Claims:1. An improved process for the preparation of fluxapyroxad (I)

Wherein R is selected from C1-4 alkyl or aryl.
which comprises;
(a) reacting compound of formula FLX-acid with chloroformate in presence of an organic base in a suitable solvent,
(b) optionally isolating the anhydride of formula FLX-anhydride,
(c) reacting with compound of formula FLX-amine,
(d) removing the solvent,
(e) treating with an alcohol solvent, and
(f) isolating to get fluxapyroxad (I).

2. The process as claimed in claim 1, wherein the chloroformate is selected from iso-propyl chloroformate and iso-butyl chloroformate.

3. The process as claimed in claim 1, wherein the organic base is selected from group consisting of N-methyl morpholine, 1,4-dimethyl piperazine, N-methyl pyrrolidine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-diazabicyclo [2.2.2] octane (DABCO), triethanolamine, hydroxy ethyl morpholine, dimethyl aniline, 1-methylpiperidine, pyridine, and substituted pyridines.

4. The process as claimed in claim 1, wherein the solvent is selected from group consisting of tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), N, N-dimethylformamide (DMF), 1,2-dimethoxyethane (DME), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), acetonitrile, acetone, toluene, xylene, mono chlorobenzene, dichlorobenzene, 1,2-dichloromethane and 1,2-dichloroethane.

5. The process as claimed in claim 1, wherein the alcoholic solvent is selected from methanol, ethanol and isopropanol.

6. An improved process for the preparation of fluxapyroxad (I)

which comprises;
a) dissolving compound of formula FLX-acid in a suitable solvent in presence of an organic base.
b) adding alkyl phosphonic acid anhydride,
c) reacting with compound of formula FLX-amine at room temperature,
d) removing the solvent,
e) treating with an alcohol solvent, and
f) isolating to get fluxapyroxad (I).

7. The process as claimed in claim 6, wherein the alkyl phosphonic acid anhydride is propane phosphonic acid anhydride.

8. An improved process for the preparation of fluxapyroxad (I)

Wherein R1 is selected from the group consisting of alkyl or aryl.
which comprises;
(a) reacting sulfonyl chloride reagent with compound of formula FLX-acid in a suitable solvent in presence of an organic base,
(b) slowly adding compound of formula FLX-amine at 0-50 C for 5-10min,
(c) maintaining the reaction at room temperature for 5-6 hours,
(d) removing the solvent to get crude product, and
(e) recrystallizing in hydrocarbon solvent to get fluxapyroxad (I).

9. The process as claimed in claim 8, wherein the sulfonyl chloride reagent is selected from methane sulfonyl chloride or para toluene sulfonyl chloride.

10. The process as claimed in claim 8, wherein the hydrocarbon solvent is toluene, xylene and benzene.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of fluxapyroxad (I).

BACKGROUND OF THE INVENTION
Fluxapyroxad is a broad-spectrum pyrazole-carboxamide fungicide used on a large variety of commercial crops. It interferes with several key fungal life functions, including spore germination, germ tube growth, appressoria formation and mycelium growth. Specifically, it interferes with the production of succinate dehydrogenase, the complex II in the mitochondrial respiration chain, which in turn interferes with the tricarboxylic cycle and mitochondrial electron transport.

Fluxapyroxad is chemically known as 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide and represented below as formula (I).

The general synthesis of fluxapyroxad is known from WO 2006/087343. This procedure yields the compound as an amorphous solid.

The main objective of the present invention is to provide a simple, economical, commercially, and environmentally feasible process for the preparation of fluxapyroxad (I) with high yield and purity.

SUMMARY OF THE INVENTION
In one aspect of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

wherein R is selected from C1-4 alkyl or aryl.
which comprises;
(a) reacting compound of formula FLX-acid with chloroformate in presence of an organic base in a suitable solvent,
(b) optionally isolating the anhydride of formula FLX-anhydride,
(c) reacting with compound of formula FLX-amine,
(d) removing the solvent,
(e) treating with an alcohol solvent, and
(f) isolating to get fluxapyroxad (I).

