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Method for preparing Besifovir

A compound, methyl technology, applied in the field of new intermediates, can solve the problems of increasing experimental costs and expensive prices, and achieve the effects of reducing the difficulty of purification, increasing yield, and reducing costs

Active Publication Date: 2018-12-14
广州粤美医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Compared with route three, this route avoids the use of sodium azide, but still uses expensive 2,5-diamino-4,6-dichloropyrimidine, which increases the cost of the experiment

Method used

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  • Method for preparing Besifovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0049] Step 1: Preparation of 2-((tert-butyl(diphenyl)silyl)oxy)ethyl acetate (2):

[0050] 1 (100.0g, 960.52mmol) and imidazole (77.3g, 1.15mol) were dissolved in dichloromethane (1.5L), and tert-butyldiphenylchlorosilane was slowly added dropwise with a constant pressure dropping funnel under ice-cooling conditions (264.0 g, 960.52 mmol). After the dropwise addition was completed, it was transferred to room temperature for 16 h. Filtrate, wash the filtrate with 1.0mol / L hydrochloric acid solution (300ml×2), wash the dichloromethane layer with saturated sodium bicarbonate solution (100ml×2), dry over anhydrous sodium sulfate, and concentrate to give white transparent liquid 2 (297.7g ,91%). ESI-MS(m / z):365.1564[M+Na] + ; 1 H NMR (300MHz, CDCl3) δ: 7.87~7.76 (m, 4H), 7.47 (q, J = 5.4Hz, 6H), 4.35 (s, 2H), 4.22 (q, J = 7.1Hz, 2H), 1.28 (t,J=7.1Hz,3H),1.21(s,9H); 13 CNMR (75MHz, CDCl3) δ: 171.2, 135.7, 132.9, 130.0, 127.9, 62.4, 60.7, 26.8, 19.4, 14.2.

[0051] Step 2: Pr...

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Abstract

The invention relates to a method for preparing P-[[[1-[(2-amino-9H-purine-9-yl) methyl] cyclopropyl] oxy] methyl]-phosphoric acid (Besifovir). The method comprises the following steps: 1) enabling acompound of formula (1) as shown in the specification to react with tertiary butyl diphenylchlorosilane so as to prepare a compound of formula (2) as shown in the specification; 2) enabling the compound of formula (2) to react with ethyl magnesium bromide so as to prepare a compound of formula (3) as shown in the specification; 3) enabling the compound of the formula (3) to react with p-toluenesulfonyl oxymethyldiethoxyphosphine under a condition that tertiary butanol lithium is adopted as an alkali so as to prepare a compound of formula (23) as shown in the specification; 4) carrying out ammonium fluoride hydrolysis on the compound of formula (23) so as to prepare a compound of formula (24) as shown in the specification; 5) enabling the compound of formula (24) to react with a compound offormula (28) as shown in the specification so as to prepare a compound as a solid of formula (22) as shown in the specification; 6) carrying out reduction dechloridation on the compound of formula (22) as shown in the specification under a condition of a catalyst and a hydrogen supplier so as to prepare a compound as a solid of formula (25) as shown in the specification; 7) carrying out trimethylbromide silane hydrolysis on the compound of formula (25), so as to obtain Besifovir as shown in the specification. The method is cheap in raw material and intermediate material, easy in raw materialand intermediate material obtaining, low in cost, high in yield, gentle in condition and good in security.

Description

Technical field: [0001] The present invention relates to a method for preparing P-[[[1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl]oxy]methyl]-phosphoric acid (Besifovir, Besifovir) method, the present invention also relates to novel intermediates. Background technique: [0002] Hepatitis B is caused by hepatitis B virus and can be transmitted through blood, mother to child, sexual transmission, and skin and mucous membrane damage. The current drugs for the treatment of chronic hepatitis B can be divided into nucleoside analogs and immunosuppressants. The main mechanism of action of nucleoside anti-HBV drugs is to inhibit the activity of HBV virus polymerase, prevent endogenous nucleotides from participating in HBV DNA replication through competitive inhibition, and cannot completely kill HBV. Drug rebound and drug-resistant side effects are prone to occur, and it will also cause patients to burden long-term treatment. Therefore, in the current treatment of chronic hepatit...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07F9/40
CPCC07F9/4006C07F9/4075C07F9/65616
Inventor 郭忠武郝玲花仲伯华郑俊霞
Owner 广州粤美医药科技有限公司
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