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Preparation method of dolutegravir mother nucleus intermediate

A technology of dolutegravir and intermediates, which is applied in the field of organic synthetic medicinal chemistry, can solve the problems of low yield of intermediates, difficult industrialization, and large pollution, and achieve the effects of high selectivity, high safety, and low cost

Inactive Publication Date: 2021-03-16
内蒙古永太化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, the synthesis of this intermediate generally has problems such as low yield, high cost, large pollution, and difficult industrialization. Industrialization urgently needs to improve these problems to realize the industrialization of pregabalin

Method used

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  • Preparation method of dolutegravir mother nucleus intermediate
  • Preparation method of dolutegravir mother nucleus intermediate
  • Preparation method of dolutegravir mother nucleus intermediate

Examples

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preparation example Construction

[0040] 1. Preparation of Compound P3

[0041]

[0042] In the following examples, N,N-ethyl dimethacrylate, N,N-ethyl dimethacrylate, dimethyl oxalate monoacyl chloride, and pyridine were all purchased from McLean Reagent Company.

Embodiment 11

[0044] Add 143g of N,N-ethyl dimethacrylate, 500g of dichloromethane, and 95g of pyridine into a 2L four-neck flask, stir well, cool to -15°C, slowly add 122g of dimethyl oxalate monoacyl chloride dropwise, and control the internal temperature When the temperature is lower than -5°C, keep stirring for 2 hours after adding, and the raw materials basically disappear by pointing the plate, slowly add aqueous sodium bicarbonate solution, adjust the pH to weak alkaline, separate the liquids, extract the aqueous phase again with dichloromethane, and combine the organic phases, 100g Washed with water, concentrated dichloromethane, refined with tertiary methyl ether to obtain 218g of pure product, with a yield of 95% and a purity of 99.5%.

Embodiment 12

[0045] Embodiment 1.2 (alkali and P2 equivalent molar ratio 3: 1)

[0046] Add 143g of N,N-ethyl dimethacrylate, 500g of dichloromethane, and 237g of pyridine into a 2L four-neck flask, stir evenly, cool to -15°C, slowly add 122g of dimethyl oxalate monoacyl chloride dropwise, and control the internal temperature When the temperature is lower than -5°C, keep stirring for 2 hours after adding, and the raw materials basically disappear by pointing the plate, slowly add aqueous sodium bicarbonate solution, adjust the pH to weak alkaline, separate the liquids, extract the aqueous phase again with dichloromethane, and combine the organic phases, 100g Washed with water, concentrated dichloromethane, refined with tertiary methyl ether to obtain 210 g of pure product, with a yield of 92% and a purity of 99.6%.

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Abstract

The invention discloses a preparation method of a dolutegravir intermediate, and relates to the field of organic synthetic medicinal chemistry. The preparation method comprises the following steps: (1) carrying out condensation reaction on a compound P1 and a compound P2 to obtain a compound P3; (2) carrying out substitution reaction on the compound P3 and aminoacetaldehyde dimethyl acetal to obtain a compound P4; (3) reacting the compound P4 with halogenated acetate to obtain a compound P5, and further performing intramolecular cyclization on the compound P5 to obtain a compound P6; and (4) carrying out hydrolysis reaction on the compound P6 to obtain the dolutegravir mother nucleus intermediate P7. The method is simple to operate, high in chemical reaction yield, less in three wastes, low in raw material cost, high in finished product purity and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis medicinal chemistry, in particular to a preparation method of a dolutegravir intermediate. Background technique [0002] Dolutegravir (DTG, trade name Tivicay) is a new anti-AIDS drug jointly developed by British pharmaceutical giant GlaxoSmithKline (GSK) and Japanese Shionogi Pharmaceutical Company (Shionogi). In July 2012, GlaxoSmithKline Pharmaceuticals and Shionogi Pharmaceuticals announced the results of Phase III clinical trials of Dolutegravir. After 48 weeks of treatment with Dolutegravir and two other older AIDS drugs, 88% of the virus in the patient's body was successfully suppressed, and after taking the three-in-one oral drug Atripla (Efavienz / Emtricitabine / Tenofovir Fumaric Acid Tablets) from Gilead Sciences, The virus was suppressed in 81% of the patients, showing that GlaxoSmithKline's dolutegravir drug was slightly better. In the comparative trial, 10% of patients eventually stop...

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 孔佳辉陈豪史博峰夏海建
Owner 内蒙古永太化学有限公司
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