Process for the Preparation of Renofluthrin

Background of the invention

A pyrethroid is an organic compound similar to natural pyrethrin. Pyrethroid compounds constitute majority of the commercial household insecticides. Mosquito repellent products used on regular basis in household contain mostly pyrethroid derived compounds. Transfluthrin; Metofluthrin, Meperfluthrin, Dimefluthrin; D-trans allethrin are amongst few known in the art.
Indian Patent application No. 8431/DELNP/2011 discloses Meperfluthrin i.e. 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl (lR,3S]-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, having (1R,3S) trans single optically active isomer.
Indian Patent application No. 4121/MUM/2013 discloses an isomeric composition of 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl-3-(2,2-dichloro vinyl)-2,2-dimethylcyclopropanecarboxylate with specific Cis and Trans isomeric ratio namely Renofluthrin. Meperfluthrin and Renofluthrin have the same chemical structure; nevertheless, the isomeric ratio is different. Renofluthrin has total trans isomers ranging from 90% to 99.90% and the rest being cis isomers i.e. 0.1% to 10%. Therefore Renofluthrin is a mixture of 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl (lR,3S)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate; 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl (lS,3R)-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate; 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl (lR,3R)-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropanecarboxylate; 2,3,5,6-tetrafluro-4-(methoxymethyl)benzyl (1S,3S)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, wherein the total trans isomers (1R,3S and 1S,3R] are present in the range of 90% to 99.9% and the cis isomers (lR,3Rand 1S,3S) are present in.the range of 0.1% to 10%.
The 4121/MUM/2013 application also discloses a process for the preparation of Renofluthrin starting from Cypermethric acid (CMA); followed by its conversion to High Trans Cypermethric acid (HTCMA). HTCMA is subsequently converted to HTCMAC i.e. High Trans Cypermethric Acid Chloride. HTCMAC is condensed with 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol to generate Renofluthrin having specific Cis - Trans isomeric ratio, with higher trans content as defined above.
In the reported process of the 4121/MUM/2013 application for the conversion of CMA to HTCMA, acetic anhydride and sulfonic acid are used. Acetic anhydride is a narcotic controlled substance and its use at an industrial scale poses a concern. The final stage of the above process involves condensation of 2,3,5,6-tetrafluoro-4-(methoxymethyl) benzyl alcohol and HTCMAC in the presence of acid scavengers like 4-DMAP. This reaction sequence results in the formation of impurities like Cypermethric acid anhydride, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl chloride which is a severe eye irritant. Removal of these impurities to meet the regulatory requirements to obtain pure active ingredient calls for a very tedious work up. Thus the reported process suffers from numerous setbacks and is not an industrially viable process. The inventors of the present invention therefore have come up with a novel process, which circumvents all the drawbacks of the reported procedure for the preparation of Renofluthrin.

Detailed description of the invention
The process of the present invention involves two stages. The first stage covers preparation of high trans cypermethric acid starting from cypermethric acid chloride. The CMA obtained by this conversion has high trans content ranging from 90% to 99.9% while the starting compound i.e. cypermethric acid chloride has a trans content of 75%. Thus the reaction enhances the trans content of the CMA and forms a part of the present invention. The content of the Trans isomers of CMA is dependent on the temperature at which the final product is isolated. Therefore at a temperature ranging from 0 - 5°C, CMA with 90% trans isomers is obtained; at a temperature ranging from 20 - 22°C 98% trans isomers is obtained while the temperature ranging from 30 - 35°C, 99.5% trans isomers is obtained. Therefore, the final step of isolating trans CMA in the first stage of the synthesis is carried out at temperatures ranging from 0- 50°C.

