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Method for synthesizing emtricitabine intermediate

A synthesis method and thiolane technology are applied in the synthesis field of emtricitabine intermediates, can solve problems such as affecting the health and safety of operators, high toxicity of raw materials, pollute the environment of the environment, etc., and achieve low production cost, The effect of simplifying the reaction steps and saving production costs

Active Publication Date: 2009-03-25
JIANGSU COBEN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this reaction, due to the use of thionyl chloride as the chlorination reagent, the raw materials are highly toxic. At the same time, a large amount of sulfur dioxide waste gas is generated during the reaction process, which seriously corrodes the equipment and seriously pollutes the environment, affecting the health and safety of operators.

Method used

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  • Method for synthesizing emtricitabine intermediate
  • Method for synthesizing emtricitabine intermediate
  • Method for synthesizing emtricitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of chlorinated compounds: in a 250mL three-necked flask, add 28.8 grams of (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) ( 0.1mol), N, N-dimethylformamide 7.3g, 100mL dichloromethane, and keep stirring until compound III dissolves. Cool to about 0°C, control the temperature at 5-10°C, add dropwise a mixed solution of 11.9 grams (0.04mol) of bis(trichloromethyl)carbonate in 50mL of dichloromethane, and slowly heat up to 30 -35°C, keep warm for 2 hours. The resulting reaction solution is a chloride (compound IV) solution, ready for use.

[0028] Preparation of N,O-bis(trimethylsilyl)5-fluorocytosine: In a 500mL three-neck flask, add 12.9 grams (0.1mol) of 5-fluorocytosine, 24.5 grams of hexamethyldisilazane, 100mL toluene, 3 Drop methanesulfonic acid, heat to reflux for 2 hours, until the solution is clear, then cool slightly, this is the toluene solution of N,O-bis(trimethylsilyl)5-fluorocytosine.

[0029] Preparation...

Embodiment 2

[0032] Preparation of chlorinated compounds: in a 250mL three-necked flask, add 28.8 grams of (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) ( 0.1mol), N, N-dimethylformamide 7.3g, 100mL dichloromethane, and keep stirring until compound III dissolves. Cool to about 0°C, control the temperature at 5-10°C, add dropwise a mixed solution of 14.9 grams (0.05mol) of bis(trichloromethyl)carbonate in 50mL of dichloromethane, and slowly heat up to 30 -35°C, keep warm for 2 hours. The resulting reaction solution is a chloride (compound IV) solution, ready for use.

[0033] Preparation of N, O-bis(trimethylsilyl) 5-fluorocytosine: same as Example 1.

[0034] Preparation of (2R, 5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester: same as Example 1

[0035] Post-treatment: same as Example 1, to obtain 27.1 g of white solid product, HPLC purity: 99.50%, chiral purity: 99.35%, melting point: 220.1-220.9°C, yield: 67.9%. ...

Embodiment 3

[0036] Example 3 One Pot Method

[0037] In a 500mL three-necked flask, add 12.9g (0.1mol) of 5-fluorocytosine, 24.5g of hexamethyldisilazane, 100mL of toluene, and 3 drops of methanesulfonic acid, heat and reflux for 2 hours until the solution is clear, this is N, O-bis(trimethylsilyl)5-fluorocytosine in toluene. Slightly cold, add 7.3g (0.1mol) of N,N-dimethylformamide, 12g of triethylamine, at a temperature of about 20-25°C, slowly add the (2R,5R)-5-hydroxy -1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and bis(trichloromethyl)carbonate 11.9 grams (0.04mol) were dissolved in 150mL of the mixed solution of dichloromethane, after dripping, keep warm for 2 hours, then slowly raise the temperature to 40-45°C, and react for 8 hours. Stop responding.

[0038] Post-treatment: Pour the reaction solution into a mixed solution containing 100g of water, 12g of triethylamine, and 50g of n-hexane, stir for 8 hours, filter, and rinse the resultin...

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Abstract

The invention discloses a synthetic method of emtricitabine intermediates, namely, (2R, 5S)-5-(5'-fluoro-cytimidine-1-group)-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester having the structural formula of (VI), (2R, 5S)-5-hydroxy-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester having the structural formula of (III) is taken as raw material to obtain chloro compounds having the structural formula of (IV) by chlorination reaction, then the chloro compounds (IV) are treated with condensation and hydrolyzation reactions with N, O-bis(trimethoxy)5-flurocytosin having the structural formula of (V), thus obtaining the (2R, 5S)-5-(5'-fluoro-cytimidine-1-group)-1, 3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI). The invention uses bis(trichloromethyl) carbonic ester to replace the thionyl chloride in the prior art so as to be taken as a chlorination reagent, thus having the advantages of safe and reliable operation and environmental protection.

Description

(1) Technical field [0001] The present invention relates to a synthetic method of an emtricitabine intermediate, in particular to (2R, 5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-oxathiolane- Synthetic method of 2-carboxylate-L-menthyl ester. (2) Background technology [0002] Emtricitabine (Compound I) is an anti-AIDS drug developed in recent years. It is a new nucleoside reverse transcriptase inhibitor and is a highly efficient and selective inhibitor of HIV and HBV. [0003] There are many reports in the literature on the synthesis of emtricitabine, and the main routes are: (1) using glyoxylic acid as a raw material, reacting with 2,5-dithiane-1,4-diol, and then introducing chiral prosthetic groups, glycosides (Mansour T, et al EP: 515157 (1992)), (2) L-gulose obtained by multi-step reaction (Jeong L., et al. J Med Chem, 36 (2): 181 —195(1993)); (3) using (S)-(+)-mandelic acid as raw material, obtained by multi-step reaction (Keshava M., et al., US: 6380388, (2002)); (4) Using...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04
Inventor 游金宗蒋善会
Owner JIANGSU COBEN PHARMA CO LTD
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