FIELD OF THE INVENTION

The present invention provides an improved process for preparation of oxo ester of formula I and derivatives thereof,

Formula I
wherein R1 is methyl, ethyl, propyl, isopropyl and R2 is alkyl or cycloalkyl group.

BACKGROUND OF THE INVENTION
Oxo ester derivatives of formula I are very useful intermediates in pharmaceutical industry and in the production of photographic light sensitive material.
WO2001089457 discloses a process for preparation of methyl 3-cyclopropyl-3-oxopropionate by reacting cyclopropyl methyl ketone and diethyl carbonate using 60% sodium hydride as a base. The process uses benzene as solvent. It is known that benzene is carcinogenic and inflammable thus not recommended at industrial scales.
WO2004060890 also describes a process for preparation of methyl 3-cyclopropyl-3-oxopropionate by reacting cyclopropyl methyl ketone and diethyl carbonate in presence of a base in anhydrous tetrahydrofuran.
Guangdong Huagong, 40(6), 50-51; 2013 provides a process for preparation of methyl 3-cyclopropyl-3-oxopropionate in toluene.
The processes described above are carried out in presence of large quantity of solvents that limit their industrially viability. The present invention provides a process for preparation of oxo ester derivatives in absence of a solvent.
SUMMARY OF THE INVENTION
In first aspect, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein R1 is methyl, ethyl, propyl, isopropyl and R2 is alkyl or cycloalkyl group.
comprising the steps of:
a) reacting a compound of formula II with dialkyl carbonate to obtain the compound of formula I, wherein process is carried out in absence of a solvent.

Formula II
wherein R2 is alkyl or cycloalkyl group.

OBJECT OF THE INVENTION
The main object of present invention is to provide an industrially viable process for preparation of oxo ester derivatives by eliminating the use of solvent from the process.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein R1 is methyl, ethyl, propyl, isopropyl and R2 is alkyl or cycloalkyl group.
comprising the steps of:
a) reacting a compound of formula II with dialkyl carbonate to obtain the compound of formula I, wherein process is carried out in absence of solvent.

Formula II
wherein R2 is alkyl or cycloalkyl group.

