Technology for preparing key intermediate of telbivudine

A technology for telbivudine and intermediates, which is applied in the preparation of sugar derivatives, sugar derivatives, esterified saccharides, etc., can solve the problems of expensive raw materials and high cost, and achieves easy availability of raw materials, low cost and high yield. high effect

Inactive Publication Date: 2012-05-30
FUAN PHARMA LYBON PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

International application WO9520595 discloses a method for preparing Hoffer's chlorosugar with L-arabinose as a starting mat

Method used

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  • Technology for preparing key intermediate of telbivudine
  • Technology for preparing key intermediate of telbivudine
  • Technology for preparing key intermediate of telbivudine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Dissolve 200g (1.12mol) of vitamin C (compound 2), 88ml (1.2mol) of acetyl chloride in 500ml of acetone, heat up to 40°C, keep stirring for 2 hours, cool the reaction solution to 0°C, filter, and dissolve in 100ml of acetone Wash the filter cake, and then dry the filter cake to obtain 230 g of compound (3) (yield: 95%): white solid; mp: 212-214°C [lit: 218-219°C]; 1 HNMR (250MHz, D 2 O), δ1.38 (s, 6H), 4.18 (dd, J=9.1, 5.0, 2.1H), 4.32 (dd, J=9.1, 7.2Hz, 1H), 4.60 (ddd, J=7.2, 5.0, 2.2Hz, 1H), 4.93(d, J=2.2Hz, 1H)

Embodiment 2

[0028] Add compound (3) (220g, 1mol) and 500ml deionized water into a 2L reaction flask, add 30% NaOH solution (75ml) dropwise under stirring, and add NaHCO 3 (215g, 2.56mol), then slowly add 30% hydrogen peroxide (200ml, 2.1mol) dropwise, and stir at room temperature for 1 hour after dropping.

[0029] Sodium sulfite (12.6g, 0.1mol) and sodium bicarbonate (105g, 1.25mol) were added to the reaction solution, and the temperature was raised to 40°C, and dimethyl sulfate (375ml, 4mol) was added dropwise. At room temperature, extract with dichloromethane (500ml×2), combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain 173g of compound (5) (yield: 90%): colorless oil; 1 H NMR (250MHz, CDCl 3 )δ1.28(s, 3H), 1.36(s, 3H).3.07(d, J=8.1Hz, 1H), 3.83(s, 3H), 3.99-4.17(m, 3H), 4.40(td, Jt =6.7Hz, Jd=2.8Hz, 1H)

Embodiment 3

[0031] Weigh 130g (0.68mol) of compound (5) and 15ml of triethylamine into a 500ml reaction bottle, add 100ml of dichloromethane and stir to dissolve, cool down to 0-5°C in an ice-water bath, add 129g (0.68mom) of p-toluenesulfonyl chloride dropwise 200ml of dichloromethane solution, after dropping, raised to room temperature and stirred for 6 hours, washed with water until neutral, dried the organic layer, and concentrated under reduced pressure to obtain 220g of compound (6), with a yield of 86%.

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Abstract

The invention discloses a new technology for preparing a key intermediate Hoffer's chlorosugar of telbivudine. The technology is characterized in that the technology comprises the following steps: 1, obtaining an epoxide by carrying out condensation, oxidation ring-opening, methylation, tosylation, reduction and epoxidation on vitamin C which is massively supplied in China and is treated as an initial raw material; 2, carrying out ring-opening cyaniding on the obtained epoxide; 3, carrying out sulfuric acid hydrolysis and lactonization on the generated cyan butanetriol derivative; and 4, carrying out hydroxy protection with p-toluoyl chloride, reducing with sodium triacetoxyborohydride to obtain a reduction product, and directly chloridizing the reduction product to obtain the target compound Hoffer's chlorosugar without separation, wherein the Hoffer's chlorosugar is 1-choro-3,5-bis-O-p-toluyl-2-deoxy-L-ribose. According to the technology, the total route yield is 42%, and the product purity is greater than 98%.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new process for preparing Hoffer's chlorosugar, a key intermediate of telbivudine. Background technique [0002] Telbivudine, a synthetic thymidine analogue developed by Novartis, has strong and selective inhibitory activity of hepatitis B virus deoxyribonucleic acid polymerase, and has been approved in the United States, the European Union, China, etc. listed. As the key intermediate Hoffer'schlorosugar in the synthetic route of this variety, that is, 1-chloro-3,5-bis-O-p-toluoyl-2-deoxy-L-ribose (as shown in Figure 1 below), domestic and foreign Although there is research and production, it is far from meeting the needs of the market due to the difficulty of its synthesis process, high production cost and difficulty in industrialization. [0003] [0004] Figure 1. Hoffer's chlorosugar [0005] At present, there is no report on the synthetic rou...

Claims

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Application Information

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IPC IPC(8): C07H13/08C07H1/00
Inventor 陈小勇李佩杰冯秀梅张稳稳
Owner FUAN PHARMA LYBON PHARMA TECH
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