Synthetic method of lamivudine intermediate

A technology of lamivudine and an intermediate, which is applied in the field of pharmaceutical synthesis, can solve the problems of difficult separation of enantiomers, easy generation of a large number of degraded impurities, easy generation of emulsification, etc., and achieves simple post-processing operations, improved separation efficiency, The effect of saving the cost of raw materials

Active Publication Date: 2015-09-23
SHANGHAI ACEBRIGHT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] After industrial production, we found that this process has some problems that are not suitable for industrial scale-up production. The main problems are that emulsification is easy to occur in the post-treatment washing process, a large amount of degradation impurities are easy to be generated in the concentration process, and enantiomers are difficult to separate.

Method used

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  • Synthetic method of lamivudine intermediate
  • Synthetic method of lamivudine intermediate
  • Synthetic method of lamivudine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 1kg of the compound shown in formula VI to 1vol% hydrochloric acid methanol solution, and react at 20-25°C for 2-2.5 hours; after the reaction is completed, add 0.05kg of potassium carbonate to the reaction bottle, and then use sodium carbonate to adjust the pH value to 7 ~8; filter with suction and concentrate at 40~45°C to obtain the compound represented by formula V (oil) for use.

[0036] Add 1.2kg95vol% ethanol and 0.2kg sodium borohydride to a 5L reaction flask; the oily compound represented by formula V obtained in the previous step is dissolved in 0.8kg95vol% ethanol, and then added dropwise to the sodium borohydride ethanol solution at 20-25°C , the dropping rate is controlled within 4.5 to 5 hours; after the dropping, the temperature is raised to 38 to 42°C, and the reaction is carried out with insulation and stirring for about 2 hours, and TLC monitors the completion of the reaction; the reaction is completed, and the pH value is adjusted to 6 with 15wt% h...

Embodiment 2

[0041]Take 50g of the mesogenic compound represented by the above formula I', add 300g of ethanol, heat to reflux and dissolve under stirring, then slowly add 500g of n-hexane dropwise under reflux, drop the temperature to 0~5°C, Insulated and stirred for 1 hour, filtered, washed, and the filter cake was collected, dried in vacuum at 50° C. for 5 hours, and the obtained 21.2 g solid was the lamivudine intermediate shown in formula I, and the mass yield was 42.4%, and the HPLC purity was 98.5%, wherein the content of diastereoisomers is 0.86%.

Embodiment 3

[0043] Take 50g of the meso compound represented by the above formula I', add 200g of n-butanol, heat to reflux and dissolve with stirring, then slowly drop in 450g of n-hexane under reflux, drop the temperature to 0-5 ℃, insulated and stirred for 1 hour, filtered, washed, collected filter cake, and dried in vacuum at 50 ℃ for 5 hours, the obtained 24.3g solid was the lamivudine intermediate shown in formula I, the mass yield was 48.6%, HPLC The purity is 98.9%, and the content of diastereoisomers is 0.35%.

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Abstract

The present invention discloses a synthetic method of lamivudine intermediate, the method comprises the following steps: a compound of formula V is obtained by methoxylation reaction of a compound of formula VI and a hydrochloric acid methanol solution; a compound of formula IV is obtained by reduction reaction of the compound of formula V and sodium borohydride in ethanol; a compound of formula III is obtained by esterification reaction of the compound of formula IV and chlorinated carbonate under the effect of an organic base for formation of bicyclic carboxylic ester; a compound of formula II is obtained by acylation reaction of the compound of formula III and acetic anhydride under the acid catalysis; a meso compound of the formula I' is obtained by glycosylation reaction of the compound of formula II and silane protected N4-acetamido cytosine under the Iodotrimethylsilane catalysis; and the lamivudine intermediate as shown in the formula I is obtained by recrystallization resolution of the meso compound of the formula I'. The method has the advantages of being simple in operation, low in cost, high in product purity, and the like.

Description

technical field [0001] The invention relates to a method for synthesizing a lamivudine intermediate, which belongs to the technical field of medicine synthesis. Background technique [0002] Lamivudine is a nucleoside reverse transcriptase inhibitor, a deoxycytidine nucleoside analog that inhibits the replication of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Its English name is Lamividine, The chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiocyclopent-5-yl)-1H-pyrimidin-2-one, and its structural formula is as follows: [0003] [0004] Lamivudine was first developed by Canadian BioChemPharma for the treatment of AIDS (WO91 / 17159) and hepatitis B (EP0474119), especially for hepatitis B has a significant effect. Lamivudine has two chiral centers, and there are 4 stereoisomers, among which the isomer in 2R, 5S (2R-cis)-configuration has the strongest anti-HIV and anti-HBV activity, and has the strongest activity against certain cells Cyt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04
CPCC07D411/04
Inventor 安晓霞吕峰马伯军
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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