The present invention provides a process for preparation of difluorocyclopropane derivatives. They are valuable intermediates in the field of agrochemical and pharmaceutical.

BACKGROUND OF THE INVENTION
Cyclopropane derivatives are very valuable insecticidal and also useful in pharmaceutical industry.
There are several methods known for the preparation of cyclopropane derivatives.
Tetrahedron Letters, 37(23), 4085-4086; 1996 and PL179695 discloses a process for preparation of difluorocyclopropane derivative by reacting dichlorocyclopropane carboxylate with an excess of potassium fluoride in presence of acetonitrile, water and tetra-butyl ammonium hydrogen sulphate as phase transfer catalyst. This process uses large quantity of solvents and reagents and has reported yield of 35%, and requires column chromatography to obtain pure compound.
The excess of potassium fluoride leads to the formation of thick slurry and tarry material that drastically affects the yield and efficiency of the process at industrial scale ups.
Therefore, there is a need to develop a process that is, economical and industrially viable and uses reasonable quantities of solvents and reagents.

OBJECT OF THE INVENTION
The main object of present invention is to provide an improved process for preparation of alkyl difluorocyclopropane carboxylate. Further, the process of present invention is economical and industrially doable as compared to existing processes.
SUMMARY OF THE INVENTION
In first aspect the present invention provides a process for preparation of alkyl difluorocyclopropane carboxylate, comprising the steps of:
a) reacting alkyl dichlorocyclopropane-1-carboxylate with potassium fluoride in a polar aprotic solvent in presence of a phase transfer catalyst and a small amount of water to obtain a reaction mixture; and
b) isolating the alkyl difluorocyclopropane-1-carboxylate from the reaction mixture of step a).
In second aspect the present invention provides an improved process for preparation of difluorocyclopropane-1-carboxylic acid, comprising the steps of:
a) reacting alkyl dichlorocyclopropane-1-carboxylate with potassium fluoride in a polar aprotic solvent in presence of a phase transfer catalyst and a small amount of water to obtain a reaction mixture;
b) removing solvent from the reaction mixture of step a) to obtain a mixture containing alkyl difluorocyclopropane-1-carboxylate;
c) hydrolysing alkyl difluorocyclopropane-1-carboxylate; and
d) isolating difluorocyclopropane-1-carboxylic acid from the reaction mixture of step d).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an economical process for preparation of alkyl difluorocyclopropane carboxylate.
As used herein, “alkyl” group refers to methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl or like.
As used herein, “phase transfer catalyst” refers to a catalyst which facilitate the migration of reactant from one phase to another phase and is selected from a group consisting of tetrabutylammonium chloride, tetrabutylammonium fluoride, triethylmethylammonium chloride, tetramethylammonium sulphate, tetrabutylammonium hydrogen sulphate, triethylphenylammonium chloride, trioctylmethylammonium chloride or like.
In an embodiment of the present invention, the polar aprotic solvent is selected from a group consisting of acetonitrile, water, monoglyme, dimethylsulfoxide, dimethylformamide, dimethylacetamide, diglyme, dioxane, tetrahydrofuran or the like and mixture(s) thereof.
In a preferred embodiment, the process is carried out in acetonitrile.
In another embodiment of the present invention, the weight ratio of acetonitrile to alkyl dichlorocyclopropane carboxylate may be selected in the range of 4-7.
In another embodiment, step a) is carried out at a temperature range of 70-90°C and preferably at 75-80°C.
The small quantity of water used in the step a) ranges from 0.5 to 1.2 (by weight ratio) to alkyl dichlorocyclopropane carboxylate.
In one embodiment, the weight ratio of water to alkyl dichlorocyclopropane carboxylate is 1.
In another embodiment, the weight ratio of water to alkyl dichlorocyclopropane carboxylate is in the range 0.7-0.8.
In one embodiment, the molar ratio of potassium fluoride to dichlorocyclopropane may be selected in the range 2-15, more preferably in the range of 5-12 and most preferably in the range of 8-10.
