DESC:FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula 1,

Formula 1
wherein R is an alkyl group selected from methyl, ethyl and propyl.

BACKGROUND OF THE INVENTION
Orthoesters are used in preparation of complexed molecules for pharmaceutical and cosmetic industries. They are also used in general organic synthesis as protecting group for esters and find applications in chemical industry.
Chinese Patent No. 105384614 provides a process for preparation of trimethylorthoacetate by reacting a mixture of acetonitrile and methanol with hydrogen chloride in hexane at a temperature of -20 to -5°C.
Chinese Patent No. 102060678 provides a process for preparation of trimethylorthoacetate by reacting acetonitrile and methanol with hydrogen chloride at -20 to -5°C in hexane, followed by addition of methanol and ammonia to isolate trimethylorthoacetate.
The processes known for preparation of trimethylorthoacetate in the art, are carried out at a temperature of below 0°C. The sub-zero temperature leads to accumulation of hydrogen chloride in the reaction mixture that results in an abrupt increase in the temperature due to high exothermicity and may lead to an explosion during commercial scale ups.
Thus, there is a need in the art to develop an economical and safer process for preparation of orthoesters.
The present invention provides a process for preparation of orthoesters. The process is carried out an optimal temperature range that minimizes the accumulation of hydrogen chloride, thereby overcomes the safety concern posed in the known processes.

OBJECT OF THE INVENTION
The object of the present invention is to provide an economical and safer process for preparation of orthoesters of formula I.

Formula I
wherein R is an alkyl group selected from methyl, ethyl and propyl.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R is an alkyl group selected from methyl, ethyl and propyl
comprising the steps of:
a) passing an anhydrous hydrochloride to a mixture comprising acetonitrile, an alcohol at 5 to 15°C;
b) adding an alcohol to the reaction mixture of step a)
c) neutralizing the reaction mixture of step b) using an anhydrous ammonia gas to obtain an orthoester of formula I.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “anhydrous” refers to a process containing moisture less than 1000 ppm during reaction.
In an embodiment, process of present invention for preparation of trimethylorthoacetate is anhydrous.
In an embodiment, an alcohol, acetonitrile, hydrogen chloride and ammonia used in present invention are anhydrous.
In an embodiment of the present invention, the step of passing of hydrogen chloride is carried out in presence of a phase transfer catalyst selected from a group consisting of cetyltrimethylammonium chloride, tetrabutylammonium chloride, triethylmethylammonium chloride, methyltrioctylammonium chloride, tetramethyl ammonium chloride, cetyltrimethylammonium bromide, tetrabutylammonium bromide, triethylmethylammonium bromide, methyltrioctylammonium bromide, tetramethylammonium bromide or like.
The molar ratio of phase transfer catalyst to alcohol is in the range from 0.0001 to 0.0005.
In another embodiment of the present invention, the step of passing of hydrogen chloride is carried out in a non-polar solvent selected from a group consisting of toluene, ethylbenzene, cyclohexane, dimethyl benzene, isooctane, petroleum ether, xylene, biphenyls or like and hexane. The molar ratio of solvent to alcohol is in the range from 2-20 and preferably in the range from 2-10.
In another embodiment of the present invention, the step of passing hydrogen chloride in a reaction mixture of acetonitrile, an alcohol and solvent is carried at a temperature of 5-15°C.
It is observed by present inventors that hydrogen chloride is accumulated in the reaction mixture due to slow reaction rate at a temperature of below 0°C. After addition of hydrogen chloride, it is required to increase temperature to room temperature for formation of methylacetimidate hydrogen chloride. The increased temperature accelerates reaction rate and leads to sudden rise in temperature up to 50°C or explosion, in case of failure of any utility such as cooling or stirring.
Further, it is found that at temperature greater than 15°C, there is degradation of methylacetimidate hydrogen chloride intermediate resulting in loss of yield of final compound of formula I.
The below table shows hydrogen chloride conversion and formation of methylacetimidate hydrogen chloride intermediate at different temperature ranges.
Temperature range HCl conversion (%) Intermediate (%)
-10 to -5°C 50 100%
-5 to 0°C 80 100%
0 to 5°C 90 100%
5 to 10°C 100 100%
10 to 15°C 100 99%
15 to 20°C 100 95%
20 to 25°C 100 80%
25 to 30°C 100 70%