The second stage of the synthesis involves a clean esterification reaction between trans CMA and 4-methoxymethyl-2,3,5,6-tetrafluoroberizyl alcohol with simultaneous azeotropic removal of water.
The thus obtained high trans Cypermethric acid is reacted with 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol. The reaction is performed in a water immiscible organic solvent, which is selected from aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons like benzene, toluene, xylene, mesitylene, tetralin, chlorobenzene, dichlorobenzene, bromobenzene, nitrobenzene, hexane, cyclohexane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethane, tetrachloroethane, esters such as ethyl acetate, methyl acetate, dimethyl carbonate, diethyl carbonate, ethoxyethyl acetate, methoxyethyl acetate, ethers such as diisopropyl ether, dibutyl ether or the like and mixtures thereof. The reaction is performed in the presence of esterification catalyst like PTSA, sulfuric acid, Phosphoric acid, Nitric acid. The reaction is performed at temperatures ranging from 90 - 120°C for 10 hours by continuously removing water azeotropically. The isomeric content in the final product is proportional to the isomeric content of the CMA employed at the starting stage and Renofluthrin obtained in the above process has a trans content ranging from 90% to 99.5% and forms yet another part of the present invention.
The following examples further illustrate the present invention, but should not be construed in any way as to limit its scope.

Example - 1: Preparation of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-(2f2-dichIorovinyl)-2,2-dimethylcyclopropane carboxylate with 90% trans content

Step 1: Preparation of high trans CMA (90% trans content): 300 ml of water was charged to a 1 liter RB flask and 250 grams of trans CMA with a trans content of 75% was charged to it over a period of 1 - 1.5 hours at 80 - 90°C. The reaction mass was stirred at 80 - 100°C for a further period of 4 - 5 hours. The mass was cooled to 50°C and 400 ml of hexane was charged to it. The layers were separated and the organic solution was stirred at 0 - 5°C for a period of 4 -5 hours. The resultant slurry was filtered, washed with 50 ml of ice cold hexane (0 - 5°C) and air dried to yield to yield 205 grams of high trans CMA with a trans content of 90%.

Step 2: Preparation of 4-methoxymethyI-2,3,5,6-tetrafluorobenzyI-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate with 90% trans content: 450 ml of toluene was charged to a 2 liter capacity 4-necked RB flask fitted with a mechanical stirrer, thermometer pocket with thermometer, a reflux condenser circulated with cold water fitted over a Dean-Stark apparatus. 224 grams (1 mole) of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, 215.3 grams (1.03 moles) of high trans cypermethric acid (90% trans & 10% cis) and 3 grams of concentrated sulfuric acid were charged to the reactor under stirring. The mass was gradually heated to reflux temperature (113 - 117°C), wherein water was removed azeotropically. After complete recovery of moisture, the mass was cooled to 45 - 50°C. The reaction mass was washed with 100 ml of water, 100 ml of 5% sodium carbonate solution and finally twice with 100 ml of water. The organic solution was distilled at 65 - 70°C under vacuum of 15 - 25 mmHg to recover solvent toluene. The remaining residue was cooled and vacuum released under nitrogen atmosphere to yield 385 grams (93% yields) 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate in overall 97% + purity. The product was analysed by reverse phase HPLC and showed a trans content of 90% and cis content of 10%.

Example - 2: Preparation of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-(2,2-dichlorovinyl)-2/2-dimethylcyclopropane carboxylate with 98% trans content

Step 1: Preparation of high trans CMA (98% trans content): 300 ml of water was charged to a 1 liter RB flask and 250 grams of trans CMA with a trans content of 75% was charged to it over a period of 1 - 1.5 hours at 80 - 90°C. The reaction mass was stirred at 80 - 100°C for a further period of 4 - 5 hours. The mass was cooled to 50°C and 500 ml of hexane was charged to it. The layers were separated and the organic solution was stirred at 20 - 22°C for a period of 4-5 hours. The resultant slurry was filtered, washed with 50 ml of cold hexane (20 - 22°C) and air dried to yield 140 grams of high trans CMA with a trans content of 98%.