In one embodiment, potassium chloride and potassium hydrogen sulphate are filtered out from reaction mixture.
In one embodiment, solvent used for isolation of difluorocyclopropane-1-carboxylate and difluorocyclopropane-1-carboxylic acid is selected from a group consisting of diethyl ether, dichloromethane, acetonitrile, tetrahydrofuran or mixture thereof.
In one embodiment, the purity of isolated alkyl difluorocyclopropane carboxylate is greater than 90%.
In one embodiment, the purity of isolated 2,2-difluorocyclopropane carboxylic acid is greater than 99%.
In one embodiment, the hydrolysis is carried out in presence of metal hydroxide selected from a group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide or like.
In another embodiment, the metal hydroxide is used in an aqueous solution.
In another embodiment, the concentration range of aqueous metal hydroxide is selected from 5-20%.
In another embodiment, molar ratio of metal hydroxide to alkyl difluorocyclopropane-1-carboxylate is in the range of 1-5.
In another embodiment, the hydrolysis is carried out at a temperature of below 40°C.
In another embodiment, the alcohol generated during the step of hydrolysis is recovered and recycled in the process.
In another embodiment, reaction mass of hydrolysis is acidified to obtain product and is used in anhydrous or liquid form.
In another embodiment, the alcohol generated as side product in the hydrolysis is recycled.
The hydrolysis product may be isolated using a method selected from filtration, extraction, distillation, boil-off, crystallization.
The preferred method for purification of 2, 2-difluorocyclopropane carboxylic acid is crystallization. The crystallization is carried out in a solvent selected from hexane, petroleum ether or heptane.
In another embodiment, alkyl dichlorocyclopropane-1-carboxylate are prepared by a process, comprising the steps of:
a) reacting allyl alcohol and trimethylorthoformate to obtain triallylorthoformate;
b) reacting triallylorthoformate and chloroform to obtain tris-(2,2-dichlorocyclopropylcarbinyl)orthoformate;
c) reacting tris-(2,2-dichlorocyclopropylcarbinyl)orthoformate and nitric acid to obtain 2,2-dichlorocyclopropane carboxylic acid; and
d) reacting 2,2-dichlorocyclopropane carboxylic acid and an alcohol to obtain alkyl dichlorocyclopropane-1-carboxylate.
In one embodiment, concentration of nitric acid is chosen from 60-70%.
The preparation of 2,2-dichlorocyclopropane carboxylic acid involves generation of nitric oxide and formic acid as side product.
In one embodiment, the nitric oxide is quenched in an alkaline solution preferably an aqueous sodium hydroxide to prevent any release in atmosphere.
In one embodiment, the formic acid is recovered from dichlorocyclopropane-1-carboxylate reaction mixture.
In one embodiment, triallylorthoformate may comprise of diallylorthoformate in the range of 1-20%.
In one embodiment, the triallylorthoformate preparation is carried out at 90-100°C for maximum conversion of allyl alcohol to triallylorthoformate.
In one embodiment, the preparation of triallylorthoformate involves generation of methanol as side product that is recovered.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
The reagents used in the above process are obtained commercially.
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: Preparation of butyl-2,2-difluorocyclopropane carboxylate
Butyl-2,2-dichlorocyclopropane carboxylate (40g), potassium fluoride (220g) and tetrabutylammonium hydrogen sulphate (193g) were added to a round bottom flask. Then, acetonitrile (430g) and water (74g) were added in the flask. The reaction mass was heated to 80°C and stirred. The reaction mass was cooled to 20-30°C and filtered. Reaction mixture became thick slurry and lump formation was observed. The filtered solid was washed with acetonitrile. The both filtrates were combined and concentrated. The distilled water was added to the concentrated residue and extracted with dichloromethane. The organic layer was washed with an aqueous hydrochloric acid under stirring. The organic and aqueous layers were separated and organic layer was concentrated to obtain crude product.
Example 2: Preparation of butyl-2,2-difluorocyclopropane carboxylate
The example 1 process was repeated without using water. No conversion observed. It shows water is an essential element for process.
