FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of cyclopropane carboxylic acids of Formula I, and intermediates thereof.

Formula I wherein R ¹ is independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z can be halogen, halogenated alkyl group.

BACKGROUND OF THE INVENTION

Cyclopropane carboxylic acid derivatives are very useful intermediates for pharmaceuticals or agrochemicals.

US Patent No. 4,332,815, describes a process for preparation of cis and trans isomers of 3-[2- chloro-3,3,3-trifluoropropenyl]-2,2-dimethylcyclopropane carboxylic acid by cyclizing methyl

3.3-dimethyl-4,6,6-trichloro-7,7,7-trifluoroheptanoate using potassium t-butoxide in t-butanol followed by its dehydrohalogenation and hydrolysis using potassium hydroxide and hydrochloric acid respectively. The method is not effective for selective preparation of cis isomer of 3-[2-chloro-

3.3.3-trifluoropropenyl]-2,2-dimethylcyclopropane carboxylic acid.

It also discloses a process for preparation of the intermediate, Ethyl 3,3-dimethyl-4,6,6-trichloro- 7,7,7-trifluoroheptanoate by reacting ethyl 3,3-dimethyl-4-pentenoate with 1,1,1- trichlorotrifluoroethane in t-butanol in presence of ethanolamine and cuprous chloride. The process is very exothermic and a sudden increase in the heat of reaction pose safety concerns at commercial scale up. The exothermicity induces degradation and thereby reduces the yield and purity of the intermediate. Also, the isolation of the intermediate requires large quantities of an acid that increases the effluent load and increases the overall cost of the process.

Thus, with this state of the art in mind, there is a need to provide improved process over the existing one. The present invention provides a simple, safe and improved cost effective method with reduced effluent load for preparing cyclopropane carboxylic acids and intermediates thereof.

OBJECT OF THE INVENTION The main object of present invention is to provide an industrially viable process for the selective preparation of cis isomer of cyclopropane carboxylic acid derivatives and intermediates thereof.

SUMMARY OF THE INVENTION

A first aspect of present invention provides an improved process for preparation of cyclopropane carboxylic acid of Formula I,

Formula I wherein R ¹ are independently selected from hydrogen, alkyl, halogenated alkyl; X ₂ and Z can be halogen, halogenated alkyl group, comprising the steps of: a) concurrently adding to a continuous stirred reactor containing a first solvent, a compound of Formula II,

Formula II wherein R ² is alkyl; Xi is halogen; R ¹ , X ₂ , Z are as defined above, and a first base to obtain a compound of Formula III; and

Formula III wherein R ² , R ¹ , X ₂ , Z are as defined above, b) converting the compound of Formula III to a compound of Formula I.

A second aspect of present invention provides an improved process for preparation of cyclopropane carboxylic acid of Formula I,

Formula I wherein R ¹ are independently selected from hydrogen, alkyl, halogenated alkyl; X ₂ and Z can be halogen, halogenated alkyl group, comprising the steps of: a) concurrently adding to a continuous stirred reactor containing a first solvent, a compound of Formula II,

Formula II wherein R ² is alkyl; Xi is halogen; R ¹ , X ₂ , Z are as defined above, and a first base to obtain a compound of Formula III;

Formula III wherein R ² , R ¹ , X ₂ , Z are as defined above, b) concurrently adding to a loop reactor, the compound of Formula III in a second solvent and a second base to obtain a compound of Formula IV ; and

Formula IV wherein R ² , R ¹ , X ₂ , Z are as defined above, c) converting the compound of Formula IV to a compound of Formula I.

A third aspect of present invention provides an improved process for preparation of cyclopropane carboxylic acid of Formula I,

Formula I wherein R ¹ is independently selected from hydrogen, alkyl, halogenated alkyl; X ₂ and Z is halogen, halogenated alkyl group, comprising the steps of: a) concurrently adding, to a first solvent or mixture thereof, a compound of Formula II,

Formula II wherein R ² is alkyl; Xi is halogen; R ¹ , X ₂ , Z are as defined above, and a first base to obtain a compound of Formula III;

Formula III wherein R ² , R ¹ , X ₂ , Z are as defined above, b) concurrently adding to a reactor, the compound of Formula III in a second solvent and a second base to obtain a compound of Formula IV ; and

Formula IV wherein R ² , R ¹ , X ₂ , Z are as defined above, c) hydrolysing the compound of Formula IV using an acid to obtain the cyclopropane carboxylic acid of Formula I.

