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Preparation method of velpatasvir intermediate and analogue thereof

A technology for compounds and mixtures, applied in the field of chemical synthesis, can solve problems such as uneven heating and restricting industrial production.

Active Publication Date: 2018-06-12
XILING LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] Easwaramurthy M. etc. have obtained the compound of formula (E) by using microwave reaction of N-acetyl o-toluidine under the action of aluminum trichloride in one step, but there is no good industrialized equipment for microwave reaction at present, and Ravi Subban etc. have used similar strategy, they melted N-acetyl o-toluidine under the action of titanium tetrachloride to obtain the compound of formula (E). Similarly, when the melting reaction is industrially scaled up, it is prone to uneven heating, which limits its industrial production

Method used

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  • Preparation method of velpatasvir intermediate and analogue thereof
  • Preparation method of velpatasvir intermediate and analogue thereof
  • Preparation method of velpatasvir intermediate and analogue thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Embodiment 1 prepares o-methylacetanilide

[0125] method 1:

[0126]

[0127] Take 5.0 kg of o-methylaniline, put 30 L of dichloromethane in a 50 L reactor, stir and dissolve, then add 5.2 kg of triethylamine, and slowly add 4.8 kg of acetic anhydride thereinto under ice bath. After addition, slowly rise to room temperature and stir for 2h. 10 L of water was added to the reaction solution and stirred for 10 min, and the organic layer was washed with 2 L of 5% hydrochloric acid solution. Sample HPLC quantification, yield 93.0%, HPLC purity 97.1%. The resulting product was directly subjected to the next reaction without isolation.

[0128] Method 2:

[0129]

[0130] Take 5.0 kg of o-methylaniline and 30 L of dichloromethane in a 50 L reactor, stir and dissolve, then add 5.2 kg of triethylamine, and slowly add 3.7 kg of acetyl chloride dropwise therein under an ice bath. After addition, slowly rise to room temperature and stir for 2h. 10 L of water was added ...

Embodiment 2

[0131] Embodiment 2 prepares 4-bromo-2-methylacetanilide

[0132] method 1:

[0133]

[0134] Take 5.0 kg of o-methylacetanilide obtained in Method 1 of Example 1, put 25 L of acetic acid in a 50 L reactor, add 5.4 kg of elemental bromine dropwise thereto at room temperature, and react at 50°C for 1.5 h after the dropwise addition is completed. After the reaction was completed, 15L of ethyl acetate was added to the reaction solution to dissolve, and then ice-water was added to separate the layers. The aqueous layer was extracted with 2L of ethyl acetate, and the organic layer was combined. The organic layer was washed successively with 2L of saturated sodium sulfite solution and 2L of water. The organic layer was anhydrous. Drying over sodium sulfate, sample HPLC quantification, yield 96.6%, HPLC purity 95.3%. The resulting product was directly subjected to the next reaction without isolation.

[0135] 1 H NMR (300MHz, CDCl 3 ) δ 7.64 (d, J = 8.0 Hz, 1H), 7.30 (s, 2H), ...

Embodiment 3

[0139] Embodiment 3 prepares 4-iodo-2-methylacetanilide

[0140]

[0141] Take 5.0 kg of o-methylacetanilide obtained in Method 2 of Example 1, put 25 L of dichloromethane in a 50 L reaction kettle, add 9.4 kg of iodine element at room temperature, and react with 8.4 kg of sodium bicarbonate at room temperature for 3 hours. Subsequently, 3L of saturated sodium sulfite solution was added to the reaction liquid to quench the reaction, the organic layer was washed with 10L of water, and the organic layer was sampled for HPLC quantification. The yield was 92.1%, and the HPLC purity was 92.5%. The resulting product was directly subjected to the next reaction without isolation. 1 H NMR (300MHz, CDCl 3 ) δ 7.46 (m, 3H), 6.94 (s, 1H), 2.13 (s, 6H).

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Abstract

The invention discloses a preparation method of a compound shown by formula (E), a velpatasvir intermediate shown by formula (K) and an analogue thereof. Materials adopted in the method disclosed by the invention are low-cost and easily obtained; the technological operation is simple; the intermediate and the product need not be subject to column chromatography separation; and the preparation method is suitable for industrialized mass production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of a velpatasvir intermediate and analogues thereof. Background technique [0002] Velpatasvir (Velpatasvir) is a pan-genotypic NS5A inhibitor, which was approved by the US FDA in June 2016 for the treatment of adult chronic hepatitis C virus (HCV) 1-6 in combination with sofosbuvir Genotypic infection is another blockbuster drug in the field of hepatitis C treatment, and its trade name is Epclusa. The structural formula of velpatasvir is as follows: [0003] [0004] Velpatasvir is a new anti-hepatitis C drug developed by Gilead Sciences Inc., in which 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c,g]chromen-8(9H)one (Vel-SM1) is an important structural fragment for the synthesis of velpatasvir. [0005] [0006] WO 2013075029 discloses a synthesis method of Vel-SM1, which uses 2-bromo-5-chlorobenzyl bromide as a raw material, and undergoes ...

Claims

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Application Information

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IPC IPC(8): C07C221/00C07C225/22C07D311/78
CPCC07C221/00C07C231/12C07D311/78C07C225/22C07C233/33C07C233/15Y02P20/55
Inventor 吴成龙曾文刘芍利龚家福黄金昆谢德建
Owner XILING LAB CO LTD
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