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Synthesis method of dolutegravir key intermediate

A technology of dolutegravir and a synthesis method, which is applied in the field of dolutegravir compound synthesis, can solve the problems of unfavorable industrialized production, high price of raw materials and high production cost, and achieves the effects of low cost, good product quality and mild reaction conditions

Inactive Publication Date: 2019-10-01
SHAXING CHEM TAIZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In the synthetic method disclosed in the patent WO2011119566, the reaction conditions of this method are relatively mild, but high-priced raw materials are also used, such as N,N-dimethylformamide dimethyl acetal and lithium hydroxide, which are expensive , leading to high final production cost and low yield, which is not conducive to industrial production

Method used

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  • Synthesis method of dolutegravir key intermediate
  • Synthesis method of dolutegravir key intermediate
  • Synthesis method of dolutegravir key intermediate

Examples

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Effect test

specific Embodiment 1

[0027] The specific synthetic method of compound 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid:

[0028] Add 18.8g of methyl 4-methoxy-2-methoxymethyleneacetoacetate and 100g of methanol into a 500mL four-neck flask, stir, add 10.1g of aminoacetaldehyde dimethyl acetal dropwise at room temperature, and then React for 2 hours. After the reaction is completed, add 6.48g of sodium methoxide, then raise the temperature to 30-35°C, add 13g of dimethyl oxalate in batches, and stir for another 5 hours after the addition is completed. After the reaction is completed, cool down to 0-5°C. ℃, add 44g of 10% sodium hydroxide solution, after the reaction is completed, adjust pH=3~3.5, precipitate solid, stir and crystallize for 3 hours, add appropriate amount of water, filter, and obtain 28.8g of the target product after drying, yield 91.4%, content 99.51%.

specific Embodiment 2

[0030] The specific synthetic method of compound 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid:

[0031] Add 20.2 g of methyl 4-methoxy-2-ethoxymethylene acetoacetate and 100 g of methanol into a 500 mL four-neck flask, stir, add 10.1 g of aminoacetaldehyde dimethyl acetal dropwise at room temperature, and then React for 2 hours. After the reaction is completed, add 6.48g of sodium methoxide, then raise the temperature to 30-35°C, add 13g of dimethyl oxalate in batches, and stir for another 5 hours after the addition is completed. After the reaction is completed, cool down to 0-5°C. ℃, add 44g of 10% sodium hydroxide solution, after the reaction is completed, adjust the pH=3 to 3.5, precipitate the solid, stir and crystallize for 3 hours, add an appropriate amount of water, filter, and dry to obtain the target product 28.6g, the yield 90.8%, content 99.51%.

specific Embodiment 3

[0033] The specific synthetic method of compound 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid:

[0034] Add 18.8g of methyl 4-methoxy-2-methoxymethyleneacetoacetate and 100g of methanol into a 500mL four-neck flask, stir, add 10.1g of aminoacetaldehyde dimethyl acetal dropwise at room temperature, and then React for 2 hours. After the reaction is completed, add 6.48g of sodium methoxide, then raise the temperature to 60-65°C, add 13g of dimethyl oxalate in batches, and stir for another 5 hours after the addition is completed. After the reaction is completed, cool down to 0-5°C. ℃, add 44g of 10% sodium hydroxide solution, after the completion of hydrolysis, adjust the pH=3~3.5, precipitate solid, continue to stir and crystallize for 3 hours, then add an appropriate amount of water, filter, and obtain 26.8g of the target product after drying. The rate is 85.2%, and the content is 97.6%.

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Abstract

The invention discloses a synthesis method of an dolutegravir key intermediate, and relates to the field of dolutegravir compounds. The method includes the synthesis of 1-(2,2-dimethoxyethyl)-5-methoxyl-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3 carboxylic acid, 4-methoxyl-2-methoxymethylene acetoacetate or 4-methoxyl-2-ethoxymethylene acetoacetate is taken as a raw material to synthesize the target product 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3 carboxylic acid through substitution, cyclization and hydrolysis reaction. The operation of synthesis is simple, the reaction conditions are mild, the cost is low, the product quality is good, the yield is high, the total yield is more than 90%, and the dolutegravir key intermediate is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of dolutegravir compounds, in particular to a synthesis method of a key intermediate of dolutegravir. Background technique [0002] Dolutegravir is a new anti-AIDS drug jointly developed by the British pharmaceutical giant GlaxoSmithKline and the Japanese Shionogi Pharmaceutical Company. It has strong drug resistance and high safety. It was approved by the U.S. FDA in 2013 for the treatment of HIV-1 virus. It is expected to become a drug with annual sales of billions of dollars, and will become a strong competitor of the HIV compound drug Atripla. Among them, 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxo-1,4-dihydropyridine-3 carboxylic acid is the synthetic One of the key intermediates of Dolutegravir, the study of the synthesis of this key intermediate is of great significance to the synthesis technology of dolutegravir. [0003] At present, some literatures have reported the synthesis meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/80C07D213/803
CPCC07D213/80C07D213/803
Inventor 黄小庭高尤剑熊辉瑜吴金跃
Owner SHAXING CHEM TAIZHOU CITY
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