In the third aspect of the invention, the step a) is carried out by concurrently adding to a continuous stirred reactor containing a first solvent, a compound of formula II and a first base to obtain a compound of formula III; or the step a) is carried out by concurrently adding to a continuous stirred reactor containing a first solvent, a compound of Formula II and a first base to obtain a compound of formula III, followed by step b) of concurrently adding to a loop reactor, the compound of formula III in a second solvent and a second base to obtain a compound of formula IV.

In the third aspect of the invention, the step b) is carried out by concurrently adding to a loop reactor, the compound of formula III in a second solvent and a second base to obtain a compound of formula IV.

A fourth aspect of present invention provides an improved process for preparation of cyclopropane carboxylic acid of Formula I,

Formula I wherein R ¹ are independently selected from hydrogen, alkyl, halogenated alkyl; X ₂ and Z can be halogen, halogenated alkyl group, comprising the steps of: a) concurrently adding, to a continuous stirred reactor containing a first solvent or mixture thereof, a compound of Formula II,

Formula II wherein R ² is alkyl; Xi is halogen; R ¹ , X ₂ , Z are as defined above, and a first base to obtain a compound of Formula III; and

Formula III wherein R ² , R ¹ , X ₂ , Z are as defined above, b) concurrently adding to a loop reactor, the compound of Formula III in a second solvent and a second base in the second solvent to obtain a compound of Formula I.

A fifth aspect of present invention provides an improved process for preparation of intermediates of cyclopropane carboxylic acid of Formula II,

Formula II wherein R ¹ , R ² _, Ci, X ₂ and Z are as defined above, comprising the step of adding a mixture of compound of Formula Ila and an organic ligand in a polar solvent, Formula Ila wherein R ¹ and R ² are as defined above, to a mixture of a compound of formula Ilia and catalyst in a polar organic solvent,

Formula Ilia wherein Xi, X ₂ and Z are as defined above, to obtain the compound of Formula la.

A sixth aspect of present invention provides an improved process for preparation of intermediates of cyclopropane carboxylic acid of Formula II,

Formula II wherein R ¹ , R ² _, Ci, X ₂ and Z are as defined above, comprising the steps of: a) adding a compound of Formula Ila and an organic ligand in a polar solvent,

Formula Ila wherein R ¹ and R ² are as defined above, to a mixture of a compound of formula Ilia and catalyst in a polar organic solvent, and Formula Ilia wherein Xi, X ₂ and Z are as defined above, b) isolating the compound of formula II using polymeric solvents.

DETAILED DESCRIPTION OF THE DRAWINGS

Figure 1: Description of continuous stirred tank reactor The continuous stirred tank reactor is equipped with an entry mixer 1, a pump 2, an initial mixing tank reactor 3, fitted with stirrer 4 and inlet port 5 and 6, a tank reactor 7, fitted with stirrer 8 and a product tank 9.

The compound of Formula II is fed to entry mixer 1 containing the solvent or mixture thereof. The mixture thus formed in the entry mixer 1 is continuously fed via pump 2, to initial mixing tank reactor 3, which is continuously stirred with the help of stirrer 4, and fed with first base through the inlet port 6. The contents in the initial mixing tank reactor 3 are continuously stirred and transferred to the tank reactor 7. The contents of the tank reactor 7 are continuously stirred and the product is removed to product tank.

Figure 2: Description of loop reactor

The loop reactor is equipped with entry mixers 1 and 2, circulating pumps 3 and 4, heat exchanger 5 and preheated coil 6, tube reactor 7 and heat exchanger 8, outlet 9 and product collection tank 10.

The compound of Formula III is fed to entry mixer 1 containing the solvent and the second base is fed to entry mixer 2. The mixtures thus formed in the entry mixer 1 and 2 are continuously fed via pump 2 and 3 respectively to preheated coil 6 at 50-70°C. The outlet of the coil is attached to a tube reactor 7. The homogeneous mass is fed into the tube reactor through the preheated coil. The content of the tube reactor 7 is continuously discharged in product collection tank 10 through outlet 9.

