Field of the Invention
The present invention relates to an improved process for preparation of trifluoropyruvate compounds.

Background of the invention
Trifluoropyruvate compounds play an important role in the synthesis of organic fluorine chemicals. Such compounds have two reaction centres (carbonyl and ester groups), which enable the synthesis of trifluoromethyl heterocyclic compounds and other complex compounds. These compounds are very useful to synthesize anti-inflammatory drugs, anti-cancer drugs, anti-viral drugs and pesticides.

The J. Org. Chem. 1984, 49, 4007-4008 provides a process for preparation of ethyl 3, 3, 3-trifluoro pyruvate by reacting ethyl 2-fluoro-2-ethoxy-trifluoropropionate with SbF6. This process is not commercially suitable as use of antimony pentafluoride makes the process uneconomic.

The J. Am. Chem. Soc. 1993, 115, 5430-5439 provides a process for preparation of ethyl 3, 3, 3-trifluoro pyruvate by reacting ethyl 2-fluoro-2-ethoxy-trifluoropropionate with concentrated sulfuric acid and silica gel at 140°C. Silica reacts with reaction by-product such as hydrogen fluoride to produce water. The trifluoroacetate compounds can easily react with water to produce 2, 2-dihydroxytrifluoropropionate. So use of silica results in undesired side products and hence lowering product yield.

The Chinese Publication No. 102391113 provides a process for preparation of ethyl 3, 3, 3-trifluoro pyruvate by reacting ethyl 2-fluoro-2-ethoxy-trifluoropropionate with 98% concentrated sulfuric acid in presence of white carbon black and phosphorus pentoxide at 125°C under reduced pressure and product was obtained by distillation.

Although this process overcomes the problem associated with known prior art but use of phosphorous pentoxide is industrially unsafe as it is corrosive in nature.

The Journal of Fluorine Chemistry 2008,129, 332–334 provides a process for preparation of methyl trifluoropyruvate by reacting 2-alkoxytetrafluoropropionic acid methyl ester with a novel class of solid acids such as nickel (II) and iron (III) sulphates supported on aluminium oxide, titanium dioxide, zirconium dioxide and sulphated titania– titanium dioxide/ sulphate at 150–170°C and obtaining the product by vacuum distillation.

The Journal of fluorine chemistry 2002, 115, 67-74 provides a process for preparation of methyl 3, 3, 3-trifluoro pyruvate by reacting methyl 2-fluoro-2-ethoxy-trifluoropropionate with concentrated phosphoric acid and silica gel. This process also suffers from the formation of by products such as hydrate of methyl 3, 3, 3-trifluoropyruvate and dimer of methyl 3, 3, 3-trifluoropyruvate.

Thus, there is an urgent need to develop an improved process for preparation of trifluoropyruvate compounds which is simple, cost effective and high product purity.

Summary of the invention
In first aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula-2 with strong mineral acid in absence of dehydrating agent to obtain a compound of formula 1, and
b) isolating the compound of formula 1, obtained from step a).

Formula-2
wherein R1 and R2 are independently alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary butyl.

In second aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula-2 with strong mineral acid in presence of inert gas at suitable flow rate to obtain a compound of formula 1, and
b) isolating the compound of formula 1, obtained from step a).

Formula-2
wherein R1 and R2 are independently alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary butyl.

In third aspect, the present invention provides a process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula 3 with a base to obtain a compound of formula 1, and
b) isolating the compound of formula 1, obtained from step a).

Formula-3
wherein R2 is alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl.

Detailed description of the invention
In an embodiment of first aspect, the present invention provides a process for preparation of a compound of formula 1a,

Formula 1a
comprising:
a) contacting a compound of formula-2a with strong mineral acid in absence of dehydrating agent to obtain a compound of formula 1a, and
b) isolating the compound of formula 1a, obtained from step a).

Formula-2a

In an embodiment of second aspect, the present invention provides a process for preparation of a compound of formula 1a,

Formula 1a
comprising:
a) contacting a compound of formula-2a with strong mineral acid in presence of inert gas at suitable flow rate to obtain a compound of formula 1a, and
b) isolating the compound of formula 1a obtained from step a).

Formula-2a

In the present invention, reaction of compound of formula 2 with strong mineral acid also results in the formation of by-product of formula 3

Formula 3
wherein R2 is alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary butyl.

The by-product of formula 3 can be removed from the reaction mixture by fractional distillation or can be converted to the compound of formula 1.

The strong mineral acid used in the step a) is selected from concentrated sulfuric acid, concentrated phosphoric acid, concentrated nitric acid wherein concentration of sulfuric acid is selected from 90 to 98%, concentration of phosphoric acid is selected from 90% and above and concentration of nitric acid is selected from 90% to 95%.
The most common dehydrating agents used in the prior art are selected from silica, calcium chloride, molecular sieves and phosphorous pentoxide or mixture thereof.

The step a) may be carried out at temperature between –50 to 180°C for about 0.5 hours to 20 hours.

The step a) of second aspect of the present invention is carried out in presence of inert gas selected from nitrogen and argon at suitable flow rate.
The suitable flow rate is selected from 150 to 200 centimeter3/minute.

In an embodiment of third aspect, the present invention provides a process for preparation of a compound of formula 1a,

Formula 1a
comprising:
a) contacting a compound of formula-3a with a base to obtain a compound of formula 1a, and
b) isolating the compound of formula 1a, obtained from step a).

Formula-3a

The base used in step a) above is selected from organic base and inorganic base or mixture thereof.
The organic base used in step a) is selected from pyridine, alkyl substituted pyridines and aliphatic amines or mixture thereof.

