The present invention relates to an industrially advantageous and process for preparation of difluoropropiomc acid and its ester derivatives.
BACKGROUND OF THE INVENTION
Organic compounds containing fluorine have achieved technical importance in recent years because of unusual chemical and physical properties such as high thermal stability and marked resistance to oxidative decomposition. Simple and economical methods of obtaining fluorinated compounds have, therefore, become important.
The difluoropropiomc acid and its ester derivatives are valuable intermediates in the field of medicine and agricultural chemicals. Furthermore, the difluoropropiomc acid and its ester derivatives are used for preparing cyclized product having difluoro group.
Journal of Fluorine Chemistry 2010, 131 (9)pp: 942-950 discloses process for preparation of ethyl 3,3-difluoropropionate by oxidative desulfurization-difluorination of ethyl 3-(arylthio)propionate.
The said process results in formation of several bromo substituted side reaction impurity . Therefore, purification step is essential to get pure ethyl 3,3-difluoropropionate. Eventually, the said process is not industrially attractive for preparing difluoro ester derivatives.
There is a need in the art to develop an alternate commercially viable process for preparation of difluoropropiomc ester or difluoropropiomc acid derivatives.

OBJECT OF THE INVENTION
The main object of the present invention is to provide simple, cost effective and industrially applicable processes for preparation of difluoropropiomc acid and its ester derivatives of formula I,
F O

F" ^^ OR Formula I
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms.
SUMMARY OF THE INVENTION
A first aspect of the present invention provides a process for preparation of
compound of formula I,
F O
F^ ^^ OR Formula I
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms
comprising the steps of:
i) reacting a compound of formula II,
o o

F
Formula II
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms; acyl group; alkylaryl group or arylalkyl group which are optionally substituted; with an acid to give compound of formula III,

o

Formula III
ii) halogenating the compound of formula III to give a compound of formula IV,


o
x
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I iii) converting the compound of formula IV to a compound of formula V,
OH
OR
F O
Formula V
wherein R represents hydrogen; alky I group having 1 to 6 carbon atoms iv) reducing the compound of formula V to a compound of formula I.
A second aspect of the present invention provides a process for preparation of compound of formula I,
o
F" ^~^ OR Formula I
wherein R represents alky I group having 1 to 6 carbon atoms comprising the step of:

i) halogenating a compound of formula III,
O

Formula III
to give a compound of formula IV,

o
F x
Formula IV
wherein X represents halogen independently selected from CI, Br or I
ii) converting the compound of formula IV to a compound of formula V,


OH
F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms
iii) reducing the compound of formula V to compound of formula I.

A third aspect of the present invention provides a process for preparation of compound of formula IV,


o
X
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I comprising the step of halogenating a compound of formula III to give the compound of formula IV.

A fourth aspect of the present invention provides a process for preparation of compound of formula V,
OH

F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms comprising the steps of: i) halogenating the compound of formula III,
O
F,

Formula III
to give compound of formula IV,


o
x
F X
Formula IV

wherein X represents halogen independently selected from CI, Br or I

ii) converting the compound of formula IV to compound of formula V.
The fifth aspect of present invention provides a process for preparation of compound of formula I,

Formula I
wherein R represents alkyl group having 1 to 6 carbon atoms using a compound of formula V,
OH

F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "acid" refers to an inorganic acid or an organic acids selected from the group consisting of sulfuric acid (H2SO4), phosphoric acid (H3PO4), hydrochloric acid, methane sulfonic acid (CH3SO3H), p-toluenesulfonic acid, trifluoroacetic acid and the like or mixture thereof.
As used herein, the term "halogenating" refers to the reaction of a compound with a halogenating agent selected from chlorine, bromine and iodine at a temperature range of 20 to 100°C.
The step of halogenation is preferably carried out at a temperature range of 30 to 70°C and more preferably at a temperature range of 40 to 50°C.