The loop reactors are advantageous over the traditional stirring still reaction The liquid is atomized into micron level or the small liquid of nanoscale via entry mixers, that increases the contact area with liquid-liquid, thus mass transfer and heat transfer efficiency can be greatly increased compared with batch agitator kettle.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “alkyl” refers to C1-C2 alkyl. Examples of alkyl include methyl, ethyl. The alkyl may be substituted by halogen at one or more positions to form halogenated alkyl group. The examples of halogenated alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl or the like.

As used herein, “first base” refers to hydroxides, carbonates, alkoxides, and hydrides of alkali metals. Examples of first base includes sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium t-butoxide, sodium hydride, potassium hydride soidium carbonate, potassium carbonate or the like. Preferably, alkali metal alkoxides are used as the first base. More preferably, alkali metal alkoxides are generated in-situ and supplied to the reactor.

As used herein, “first solvent” refers to polar protic or aprotic solvents. Examples of the first solvent includes isopropanol, butanol, t-butanol, pentanol, isopentanol, t-pentanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, or the mixture thereof. Preferably, the first solvent include a mixture of a polar protic and aprotic solvent.

As used herein, “second base” refers to hydroxides, carbonates, of alkali metals. Examples of first base includes sodium carbonate, potassium carbonate or the like. Preferably, alkali metal hydroxides are used as the second base.

As used herein, “second solvent” refers to a polar organic such as alcohols, Examples of alcohol includes, methanol, ethanol, butanol, propanol, isopropanol, butanol, t-butanol, pentanol, isopentanol, t-pentanol or the mixture thereof.

As used herein, “an acid” refers to a mineral acid selected from hydrochloric acid, sulfuric acid or the like.

In an embodiment of the present invention, the first solvent is used in an amount 1 to 10 times of the staring material

In another embodiment of the present invention, the selectivity of cis is 80-95%.

In another embodiment of the second aspect of the present invention, both the steps a) and b) are carried out in continuous stirred tank reactor.

In another embodiment of the third aspect of the present invention, all the steps a) to c) are carried out in a continuous stirred tank reactor.

In another embodiment of the second aspect of the present invention, both the steps a) and b) are carried out in loop reactor.

In another embodiment of the third aspect of the present invention, all the steps a) to c) are carried out in a loop reactor.

In another embodiment of the second aspect of the present invention, both the steps a) and b) are carried out without isolation of the intermediate and isolation of final product.

In another embodiment of the third aspect of the present invention, all the steps a) to c) are carried out are carried out without isolation of the intermediate and isolation of final product.

In another embodiment of the present invention, when alkali metal alkoxides are used as first base, may be generated in-situ by the reaction of a strong base with an alcohol and supplied to the reactor. Examples of a strong base include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide or the like. In an embodiment of the aspects 1 to 4 of the present invention, the solvent used is recovered, recycled and reused.

In an embodiment of the aspects 1 to 4 of the present invention, the process resulted in the formation of an alcohol as a by-product that is recovered and recycled.

In a particular embodiment, the present invention provides an improved process for preparation of 3 - [( 1 Z)-2-chloro-3 ,3 ,3 -trifluoroprop- 1 -en- 1 -yl] -2,2-dimethylcyclopropane- 1 - carboxylic acid comprising the step of: a) concurrently adding a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide to a reactor to obtain methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcy clopropane-l-carboxylate; b) concurrently adding a solution of methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2- dimethylcyclopropane-l-carboxylate in an alcohol solvent and a strong base to obtain 3-[(lZ)-2- chloro-3,3,3-trifluoroprop-l-en-l-yl]-2,2-dimethylcyclopropa ne-l-carboxylic acid.

In another particular embodiment of the present invention, the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide is carried out in a continuous stirred tank reactor.

In another particular embodiment of the present invention, the concurrent addition of a solution of 3-methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl cyclopropane-l- carboxylate in an alcohol solvent and a strong base is carried out in a loop reactor.

In another particular embodiment of the present invention, the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide and the concurrent addition of a solution of 3-methyl- 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcycloprop ane-l-carboxylate in an alcohol solvent and a strong base are both carried out in a continuous stirred tank reactor.

In another particular embodiment of the present invention, the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide and the concurrent addition of a solution of 3-methyl- 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcycloprop ane-l-carboxylate in an alcohol solvent and a strong base are both carried out in a loop reactor.

