Claims:WE CLAIM:

1. A process for preparing Methyl-4-methoxyacetoacetate by reacting Ethyl-4-chloroacetoacetate in presence of sodium methoxide and methanol in presence of an organic solvent and finally quench with an acid, which is schematically represented as follows:

2. The process according to claim 1, wherein organic solvent is selected from the group of methanol, tetrahydrofuran, acetonitrile and cyclohexane.

3. The process according to claim 1, wherein acid is selected from the group of acetic acid, formic acid, propanoic acid and aqueous hydrochloric acid.

4. The process according to claim 1, wherein the Methyl-4-methoxyacetoacetate contains less than 0.5% of Ethyl 4-methoxyacetoacetate.
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Methyl-4-methoxyacetoacetate of formula I, a key intermediate useful in the preparation of Dolutegravir,

Formula I

BACKGROUND OF THE INVENTION

Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), which is marketed under the trade name Tivicay®. Dolutegravir is chemically known as (4R,12aS)—N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide.

4-methoxy methyl acetoacetate is the key raw material used in the preparation of Dolutegravir, various literatures reports the preparation of 4-methoxy methyl acetoacetate.

US 4,564,696, A assigned to Lonza Ltd, discloses a process for the preparation of 4-alkoxyacetoacetic acid ester by reacting a 4-chloroacetoacetic ester or a 4-bromoacetoacetic ester with alkali alcoholate in presence of aprotic solvent.

CN 104478719 A assigned to Henan Normal University, discloses a process for preparing 4-methoxy methyl acetoacetate comprising reacting methyl-4-chloroacetoacetate with sodium hydride and alkaline metal compound in presence of tetrahydrofuran, methanol and HCl.

CN 109503380, assigned to Nanjing Jieyun Pharmaceutical Technology Co., Ltd discloses a process for preparation of 4-alkoxy acetoacetate.

CN 109456186 assigned to Nanjing Lake Shide Pharmaceutical Co., Ltd, discloses a process for preparing 4-methoxy methyl acetoacetate comprising reacting methyl-4-chloroacetoacetate with sodium methoxide in presence of toluene and HCl.

CN 105418420 assigned to Henan Normal University, discloses a process for preparing methyl 4-methoxyacetoacetate comprising reacting methyl-4-chloroacetoacetate with sodium hydride and potassium methoxide in presence of tetrahydrofuran and HCl.

CN 105481694 assigned to Anhui Huachang High-tech Pharmaceutical Co., Ltd. discloses a process for preparing 4-methoxy methyl acetoacetate comprising reacting methyl-4-chloroacetoacetate with 1:2-2.5 mole ratio sodium hydride and in presence of tetrahydrofuran and methanol.

The present invention involves the tandem substitutions of 4-halo and -ethoxy groups with -methoxide group. This new approach provides a simple process for the preparation of Methyl-4-methoxyacetoacetate, which is a very important key starting material for the preparation of Dolutegravir.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a novel, simple, economic, cost effective and industrially feasible process for the preparation of Methyl-4-methoxyacetoacetate.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Methyl-4-methoxyacetoacetate by reacting Ethyl-4-chloroacetoacetate with methanolic sodium methoxide in presence of an organic solvent and finally quench with an acid, which is schematically represented as follow:

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for the preparation of Methyl-4-methoxyacetoacetate

Formula I

According the present invention, Methyl-4-methoxyacetoacetate is prepared by reacting Ethyl-4-chloroacetoacetate with methanolic sodium methoxide in presence of an organic solvent and finally quench with an acid, which is schematically represented as follows:

According to the present invention the -halo and -ethoxy groups replace simultaneously. After 10-12 hr of reaction at 60-65oC, Ethyl-4-chloroacetoacetate is converted into methyl 4-methoxyacetoacetate along with Ethyl 4-methoxyacetoacetate in 7-8% level, wherein the Ethyl 4-methoxyacetoacetate completely converted into methyl 4-methoxyacetoacetate during the distillation of the solvent, which is facilitated by the excess amount of methanol in presence of base (transesterification).

According to another embodiment, this process control the formation of ethyl 4-methoxyacetoacetate, a potential impurity below 0.5% level.

