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Novel method for preparing dolutegravir

A technology of dolutegravir and a new method, which is applied in the field of preparation of dolutegravir, can solve the problems of expensive materials, high cost, instability, etc., and achieve the effects of simple operation, improved utilization rate, and improved total yield

Inactive Publication Date: 2017-04-19
厦门蔚扬药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] PCT application WO 2006116764 first disclosed the compound structure of dolutegravir and its preparation method, followed by PCT application WO 2015019310, PCT application WO 2015009927, etc. also disclosed the improved synthesis process of dolutegravir, but the currently reported preparation method of dolutevir There are the following disadvantages: PCT application WO 2015019310 has a total yield of only 20.76%, and the starting material used contains borate ester, which is unstable and explosive; PCT application WO2015009927, the materials used in the synthesis process are expensive, resulting in high cost, among which The yield of one-step hydrolysis reaction is only 43.6%

Method used

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  • Novel method for preparing dolutegravir

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1 1-(2,2-dimethoxyethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzaminoyl) Preparation of pyridine-2-methyl ester (compound B)

[0030]

[0031] Put tetrahydrofuran (700g), compound A (80g, 0.254mol) and CDI (49.4g, 1.2eq) into the reaction flask; heat up to reflux (70°C), stir for 2.5h; put in CDI (12.4g, 0.3eq), continue Reflux and stir for 2.0h; cool down to 20-25°C, add 2,4-difluorobenzylamine (40.0g, 1.1eq); maintain 20-25°C and stir for 5h; after the reaction is complete, add methyl tert-butyl ether ( 600g) and 3% hydrochloric acid (600g); Stir for 10 minutes, leave standstill for 10 minutes; Layer, organic layer drops into 3% sodium hydroxide (600g); Stir for 10 minutes, leave standstill for 10 minutes; Layer, organic layer drops into water (600g); Stir for 10 minutes, leave standstill for 10 minutes; separate layers, concentrate the organic phase to dryness, and directly carry out the next step reaction.

Embodiment 2

[0032] Example 2 1-(2-oxoethyl)-1,4-dihydro-3-methoxy-4-oxo-5-(2,4-difluorobenzyl)pyridine-2- Preparation of Methyl Ester (Compound C)

[0033]

[0034] Add formic acid (240g) to the concentrate obtained in Example 1; heat up to 60°C, stir for 3 hours; steam the formic acid under reduced pressure, drop in 10% sodium dihydrogen phosphate (600g) and dichloromethane (800g); stir for 10 Minutes, let stand for 10 minutes; Layered, the aqueous layer was extracted once with dichloromethane (400g); Layered, combined organic layer, after evaporating the solvent, drop into methyl tert-butyl ether (240g); Stir at room temperature for 3h, filter , Compound C was collected as a white solid with a yield of 92%.

Embodiment 3

[0035] The preparation of embodiment 3 degree lutevir

[0036]

[0037]Put acetonitrile (700g) and compound C (90g, 0.228mol) into the reaction flask; stir and heat up to 50°C, add acetic acid (13.7g, 1eq); heat up to 60-65°C, add dropwise R-3-amino-1 - Butanol (22.3g, 1.1eq) and acetonitrile (100g); Insulated and stirred reaction 15h to the HPLC purity of compound (D) in the liquid phase is 98.0% after dropping into magnesium bromide hexahydrate (199.7g, 3eq), warming up to 80°C, stirred for 2 hours; after the reaction was completed, 3% hydrochloric acid (830g) and dichloromethane (1200g) were added; layered, the water layer was dropped into dichloromethane (600g); layered, the combined organic layers were concentrated to dryness, and ethanol was added , and concentrated to dryness again to obtain dolutegravir (yield 90.9%).

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PUM

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Abstract

The invention discloses a novel method for preparing dolutegravir (E) defined in the description, and relates to the field of medicinal chemistry. The method comprises the following steps of 1) performing a condensation reaction of a compound (A) and 2,4-difluorobenzylamine to prepare a compound (B) defined in the description; 2) performing aldehyde group protecting group removal on the compound (B) to obtain a compound (C) defined in the description; 3) performing a cyclization reaction of the compound (C) and R-3-amino-1-butanol to prepare a compound (D) defined in the description; and 4) performing a demethylation reaction of the compound (D) to obtain the dolutegravir (E). According to the method, a novel route is adopted, and reaction conditions are continuously optimized, so that the total yield is greatly increased; and the total yield calculated by taking the compound (A) as a starting material is 75% or more, and the yields of single reactions are all 90% or more.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing dolutegravir. 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-methanol Amide, CAS.NO: 1051375-16-6, molecular formula: C 20 h 19F2 N 3 o 5 , its structural formula is shown in formula (E) (E), Dolutegravir is a new anti-HIV drug owned by the British pharmaceutical giant GlaxoSmithKline (GSK). On August 12, 2013, the U.S. Food and Drug Administration (FDA) approved it for previously treated or initially treated HIV-1 infection in adults and children aged 12 and over weighing at least 40 kg. Dolutegravir [0003] It is a once-a-day drug that has achieved comparable efficacy to Merck & Co's HIV / AIDS drug Raltegravir (Isentress) in Phase III clinical trials. FDA officials said that H...

Claims

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Application Information

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IPC IPC(8): C07D498/14C07D213/82
CPCY02P20/55C07D498/14C07D213/82
Inventor 顾世海纪毅东肖清泉蔡惠坚
Owner 厦门蔚扬药业有限公司
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