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Non-enantioselective prepn process of emtricitabine

A technology of emtricitabine and diastereomer, applied in the field of drug preparation, can solve the problems that the optical purity of the product does not reach the medicinal standard, is not suitable for industrial production, and the yield is not high, and achieves huge social and economic benefits, The effect of low cost and easy operation

Inactive Publication Date: 2007-11-07
葛建利
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Problems solved by technology

[0004] Chinese patent CN92101981.5 discloses "the preparation method of 2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiopentane", and introduces the synthesis of emtricitabine method, using expensive fluorosilylating reagents during condensation with flucytosine, the cost is very high, and the final product is resolved by chiral HPLC, which is not suitable for industrial production
The yield of this route is not high, the cost is high, and the optical purity of the obtained product cannot reach the pharmaceutical standard

Method used

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Embodiment Construction

[0027] The invention will be further described below through specific examples.

[0028] As shown in Figure 1, the diastereoselective preparation method of emtricitabine is synthesized through the following steps:

[0029] 1. Preparation of trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid-L-menthol ester (III).

[0030]

[0031] Under nitrogen protection, mix glyoxylic acid-L-menthyl ester (100g, 0.43mol), dithiothiane (33g, 0.215mol) and 400ml toluene, heat to dissolve, add p-toluenesulfonic acid (2.22g, 0.0129mol), the temperature was raised to react, and the water in the reaction system was separated with a water trap until no more water came out, about 5 hours. Cool, add triethylamine to adjust the pH to 7-8, wash the organic layer with deionized water, remove the solvent from the obtained organic layer, add petroleum ether, let stand at room temperature, filter, and dry to obtain 110 g of white powdery solid, yield 88.7% . 1 H-NMR (CDCl 3 )δ: 0.71~2.09(m, 18H, 2’~...

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Abstract

The present invention discloses non-enantioselective preparation process of emtricitabine. The preparation process includes condensation of glyoxalic acid as the initial material and 2, 5-dihydroxy-1, 4-dithiane under the asymmetric induction of optically active alcohol ester to obtain trans-5-hydroxy-1, 3-oxythiacyclopentane-2-carboxylate; halogenating and coupling with silylated 5-flucytosine, and reducing to obtain initial product; reaction with salicylic acid to form salt, purification and separation to obtain optically pure emtricitabine. The present invention has mild reaction condition, simple operation, low cost, less environmental pollution and high product purity reaching medicinal standard, and is suitable for industrial production. The product is used in treating hepatitis B and AIDS.

Description

Technical field [0001] The invention belongs to a preparation method of medicine, in particular to a diastereoselective preparation method of emtricitabine. Background technique [0002] Emtricitabine (Emtricitabine) is a deoxyribose flucytosine nucleoside derivative, its chemical name is 2R-hydroxymethyl-5S-(5-fluorocytosine-1-yl)-1,3-oxosulfur Heterocyclopentane. The latest research shows that emtricitabine can significantly improve the histology, virology and biochemistry of patients with chronic hepatitis B (HBV). It is also approved for the treatment of HIV infection and has good anti-HIV and hepatitis B virus effects. The chemical structural formula is as follows: [0003] [0004] Chinese patent CN92101981.5 discloses "the preparation method of 2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiopentane", and introduces the synthesis of emtricitabine In the method, an expensive fluorosilylating reagent is used in the condensation with flucytosine, the cost is v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04
Inventor 葛建利彭智勇
Owner 葛建利
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