According to the first embodiment of the present invention, the solvent is selected from the group of methanol, tetrahydrofuran, acetonitrile and cyclohexane.

According to the second embodiment of the present invention, the acid is selected from the group of Acetic acid, formic acid, propanoic acid, and aqueous HCl.

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 present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLE 1

328.0 g (6.08 mol) of sodium methoxide was suspended in 600 mL of tetrahydrofuran at room temperature and stirred for 30 min. To this well-stirred suspension, 200 mL of methanol was added below 30oC under nitrogen atmosphere. To this reaction mixture 200.0 g (1.22 mol) of Ethyl 4-chloroacetoacetate was added dropwise and the reaction was maintained at 60°C for 10-12 h. After completion of the reaction, 80% of solvent was distilled. The reaction mass was slowly suspended into a pre cooled (0-5oC) solution mixture of 20 mL of glacial acetic acid and 400 mL of methylene dichloride, then, 36% hydrochloric acid was introduced dropwise till the pH was 5. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 mL and then twice each time with 100 ml of methylene dichloride. The organic layers were mixed and concentrated below 50oC under vacuum. The raw product was purified by high vacuum distillation and Methyl 4-methoxyacetoacetate was obtained in 75% yield, with a purity of 99.0%.

EXAMPLE 2
328.0 g (6.08 mol) of sodium methoxide was suspended in 1000 mL of methanol at 30oC under nitrogen atmosphere. To this well-stirred suspension, 200 mL of methanol was added below 30oC under nitrogen atmosphere. To this reaction mixture 200.0 g (1.22 mol) of Ethyl 4-chloroacetoacetate was added dropwise and the reaction was maintained at 65°C for 10 h. After completion of the reaction, 80% of solvent was distilled. The reaction mass was slowly suspended into a pre cooled (0-5oC) solution mixture of 20 mL of glacial acetic acid and 400 mL of methylene dichloride, then, 36% hydrochloric acid was introduced dropwise till the pH was 5. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 mL and then twice each time with 100 ml of methylene dichloride. The organic layers were mixed and concentrated below 50oC under vacuum. The raw product was purified by high vacuum distillation and Methyl 4-methoxyacetoacetate was obtained in 50% yield, with a purity of 98.0%.

EXAMPLE 3

394.0 g (7.30 mol) of sodium methoxide was suspended in 600 mL of cyclohexane at 25oC under nitrogen atmosphere. To this well-stirred suspension, 200.0 g (1.22 mol) of Ethyl 4-chloroacetoacetate was added dropwise and the reaction was maintained at 65°C for 12 h. After completion of the reaction, 80% of solvent was distilled. The reaction mass was slowly suspended into a pre cooled (0-5oC) solution mixture of 20 mL of glacial acetic acid and 400 mL of methylene dichloride, then, 36% hydrochloric acid was introduced dropwise till the pH was 5. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 mL and then twice each time with 100 ml of methylene dichloride. The organic layers were mixed and concentrated below 50oC under vacuum. The raw product was purified by high vacuum distillation and Methyl 4-methoxyacetoacetate was obtained in 45% yield, with a purity of 96.0%.

EXAMPLE 4

328.0 g (6.08 mol) of sodium methoxide was suspended in 600 mL of acetonitrile at 30oC under nitrogen atmosphere. To this well-stirred suspension, 200 mL of methanol was added below 30oC under nitrogen atmosphere. To this reaction mixture 200.0 g (1.22 mol) of Ethyl 4-chloroacetoacetate was added dropwise and the reaction was maintained at 65°C for 10 h. After completion of the reaction, 80% of solvent was distilled. The reaction mass was slowly suspended into a pre cooled (0-5oC) solution mixture of 20 mL of glacial acetic acid and 400 mL of methylene dichloride, then, 36% hydrochloric acid was introduced dropwise till the pH was 5. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 mL and then twice each time with 100 ml of methylene dichloride. The organic layers were mixed and concentrated below 50oC under vacuum. The raw product was purified by high vacuum distillation and Methyl 4-methoxyacetoacetate was obtained in 45% yield, with a purity of 95.0%.