As used herein, dialkyl carbonate refers to a compound selected from a group consisting of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate or the like.
As used herein, alkyl group may be selected from a group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or the like.
As used herein, cycloalkyl group may be selected from a group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkene substituted cyclohexyl.
As used herein, the solvent refers to any additional solvent such benzene, toluene, tetrahydrofuran or the like used in the processes disclosed in the literature references such as WO2001089457; WO2004060890; Guangdong Huagong, 40(6), 50-51; 2013.
The molar ratio of dialkyl carbonate to formula II is selected in the range of 2-10 and preferably between 2-5.
The present invention is carried out in absence of solvent that reduces cost of process. Additionally, the process will generate less effluent, making it more economical and environment friendly.
In an embodiment, the step of reacting a compound of formula II with dialkyl carbonate to obtain compound of formula I is carried out in presence of a base.
The base is selected from a group consisting of sodium hydride, potassium hydride, sodium butoxide, potassium butoxide, lithium (hexamethylsilyl)amide, potassium (hexamethylsilyl)amide, butyl lithium, sodium metal, potassium metal, sodium ethoxide, sodium methoxide or like. The most preferred base for present invention is sodium hydride, potassium hydride.
The base for present invention is in solid form or solution form.
In an embodiment, dialkyl carbonate is recovered and used for next batches making this process more cost effective. The recovery percentage of dialkyl carbonate is greater than 70%.
It is observed by present inventors that addition of the compound of formula II in dialkyl carbonate in presence of base is exothermic in nature. To control the exothermicity of process, the compound of formula II is added in lots/parts.
The compound of formula II is added to a mixture of a base and dialkyl carbonate at a temperature of 20-100°C in multiple lots.
In one embodiment, present invention provides a process for preparation of a compound of formula I comprising:
a) charging dialkyl carbonate and base under inert atmosphere to a reactor to obtain a reaction mixture;
b) adding a compound of formula II to the reaction mixture of step a);
c) heating the reaction mixture to obtain the compound of formula I.
In another embodiment, present invention provides a process for preparation of a compound of formula I, comprising:
a) charging dialkyl carbonate and a base under inert atmosphere to a reactor to obtain a reaction mixture;
b) adding a compound of formula II to the reaction mixture of step a);
c) heating the reaction mixture of step b) to obtain the compound of formula I,
wherein the process involves recovering excess dialkyl carbonate from the reaction mixture of step c).
The inert atmosphere is maintained by using nitrogen, helium or argon.
In an embodiment, reaction mixture is heated at a temperature of 60-130°C.
The present invention provides a simple isolation method for a compound of formula I by solvent extraction and distillation.
In a preferred embodiment, reaction mixture was cooled to a room temperature and added water. The process of present invention is easy to operate as the basic operation are involved in the process.
In a specific embodiment, methyl-3-cyclopropyl-3-oxopropanoate is prepared from cyclopropyl methyl ketone using dimethyl carbonate and sodium hydride.
In another specific embodiment, ethyl-3-cyclopropyl-3-oxopropanoate is prepared from cyclopropyl methyl ketone using diethyl carbonate and sodium hydride.
In specific embodiment, cyclopropyl methyl ketone is added to a mixture of sodium hydride and dimethyl carbonate at 20-70°C to obtain methyl-3-cyclopropyl-3-oxopropanoate.
In specific embodiment, cyclopropyl methyl ketone is added to a mixture of sodium hydride and diethyl carbonate at 20-90°C to obtain ethyl-3-cyclopropyl-3-oxopropanoate.
The purity of compound of formula I in present invention is greater than 95%.
The yield obtained for a compound of formula I is greater than 70%.
The compound of formula I may be isolated or can be used in situ for preparation other compounds used in agrochemical industry. The compound of formula I in situ may be used to prepare cycloalkyl chloromethyl ketone.
In an embodiment, compound of formula I may be used for the preparation of 3-oxo-cyclopropanepropanoic acid.
In an embodiment, compound of formula I may be used in situ to prepare cycloalkyl chloromethyl ketone.
The compound of Formula I is isolated by any method 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.
The compound of formula II and other 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 methyl-3-cyclopropyl-3-oxopropanoate.
Dimethyl carbonate (350g) and sodium hydride (28.5g) were added to a reactor under nitrogen gas. Reaction mixture was stirred for 10-15 minutes and cyclopropyl methyl ketone (40g) was added and was slowly heated to 70°C. The reaction mass was stirred at 65-70°C for 1-2 hours. After completion of the reaction, reaction mass was cooled to 15-20°C and distilled water (200g ) was added using dropping funnel and stirred for 20 minutes. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate. Intially organic layer was distilled to recover dimethyl carbonate. Further, crude mass was distilled under 4mbar reduced pressure to isolate product.
Purity: 97.7%; Yield: 70%.
Recovery % of dimethyl carbonate: 70%;
Purity of dimethyl carbonate recovered: 98%
Example 2: Preparation of ethyl-3-cyclopropyl-3-oxopropanoate.
Sodium hydride (14g) and diethyl carbonate (224g) were charged under nitrogen gas. Reaction mixture was stirred for 15 minutes and cyclopropyl methyl ketone (20g) was added in the flask at 25 to 35°C. The reaction mass was slowly heated to 80°C and stirred at 80°C for 1-2 hours. The reaction mass was cooled to 15-20°C and water (100g ) was added using dropping funnel and stirred for 20 minutes. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer are distilled at to recover diethyl carbonate. Further, crude mass was distilled to isolate product.
Purity: 98%; Yield: 80%.
Recovery % of diethyl carbonate: 73%;
Purity of diethyl carbonate recovered: 98%.
Example 3: Preparation of ethyl-3-cyclopropyl-3-oxopropanoate.
Diethyl carbonate (200g) and sodium tert-butoxide (25.7g) were added in a round bottom flask fitted under nitrogen gas. Reaction mixture was stirred for 10-15 minutes and cyclopropyl methyl ketone (20g) was added in the flask at temperature below 20°C. Reaction mass was slowly heated to 70°C and stirred at 65-70°C for 1-2 hours. After reaction completed, reaction mass was cooled to 15-20°C and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled at to recover dimethyl carbonate. Further, crude mass was distilled under reduced presure to isolate product.
Purity: 98%; Yield: 82%.
Recovery % of diethyl carbonate: 71%;
Purity of diethyl carbonate recovered: 97.9%.
Example 4: Preparation of methyl-3-cyclopropyl-3-oxopropanoate.
Dimethyl carbonate (100g) and potassium tert-butoxide (16g) were added in a round bottom flask fitted with mechnical stirrer under nitrogen gas. Reaction mixture was stirred for 10-15 minutes and cyclopropyl methyl ketone (10g) was added in the flask at temperature below 20°C. Reaction mass was slowly heated to 70°C and stirred at 65-70°C for 1-2 hrs. After reaction completed, reaction mass was cooled to 15-20°C and water (80g ) was added using dropping funnel and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled at 40-50°C to recover dimethyl carbonate. Further, crude mass was distilled under reducced pressure to isolate product.
Purity: 98%; Yield: 77%.
Recovery % of dimethyl carbonate: 75%;
Purity of dimethyl carbonate recovered: 98.7%.

