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Novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone

A bromoacetyl, dihydrogen technology, applied in the field of pharmaceutical preparation, can solve the problems of high price, high price and high production cost, and achieve the effect of reducing production cost

Active Publication Date: 2016-07-06
SULI PHARMA TECH JIANGYIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Scheme2 raw material 1-bromo-2-bromomethyl-4-chloro is expensive, trimethylsilyl acetylene is used in a large amount and the price is also very expensive, and a two-step precious metal catalyzed reaction is carried out, and the overall yield is only 7%.
[0008] The starting material D1 of Scheme3 is expensive and has few sources, so the production cost is very high

Method used

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  • Novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone
  • Novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone
  • Novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0041]

[0042] Add 4-bromo-3-methylbenzoic acid (30 g, 0.14 mol) and sodium wire-dried tetrahydrofuran (150 mL) into a 500 mL three-neck reaction flask to replace nitrogen. After cooling to -40°C, methyllithium ether solution (175 mL, 1.6M) was slowly added dropwise thereto under nitrogen protection, and the temperature was controlled not to exceed -20°C. After the dropwise addition was completed, the mixture was stirred at -20°C for 2 hours, and the reaction was detected by TLC. The reaction mixture was poured into ice water (300 g), stirred for 5 minutes and separated. The aqueous phase was extracted with methyl tert-butyl ether, the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. After the filtrate was spin-dried, 27.4 g of a light yellow oily liquid was obtained, with a yield of 92%.

[0043] 1 HNMR (400MHz, Chloroform-d) δ7.83(dt, J=1.7,0.9Hz,1H),7.67–7.60(m,2H),2.60(s,3H),2.48(d,J=0.8Hz...

Embodiment 1-2

[0045] In Example 1-1, the methyl lithium was replaced by methyl magnesium chloride, and other conditions and operations remained unchanged to obtain 8.31 g of the product with a yield of 28%.

Embodiment 1-3

[0047]

[0048] Add 4-bromo-N-methoxy-N,3-dimethylbenzamide (20 g, 77.5 mmol) and tetrahydrofuran (100 mL) dried over sodium silk into a 500 mL three-necked reaction flask, and replace nitrogen. After cooling to -20°C, methylmagnesium chloride tetrahydrofuran solution (116 mL, 1M) was slowly added dropwise thereto under the protection of nitrogen, and the temperature was controlled not to exceed -10°C. After the dropwise addition was completed, the mixture was stirred at -10°C for 2.5 hours, and the reaction was detected by TLC. The reaction mixture was poured into 1M dilute hydrochloric acid, stirred for 5 minutes and separated. The aqueous phase was extracted with methyl tert-butyl ether, and the combined organic layers were washed with saturated sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate, and filtered. After the filtrate was spin-dried, 14.9 g of a light yellow oily liquid was obtained, with a yield of 90%.

[0049] 1 HNMR (4...

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Abstract

The invention relates to a novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone. Cheap and available raw materials are utilized; the obtained compound can be applied to synthesis of an anti-hepatitis c medicine velpatasvir; the reaction is shown in the specification.

Description

technical field [0001] The invention relates to the field of medicine preparation, specifically, the invention provides a method for synthesizing 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromene -New method for 8(9h)-ketones. technical background [0002] Velpatasvir is a hepatitis C treatment drug developed by GileadSciences. The clinical cure rate of type 1-6 hepatitis C is 83-98% when this product is combined with Sofosbuvir orally. 9-Bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9h)-one is a key intermediate in the synthesis of velpatasvir. [0003] US2015361073 and US2013309196 disclose several methods for synthesizing 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9h)-one, See the reaction below. In Scheme1, intermediate B2 is obtained by reacting B1 with 5-hydroxy-1-tetralone, intermediate B3 is obtained by self-cycling under palladium catalysis, and intermediate B4 is obtained by reacting with vinyl fluoroborate un...

Claims

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Application Information

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IPC IPC(8): C07D311/78
CPCC07D311/78
Inventor 高照波雷鹏邵军超马法书
Owner SULI PHARMA TECH JIANGYIN
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