A kind of method of synthesizing 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: 2020-03-24
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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  • A kind of method of synthesizing lamivudine intermediate
  • A kind of method of synthesizing lamivudine intermediate
  • A kind of method of synthesizing lamivudine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] 1kg of compound shown in formula VI was added to 1vol% hydrochloric acid methanol solution, and reacted at 20~25°C for 2~2.5 hours; after the reaction, 0.05kg of potassium carbonate was added to the reaction flask, and then the pH value was adjusted to 7 with sodium carbonate. ~8; filter with suction and concentrate at 40-45°C to obtain the compound represented by formula V (oily substance), which is ready for use.

[0036] Add 1.2kg95vol% ethanol and 0.2kg sodium borohydride to the 5L reaction flask; after the compound shown in the oily formula V obtained in the previous step is dissolved with 0.8kg95vol% ethanol, it is added dropwise to the sodium borohydride ethanol solution at 20~25°C , the dripping rate is controlled to be dripped within 4.5 to 5 hours; after dripping, the temperature is raised to 38 to 42 ° C, and the reaction is kept stirring for about 2 hours, and the reaction is monitored by TLC; ~6.5; then extract with dichloromethane, collect the organic phas...

Embodiment 2

[0041]Take 50g of the meso compound shown in the above-mentioned formula I', add 300g of ethanol, heat to reflux and dissolve under stirring, then slowly drip 500g of n-hexane under the reflux state, dripping is completed, and cool to 0~5 ℃, Incubate and stir for 1 hour, filter, wash, collect the filter cake, vacuum-dry at 50 ° C for 5 hours, the obtained 21.2g solid is the lamivudine intermediate shown in formula I, the mass yield is 42.4%, and the HPLC purity is 98.5%, of which the content of diastereomers is 0.86%.

Embodiment 3

[0043] Get 50g meso compound shown in above-mentioned formula I ', add 200g n-butanol, under stirring, heat to reflux and dissolve clear, then slowly drip 450g n-hexane under reflux state, drip complete, cool down to 0~5 ℃, keep stirring for 1 hour, filter, wash, collect filter cake, vacuum-dry at 50 ℃ for 5 hours, the obtained 24.3g solid is the lamivudine intermediate shown in formula I, mass yield is 48.6%, HPLC The purity was 98.9%, and the content of diastereomers was 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 an intermediate of lamivudine, and belongs to the technical field of drug synthesis. Background technique [0002] Lamivudine, a nucleoside reverse transcriptase inhibitor, is a deoxycytosine nucleoside analog that inhibits the replication of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). The chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxothiohybrid cyclopent-5-yl)-1H-pyrimidin-2 ketone, 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 with significant curative effect. Lamivudine has two chiral centers and exists in 4 stereoisomers, of which the isomer in the 2R, 5S (2R-cis)-configuration has the strongest anti-HIV and anti-HBV activity, and has the strongest anti-HIV and anti-HBV activity against certain cel...

Claims

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Application Information

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Patent Type & Authority Patents(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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