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Suitqable to industrialized method for preparing emtricitabine

A technology of emtricitabine and catalyst, applied in the field of preparation of emtricitabine, can solve the problems of unsuitability for industrialized large-scale production, high cost, loss of intermediates, etc., and achieves easy large-scale production, high safety, and yield. high effect

Active Publication Date: 2005-01-12
SHANDONG WEIFANG PHARMA FACTORY
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Problems solved by technology

[0003] Chinese patent CN92101981.5 discloses the preparation method titled "2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane" and introduces emtricitabine In this method, more expensive organofluorosilylating reagents are used in the condensation with flucytosine, and the cost is higher. Finally, chiral HPLC is used for resolution, which is not suitable for large-scale industrial production
[0004] Gong Pingping used a one-pot synthesis method in "Chinese Journal of Medicinal Chemistry" 2002: NO.1: 34-36 to synthesize trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid- (1`R, 2`S, 5`R) menthyl ester (40% yield), the intermediate 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid generated by this process is very easy Soluble in water, but this article washes this intermediate with water to remove p-toluenesulfonic acid, resulting in the complete loss of this intermediate, which cannot react with 2,5-dihydroxy-1,4-dithiothiane and cannot be reproduced
In addition, when introducing flucytosine, trimethylsulfonic acid, which is an extremely expensive silylating reagent, was used in this paper

Method used

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  • Suitqable to industrialized method for preparing emtricitabine
  • Suitqable to industrialized method for preparing emtricitabine
  • Suitqable to industrialized method for preparing emtricitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Preparation of glyoxylic acid (1`R, 2`S, 5`R)-menthyl ester (V)

[0026]

[0027] In a three-necked round bottom flask equipped with a water separator, put 0.11mol of solid glyoxylic acid at room temperature, add 120ml of methyl ether, 0.1mol of menthol, and 1.5g of p-toluenesulfonic acid, heat and stir to dissolve the solid completely, and heat to reflux for 7- After 8 hours, the reaction solution was cooled to room temperature, filtered, washed with 50ml*3 water, the organic phase was collected, dried with anhydrous sodium sulfate overnight, filtered, the solvent was removed under low pressure, the remaining solid was dissolved with a small amount of petroleum ether, and a white solid was obtained 22.4g, melting range: 77-82°C, yield: 90%.

[0028] (2) Preparation of trans-5-hydroxyl-1,3-oxathiolane-2 carboxylic acid-(1`R, 2`S, 5`R)-menthyl ester (IV)

[0029]

[0030] Put 0.1mol glyoxylic acid (1`R, 2`S, 5`R)-menthyl ester, 120ml methyl ether, 2,5-dihydrox...

Embodiment 2

[0041] Preparation of trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid-(1`R,2`S.5`R)-menthyl ester (IV)

[0042]

[0043] In a three-necked round bottom flask equipped with a water separator, put 0.11mol of solid glyoxylic acid at room temperature, add 120ml of methyl ether, 0.1mol of menthol, and 1.5g of p-toluenesulfonic acid, heat and stir to dissolve the solid completely, and heat to reflux for 7- After 8 hours, cool the reaction solution to room temperature, filter, wash with 50ml*3 water, collect the organic phase, transfer it to a three-neck round bottom flask, add 0.05mol of 5-dihydroxy-1,4-dithiothiane, heat and stir to 40 ℃, until the white solid is completely dissolved, heat and reflux for 5-6 hours, cool the reaction solution to room temperature, filter, remove the solvent under low pressure, dissolve the remaining white solid with a small amount of petroleum ether, and freeze to obtain an odorous white solid. Yield 45 %, melting range: 110-112°C.

Embodiment 3

[0045] 5S-(5`-fluorocytosinyl-1`)-1,3-oxathiolane-2-carboxylic acid-(1`R, 2`S, 5`R) menthyl ester (II) preparation

[0046]

[0047] (1) Add 3.0g trans-5-hydroxyl-1,3-oxathiolane-2 carboxylic acid-(1`R, 2`S, 5`R)-menthyl ester into a round bottom flask, dissolve In 30ml of dichloromethane, drop 1ml of N,N-dimethylformamide solution dissolved with two drops of methanesulfonic acid, cool to about 8°C, slowly drop into 0.8ml of thionyl chloride, and the mixture is kept at 10- Stir at 15°C for 1.5 hours, evaporate about 20ml of solvent under normal pressure, cool to room temperature, and set aside.

[0048] (2) Add 1.34 grams of 5-fluorocytosine, 3 ml of hexamethylazrosilane, 3 ml of toluene, and two drops of methanesulfonic acid into a round bottom flask, heat to reflux, and reflux for 1.5 hours to form a colorless solution. Add 1.5ml of triethylamine dropwise, then slowly drop into the solution obtained in (1), wash and add with 3ml of dichloromethane, reflux the mixture fo...

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Abstract

This invention prepn. method consists procedures (as shown in route chart) of: (1). hydrated glyoxalic acid is reacted with menthol in solvent and catalyst to produce stable intermediate-glyoxalic (1,R,2,5,5,R) menthol ester (V); then, reacting with 2,4-dihydroxy-1,4-dithiothiane to produce menthol ester (IV); (2). said product being proceeded acidylation by hydroxy to produce menthol ester (III); (3) being condensed with 5-fluorocytosine under the protection of silanized reagent, after purification to obtain menthol ester (II); (4). above-said product is reduce by reducing agent to obtain final invention product enqutabin (I) This invention has advantages of: available raw material, high yield, safety and commercialization prodn.

Description

(1) Technical field [0001] The invention belongs to the preparation method of emtricitabine. [0002] Emtricitabine (Emtricitabine) is a deoxyribose flucytosine nucleoside analogue, its chemical name is 2R-hydroxymethyl-5S-(5-fluorocytosine-1-yl)-1,3-oxathia Methylene, has good anti-HIV and hepatitis B virus effect. (2) Background technology [0003] Chinese patent CN92101981.5 discloses the preparation method titled "2-hydroxymethyl-5-(5-fluorocytosine-1-yl)-1,3-oxathiolane" and introduces emtricitabine In this method, more expensive organofluorosilylating reagents are used in the condensation with flucytosine, and the cost is higher. Finally, chiral HPLC is used for resolution, which is not suitable for large-scale industrial production. [0004] Gong Pingping used a one-pot synthesis method in "Chinese Journal of Medicinal Chemistry" 2002: NO.1: 34-36 to synthesize trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid- (1`R, 2`S, 5`R) menthyl ester (40% yield), the interme...

Claims

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Application Information

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IPC IPC(8): A61P1/16A61P31/12C07D411/04
Inventor 冉东升
Owner SHANDONG WEIFANG PHARMA FACTORY
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