In another particular embodiment of the present invention, the step a) of the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide; the step b) of the concurrent addition of a solution of 3-methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl cyclopropane-l- carboxylate in an alcohol solvent and a strong base and the step c) of hydrolysis are all carried out in a continuous stirred tank reactor.

In another particular embodiment of the present invention, the step a) of the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide; the step b) of the concurrent addition of a solution of 3-methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl cyclopropane-l- carboxylate in an alcohol solvent and a strong base and the step c) of hydrolysis are all carried out in a loop reactor.

In another particular embodiment of the present invention, any two or more of the steps of step a) of the concurrent addition of a solution of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate in alcohol and aprotic polar solvent and an alkali metal alkoxide; the step b) of the concurrent addition of a solution of 3-methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2- dimethylcyclopropane- 1 -carboxylate in an alcohol solvent and a strong base and the step c) of hydrolysis, are carried out without isolation of any of the intermediate.

The compound of Formula I is isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.

The compound of Formula I so obtained by the present invention has a purity greater than 95 %, more preferably greater than 98 %, most preferably greater than 99.6 % by gas chromatography.

As used herein, “catalyst” refers to metal ions and neutral metallic species. Suitable catalysts include cuprous salts, organometallic cuprous compounds, iron wire, iron shavings, iron powder, and iron chlorides. Examples of cuprous salts and organometallic cuprous compounds include, without limitation, cuprous chloride (CuCl), cuprous bromide, cuprous cyanide, cuprous sulfate, cuprous phenyl and in-situ generated organometallic cuprous compounds. The iron powder useful in this invention is preferably a fine powder of pure metallic iron. Preferably, cuprous chloride or iron powder is used as the catalyst. Most preferably cuprous chloride is used as a catalyst.

As used herein, “an organic ligand” refers to organic ligands capable of forming a complex with the catalyst and capable of bringing the catalyst into solution. Suitable ligands include organic amines, such as, without limitation, ethanolamine, N,N,N'.N'-tetramethylethylenediamine diethanolamine, propanolamine, pyridine tert-butylamine, n-butylamine, sec-butylamine, 2- propylamine, benzylamine, tri-n-butylamine, pyridine and combinations thereof. Preferably, ethanolamine is used as a catalyst.

As used herein, “solvent” refers to a polar organic such as alcohols, ethers, nitriles, or the like. Suitable solvent includes acetonitrile, ethanol, methanol, propanol, isopropanol, butanol, t- butanol, pentanol, n-pentanol, iso-pentanol, t-pentanol, tetrahydrofuran or the like As used herein, “polymeric solvent” includes polyhydric solvents and “polyamines”. Examples of polyhydric alcohol includes glycerol, chloroethylene glycol, dimethyl ether of diethylene glycol, ethoxy ether, ethylene glycol, polyethylene glycol, polypropylene glycol, polytetramethylene glycol or polytetramethylene ether glycol, Examples of polyamine includes diethylenetriamine, triethylenetetramine, pentaethylenehexamine, tetraethylenepentamine, Macrocyclic poly amines, 1,4,7-triazacyclononane or the like.

In an embodiment of the present invention, the compound of formula II is prepared by controlled addition of a compound of formula Ila and ethanolamine in a polar organic solvent,

Formula Ila wherein R ¹ and R ² are as defined above, to a mixture of a compound of formula Ilia,

Formula Ilia wherein, Xi, is halogen; X2 and Z is selected from halogen, alkyl, halogenated alkyl group, and copper chloride in a polar organic solvent maintaining the temperature between 80- 110°C, and isolating the compound of formula II using a polymeric solvent.

In an embodiment of the present invention, the mixture of compound of Formula Ila and an organic ligand is added to a mixture of a compound of formula Ilia and a catalyst, slowly in a controlled manner to maintain the heat of reaction slowly in a controlled manner to maintaining the temperature of reaction between 80°C to 110°C.

This reaction is highly exothermic, the heat of the reaction generated is so high that it leads to run-away condition in the plant scale in case of normal addition of all the raw materials. So, in such cases, raw materials are added in controlled manner in order to control the heat of the reaction and make the process safer.

