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A kind of synthetic method of dolutegravir intermediate and its related substance detection method

A technology of dolutegravir and related substances, applied in the field of medicinal chemistry, can solve the problems of cumbersome steps, multiple detection methods, and long synthesis routes, and achieve the effects of simple analysis methods, simple reaction conditions, and universal conditions

Active Publication Date: 2020-10-20
汉瑞药业(荆门)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 2,5-Pyridinedicarboxylic acid, 1-(2,2-dimethoxyethyl)-1,4-dihydro-4-oxo-3-benzyloxy-2,5-dimethyl ester A basic and key intermediate in the synthesis of Dolutegravir, which is of great significance for the synthesis of dolutegravir finished products. The existing synthetic intermediates 2,5-pyridinedicarboxylic acid, 1-(2,2-dimethyl Oxyethyl)-1,4-dihydro-4-oxo-3-benzyloxy-2,5-dimethyl ester takes maltol [formula (2)] as the starting material, and the synthetic route is relatively long, and the steps It is relatively cumbersome, involving many types of solvents and raw materials, which is not conducive to large-scale production, and involves many detection methods, which is not conducive to the development of detection methods and actual detection

Method used

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  • A kind of synthetic method of dolutegravir intermediate and its related substance detection method
  • A kind of synthetic method of dolutegravir intermediate and its related substance detection method
  • A kind of synthetic method of dolutegravir intermediate and its related substance detection method

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Effect test

Embodiment 1

[0031] Synthesis of 4-(Benzyloxy)-3-oxobutyric acid methyl ester

[0032] Add 50mol methyl 4-chloroacetoacetate, 60mol benzyl alcohol, 20mol cesium carbonate and 500ml toluene into the reaction flask, put the reaction flask into an oil bath, heat to 110°C, reflux for 12h, after the reaction is completed, cool to room temperature, Filtration, rotary evaporation to remove the toluene solvent, and then use column chromatography to separate the crude product, the eluent is petroleum ether:dichloromethane=10:3, thereby obtaining 4-(benzyloxy)-3-oxo Methyl butyrate, the yield is 92%;

[0033]

Embodiment 2

[0035] Synthesis of methyl 4-benzyloxy-2-((dimethylamino)methylene)-3-acetoacetate

[0036] Put 40mol of 4-(benzyloxy)-3-oxobutanoic acid methyl ester obtained in Example 1 and 120mol N,N-dimethylformamide dimethyl acetal, 40mol sodium methylate and 400ml toluene into the reaction flask Next, put the reaction bottle into an oil bath, heat to 100°C, and reflux for 5 hours. After the reaction is completed, cool to room temperature, add saturated sodium chloride solution and 3% hydrochloric acid to the reaction bottle, shake for 10 minutes, and divide layer, the organic layer was poured out, and the solvent was removed by a rotary evaporator to obtain a crude product, which was then separated by column chromatography, and the eluent was petroleum ether:methanol=5:1, thereby obtaining 4-benzyl Oxy-2-((dimethylamino)methylene)-3-acetoacetic acid methyl ester, the yield is 95%;

[0037]

Embodiment 3

[0039] Synthesis of dimethyl 4-oxo-3-benzyloxy-4H-pyran-2,5-dicarboxylate

[0040] 30mol of 4-benzyloxy-2-((dimethylamino)methylene)-3-acetoacetate methyl ester obtained in Example 2 and 45mol dimethyl oxalate, 15mol sodium tert-butoxide and 300ml toluene were put into reaction bottle, then put the reaction bottle into an oil bath, heat to 105°C, and reflux for 6h. After the reaction is completed, cool to room temperature, filter, and remove the toluene solvent by rotary evaporation, and then use column chromatography to separate the crude product. The eluent is n-hexane:ethyl acetate=9:4, thus obtaining dimethyl 4-oxo-3-benzyloxy-4H-pyran-2,5-dicarboxylate with a yield of 90%;

[0041]

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Abstract

The invention discloses a synthesis method of a dolutegravir intermediate, and a related substance detection method thereof. 4-chloroacetoacetic acid methyl ester and phenylcarbinol are adopted as starting materials, and the dolutegravir intermediate i is obtained through four steps of reaction; the reaction conditions are simple, only methylbenzene is used as a solvent in reaction, the raw materials are easy to get, the obtained product is treated and purified through column chromatography, the yield of the product obtained by each step reaches up to 90 percent or above, and the synthesis method is suitable for industrial production; the related substance detection method of the dolutegravir intermediate i adopts high performance liquid chromatography; through testing, the content of thedolutegravir intermediate i related substance is 99.6 percent, the separation degree of each impurity is larger than 3.0, and the separation degree is better.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of a dolutegravir intermediate and a detection method for related substances. Background technique [0002] Dolutegravir, whose chemical name is (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, CAS registration number is 1051375-16-6, its structural formula is shown in formula (1), dolutegravir is a new anti-HIV drug under the British pharmaceutical giant GlaxoSmithKline (GSK), August 12, 2013 The U.S. Food and Drug Administration (FDA) approved it for previously treated or newly treated HIV-1 adults and children aged 12 and over with a body weight of at least 40 kg. [0003] [0004] Dolutegravir is a once-daily drug, which has achieved comparable efficacy to Merck's HIV / AIDS drug Raltegravir (Isentress) in phase III clinical trials...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/79C07D213/803G01N30/89
CPCC07D213/79C07D213/803G01N30/89
Inventor 任磊
Owner 汉瑞药业(荆门)有限公司
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