Field of the invention
The present invention provides a process for preparation of difluoro acid and its 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 difluoro acid and its derivatives are valuable intermediates in the field of medicine and agricultural chemicals. Furthermore, the difluoro ester derivatives are also used as electrolytes for secondary batteries and the batteries.
The difluoro acid and its derivatives are prepared by fluorination of pyruvate derivatives and pyruvic acid respectively with sulfur tetrafluoride in the presence of metal fluoride in ether or hydrogen fluoride.
Zhurnal Organicheskoi Khimii, Volume: 17, Issue: 7, Pages: 1417-20, Journal, 1981 reports reaction of ethyl pyruvate with sulfur tetrafluoride in the presence of hydrogen fluoride to yield 78% of ethyl 2,2-difluoropropionate.
A Canadian patent CA985684A discloses process for the preparation of ethyl 2,2-difluoropropionate by adding ethyl pyruvate and sulfur tetrafluoride in the cold evacuated vessel having temperature of -78ºC under nitrogen. The vessel is then sealed; heated at 90ºC for 10 hours and then the liquid poured into sodium fluoride in ether followed by distillation of ethereal solvent under vacuum to yield ethyl 2,2-difluoropropionate.
The processes cited in the prior art require cryogenic conditions initially and high temperature during the course of the reaction, making the process costly and less viable on commercial scale. The isolation of the product involves distillation, resulting in the loss of yield.
There is a need in the art to develop an alternate commercially viable process for preparation of difluoro acid or difluoro ester 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 difluoro acid and its ester derivatives of formula I.

Formula I
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms; acyl group; alkylaryl group or arylalkyl group which are optionally substituted.
Summary of the invention
A first aspect of the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms; acyl group; alkylaryl group or arylalkyl group which are optionally substituted;
comprising the step of:
reacting compound of formula II,

Formula II
wherein R1 is same as defined above;
with sulfur tetrafluoride at a temperature in the range of -20ºC to 50ºC to obtain the compound of formula I.
A second aspect of the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms; acyl group; alkylaryl group or arylalkyl group which are optionally substituted;
comprising the step of:
reacting compound of formula II with a mixture of sulfur tetrafluoride and solvent,

Formula II
wherein R1 is same as defined above.
A third aspect of the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms, acyl group, alkylaryl group or arylalkyl group which are optionally substituted;
comprising the steps in the following sequence:
a) adding compound of formula II in a reactor;

Formula II
wherein R1 is same as defined above;
b) adding solvent and sulfur tetrafluoride in the reactor to obtain a reaction mixture; and
c) isolating the compound of formula I from the step b.
A fourth aspect of the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R1 represents hydrogen; alkyl group having 1 to 6 carbon atoms, acyl group, alkylaryl group or arylalkyl group which are optionally substituted;
comprising the steps in the following sequence:
a) adding solvent and sulfur tetrafluoride in a reactor;
b) adding compound of formula II,

Formula II
wherein R1 is same as defined above;
in the reactor to obtain a reaction mixture; and
c) isolating the compound of formula I from the step b.
A fifth aspect of the present invention provides a process for preparation of ethyl 2,2-difluoropropionate, comprising the steps in the following sequence:
a) adding hydrogen fluoride and sulfur tetrafluoride at a temperature in the range of -20ºC to 10ºC in a reactor;
b) adding ethylpyruvate in the reactor at a temperature in the range of -20ºC to 50ºC to obtain a reaction mixture;
c) isolating the compound of ethyl 2,2-difluoropropionate from the step b).