Example 3: Preparation of butyl-2,2-difluorocyclopropane carboxylate
Butyl-2,2-dichlorocyclopropane carboxylate (40g), potassium fluoride (108g) and tetrabutylammonium hydrogen sulphate (193g) were added to a round bottom flask. Then acetonitrile (233g) and water (34g) were added in the flask. The reaction mass was heated to 80°C and stirred. The reaction mass was cooled to room temperature and filtered. The filtered solid was washed with acetonitrile. The both filtrates were combined and concentrated. The distilled water was added to the concentrated residue and extracted with dichloromethane. The organic layer was washed with aqueous hydrochloric acid under stirring. The organic and aqueous layers were separated and organic layer was concentrated to obtain crude product. The crude product was distilled to obtain pure butyl difluorocyclopropane carboxylate.
Yield: 40%; Purity: 89%
Example 4: Preparation of 2,2-difluorocyclopropane carboxylic acid
Butyl-2,2-difluoro cyclopropane carboxylate (45g) and 7% aqueous solution of sodium hydroxide (450g) were charged in a round bottom flask and stirred at 30°C. The reaction mass was analysed at gas chromatography for reaction completion. Dichloromethane was added in the reaction mass and separated aqueous and organic layer. The aqueous layer was concentrated to half quantity of water and acidified with aqueous hydrochloric acid to pH below 1. The acidified reaction mass was extracted with diethyl ether and diethyl ethyl organic layer was concentrated to obtain solid. The solid was purified using n-hexane to get 2,2-difluorocyclopropane carboxylic acid.
Purity: 99%; Yield: 80%

Example 5: Preparation of propyl-2,2-difluorocyclopropane carboxylate
Propyl-2,2-dichlorocyclopropane carboxylate (20g), potassium fluoride (41g) and tetrabutylammonium hydrogen sulphate (95g) were added in a round bottom flask. Then acetonitrile (110g) and water (17g) were added in the flask. The reaction mass was heated to 80°C and stirred. The reaction mass was cooled to room temperature and filtered. The filtered solid was washed with acetonitrile. The both filtrates were combined and concentrated. The distilled water was added in concentrated residue and extracted with dichloromethane. The organic layer was washed with aqueous hydrochloric acid under stirring. The organic and aqueous layers were separated and organic layer was concentrated to obtain crude product. The crude product was distilled to obtain pure propyl-2,2-difluorocyclopropane carboxylate. Propyl-2,2-difluoro cyclopropane carboxylate (20g) and 6% aq. Sodium hydroxide (311g) was charged in a round bottom flask and stirred at 30°C. The reaction mass was analysed at gas chromatography for reaction completion. Dichloromethane was added in the reaction mass and separated aqueous and organic layer. The aqueous layer was concentrated to half quantity of water and acidified with aqueous hydrochloric acid to pH below 1. The acidified reaction mass was extracted with diethyl ether and diethyl ethyl organic layer was concentrated to obtain solid. The solid was purified using n-hexane to get 2,2-difluorocyclopropane carboxylic acid.
Purity: 90%; Yield: 40%
Example 6: Preparation of 2,2-difluorocyclopropane carboxylic acid
Propyl-2,2-dichlorocyclopropane carboxylate (20g), potassium fluoride (41g) and tetrabutylammonium fluoride (74g) were added in a round bottom flask. Then, acetonitrile (110g) and water (17g) were added in the flask. The reaction mass was heated to 80°C and stirred. The reaction mass was cooled to room temperature and filtered. The filtered solid was washed with acetonitrile. The both filtrates were combined and concentrated. The distilled water was added in concentrated residue and extracted with dichloromethane. The organic layer was washed with aqueous hydrochloric acid under stirring. The organic and aqueous layers were separated and organic layer was concentrated to obtain crude product.