The step of halogenation is carried out in the presence of an acid and solvent.
The solvent for the step of halogenation is selected from water, carbontetrachloride, dichloromethane, toluene, tetrahydrofuran, and the like or mixtures thereof.
The conversion of the compound of formula IV to the compound of formula V is carried out via the steps of hydrolysis and optionally the step of esterification.
The step of hydrolysis is carried out in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or the like at a temperature range of 0 to 50°C.
The step of hydrolysis is preferably carried out at a temperature range of 10 to 20°C.
The step of esterification is carried out using an alcohol in the presence of an acid in a polar solvent selected from water, methanol, ethanol, isopropanol, tertiary butanol, pentanol, acetonitrile, tetrahydrofuran, or the like.
The step of esterification is carried out at a temperature range of 40°C to 100°C, preferably at a temperature range of 50°C to 80°C.
As used herein, the term "reduction" refers to a reaction with a reducing agent selected from triphenylphosphine or chlorodiphenylphosphine in presence of an additive, optionally in presence of a base, in a solvent at a temperature range of 20 to 60°C. The additive is selected from iodine, carbontetraiodide, triiodoimidazole or the like.
The base is an organic base selected from trimethylamine, trimethylamine, tributylamine, pyridine, imidazole, pyrazole, piperidine, or the like.
The solvent for the step of reduction is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, or the like.
The step of reduction is preferably carried out at a temperature range of 40 to 50°C.

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: Process for preparation of difluoroacetone
Ethyldifluoroacetoacetate (95 %, 250 g) was added to a mixture of sulfuric acid (98 5%, 53g), and water (105 g) at a temperature of 80 °C. After the addition of ethyldifluoroacetoacetate, the reaction temperature was slowly increased to 90 °C. Mixture of ethanol and product was collected from the top of condenser. When collection of product was stopped, the reaction mass was cooled to 0 °C and concentrated sulphuric acid (98%) was added to reaction mass. The titled compound (93 g, 64%) was isolated by distillation.
EXAMPLE 2: Process for preparation of dibromodifluoro acetone
Difluoroacetone (70.5 g) was added to concentrated sulphuric acid (96%, 250g) at a temperature of -10 °C. The temperature of the reaction mixture was raised to 0 °C and bromine (119g) was added. After addition, the reaction mixture was heated at a temperature of 35 °C and was maintained at the same temperature for three hours. Again bromine (25 g) was added and the reaction mass was further heated to a temperature of 40 °C for 5 hour. The reaction mixture was allowed to settle and the layers were separated. Dichloromethane (70mL) was added to the product

layer and sodium thiosulphate was added to neutralize unreacted bromine. Organic layer was concentrated to get titled compound (158 g; 84 %). The sulphuric acid was recovered and reused in the reaction.
EXAMPLE 3: Process for preparation of difluorolactic acid
A solution of sodium hydroxide (35%) and dibromodifluoro acetone (198g) was added to the reactor at 0 °C to obtain a reaction mixture. The reaction mixture was heated to a temperature of 60 °C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of hydrochloric acid (35%). The reaction mixture was heated at 70-80°C and concentrated under reduced pressure to distill out water to obtain a residue. Ethanol (350ml) was added to the residue. The resulting mixture was filtered and filtrate was carried forward for next step.
EXAMPLE 4: Process for preparation of ethyl difluorolactate
Sulphuric acid (98%; 44g) was slowly added to mixture of difluorolactic acid (example 3) in ethanol (500ml) at a temperature of about 0°C. The reaction mixture was heated to a temperature of 80°C for 2 hours. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mixture was allowed to cool to room temperature. Dichloromethane (200ml) and water (200ml) was added the reaction mixture. The reaction mixture was allowed to settle and the layers were separated. The aqueous layer was washed with dichloromethane (50ml). The organic layers were combined and concentrated at a temperature of 50-60°C to get the titled product (5 lg; 42%).
EXAMPLE 5: Process for preparation of ethyl difluoropropionate
A solution of iodine (5%; 37g) in dichloromethane (700ml) was slowly added to a solution of ethyl difluorolactate (22.8g), triphenyl phosphine (50. lg) and imidazole