Example 5: Preparation of methyl-3-cyclobutyl-3-oxopropanoate.
Dimethyl carbonate (40g) was added in a round bottom flask fitted with mechnical stirrer under nitrogen gas. Reaction mass was cooled and added Lithium bis(trimethylsilyl)amide (53g). Reaction mixture was stirred for 10-15 minutes and cyclobutyl methyl ketone (5g) was added in the flask at temperature below 20°C in 3 equal lots. Reaction mass was heated to 70°C and stirred at 65-70°C for 1-2 hrs. After reaction completed, reaction mass was cooled to 15-20°C and water (20g ) was added using dropping funnel and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled recover dimethyl carbonate. Further, crude mass was distilled under reduced pressure to isolate product.
Purity: 98%; Yield: 76%.
Recovery % of dimethyl carbonate: 73%;
Purity of dimethyl carbonate recovered: 98.1%
Example 6: Preparation of methyl-3-cyclopropyl-3-oxopropanoate.
Dimethyl carbonate (10g) was added in a round bottom flask fitted with mechnical stirrer under nitrogen gas. Reaction mass was cooled and added butyllithium (9g). Reaction mixture was stirred for 10-15 minutes and cyclopropyl methyl ketone (1g) was added in the flask at temperature below 20°C. Reaction mass was heated to 70°C and stirred at 65-70°C for 1-2 hrs. After reaction completed, reaction mass was cooled to 15-20°C and water (10g ) was added using dropping funnel and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled to recover dimethyl carbonate. Further, crude mass was distilled under reduced pressure to isolate product.
Purity: 97%; Yield: 73%.
Recovery % of dimethyl carbonate: 3%
Purity of dimethyl carbonate recovered: 97.9%
Example 7: Preparation of methyl-3-cyclobutyl-3-oxopropanoate.
Dimethyl carbonate (100g) and sodium tert-butoxide (12.7g) were added in a round bottom flask fitted with mechnical stirrer under nitrogen gas. Reaction mixture was stirred for 10-15 minutes and cyclobutyl methyl ketone (10g) was added in the flask at temperature below 20°C. Reaction mass was slowly heated to 70°C and stirred at 65-70°C for 1-2 hrs. After reaction completed, reaction mass was cooled to 15-20°C and distilled water (50g ) was added using dropping funnel and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled to recover dimethyl carbonate. Further, crude mass was distilled under reduced pressure to isolate product.
Purity: 98%; Yield: 80%.
Recovery % of dimethyl carbonate: 71%;
Purity of dimethyl carbonate recovered: 97%.
Example 8: Preparation of methyl-3-cyclopropyl-3-oxopropanoate.
Dimethyl carbonate (80g) and potassium hydride (7.48g) were added in a round bottom flask fitted with mechnical stirrer under nitrogen gas. Reaction mixture was stirred for 10-15 minutes and cyclopropyl methyl ketone (5g) was added in the flask at 25 to 35°C in 4 equal lots. `Reaction mass was slowly heated to 70°C and cyclopropyl methyl ketone (5g) was added at 65°C. The reaction mass was stirred at 65-70°C for 1-2 hrs. After reaction completed, reaction mass was cooled to 15-20°C and water (200g ) was added using dropping funnel and stirred for 20 min. Organic and aqueous layers from reaction mass were separated and aqueous layer was further extracted with dichloromethane. Combined the organic layers and dried over sodium sulfate. Intially organic layer was distilled to recover dimethyl carbonate. Further, crude mass was distilled to isolate product.
Purity: 97.7%; Yield: 76%.
Recovery % of dimethyl carbonate: 72%;
Purity of dimethyl carbonate recovered: 98%.

We Claim:

1. A process for preparation of a compound of formula I,

Formula I
wherein R1 is methyl, ethyl, propyl, isopropyl and R2 is alkyl or cycloalkyl group.
comprising the steps of:
a) reacting a compound of formula II with dialkyl carbonate in presence of a base to obtain the compound of formula I, wherein the process is carried out in absence of a solvent,

Formula II
wherein R2 is alkyl or cycloalkyl group.

2. The process as claimed in claim 1, wherein the step a) is carried out by adding a compound of formula II to a mixture of dialkyl carbonate and a base.
3. The process as claimed in claim 1 and 2, wherein base is selected from a group consisting of sodium hydride, potassium hydride, sodium butoxide, potassium butoxide, lithium (hexamethylsilyl)amide, potassium (hexamethylsilyl)amide, butyl lithium, sodium metal, potassium metal, sodium ethoxide and sodium methoxide or a mixture thereof.
4. The process as claimed in claim 1, wherein dialkyl carbonate is selected from a group consisting of dimethyl carbonate, diethyl carbonate, dipropyl carbonate and diisopropyl carbonate.
5. The process as claimed in claim 1, wherein molar ratio of dialkyl carbonate to compound of formula II is selected in the range of 2-10.
6. The process as claimed in claim 1, wherein the compound of formula II is added to a mixture of dialkyl carbonate and base and heated at a temperature of 20-100°C.
7. The process as claimed in claim 1, wherein dialkyl carbonate is recycled.
8.The process as claimed in claim 1, wherein the compound of formula II is added to a mixture of dialkyl carbonate and a base in lots.
9. The process as claimed in claim 1, wherein the compound of formula I is obtained with a purity of greater than 95%.
10. The process as claimed in claim 1, wherein the compound of formula I is obtained with a yield of greater than 70%.