In yet another aspect of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

which comprises;
a) dissolving compound of formula FLX-acid in a suitable solvent in presence of an organic base.
b) adding alkyl phosphonic acid anhydride,
c) reacting with compound of formula FLX-amine at room temperature,
d) removing the solvent,
e) treating with an alcohol solvent, and
f) isolating to get fluxapyroxad (I).
In yet another aspect of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

wherein R1 is selected from the group consisting of alkyl or aryl.
which comprises;
(a) reacting sulfonyl chloride reagent with compound of formula FLX-acid in a suitable solvent in presence of an organic base,
(b) slowly adding compound of formula FLX-amine at 0-5 0C for 5-10 min,
(c) maintaining the reaction at room temperature for 5-6 hours,
(d) removing the solvent to get crude product, and
(e) recrystallizing in hydrocarbon solvent to get fluxapyroxad (I).

In yet another aspect of the present invention is to provide a simple, economical, and commercially feasible process for the synthesis of fluxapyroxad (I) with high yield and purity.

DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

In one embodiment of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

wherein R is selected from C1-4 alkyl or aryl.
which comprises;
(a) reacting compound of formula FLX-acid with chloroformate in presence of an organic base in a suitable solvent,
(b) optionally isolating the anhydride of formula FLX-anhydride,
(c) reacting with compound of formula FLX-amine,
(d) removing the solvent,
(e) treating with an alcohol solvent, and
(f) isolating to get fluxapyroxad (I).

According to the present embodiment, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of formula (FLX-acid) is reacted with chloroformate in presence of an organic base in a suitable solvent at room temperature for 10-30 min to obtain mixed anhydride compound of formula (FLX-anhydride). Treating compound of formula FLX-anhydride with 2-(3,4,5-trifluorophenyl) aniline of formula (FLX-amine) at a temperature of 60oC to 65oC for 2 to 3 hrs to get the crude product. Alcohol solvent is added to the crude product and stirred at 0-5oC for 10-20 min and filtered to get fluxapyroxad (I).

According to the present embodiment, the chloroformate used in the reaction is selected from iso-propyl chloroformate, iso-butyl chloroformate, ethyl chloroformate, phenyl chloroformate, preferably iso-butyl or iso-propyl chloroformate.

According to the present embodiment, the solvent used in the reaction is selected from group consisting of polar-aprotic solvents such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), N, N-dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile, propionitrile and butyronitrile; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbon solvents such as toluene, xylene, mono chlorobenzene, and dichlorobenzene; chlorinated solvents such as 1,2-dichloromethane and 1,2-dichloroethane. The preferred solvent is tetrahydrofuran.

According to the present embodiment, the organic base used in the reaction is selected from group consisting of N-methyl morpholine, N-methyl piperidine, 1,4-dimethyl piperazine, N-methyl pyrrolidine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-diazabicyclo [2.2.2] octane (DABCO), triethanolamine, hydroxy ethyl morpholine, dimethyl aniline, pyridine, and substituted pyridines. The preferred organic base is N-methyl morpholine.

According to the present embodiment, the alcoholic solvent is selected from methanol, ethanol and isopropanol.

In yet another embodiment of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

which comprises;
a) dissolving compound of formula FLX-acid in a suitable solvent in presence of an organic base.
b) adding alkyl phosphonic acid anhydride,
c) reacting with compound of formula FLX-amine at room temperature,
d) removing the solvent,
e) treating with an alcohol solvent, and
f) isolating to get fluxapyroxad (I).

According to the present embodiment, 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of formula (FLX-acid) is dissolve in a solvent in the present of an organic base. 2-(3,4,5-trifluorophenyl) aniline of formula (FLX-amine) is added followed by propane phosphonic acid anhydride. The reaction mixture is stirred at room temperature for about 7 to 10 hrs to get the crude product. The obtained crude product is stirred in an alcoholic solvent at 0-5oC for 10-15 min and filtered to get fluxapyroxad (I).

According to the present embodiment, the alkyl phosphonic acid anhydride is propane phosphonic acid anhydride.

According to the present embodiment, the solvent used in the reaction is selected from group consisting of polar-aprotic solvents such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), N, N-dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile, propionitrile and butyronitrile; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbon solvents such as toluene, xylene, mono chlorobenzene, and dichlorobenzene; chlorinated solvents such as 1,2-dichloromethane and 1,2-dichloroethane. The preferred solvent is ethyl acetate.

According to the present embodiment, the organic base used in the reaction is selected from group consisting of N-methyl morpholine, N-methyl piperidine, 1,4-dimethyl piperazine, N-methyl pyrrolidine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-diazabicyclo [2.2.2] octane (DABCO), triethanolamine, hydroxy ethyl morpholine, dimethyl aniline, pyridine, and substituted pyridines. The preferred organic base is pyridine.