Detailed description of the invention
As used herein, acyl group is referred to a compound having formula –COR, wherein R is an alkyl group selected from methyl, ethyl, propyl and a like.
The present invention provides process for the preparation of compound of formula I by reacting mixture of sulfur tetrafluoride and solvent with compound of formula II or by reacting compound of formula II with mixture of sulfur tetrafluoride and solvent to obtain a reaction mixture.
The compound of formula II can be prepared by any method known in the prior art or it can be commercially available from market.
The solvent used for the conversion of compound of formula II to compound of formula I is selected from hydrogen fluoride, chlorinated solvents such as dichloromethane, chloroform; non-polar hydrocarbon solvents such as benzene, toluene, xylene, pentane, hexane, cyclohexane, octane and mixture thereof.
In an embodiment of the present invention, the anhydrous hydrogen fluoride is used as preferred solvent.
In an embodiment of the first aspect, the present invention provides the process for the preparation of the compound of formula I, wherein the process is carried out in a particular sequence.
In an embodiment of the first aspect of the present invention, the process is carried out in a particular sequence that follows:
a) addition of hydrogen fluoride and sulfur tetrafluoride to the reactor to obtain a mixture;
b) addition of the compound of formula II to the mixture of step a);
c) isolation of the compound of formula I.
This sequence of the addition is determinative of the yield and purity of the compound of formula I.
It has been observed that compound of formula II has the tendency of degradation with time when mixed with hydrogen fluoride. The rate of degradation is a function of time and temperature.
In another embodiment of this aspect of the present invention, the process for the preparation of ethyl 2,2-difluoropropionate is carried out in a particular sequence that follows:
a) addition of hydrogen fluoride and sulfur tetrafluoride to the reactor to obtain a mixture;
b) addition of the ethylpyruvate to the mixture of step a);
c) isolation of the compound of ethyl 2,2-difluoropropionate.
Ethyl 2,2-difluoropropionate obtained by the process of present invention has purity of at least 90%, has hydrogen fluoride not more than 3%.
Ethyl 2,2-difluoropropionate obtained by the process of the present invention has moisture content of not more than 0.5%.
The mole ratio of hydrogen fluoride and sulfur tetrafluoride with respect to the compound of formula II varies from 0.1-20.0:1.0-2.0.
The mole ratio of hydrogen fluoride and sulfur tetrafluoride with respect to the compound of formula II varies from 1.5-15.0: 1.1-2.0.
The mole ratio of hydrogen fluoride and sulfur tetrafluoride with respect to the compound of formula II varies from 5.0-15.0: 1.5-2.0.
The conversion of compound of formula II to compound of formula I is carried out at a temperature in the range of -20ºC to 50ºC.
In a specific embodiment, the mole ratio of the solvent and sulfur tetrafluoride with respect to the compound of formula II is 15:1.5 or 5:1.5 or 5:1.1.
The reaction mixture is stirred for 1 hour to 6 hours to obtain the compound of formula I.
The completion of the reaction can 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.
After completion of the reaction, the dissolved gases were removed from the reaction mixture to obtain a solution of product in the solvent.
Isolation and purification of the compound of formula I after completion of the reaction is accomplished by well recognized procedures. The routine method consists in pouring the crude reaction products into an inert solvent containing a hydrogen fluoride acceptor, for example, an alkali or alkaline earth metal fluoride, agitating, filtering, removing the solvent and distilling the desired compound of formula I.
The desired compound of formula I can be isolated by using any following procedures selected from agitating, filtering, removing the solvent and simple distillation without vacuum.
Further, the present invention provides a process for the preparation of compound of formula Ia by using compound of formula IIa. The said conversion is carried out by using the method as described above.
Unless stated to the contrary, any of the words “comprising” and “comprises” 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.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Process for the preparation of ethyl 2,2-difluoropropionate
Example 1:
Anhydrous hydrogen fluoride (516gm) and sulfur tetrafluoride (280g) were added in to a reactor. Ethylpyruvate (200gm) was added in the reactor at a temperature of about 0ºC to 10ºC to obtain a reaction mixture. The reaction mixture was stirred at a temperature of 25 ºC for 1 hour. The progress of the reaction id monitored by gas chromatography (GC). After completion of the reaction, the dissolved gases were removed from the reaction mixture to obtain a solution of product in hydrogen fluoride. The pure product was isolated from hydrogen fluoride by distillation.
Yield 85%; Purity 99.4%
Example 2:
Anhydrous hydrogen fluoride (172gm) and sulfur tetrafluoride (285g) were added in to a reactor. Ethylpyruvate (200gm) was added in the reactor at a temperature of about 0ºC to 10ºC to obtain a reaction mixture. The reaction mixture was stirred at a temperature of 25 ºC for 1 hour. The progress of the reaction is monitored by GC. After completion of the reaction, the dissolved gases were removed from the reaction mixture to obtain a solution of product in hydrogen fluoride. The pure product was isolated from hydrogen fluoride by distillation.
Yield 90%; Purity 99.97%
Example 3:
Anhydrous hydrogen fluoride (172gm) and sulfur tetrafluoride (205g) were added in to a reactor. Ethylpyruvate (200gm) was added in the reactor at a temperature of about 0ºC to 10ºC to obtain a reaction mixture. The reaction mixture was stirred at a temperature of 25 ºC for 1 hour. The progress of the reaction is monitored by GC. After completion of the reaction, the dissolved gases were removed from the reaction mixture to obtain a solution of product in hydrogen fluoride. The pure product was isolated from hydrogen fluoride by distillation.
Yield 90%; Purity 99.96%
Reference example with different sequence of addition
Process for the preparation of ethyl 2,2-difluoropropionate
Ethylpyruvate (200gm) and anhydrous hydrogen fluoride (516gm) were added in a reactor. Sulfur tetrafluoride gas (280gm) was purged in the reactor at a temperature of about 0ºC to 10ºC to obtain a reaction mixture. The reaction mixture was stirred at a temperature of 25 ºC for one hour. The progress of the reaction was monitored by GC. After completion of the reaction, the dissolved gases were removed from the reaction mass to obtain a solution of product in hydrogen fluoride. The pure product from hydrogen fluoride was isolated by distillation.
Yield 70% Purity 90%.

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.

Claims:
1. A process for preparation of compound of formula I,

Formula I

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;
wherein the process comprises the steps of:
a) adding anhydrous hydrogen fluoride and sulfur tetrafluoride to a reactor;
b) adding a compound of formula II, to the reactor to obtain a reaction mixture; and
c) isolating the compound of formula I from the step b).

2. The process as claimed in claim 1, wherein molar ratio of hydrogen fluoride and sulfur tetrafluoride with respect to formula II varies from 0.1-20.0:1.0-2.0.

3. The process as claimed in claim 1, wherein the process is carried out at a temperature in the range -20 ºC to 50 ºC.

4. The process as claimed in claim 1, wherein compound of formula II obtained is having moisture not more than 0.5% and hydrogen fluoride not more than 3%.