Crude propyl-2,2-difluoro cyclopropane carboxylate (20g) and 6% aq. sodium hydroxide (311g) were charged in a round bottom flask and stirred at 30°C. The reaction mass was analysed at gas chromatography for reaction completion. Dichloromethane was added in the reaction mass and separated aqueous and organic layer. The aqueous layer was concentrated to half quantity of water and acidified with aqueous hydrochloric acid to pH below 1. The acidified reaction mass was extracted with diethyl ether and diethyl ethyl organic layer was concentrated to obtain solid. The solid was purified using n-hexane to get 2,2-difluorocyclopropane carboxylic acid.
Purity: 90%; Yield: 38%
Example 7: Preparation of 2,2-difluorocyclopropane carboxylic acid
Propyl-2,2-difluoro cyclopropane carboxylate (10g) and 6% aq. Sodium hydroxide (150g) were charged in a round bottom flask and stirred at 30°C. The reaction mass was analysed at gas chromatography for reaction completion. Dichloromethane was added in the reaction mass and separated aqueous and organic layer. The aqueous layer was concentrated to half quantity of water and acidified with aqueous hydrochloric acid to pH below 1. The acidified reaction mass was extracted with diethyl ether and diethyl ethyl organic layer was concentrated to obtain solid. The solid was purified using n-hexane to get 2,2-difluorocyclopropane carboxylic acid.
Purity: 99%; Yield: 82%
Example 8: Preparation of butyl-2,2-dichlorocyclopropane carboxylate
2,2-dichlorocyclopropane carboxylic acid (35g) and n-butanol were charged in a reactor and maintained at 30°C. 98% Sulphuric acid was slowly added in the reactor and heated to reflux. Reaction mass was analysed on GC for 2,2-dichloropropane carboxylic acid <1%. Then, reaction mass was cooled to 30°C and concentrated to remove n-butanol under vacuum. The concentrated mass was quenched with water and extracted with dichloromethane. The dichloromethane layer was concentrated to crude using rota vapour and dried at 60°C under reduced pressure.
Yield: 85%; Purity: 90%
Example 9: Preparation of 2,2-dichlorocyclopropane carboxylic acid
Tris-(2,2-dichlorocyclopropylcarbinyl) orthoformate (100g) were charged in a reactor and heated to 70-75°C. 69% Nitric acid (210) was slowly added in a reactor in 1 hour. During addition, brown fumes was observed and scrubbed in sodium hydroxide solution. After complete addition, reaction mass was stirred at 70-80°C. The reaction sample was analysed for absence of tris-(2,2-dichlorocyclopropylcaarbinyl)orthoformate and 2,2-dichlorocyclopropyl carbinol. The reaction mass was cooled to 30°C. Dichloromethane was added to mass and stirred. The aqueous layer and organic layers were separated and organic layer was concentrated under reduced pressure. The product was further dried at 60°C under reduced pressure.
Yield: 90%; Purity: 95%
Example 10: Preparation of tris-(2,2-dichlorocyclopropylcarbinyl) orthoformate
Triallylorthoformate (50g), chloroform (260g), and benzyltriethylammonium chloride (0.37g) were charged in a flask and cooled to 10°C. 50% sodium hydroxide solution was slowly added to reaction mass in 1 hour at 10°C. The reaction mass was analysed on GC till absence of triallyl and diallylorthoformate. The reaction mass was quenched with water and stirred, followed by addition of chloroform. The reaction mass was stirred and separated aqueous and organic layer. Aqueous layer was extracted with chloroform. The combined organic layer was concentrated under reduced pressure.
Yield: 75%; Purity: 75%

Example 11: Preparation of triallyl orthoformate
Trimethylorthoformate (30g) and allyl alcohol (67g) were charged in a reactor and added ammonium sulphate (0.3g) at 30°C. The reaction mass was refluxed and collected methanol. Then, reaction mixture was analysed on gas chromatography and distilled under reduced pressure at 50-60°C. Dichloromethane was added in the mixture and washed with water. The dichloromethane layer was concentrated to concentrated and dried at 60°C under reduced pressure.