In an embodiment of the present invention, the compound of Formula Ila and an organic ligand are separately added to a mixture of a compound of formula Ilia and a catalyst, slowly in a controlled manner to maintain the heat of reaction under control.

In another embodiment of the present invention, the compound of formula II is isolated using a dry work up. In a preferred embodiment the dry work up in absence of water is performed using polyhydric alcohol. Isolation of the compound of formula II is conventionally carried out by two methods, firstly, using hydrochloride solution during work-up, this method generates the aqueous effluent containing spent catalyst. Secondly, product isolation is carried out via decantation that leaves behind the spent catalyst in the reactor requiring large quantities of hydrochloric acid for its removal, thereby generating large quantities of aqueous effluent containing the catalyst. Both the methods generate large quantity of effluent that require expensive and tedious effluent treatment for removal of catalyst. On the other hand, polymeric solvents, can be easily recycled and reused, thereby generating very little catalytic effluent that can be easily incinerated or get rid of in a cost- effective way.

In another embodiment of the present invention, the “polyhydric solvent” and “Synthetic polyamines” used in the work up is recovered and recycled.

In another embodiment of the present invention, the product of formula II is isolated using an aqueous hydrochloric acid work up.

In another embodiment of the present invention, the product of formula II is isolated by direct decantation of product.

In another embodiment of the present invention, the product of formula II is isolated by direct distillation and separation of product.

In another embodiment of the present invention, the organic solvent and the compound of formula Ilia used in excess is recovered and recycled in the process.

The dry work up ensure the efficient effluent treatment and management in the process at commercial scale.

In another embodiment of the present invention, the solvent used is recovered, recycled and reused.

In an embodiment of the present invention, the process resulted in the formation of an alcohol as a by-product that is recovered and recycled.

In a particular embodiment, the present invention provides an improved process for preparation of methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate comprising the steps of slowly adding a mixture of Methyl 3,3-dimethyl-4-pentenoate and ethanolamine in t-butanol to a mixture of l,l,l-Trichloro-2,2,2-trifluoro ethane and copper chloride in t-butanol to obtain methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate.

In an embodiment of the present invention, the step of slowly adding a mixture of methyl 3,3- dimethyl- 4 -penteno ate and ethanolamine in t-butanol to a mixture of l,l,l-Trichloro-2,2,2- trifluoro ethane and copper chloride in t-butanol is carried out at a temperature below 80-110°C, within a time period of 12 to 15 hours. In another particular embodiment of the present invention, methyl 4,6,6-trichloro-7,7,7- trifluoro-3,3-dimethylheptanoate was isolated using polymeric solvent.

In another particular embodiment of the present invention, the butanol is recovered and recycled.

In another particular embodiment of the present invention, methyl 4,6,6-trichloro-7,7,7- trifluoro-3,3-dimethylheptanoate was isolated using dry work up.

In another particular embodiment of the present invention, methyl 4,6,6-trichloro-7,7,7- trifluoro-3,3-dimethylheptanoate was isolated using polyhydric alcohol and polyamines.

The compound of Formula II is isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.

The compound of Formula II so obtained by the present invention has a purity greater than 95 %, more preferably greater than 98 %, most preferably greater than 99.6 % by gas chromatography.

Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES

Example 1: Synthesis of Methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2- dimethylcyclopropane-l-carboxylate (Conventional Method)

Sodium t-butoxide (114g) was added to a solution of t-butanol (280g), DMF (120g) and methyl- 4, 6, 6-trichloro-7, 7, 7-trifluoro-3,3-dimethylheptanoate (300g ) at -10 to -15°C within 10-12 hours. Yield: 55%.

Example 2: Synthesis of Methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2- dimethylcyclopropane-l-carboxylate (performed in Continuous Stirred Tank Reactor)

The continuous stirred tank reactor is equipped with an entry mixer 1, a pump 2, an initial mixing tank reactor 3, fitted with stirrer 4 and inlet ports 5 and 6, a tank reactor 7, fitted with stirrer 8, and a product tank 9. A mixture of methyl-4, 6, 6-trichloro-7, 7, 7-trifluoro-3,3-dimethylheptanoate (300g), t-butanol (280g) and DMF (120g) is fed at -15°C through a dosing pump at a rate of 7.3mL/minute concurrently with solid sodium t-butoxide (114g) at the rate of 1.18g/10minute to a pre-cooled tank reactor, maintaining the reaction mass temperature between -10 and -15°C.