The present invention is carried out at a specific temperature range to maintain a moderate reaction rate during hydrogen chloride addition and eliminates possibility of hydrogen chloride accumulation. Additionally, there is no degradation of methylacetimidate hydrogen chloride intermediate at this specific temperature range. The specific temperature range for hydrogen chloride addition in a reaction mixture of acetonitrile, alcohol and solvent is from 5-15°C.
The molar ratio of acetonitrile to alcohol is in the range from 1-1.5
The alcohol for present invention is selected from a group consisting of methanol, ethanol and propanol. The alcohol used in step-a) and step-b) of present invention are same.
The anhydrous ammonia is continuously purged in step-c) to achieve a pH between 5.5 to 6.0.
After purging of ammonia gas, the reaction mass is filtered and the compound of formula I is distilled from the filtrate. In another embodiment of the present invention, the reaction of step c) is filtered through a “basic filtration bed” comprising an inorganic base selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like.
The compound of formula I is isolated by distillation. The distillation is carried out at temperature in the range from 70 to 140°C and more preferably 90 to 120°C. The vacuum applied during distillation may range from 50 to 200mbar.
In another embodiment, a stabiliser is added to a compound of formula I and stored at cool temperature. The stabiliser for present invention is an inorganic base.
The inorganic base may be selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, lithium carbonate or like. The inorganic base helps in preventing degradation of product, due to presence of unwanted acidic content in filtrate.
In another embodiment of the present invention, a stabilizer is added to the filtrate obtained after filtering the reaction mass post ammonia addition before isolating orthoester of formula I.
The compound of formula I is isolated in a yield of 90 to 95% with a purity of 95% to 98%.
In another embodiment, the present invention provides a process for preparation of trimethylorthoacetate, comprising the steps of:
a) passing anhydrous hydrogen chloride to a mixture of acetonitrile, methanol and hexane at 10-15°C;
b) adding an alcohol to the reaction mixture of step a);
c) passing anhydrous ammonia gas to maintain pH of 5 to 6;
d) filtering reaction mixture on a sodium carbonate bed to obtain trimethylorthoacetate.
The process of present invention is environment friendly and producing minimal waste stream.
In an embodiment, trimethylorthoacetate prepared from present invention is used for preparation of methyl-3,3-dimethyl-4-pentenoate.
In an embodiment, the solvents used for present invention are recycled and used for next batches.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
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.
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.

