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Suitable industrialized method of preparing Lamivudine

A technology of lamivudine and catalyst, applied in the field of preparation of lamivudine, can solve the problems of being unsuitable for large-scale production, time-consuming, low total yield and the like, and achieves easy large-scale production and safety. High, high-yield effect

Active Publication Date: 2005-01-12
SHANDONG WEIFANG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the HPLC method can only split a small amount of samples, while the biological enzymatic hydrolysis method has the disadvantages of cumbersome experiments, time-consuming, expensive, and difficult to recycle.
[0005] Chinese patent CN01110302.7 discloses the preparation method titled lamivudine and introduces the completion of lamividine through four steps through achiral 2-hydroxymethyl-5-cytosine-1,3-oxathiolane The resolution of furidine, this method does not involve the synthesis of raw material 2-hydroxymethyl-5-cytosine-1,3-oxathiolane and the process must be separated by column, which is not suitable for large-scale production
[0006] Haolun Jin etc. introduced in J.Org.Chem, 1995,60 (8): 2621-2623 with hydrated glyoxylic acid, 2,5-dihydroxyl-1,4-dithiothiane as starting material, through The important intermediate trans-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-(1`R, 2`S, 5`R) menthyl ester was synthesized in three steps, but the total yield The lowest is only 30%. At the same time, they also used trimethyl tert-butyl silicon trifluoromethanesulfonate as a silylating agent, which is expensive, extremely sensitive, and difficult to react

Method used

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  • Suitable industrialized method of preparing Lamivudine
  • Suitable industrialized method of preparing Lamivudine
  • Suitable industrialized method of preparing Lamivudine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1) Preparation of glyoxylic acid (1`R, 2`S, 5`R)-menthyl ester (V)

[0023]

[0024] 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%.

[0025] (2) Preparation of trans-5-hydroxyl-1,3-oxathiolane-2 carboxylic acid-(1`R, 2`S, 5`R)-menthyl ester (IV)

[0026]

[0027] Put 0.1mol glyoxylic acid (1`R, 2`S, 5`R) menthyl ester, 120ml methyl ether, 2,5-dihydroxy...

Embodiment 2

[0038] Preparation of trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid-(1`R,2`S,5`R)-menthyl ester (IV)

[0039]

[0040] 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-necked circular 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.

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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 product stable intermediate glyoxalic (1, R, 2.5, 5, R) menthol (V); then being reacted with 2,5-dihydroxy-1,4-dithiothiane to produce product and then proceeding crystallation to obtain menthol ester (IV); (2). proceeding acidylation by using hydroxy to obtain menthol ester (III); (3) being condensed by cytosine under protection of silanized reagent, to obtain menthol ester (II); (4) obove-said product is reduced by reducing agent to obain final invented product Lamifudin (I). This invention has advantages of: available raw material, high yield, high safety, and commercialization prodn.

Description

(1) Technical field [0001] The invention belongs to the preparation method of lamivudine. [0002] Lamivudine is a deoxyribocytosine nucleoside analog, its chemical name is: 2R-hydroxymethyl-5S-cytosine-1,3-oxathiolane. It has good anti-hepatitis B virus effect. (2) Background technology [0003] Chinese patent 92103921.2 discloses a method titled "Diastereoselective Synthesis of Nucleosides", which introduces the resolution of p-oxythioheterocyclic intermediates. The separation principle is that (-)-menthol forms an ester with 2-carboxy-5-acetoxy-1,3-oxathiolane, and is separated into single diastereoisomers by cryogenic freezing. Then use iodotrimethylsilane as a Lewis acid, couple cytosine through a carbon-nitrogen bond, and use the reducing agent lithium aluminum hydride to reduce the final product lamivudine to obtain lamividine with an optical rotation of [α] D 22 -135 ° (c1.01, MeOH) The total yield of this method is not high, and the chemical raw materials used a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04
Inventor 冉东升
Owner SHANDONG WEIFANG PHARMA FACTORY
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