Yield: 75%; Purity: 95%; Selectivity: 85-95% (cis isomer)

This enables the reaction to run continuously, thereby producing 800g of reaction mass in just 2 hours with desired selectivity of the product, hence, enhancing the production rate.

Example 3: Synthesis of 3-[(lZ)-2-chloro-3,3,3-trifluoroprop-l-en-l-yl]-2,2- dimethylcyclopropane- 1 -carboxylic acid

An aqueous solution of potassium hydroxide (30%; 304g in 557g of water) was added to a continuously stirred mixture of Methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2- dimethylcyclopropane-l-carboxylate (400g), methanol (250g) and water (397g) at a temperature of 100-110°C in Hastelloy reactor. The progress of the reaction was monitored by liquid chromatography and after reaction completion, heating was stopped and the temperature of the reaction mass was allowed to come to room temperature and the pH of the mass is adjusted to 6.5- 6.7 by adding aqueous sulphuric acid (50%) dropwise while maintaining 30-35°C temperature. The precipitated solid was then filtered and further washed with water to obtain solid. The obtained solid was dissolved in methanol and then filtered by pressure filter to remove salts. The methanol was distilled at 50°C under reduced pressure (400-450mm Hg) to recover methanol and obtain crude product. The crude solid is further recrystallized by aqueous methanol to get pure product. The wet solid is kept under reduced pressure at 50°C until water content of the solid is <0.15% to obtain the final product.

Yield: 75%; Purity: 99.5%; Selectivity: 99.4% (cis isomer)

Example 4: Synthesis of 3-[(lZ)-2-chloro-3,3,3-trifluoroprop-l-en-l-yl]-2,2- dimethylcyclopropane- 1 -carboxylic acid

An aqueous solution of potassium hydroxide (48%; 20g) was added to a continuously stirred mixture of Methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcy clopropane-l- carboxylate (40g), methanol (20g) and water (15g) at a temperature of 100-110°C. The progress of the reaction was monitored by liquid chromatography and after reaction completion, heating was stopped and the temperature of the reaction mass was allowed to come to room temperature and the pH of the mass is adjusted to 6.5 by adding sulfuric acid (50%) solution dropwise while maintaining 30-35°C temperature. The precipitated solid was then filtered and further washed with water to obtain solid. The obtained solid was dissolved in methanol and then filtered by pressure filter to remove salts. The methanol was distilled at 50°C under reduced pressure (400-450mm Hg) to recover methanol and obtain crude product. The crude solid is further recrystallized by aqueous methanol to get pure product. The wet solid is kept under reduced pressure at 50°C until water content of the solid is <0.15% to obtain the final product.

Yield: 75%; Purity: 98%; Selectivity: 99% (cis isomer)

Example 5: Synthesis of 3-[(lZ)-2-chloro-3,3,3-trifluoroprop-l-en-l-yl]-2,2- dimethylcyclopropane-1 -carboxylic acid (performed in Loop Reactor/Flow Reactor)

The loop reactor is equipped with entry mixers 1 and 2, circulating pumps 3 and 4, heat exchangers 5 and 7, a tube reactor 6 and a product outlet 8. cthy l-3-(2, 2-dich loro-3, 3, 3-tnfluoiOpropyl)-2,2-dimcthylcyclopropanc- 1 -carboxylatc (2022g), methanol (101 lg) at a flow rate of 6.32g/minute and of 30% an aqueous solution of potassium hydroxide (30%; 5105g) at a flow rate of 10.6g/min. are fed concurrently into a preheated coil at 60°C through a pump to make the feeding solution an homogeneous mass. The outlet of the coil is attached to a tube reactor of 200mL volume. The homogeneous mass is fed through the coil to this tube reactor with a resistance time of 13minute, at heated at a temperature of 130-140°C for 8 hours. The reaction mass is continuously discharged in the intermediate tank through a cooling coil (at 30°C) of 9mL volume.