EXAMPLE
Example 1: Preparation of trimethylorthoacetate
Acetonitrile (200g), methanol (165g), hexane (735g) and hexadecyltrimethylammonium chloride (0.47g) were charged in a reactor at 20 to 25°C, equipped with a mechanical stirrer and a purger. The reaction mass was cooled to 10 to 15°C and anhydrous hydrogen chloride (190g) was continuously purged in 8-10 hours. The reaction mass was stirred for 3-4 hours at 10 to 15°C. The reaction mass was cooled to 0°C and pre-cooled methanol (320g) was added. Then, anhydrous ammonia was purged to achieve pH of 5.2-5.6. The temperature of reaction mixture was raised slowly to 35°C and maintained at the same temperature for 4 hours. The reaction mass was filtered and filtered solid was washed with hexane (400g). The filtrate and hexane layer were combined and stabilised with addition of sodium carbonate. The combined filtrate was distilled to isolate trimethylorthoacetate.
Yield: 95%
Purity: 98%
Example 2: Preparation of triethylorthoacetate
Acetonitrile (200g), ethanol (244g), hexane (735g) and hexadecyltrimethylammonium chloride (0.21g) were charged in a reactor at 20 to 25°C, equipped with a mechanical stirrer and a purger. The reaction mass was cooled to 10 to 15°C and anhydrous hydrogen chloride (190g) was continuously purged in 8-10 hours. The reaction mass was stirred for 3-4 hours at 10 to 15°C. The reaction mass was cooled to 0°C and pre-cooled ethanol (474g) was added. Then, anhydrous ammonia was purged to achieve pH of 5.2-5.6. The temperature of reaction mixture was raised slowly to 35°C and maintained at the same temperature for 4 hours. The reaction mass was filtered and filtered solid was washed with hexane (400g). The filtrate and hexane layer were combined and stabilised with addition of sodium carbonate. The combined filtrate was distilled to isolate triethylorthoacetate.
Yield: 95%
Purity: 98%
Example 3: Preparation of tripropylorthoacetate
Acetonitrile (200g), 1-propanol (319g), hexane (735g) and hexadecyltrimethylammonium chloride (0.21g) were charged in a reactor at 20 to 25°C, equipped with a mechanical stirrer and a purger. The reaction mass was cooled to 10 to 15°C and anhydrous hydrogen chloride (190g) was continuously purged in 8-10 hours. The reaction mass was stirred for 3-4 hours at 10 to 15°C. The reaction mass was cooled to 0°C and pre-cooled 1-propanol (620g) was added to it. Then, anhydrous ammonia was purged to achieve pH of 5.2-5.6. The temperature of reaction mixture was raised slowly to 35°C and maintained at the same temperature for 4 hours. The reaction mass was filtered and filtered solid was washed with hexane (400g).

The filtrate and hexane layers were combined and stabilised with addition of sodium carbonate. The combined filtrate was distilled to isolate tripropylorthoacetate.
Yield: 85%
Purity: 98.9%

ABSTRACT
PROCESS FOR PREPARATION OF ORTHOESTERS
The present invention provides a process for preparation of compound of formula I,

Formula I
wherein R is alkyl group selected from methyl, ethyl, propyl
Orthoesters are of high importance in organic synthesis and used in preparation of complexed molecules to be used in pharmaceutical and cosmetic industries. These compounds are also used in organic synthesis as protecting group of esters.

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

Formula I
wherein R is an alkyl group selected from methyl, ethyl and propyl
comprising the steps of:
a) passing an anhydrous hydrochloride to a mixture comprising acetonitrile, an alcohol at 5 to 15°C;
b) adding an alcohol to the reaction mixture of step a); and
c) neutralizing the reaction mixture of step b) using an anhydrous ammonia gas to obtain an orthoester of formula I.

2. The process as claimed in claim 1, wherein the preparation of compound of formula 1 is carried out under anhydrous conditions.

3. The process as claimed in claim 1, wherein the step of passing of hydrogen chloride is carried out in presence of a phase transfer catalyst selected from a group consisting of cetyltrimethylammonium chloride, tetrabutylammonium chloride, triethylmethylammonium chloride, methyltrioctylammonium chloride, tetramethyl ammonium chloride, cetyltrimethylammonium bromide, tetrabutylammonium bromide, triethylmethylammonium bromide, methyltrioctylammonium bromide and tetramethylammonium bromide.

4. The process as claimed in claim 1, wherein the molar ratio of acetonitrile to alcohol is selected in the range from 1-1.5

5. The process as claimed in claim 1 further comprises a step of filtering the reaction mixture obtained after neutralization, on a sodium carbonate bed.

6. The process as claimed in claim 1, wherein the anhydrous ammonia is continuously passed to achieve a pH between 5.0 to 6.0.

7. The process as claimed in claim 5, wherein a stabilizer is added to the filtrate before isolating ortho ester of formula I.

8. The process as claimed in claim 1 is carried out in a non-polar solvent selected from a group consisting of toluene, ethylbenzene, cyclohexane, dimethyl benzene, isooctane, petroleum ether, xylene, biphenyls and hexane or a mixture thereof.