According to the present embodiment, the alcoholic solvent is from methanol, ethanol and isopropanol.

In yet another embodiment of the present invention is to provide an improved process for the preparation of fluxapyroxad (I).

wherein R1 is selected from the group consisting of alkyl or aryl.
which comprises;
(a) reacting sulfonyl chloride reagent with compound of formula FLX-acid in a suitable solvent in presence of an organic base,
(b) slowly adding compound of formula FLX-amine at 0-50 C for 5-10min,
(c) maintaining the reaction at room temperature for 5-6 hours,
(d) removing the solvent to get crude product, and
(e) recrystallizing in hydrocarbon solvent to get fluxapyroxad (I).

According to the present embodiment, 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid of formula (FLX-acid) is dissolved in a solvent in the presence of an organic base at 0-5 oC. The sulfonyl chloride reagent is added followed by 2-(3,4,5-trifluorophenyl) aniline of formula (FLX-amine) dropwise for 5 minutes at same temperature. The reaction mixture is maintained for 5-6 hrs at room temperature to get crude product. The obtained crude product is recrystallized in hydrocarbon solvent to get fluxapyroxad (I).

According to the present embodiment, sulfonyl chloride reagent is selected from methane sulfonyl chloride or p-toluene sulfonyl chloride.

According to the present embodiment, the solvent used in the reaction is selected from group consisting of polar-aprotic solvents such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), N, N-dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile, propionitrile and butyronitrile; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbon solvents such as toluene, xylene, mono chlorobenzene, and dichlorobenzene; chlorinated solvents such as dichloromethane and dichloroethane. The preferred solvent is dichloromethane.

According to the present embodiment, the organic base used in the reaction is selected from group consisting of N-methyl morpholine, N-methyl piperidine, 1,4-dimethyl piperazine, N-methyl pyrrolidine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-diazabicyclo [2.2.2] octane (DABCO), triethanolamine, hydroxy ethyl morpholine, dimethyl aniline, pyridine, and substituted pyridines. The preferred organic base is triethylamine.

According to the present embodiment, the hydrocarbon solvent is selected from toluene, xylene and benzene.

According to the present embodiment, process for the preparation of fluxapyroxad (I) provides a simple, economical, and commercially feasible with high yield and purity.

The advantage of the invention:
1. One pot synthesis
2. Mild reaction conditions with less operations
3. Use of inexpensive economically viable reagents
4. Involves simple filtration method and zero effluents
5. No further purification required
6. All solvents recovered and reused
Comparison of experimental data with various leaving groups.
Reagent Yield Purity Process feasibility
Acid chloride >75% >90% • Involves more hazardous reagents
• Involves higher temperature
• Unstable intermediates
• This process is not cost effective
Anhydride 80-85% 95-99% • Less hazardous
• Reaction completes at lower temperature
• Anhydride intermediate is stable and filterable to get pure compound
• Cost effective in comparison of acid chloride process
Phosphate 80-85% 95-99% • Less hazardous
• Reaction completes at lower temperature
• Anhydride intermediate is stable and filterable to get pure compound
• Cost effective in comparison of acid chloride process

The further embodiment of the present invention is illustrated by the following examples, which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Fluxapyroxad synthesis via mixed anhydrides using chloroformates:
Example-1:
Charge FLX-acid (2.0 gm, 1.0 eq) and THF (10 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge N-Methyl morpholine (1.14 gm, 1.0 eq) and iso-butyl chloroformate (1.55 gm, 1.0 eq) and stirred at RT for 15 minutes. Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in THF and added to Reaction mixture at 60-65oC and stirred at reflux for 2-2.5 hrs. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 85% yield and purity: 99% purity.

Example-2:
Charge FLX-acid (2.0 gm, 1.0 eq) and Toluene (20 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge N-Methyl morpholine (1.14 gm, 1.0 eq) and iso-propyl chloroformate (1.38 gm, 1.0 eq) and stirred at RT for 15 minutes Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in Toluene and added to reaction mixture at 60-65oC and stirred at reflux for 2-2.5 h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 83% yield and purity: 98% purity.

