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Improved method for synthesizing dolutegravir

A synthesis method and mixed solvent technology, applied in the synthesis field of dolutegravir, can solve the problems of low conversion rate of raw materials, complex post-treatment, long reaction route, etc., and achieve high purity, high yield and total yield, and product The effect of stable quality

Active Publication Date: 2018-07-20
仁合熙德隆药业有限公司 +2
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Problems solved by technology

[0011] The purpose of the present invention is to overcome the defects of long reaction route, low conversion rate of raw materials, complicated post-treatment and high production cost in the above-mentioned prior art, and provide an improved synthetic method for the preparation of lutevir

Method used

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  • Improved method for synthesizing dolutegravir
  • Improved method for synthesizing dolutegravir
  • Improved method for synthesizing dolutegravir

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Embodiment 1

[0033] (1) Add 100 g of compound 1, 132 g of potassium carbonate and 105 g of benzyl chloride into 300 mL of methanol, and heat to reflux for 1 hour to complete the reaction. Cool the system to room temperature, filter, concentrate the filtrate, dissolve the residue in 200 mL of dichloromethane, wash with 5% sodium hydroxide solution (50 mL×2) and saturated sodium chloride solution (50 mL) successively, dry the organic phase, and concentrate Obtain 168g of yellow oily substance, i.e. intermediate 2, yield: 98%.

[0034] (2) Add 50g of periodic acid into 350mL of acetonitrile, stir and dissolve, then add 0.2g of chromium trioxide and 20g of intermediate 2 to the system in turn, stir at room temperature for 1.5 hours, and the reaction ends. The solvent was evaporated to dryness, and 100 mL of dichloromethane and 200 mL of water were added to the residue solution. After the residue was completely dissolved, the organic phase was separated, and the aqueous phase was extracted with...

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Abstract

The invention relates to an improved method for synthesizing dolutegravir and belongs to the field of medicinal chemistry. The method takes maltol (compound 1) as a raw material, and a target is synthesized by the following route. The process raw material is cheap and easy to obtain, a reaction solvent can be recycled, the post-treatment operation is simple, the yield and the purity are high, especially the carbamoylation and debenzylation reaction are carried out in one step, the synthesis route is simplified, the cost is reduced, and the large-scale industrial production is facilitated.

Description

technical field [0001] The invention relates to a new synthesis method of dolutegravir, which belongs to the field of medicinal chemistry. Background technique [0002] Dolutegravir, chemical name: (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 , a new anti-AIDS drug developed by Glaxo SmithKline (GSK) in the UK, was approved by the FDA in August 2013. The drug belongs to the second-generation integrase inhibitor, which has very strong drug resistance properties and high safety, and has a broad market prospect. [0003] At present, several methods for synthesizing dolutegravir have been reported in relevant literature. For example, patent WO2006116764 discloses the compound structure of dolutegravir and its preparation method for the first time. In this method, maltol is used as the starting material, and dolutegravir is prepared through 16 steps of reaction. Th...

Claims

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Application Information

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IPC IPC(8): C07D498/14
CPCC07D498/14Y02P20/55
Inventor 李旭光陈水库朱松林张方杰方水霞刘从军朱慧峰罗琦孟庆乐崔浩
Owner 仁合熙德隆药业有限公司
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