Yield: 81.6%; Purity: 99.1%; Selectivity: 99.2% (cis isomer)

Example 6 (Comparative; without controlled conditions): Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate (Formula II)

A solution of methyl 3,3-dimethyl-4-pentenoate (500g) and ethanolamine (26g) in t-butanol (78g) was added to a solution of l,l,l-trichloro-2,2,2-trifluoroethane (879g) and copper chloride (35.5g) in t-butanol (26 lg). The reaction mixture was stirred for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of 1,1,1- trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass was cooled and washed with an aqueous hydrochloric acid (10%). The layers were separated, to obtain the titled compound.

Yield: 66%; Purity: 75%;

The exothermicity of the reaction is not controlled that leads to the degradation of the intermediate and formation of impurities.

Example 7: Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate (Formula II) A solution of methyl 3,3-dimcthyl-4-pcntcnoatc (500g) and ethanolamine (26g) in t-butanol (78g) was added to a solution of l,l,l-trichloro-2,2,2-trifluoroethane (879g) and copper chloride (35.5g) in t-butanol (26 lg) at 80-100°C. The reaction mixture was stirred at 80-100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of l,l,l-trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass was cooled and washed with an aqueous hydrochloric acid (10%). The layers were separated, to obtain the titled compound.

Yield: 96%; Purity: 95%

Example 8: Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate (Formula II)

A solution of methyl 3,3-dimethyl-4-pentenoate (500g) and ethanolamine (26g) in t-butanol (78g) was added to a solution of l,l,l-trichloro-2,2,2-trifluoroethane (879g) and copper chloride (35.5g) in t-butanol (26 lg) at 80-100°C. The reaction mixture was stirred at 80-100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of l,l,l-trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass was cooled and triethylenetetramine was added to it. The mixture was stirred for one hour, and separate the layers to obtain the titled compound.

Yield: 96%; Purity: 97%

Example 9: Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate (Formula II)

A solution of ethanolamine (26g) in t-butanol (78g) and methyl 3,3-dimethyl-4-pentenoate (500g) were concurrently added to a solution of l,l,l-trichloro-2,2,2-trifluoroethane (879g) and copper chloride (35.5g) in t-butanol (261g) at 80-100°C. The reaction mixture was stirred at 80-100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of l,l,l-trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass was cooled and decanted-off to obtain the titled compound.

Yield: 96%; Purity: 98%

Example 10 Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate (Formula II) A solution of copper chloride (35.5g) with ethanolamine (26g) in t-butanol (78g) and methyl 3,3- dimethyl- 4 -penteno ate (500g) were concurrently added to a solution of l,l,l-trichloro-2,2,2- trifluoroethane (879g) in t-butanol (26 lg) at 80-100°C. The reaction mixture was stirred at 80- 100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of l,l,l-trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass left was cooled and polypropylene glycol was added to it. The mixture was stirred for 3 hours, and was distilled to obtain the titled compound.

Yield: 97%; Purity: 99%

Example 11: Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate (Formula II)

A solution of l,l,l-trichloro-2,2,2-trifluoroethane (879g) and ethanolamine (26g) in t-butanol (78g) was added to a solution of methyl 3,3-dimethyl-4-pentenoate (500g) and copper chloride (35.5g) in t-butanol (26 lg) at 80-100°C. The reaction mixture was stirred at 80-100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of l,l,l-trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass left was cooled and polypropylene glycol was added to it. The mixture was stirred for 3 hours, and was distilled to obtain the titled compound.

Yield: 96%; Purity: 95%

Example 12: Process for preparation of Methyl 4,6,6-trichloro-7,7,7-trifluoro-3,3- dimethylheptanoate

Charged copper chloride (35.5g), ethanolamine (26g) and t-butanol (261g) and stirred for 1 hour. After in-situ preparation of catalyst concurrently charged a solution of l,l,l-trichloro-2,2,2- trifluoroethane (879g) in t-butanol (78g) and 3,3-dimethyl-4-pentenoate (500g) at 80-100°C. The reaction mixture was further stirred at 80-100°C for 10 hours. The progress of the reaction was monitored by Gas chromatography and after completion of the reaction, the excess of 1,1,1- trichloro-2,2,2-trifluoroethane and t-butanol was distilled out under reduced pressure for further reuse. The reaction mass left was cooled and washed with an aqueous hydrochloric acid (10%). The layers were separated, the organic layer was distilled to obtain the titled compound.

Yield: 99%; Purity: 98%