The alkyl substituted pyridines may be selected from 2-picoline, 3-picoline, 4-picoline, 2, 3-lutidine, 2, 4-lutidine, 2, 5-lutidine, 2, 6-lutidine, 3, 4-lutidine, 3, 5-lutidine, 2, 4, 6-collidine, 2-vinylpyridine, 4-vinylpyridine and 5-ethyl-2-methylpyridine or mixture thereof.

The aliphatic amines may be selected from methyl amine, ethyl amine, propyl amine, iso-propyl amine, butyl amine, iso-butyl amine, tert-butyl amine, pentyl amine, triethyl amine, di-isopropyl ethyl amine and di-isopropyl amine or mixture thereof.

The preferred inorganic base used in step a) is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride and ammonia or mixture thereof.

The step a) may be carried out at temperature between –50 to 100°C for about 0.5 hours to 8 hours.
The step a) may be carried out in presence of organic solvents.

The compound of formula-1 may be isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.

The compound of formula-1 so obtained by the present invention have a purity, greater than 95 %, more preferably greater than 98 %.

The compound of Formula-2 may be prepared by any method known in the prior art e.g., as disclosed in Journal of Fluorine Chemistry, 49(1), 43-66; 1990 or can be obtained commercially.

The compound of Formula-3 may be obtained by the process of the first and second aspect of the present invention as a by-product or can be obtained commercially.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

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

Example: 1
Preparation of ethyl 3, 3, 3-trifluoropyruvate from ethyl 2-fluoro-2-ethoxy-trifluoropropionate.
The sulfuric acid (247g, 98%) was taken into a reaction vessel and was heated to 110-115°C. Ethyl 2-fluoro-2-ethoxy-trifluoropropionate (500g, 2.29 mole) was then added dropwise into the reaction vessel using dropping funnel over the period of 2 hours. Nitrogen gas was continuously purged with a flow rate between 150 to 200 centimeter3/minute during the reaction so as to facilitate the removal of maximum hydrogen fluoride gas (by-product) formed in the reaction. After complete addition of ethyl 2-fluoro-2-ethoxy-trifluoropropionate, the reaction mixture was refluxed at 110-115°C for another 1 hour with continuous nitrogen gas purging. The reaction mixture thus obtained was distilled under reduced pressure to obtain the titled compound, ethyl 3, 3, 3-trifluoropyruvate.
Yield: 88.4%;
Selectively: 85.08% (by gas chromatography)

Example: 2
Preparation of ethyl 3, 3, 3-trifluoro pyruvate from ethyl 2-fluoro-2-hydroxy-trifluoropropionate.
The ethyl 2-fluoro-2-hydroxy-trifluoropropionate (28.5g) and 5-ethyl-2-methylpyridine (15g) was taken into a reaction vessel and stirred at 20 to 30°C temperature for 1 hour. The reaction mixture thus obtained was subjected to fractional distillation under reduced pressure to get the title compound, ethyl 3, 3, 3-trifluoropyruvate.

Yield: 85%
Purity: 98.5% (by GC chromatography)

WE CLAIM:
1. A process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula-2 with a strong mineral acid to obtain a compound of formula 1, and
b) isolating the compound of formula 1, obtained from step a).

Formula-2
wherein R1 and R2 are independently alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary butyl.
2. A process for preparation of a compound of formula 1,

Formula 1

comprising:
a) contacting a compound of formula-2 with a strong mineral acid in presence of inert gas at flow rate of 150 to 200 centimeter3/minute to obtain a compound of formula 1, and
b) isolating the compound of formula 1 obtained from step a).

Formula-2
wherein R1 and R2 are independently alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tertiary butyl.
3. A process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula-2 with a strong mineral acid to obtain a reaction mixture,
b) contacting the reaction mixture of step a) with a base to obtain a compound of formula 1, and
c) isolating the compound of formula 1, obtained from step b).

Formula-2
4. A process for preparation of a compound of formula 1,

Formula 1
comprising:
a) contacting a compound of formula-3 with a base to obtain a compound of formula 1, and
b) isolating the compound of formula 1, obtained from step a).

Formula-3
wherein R2 is alkyl or substituted alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl.
5. The process as claimed in claim 1, 2 and 3, wherein, the step a) is carried out in absence of dehydrating agent.
6. The process as claimed in claim 1, 2 and 3, wherein, the strong mineral acid used in the step a) is selected from the group consisting of concentrated sulfuric acid, concentrated phosphoric acid and concentrated nitric acid or a mixture thereof.
7. The process as claimed in claim 3 and 4, wherein, the base used is an organic base selected from a group consisting of pyridine, alkyl substituted pyridines, preferably, 2-picoline, 3-picoline, 4-picoline, 2, 3-lutidine, 2, 4-lutidine, 2, 5-lutidine, 2, 6-lutidine, 3, 4-lutidine, 3, 5-lutidine, 2, 4, 6-collidine, 2-vinylpyridine, 4-vinylpyridine and 5-ethyl-2-methylpyridine, and aliphatic amines, preferably, methyl amine, ethyl amine, propyl amine, iso-propyl amine, butyl amine, iso-butyl amine, tert-butyl amine, pentyl amine, triethyl amine, di-isopropyl ethyl amine and di-isopropyl amine or a mixture thereof.
8. The process as claimed in claim 3 and 4, wherein, the base used is an inorganic base selected from a group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium hydride, potassium hydride and ammonia or a mixture thereof.
9. The process as claimed in claim 7, wherein the organic base is recovered after obtaining the compound of formula 1.