Yield: 75%; Purity: 93%
Example 12: Preparation of butyl-2,2-difluorocyclopropane carboxylate
Butyl-2,2-dichlorocyclopropane carboxylate (40g), potassium fluoride (107g) and tetrabutylammonium hydrogen sulphate (193g) were added in a round bottom flask. Then, tetrahydrofuran (220g) and water (34g) were added in the flask. The reaction mass was heated to 80°C and stirred. The reaction mass was cooled to room temperature and filtered. The filtered solid was washed with tetrahydrofuran. The both filtrates were combined and concentrated. The distilled water was added in concentrated residue and extracted with dichloromethane. The organic layer was washed with aqueous hydrochloric acid under stirring. The organic and aqueous layers were separated and organic layer was concentrated to obtain crude product. The crude product was distilled to obtain pure butyl difluorocyclopropane carboxylate.
Yield: 36%; Purity: 88%

CLAIMS:WE CLAIM:
1. An improved process for preparation of alkyl difluorocyclopropane carboxylate,
comprising the steps of:
a) reacting alkyl dichlorocyclopropane-1-carboxylate with potassium fluoride in a polar aprotic solvent in presence of a phase transfer catalyst and a small amount of water to obtain a reaction mixture; and
b) isolating the alkyl difluorocyclopropane-1-carboxylate from the reaction mixture of step a).
2. An improved process for preparation of difluorocyclopropane-1-carboxylic acid, comprising the steps of:
a) reacting alkyl dichlorocyclopropane-1-carboxylate with potassium fluoride in a polar aprotic solvent in presence of a phase transfer catalyst and a small amount of water to obtain a reaction mixture;
b) removing solvent from the reaction mixture of step a) to obtain a mixture containing alkyl difluorocyclopropane-1-carboxylate;
c) hydrolysing alkyl difluorocyclopropane-1-carboxylate; and
d) isolating difluorocyclopropane-1-carboxylic acid from the reaction mixture of step d).
3. The process as claimed in claims 1 and 2, wherein the phase transfer catalyst is selected from a group consisting of tetrabutyl ammonium chloride, tetra butyl ammonium fluoride, triethylmethyl ammonium chloride, tetramethylammonium sulphate, tetrabutylammonium hydrogen sulphate, triethylphenyl ammonium chloride and trioctylmethyl ammonium chloride.

4. The process as claimed in claims 1 and 2, wherein the polar aprotic solvent is selected from a group consisting of acetonitrile, water, monoglyme, dimethylsulfoxide, dimethylformamide, dimethylacetamide, diglyme, dioxane and tetrahydrofuran or a mixture thereof.
5. The process as claimed in claims 1 and 2, wherein the reaction of alkyl dichlorocyclopropane-1-carboxylate with potassium fluoride is carried out at a temperature of 70-90°C.
6. The process as claimed in claim 2, wherein the hydrolysis is carried out in presence of a metal hydroxide selected from a group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide and cesium hydroxide.
7. The process as claimed in claim 2, wherein the reaction of hydrolysis is carried out at a temperature of 5 to 40°C.
8. The process as claimed in claims 1 and 2, wherein the weight ratio of water to alkyl dichlorocyclopropane carboxylate is selected in the range from 0.5 to 1.2.
9. A process for the preparation of alkyl dichlorocyclopropane-1-carboxylate, comprising the steps of:
a) reacting allyl alcohol and trimethylorthoformate to obtain triallylorthoformate;
b) reacting triallylorthoformate and chloroform to obtain tris-(2,2-dichlorocyclopropylcarbinyl)orthoformate;
c) reacting tris-(2,2-dichlorocyclopropylcarbinyl)orthoformate and nitric acid to obtain 2,2-dichlorocyclopropane carboxylic acid; and
d) reacting 2,2-dichlorocyclopropane carboxylic acid and an alcohol to obtain alkyl dichlorocyclopropane-1-carboxylate.

10. The process as claimed in claim 9, wherein the reaction of step a) is carried out at 90-100°C.