(15g) in dichloromethane (150ml) at a temperature of about -30°C. The reaction mixture was stirred for one hour at the same temperature. The progress of the reaction was monitored by gas chromatography. After completion of the reaction the mixture was concentrated at 50-60°C to recover about 80% of dichloromethane. Hexane (400ml) was added to the residue to precipitate out the titled compound. The mixture was filtered and washed with hexane (100ml) to get the titled product (5 lg; 42%>). The filtrate was also concentrated, washed and filtered to get the titled product.
EXAMPLE 6: Process for preparation of Methyl difluorolactate
Sulphuric acid (98%>; 31 lg) was slowly added to mixture of difluorolactic acid (example 3) in methanol (1292 ml) at a temperature of about 20-25°C. The reaction mixture was heated to a temperature of 80°C for 7-8 hours. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mixture was allowed to cool to room temperature and half quantity of methanol (575ml) was distilled off. Dichloromethane (200ml) and water (200ml) was added the reaction mixture. The reaction mixture was allowed to settle and the layers were separated. The organic layers were combined and concentrated at a temperature of 50-60°C to get the crude product. Pure product was isolated by fractional distillation on 1 feet column (GC purity:>99%>, Yield: 50-55%).
EXAMPLE 7: Process for preparation of Methyl difluoropyruvate
A solution of sodium hypochlorite (11%), 552g) was added to a mixture of methyl difluorolactate (100g) and tetra n-butyl ammonium hydrogen sulphate(15g) in ethylacetate (300g) at a temperature of 0-5°C. Reaction mixture was stirred for 2 hours at 0-5 °C. Reaction mixture was quenched using aqueous sodium thiosulphate solution at 0-5°C and allowed to settle layers. The organic layer was concentrated to get the crude product. Pure product was isolated by fractional

distillation of in the presence of phosphorous pentaoxide. (Yield: 40-50%, Purity: >98%).
EXAMPLE 8: Process for preparation of Methyl difluoropropionate
Methydifluorolacate (40g) was added to a mixture of iodine (80g) ,triphenyl phosphine(188g) and dichloromethane (266g) at a temperature of 10 °C. The reaction mixture was heated to 50 °C for 3 hours. After completion of reaction, the reaction mixture was concentrated to recover dichloromethane at 50-60 °C, followed by distillation at 110 °C to get the titled product (Yield: 90%, Purity:>99%).

We claim:

1. A process for preparation of compound of formula I, comprising the steps of:
i) reacting a compound of formula II with an acid to give compound of formula III,

OR

o o

Formula II
wherein R1 represents hydrogen; alky I group having 1 to 6 carbon atoms; acyl group; alkylaryl group or arylalkyl group which are optionally substituted;
o

Formula III
ii) halogenating the compound of formula III to give a compound of formula IV,


o
x
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I iii) converting the compound of formula IV to a compound of formula V,
OH
F O
.OR

Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms
iv) reducing the compound of formula V to a compound of formula I.
F O
F" ^^ OR Formula I
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms. 2. A process for preparation of compound of formula I,
O
Formula I
wherein R represents alkyl group having 1 to 6 carbon atoms comprising the step of:
i) halogenating a compound of formula III to give a compound of formula IV;
o

F
Formula III

o
x
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I

ii) converting the compound of formula IV to a compound of formula V,


OH
F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms Hi) reducing the compound of formula V to compound of formula I.
3. A process for preparation of compound of formula IV,


o
x
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I comprising the step of halogenating a compound of formula III to give the compound of formula IV.
4. A process for preparation of compound of formula V,
OH

F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms comprising the steps of: i) halogenating the compound of formula III,

o

Formula III
to give compound of formula IV,


o
x
F X
Formula IV
wherein X represents halogen independently selected from CI, Br or I ii) converting the compound of formula IV to compound of formula V.
5. A process for preparation of compound of formula I,
F O
Formula I
wherein R represents alkyl group having 1 to 6 carbon atoms
using a compound of formula V,

F O
Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms.

6. The process as claimed in claim 1, wherein acid is selected from a group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, methane sulfonic acid, p-toluene sulfonic acid, trifluoroacetic acid or mixture thereof.
7. The process as claimed in claim 1 -4, wherein halogenating agent is selected from a group consisting of chlorine, bromine or iodine.
8. The process as claimed in claim 1, claim 2 and claim 4, wherein conversion of the compound of formula IV to the compound of formula V is carried out via the steps of hydrolysis and optionally the step of esterification.
9. The process as claimed in claim 1, claim 2 and claim 5, wherein reduction is carried out using a reducing agent, selected from triphenylphosphine or chlorodiphenylphosphine.
10. The process as claimed in claim 1, claim 2 and claim 5, reduction is carried out in presence of an additive, selected from a group consisting of iodine, carbontetraiodide, triiodoimidazole or the like