed to react at 100 °C for 3 hours. Then cooled the reaction mass to room temperature and concentrated to get crude product, which was dissolved in hexane followed by filtration through silica bed to eliminate triphenylphosphine oxide (TPPO). Filtrate was concentrated to get 28g (78.7%) of title compound having purity 92.88%.

Example 4: Process for preparation of 4-(trifluoromethyl)-2H-pyran-2-one
Ethyl (2E,4E)-5-[(tert-butoxycarbonyl)amino]-3-(trifluoromethyl) penta-2,4-dienoate (20g, 0.06 mol) was taken in a clean and dry 3-necked round bottom flask equipped with thermometer pocket, condenser and then hydrochloric acid (6N, 200 ml) was added at room temperature. The resulting reaction mixture was stirred at 70°C for 2 hours. After completion of reaction, reaction mass was cooled to room temperature extracted with dichloromethane (2 x 200 ml). Mixed the organic layers followed by concentration to get 7g (63.95%) of title compound having purity 90.32%.

Example 5: Process for preparation of 4-(trifluoromethyl)-2H-pyridinone
In a 3-neck round bottom flask equipped with condenser, thermometer pocket, 4-(trifluoromethyl)-2H-pyran-2-one (6.5g) and aqueous ammonia (30 ml) were taken to obtain a mixture. The resulting mixture was stirred at 60-70°C for 2 hours. After completion of reaction, reaction mixture was cooled to 20 to 25°C and product was extracted with dichloromethane (2 x 100ml). Organic layers were mixed and concentrated to get 5.5g of the titled compound having purity 80%.

Example 6: Process for preparation of 4-(trifluoromethyl)-2H-pyridinone
The 4-(trifluoromethyl)pyridinone (5g) was contacted with methyl tert-butyl ether under stirring for 20 minutes at a temperature 20-25°C. The resulting reaction mixture was cooled to a temperature 0-5°C and then filtered to get 4-(trifluoromethyl)pyridinone. Isolating 2.95g (50%) of the titled compound having purity 99%.

Example 7: Process for preparation of 2-chloro-4-(trifluoromethyl)pyridine
In a 3-neck round bottom flask equipped with condenser and thermometer pocket, 4-(trifluoromethyl)-2H-pyridinone (5.0g) and phosphorous oxychloride (20 ml) were taken. The resulting mixture was refluxed for 2 hours. After completion of reaction, phosphorous oxychloride was boiled-off and crude residual mass was neutralized with saturated sodium bicarbonate solution. Product was extracted with dichloromethane (2 x 100ml). Organic layers were mixed and concentrated to get crude product. Crude product was boiled-off to get pure product 3.0g (54%) of titled compound, having purity 97%.

WE CLAIM:
1. A process for preparation of pyridinone derivative of formula I,

FORMULA I
comprising the steps of:
a) contacting a compound of formula II,

FORMULA II
with ammonia in the absence of an acid;
wherein ammonia is either anhydrous or in a solution with water or methanol,
b) optionally, purifying the compound of formula I using a solvent.
2. A process for preparing 4-(trifluoromethyl)-2(1H)-pyridinone comprises:
a) contacting a crude 4-(trifluoromethyl)-2(1H)-pyridinone having purity less than 80% with a solvent at a temperature in the range of 15°C to 50°C to obtain a reaction mixture;
b) cooling the reaction mixture to a temperature in the range of -5°C to 10°C; and
b) isolating 4-(trifluoromethyl)-2(1H)-pyridinone having purity of at least 90%.
3. A process for preparation of pyridinone derivative of formula I,

FORMULA I
comprising the steps of:
a) protecting a compound of formula III,

FORMULA III
to obtain a compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
a) cyclizing the compound of formula VI in presence of an acid, to obtain a compound formula II,

FORMULA II
b) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I,
wherein ammonia is either anhydrous or in solution with water or methanol.
4. A process for preparation of a pyridinone derivative of formula I,

FORMULA I
comprising the steps of:
a) contacting a compound of formula IV

FORMULA IV
wherein P1 is an amino protecting group;
with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
b) cyclizing the compound of formula VI in presence of an acid, to obtain a compound formula II,

FORMULA II
c) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I.
5. A process for preparation of a pyridinone derivative of formula I,

FORMULA I
comprising the steps of:
a) cyclizing a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
in presence of an acid to obtain a compound formula II,

FORMULA II
b) contacting the compound of formula II with ammonia in the absence of an acid to obtain the compound of formula I, wherein ammonia is either anhydrous or in solution with water and methanol.
6. A process for preparation of a compound formula II,

FORMULA II
comprising the steps of:
a) protecting a compound of formula III,

FORMULA III
to obtain compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain a compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group;
c) cyclizing the compound of formula VI, in presence of an acid to obtain the compound of formula II.
7. A process for preparation of compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group.
comprising the steps of:
a) protecting a compound of formula III,

FORMULA III
to obtain a compound of formula IV,

FORMULA IV
wherein P1 is an amino protecting group;
b) contacting the compound of formula IV with a compound of formula V,

FORMULA V
wherein R is an alkyl group selected from methyl, ethyl, propyl, tert-butyl or benzyl group; R1 is an alkyl group or hydrogen; Ph is phenyl group;
to obtain the compound of formula VI.
8. A compound of formula VI,

FORMULA VI
wherein P1 is an amino protecting group, R is an alkyl group.
9. The process as claimed in claim 1 and claim 2, wherein the solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, and ethyl acetate, hexanes or mixture thereof.
10. The pyridinone derivative of formula I, prepared by the process as claimed in previous claims is converted to 2-chloro-(4-trifluoromethyl)pyridine.

Dated this 23rd day of March 2017.


Kapil
Senior Research Associate (IPR)
SRF Limited