Step 2: Preparation of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate with 98% trans content; 450 ml of toluene was charged to a 2 liter capacity 4-necked RB flask fitted with a mechanical stirrer, thermometer pocket with thermometer, a reflux condenser circulated with cold water fitted over a.Dean-Stark apparatus. 224 grams (1 mole) of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, 215.3 grams (1.03 moles) of high trans cypermethric acid (98% trans & 2% cis) and 3 grams of concentrated sulfuric acid were charged to the reactor under stirring. The mass was gradually heated to reflux temperature (113 - 117°C), wherein water was removed azeotropically. After complete recovery of moisture, the mass was cooled to 45 - 50°C. The reaction mass was washed with 100 ml of water, 100 ml of 5% sodium carbonate solution and finally twice with 100 ml of water. The organic solution was distilled at 65 - 70°C under vacuum of 15 - 25 . mmHg to recover solvent toluene. The remaining residue was cooled and vacuum released under nitrogen atmosphere to yield 380 grams (92% yields) of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate in overall 97%+ purity. The product was analysed by reverse phase HPLC and showed a trans content of 98% and cis content of 2%.

Example - 3: Preparation of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyI-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate with 99.5% trans content

Step 1: Preparation of high trans CMA (99.5% trans content): 300 ml of water was charged to a 1 liter RB flask and 250 grams of trans CMA with a trans content of 75% was charged to it over a period of 1 - 1.5 hours at 80 - 90°C. The reaction mass was stirred at 80 - 100°C for a further period of 4 - 5 hours. The mass was cooled to 50°C and 600 ml of hexane was charged to it. The layers were separated and the organic solution was stirred at 30 - 35°C for a period of 4-5 hours. The resultant slurry was filtered, washed with 50 ml of hexane and air dried to yield 120 grams of high trans CMA with a trans content of minimum 99.5%.

Step 2: Preparation of 4-methoxymethyl-2,3,5,6tetrafluorobenzyl-3(2,2-dichlorovinyl)~2,2-dimethylcyclopropane carboxylate with minimum 99.5% trans content: 450 ml of toluene was charged to a 2 liter capacity 4-necked RB flask fitted with a mechanical stirrer, thermometer pocket with thermometer, a reflux condenser circulated with cold water fitted over a Dean-Stark apparatus. 224 grams (1 mole) of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, 215.3 grams (1.03 moles) of high trans cypermethric acid (99.5% trans & 0.5% cis) and 3 grams of concentrated sulfuric acid were charged to the reactor under stirring. The mass was gradually heated to reflux temperature (113 - 117°C), wherein water was removed azeotropically. After complete recovery of moisture, the mass was cooled to 45 - 50°C. The reaction mass was washed with 100 ml of water, 100 ml of 5% sodium carbonate solution and finally twice with 100 ml of water. The organic solution was distilled at 65 - 70°C under vacuum of 15 - 25 mmHg to recover solvent toluene. The remaining residue was cooled and vacuum released under nitrogen atmosphere to yield 400 grams (96% yields) of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-3-2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylate in overall 97%+ purity. The product was analysed by reverse phase HPLC and showed a trans content of 99.5% and cis content of 0.5%.

Claims

1. A process for the preparation of Renofluthrin comprising
i) hydrolysis of cypermethric acid chloride to high trans cypermethric acid (HTCMA) if) Clean esterification reaction between HTCMA and 4-methoxymethyl-2,3,5,6- tetrafluorobenzyl alcohol to generate Renofluthrin containing trans isomers in the range of 90% to 99.9%

2. The process of claim 1 wherein the hydrolysis of step i) is performed in water

3. The process of claim 1 wherein step ii is performed in water immiscible organic solvents selected from aromatic, aliphatic and alicyclic hydrocarbons and halogenated hydrocarbons like benzene, toluene, xylene, mesitylene, tetralin, chlorobenzene, dichlorobenzene, bromobenzene, nitrobenzene, hexane, cyclohexane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethane, tetrachloroethane, esters such as ethyl acetate, methyl acetate, dimethyl carbonate, diethyl carbonate, ethoxyethyl acetate, methoxyethyl acetate, ethers such as diisopropyl ether, dibutyl ether or mixtures thereof

4. The process of claim 1 wherein the hydrolysis of step i) is followed by treating the reaction mass with hexane, separating the biphasic organic liquid and cooling to temperatures ranging from 0°C - 50°C to obtain High trans cypermethric acid with trans isomer content ranging from 99.9% to 90%

5. Renofluthrin obtained by the process of claim 1.