Example-3:
Charge FLX-acid (2.0 gm, 1.0 eq) and THF (10 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge 1,4-dimethylpiperazine (1.3 gm, 1.0 eq) and iso-butyl chloroformate (1.55 gm, 1.0 eq) and stirred at RT for 15 minutes. Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in THF and added to Reaction mixture at 60-65oC and stirred at reflux for 2-2.5 h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 84% yield and purity: 98% purity.

Example-4:
Charge FLX-acid (2.0 gm, 1.0 eq) and THF (10 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge N-methylpyrrolidine (0.96 gm, 1.0 eq) and iso-butyl chloroformate (1.55 gm, 1.0 eq) and stirred at RT for 15 minutes. Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in THF and added to Reaction mixture at 60-65oC and stirred at reflux for 2 – 2.5 h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 84% yield and purity: 99% purity.

Example-5:
Charge FLX-acid (2.0 gm, 1.0 eq) and Toluene (10 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge N-Methyl morpholine (1.14 gm, 1.0 eq) and iso-butyl chloroformate (1.55 gm, 1.0 eq) and stirred at RT for 15 minutes. Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in Toluene and added to Reaction mixture at 60-65oC and stirred at 80oC for 2 – 2.5 h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 85% yield and purity: 98% purity.

Example-6:
Charge FLX-acid (2.0 gm, 1.0 eq) and 1,2-Dichloroethane (10 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. Charge N-Methyl morpholine (1.14 gm, 1.0 eq) and iso-butyl chloroformate (1.55 gm, 1.0 eq) and stirred at RT for 15 minutes. Then FLX-amine (2.52 gm, 1.0 eq) was dissolved in EDC and added to Reaction mixture at 60-65oC and stirred at 60-65oC for 2 – 2.5 h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 83% yield and purity: 98% purity.

Fluxapyroxad synthesis with Phosphonate’s reagent:
Example-7:
Charge FLX-acid (2.0 gm, 1.0 eq) and Ethyl acetate: Pyridine (2 mL: 4 mL) in a three neck RBF equipped with chilled water condenser and thermometer pocket. FLX-amine (2.52 gm, 1.0 eq) was added and followed by propane phosphonic acid anhydride in ethyl acetate(1M) (17.0 mL, 1.5 eq) was added. The reaction was stirred at 25oC for 8-9h. After completion of reaction, remove the solvent under reduced pressure. Methanol was added to the obtained crude product and stirred at 0-5oC for 10 minutes and filtered to get Fluxapyroxad. Yield: 83% yield and purity: 98% purity.

Fluxapyroxad synthesis via sulfonyl intermediates using methyl sulfonyl chloride and 4-Toluene sulfonyl chloride:
Example-8:
A suspension of 3-(difluoro methyl)-1-methyl-1H-pyrazole-4-carboxylicacid (FLX-acid) (1.0 g, 1.0 eq) in dichloromethane (5 mL) was stirred at 0-5oC. TEA (0.688g, 1.2 eq) was added and maintained for 10 minutes. Methane sulfonyl chloride (0.64 g, 1.0 eq) was added for 10 minutes and maintained for 30 minutes. 3', 4’, 5’-trifluoro- [1, 1’-biphenyl]-2-amine (FLX-amine) (1.26 g, 1.0 eq) was solution in dichloromethane (5 mL) was added dropwise for 5 minutes at 0-5°C. The reaction mixture was allowed to rt and maintain the reaction for 5-6 hrs at 25°C. Water was added. The organic layer was separated and concentrated under vacuum and the crude was recrystallize from toluene to obtained Fluxapyroxad. Yield: 80% yield and purity: 99% purity.

Example-9:
A suspension of 3-(difluoro methyl)-1-methyl-1H-pyrazole-4-carboxylicacid (FLX-acid) (1.0 g, 1.0eq) in dichloromethane (5 mL) was stirred at 0-5oC. TEA (0.688g, 1.2 eq) was added and maintained for 10 minutes. 4-Toluene sulfonyl chloride (1.08 g, 1.0 eq) was added for 10 minutes and maintained for 30 minutes. 3', 4’, 5’-trifluoro- [1, 1’-biphenyl]-2-amine (FLX-amine) (1.26 g, 1.0 eq) was solution in dichloromethane (5 mL) was added dropwise for 5 minutes at 0-5°C. The reaction mixture was allowed to rt and maintain the reaction for 6-8 hrs at 25°C. Water was added. The organic layer was separated and concentrated under vacuum and the crude was recrystallize from toluene to obtained Fluxapyroxad. Yield: 80% yield and purity: 99% purity.