The present invention provides an improved process for the preparation of cyclopropane carboxylic acid and derivatives thereof of Formula I,

Formula I
wherein R1 are 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 intermediate 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.
Thus with this state of the art in mind, there is need to provide improved the selectivity towards formation of cis isomer of cyclopropane carboxylic acid. The present invention provides a simple, safe and selective and cost effective method for preparing intermediates of cyclopropane carboxylic acid.

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.

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 R1 are independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z can be halogen, halogenated alkyl group,
comprising the step of:
a) concurrently adding to a continuous stirred reactor containing a first solvent, a compound of Formula II,

Formula II
wherein R2 is alkyl; X1 is halogen; R1, X2, Z are as defined above,
and a first base to obtain a compound of Formula III;

Formula III
wherein R1, R2, X2, 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 R1 are independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z can be halogen, halogenated alkyl group,
comprising the step of:
a) concurrently adding to a continuous stirred reactor containing a first solvent, a compound of Formula II,

Formula II
wherein R2 is alkyl; X1 is halogen; R1, X2, Z are as defined above,
and a first base to obtain a compound of Formula III;

Formula III
wherein R2, R1, X2, 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;

Formula IV
wherein R2, R1, X2, 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 R1 are independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z can be halogen, halogenated alkyl group,
comprising the step of:
a) concurrently adding, to a first solvent or mixture thereof, a compound of Formula II,

Formula II
wherein R2 is alkyl; X1 is halogen; R1, X2, Z are as defined above,
and a first base to obtain a compound of Formula III;

Formula III
wherein R2, R1, X2, Z are as defined above,
b) concurrently adding the compound of Formula III in a second solvent and a second base to obtain a compound of Formula IV;

Formula IV
wherein R2, R1, X2, Z are as defined above,
c) hydrolysing the compound of Formula IV using an acid to obtain the cyclopropane carboxylic acid of Formula I.
A fourth aspect of present invention provides an improved process for preparation of cyclopropane carboxylic acid of Formula I,

Formula I
wherein R1 are independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z can be halogen, halogenated alkyl group,
comprising the step of:
a) concurrently adding, to a continuous stirred reactor containing a first solvent or mixture thereof, a compound of Formula II,

Formula II
wherein R2 is alkyl; X1 is halogen; R1, X2, Z are as defined above,
and a first base to obtain a compound of Formula III;

Formula III
wherein R2, R1, X2, 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.
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 and 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 sodium carbonate and potassium carbonate or the like.
Preferably, alkali metal alkoxides are used as the first base. More preferably, alkali metal alkoxides are generated insitu 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 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 3-[(1Z)-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-dimethylcyclopropane-1-carboxylate;
b) concurrently adding a solution of methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcyclopropane-1-carboxylate in an alcohol solvent and a strong base to obtain 3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-2,2-dimethylcyclopropane-1-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-dimethylcyclopropane-1-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-dimethylcyclopropane-1-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-dimethylcyclopropane-1-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-dimethylcyclopropane-1-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-dimethylcyclopropane-1-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.
In an embodiment of the present invention, 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoate is prepared following the step of slowly adding a mixture of methyl 3,3-dimethyl-4-pentenoate and ethanolamine in t-butanol to a mixture of 1,1,1-Trichloro-2,2,2-trifluoro ethane and copper chloride in t-butanol is carried out at a temperature below 100-120°C, within a time period of 12 to 15 hours.
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.
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 example is 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-1-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-1-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% Cis content
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-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-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-1-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%; Selectivity: : 99% Cis content.
Example 4: Synthesis of 3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-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-dimethylcyclopropane-1-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: 99%; Selectivity: : 99% Cis content
Example 5: Synthesis of 3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-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.
Methyl-3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethylcyclopropane-1-carboxylate (2022g), methanol (1011g) 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: 87.6%; Purity: >99%; Selectivity: >99% Cis content

WE CLAIM:

1. A process for preparation of cyclopropane carboxylic acid of formula I,

Formula I
wherein R1 is independently selected from hydrogen, alkyl, halogenated alkyl; X2 and Z is selected from halogen, halogenated alkyl group,
comprising the steps of:
a) concurrently adding, to a first solvent, a compound of formula II,

Formula II
wherein R2 is alkyl; X1 is halogen; R1, X2, Z are as defined above,
and a first base to obtain a compound of formula III;

Formula III
wherein R2, R1, X2, Z are as defined above,
b) concurrently adding the compound of formula III in a second solvent and a second base to obtain a compound of formula IV; and

Formula IV
wherein R2, R1, X2, Z are as defined above,
c) hydrolysing the compound of formula IV using an acid to obtain cyclopropane carboxylic acid of formula I.
2. The process as claimed in claim 1, wherein 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.
3. The process as claimed in claim 1, wherein the step 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.
4. The process as claimed in claim 1, wherein 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.
5. The process as claimed in claims 1, wherein the “first base” is selected from a group consisting of alkoxides and hydrides of alkali metals.
6. The process as claimed in claims 1, wherein the “first solvent” is a polar protic or aprotic solvent selected from a group consisting of isopropanol, butanol, t-butanol, pentanol, isopentanol, t-pentanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide or a mixture thereof.

7. The process as claimed in claims 2, wherein the “second base” is selected from a group consisting of hydroxides and carbonates of alkali metals.
8. The process as claimed in claims 2, wherein the “second solvent” is an alcohol solvent selected from a group consisting of methanol, ethanol, butanol, propanol, isopropanol, butanol, t-butanol, pentanol, isopentanol and t-pentanol or a mixture thereof.
9. The process as claimed in claim 1, wherein “the acid” is a mineral acid selected from a group consisting of hydrochloric acid and sulfuric acid.
10. The process as claimed in claims 2 to 4, wherein the continuous stirred tank reactor and loop reactor are as described in figures 1 and 2 respectively.