Process for stereoselective synthesis of lamivudine

a technology of lamivudine and stereoselective synthesis, which is applied in the field of stereoselective synthesis of lamivudine, can solve the problems of high production cost and inability to easily control the operation of production, and achieve the effect of efficient recrystallization

Inactive Publication Date: 2011-05-19
JIANGSU PUXIN PHARMA CO LTD
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] In a preferred example of the present invention, step (a) can be specifically described as follows: cytosine or 4-amino protected cytosine is reacted with hexamethyldisilazane to give silylated 4-amino protected cytosine; which is then reacted with the compound of formula (I) at 10-80° C. for 1-20 hours; finally, the resulting glycosylated product is separated by recrystallization to give 2R,5S-intermediate of formula (II) of high optical purity.
[0018] The solvent is preferably an alcohol. The alcohol is preferably ethanol. Of course, the solvent is not limited to an alcohol, as long as it will not destroy the glycosylated product and can efficiently recrystallize and separate the diastereomers.
[0028] In order to enhance the yield of the glycosylation reaction, the intermediate of formula (IV) for chiral control can be transformed to a compound of formula (V), which then undergoes a glycosylation reaction with protected cytosine. In this manner, the expensive trifluoromethanesulfonic acid trimethylsilanol ester (a Lewis acid catalyst) can be replaced by trimethyliodosilane which is much cheaper, thus greatly reducing the cost of the starting materials. The reaction scheme is as follows:
[0030] The present process has the following advantages: the reaction condition is mild, the stereoselectivity of the intermediate is high, the diastereomer can be separated by simple recrystallization, and the operation is simple and suitable for industrial production.

Problems solved by technology

In the above two schemes of this process, chirality was not controlled, and the final product was obtained by column chromatography, thus the yield was low and the requirement on the equipment was high, resulting in that the production cost was high and the operation in the production could not be controlled easily.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for stereoselective synthesis of lamivudine
  • Process for stereoselective synthesis of lamivudine
  • Process for stereoselective synthesis of lamivudine

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Preparation of L-Menthol Chloroformate

[0032] Under a nitrogen atmosphere, triphosgene (314.9 g, 1.19 mol) and toluene (6 L) were added to a reaction flask, and stirred to make triphosgene totally dissolved in toluene. At −10° C., L-menthol (546.5 g, 3.50 mol) was added, and stirred to make it dissolved in the above mixture, and then pyridine (451.0 g, 3.50 mol) was added dropwise. After the addition was complete, the reaction was conducted for 2 hours at that temperature. The reaction liquid was washed by water thrice (50 ml×3), the organic layer was dried by anhydrous sodium sulfate, and the solvent was evaporated under normal atmosphere to obtain oil, which was distilled under reduced pressure (5 mmHg). The fraction of 90-93° C. was collected to obtain the title compound, and the yield was 75%.

example 2

(2,2-dimethyl-1,3-dioxolan-4-yl)-methyl-(1R,2S,5R)-2-isopropyl-5-methyl cyclohexyl carbonic acid diester

[0033] At 0° C., L-menthol chloroformate (2.2 g, 0.01 mol), (2,2-dimethyl-1,3-dioxolan-4-yl)-methanol (2.2 g, 0.01 mol), N,N-dimethylamino pyridine (0.1 g, 1.0 mmol) and dichloromethane (15 ml) were added to a reaction flask. Triethylamine (3.2 g, 0.03 mol) was slowly added under vigorous stirring. After the addition was complete, the mixture was stirred for 0.5 hour, after which the reaction was stopped. The organic layer was washed by saturated sodium bicarbonate and water and then the solvent was evaporated. The crude product was purified by a silica gel column (eluted by ethyl acetate: petroleum ether=1:10), to give 2.4 g of the title compound, and the yield was 76%. 1H-NMR (CDCl3) δ: 4.50 (m, 1H), 4.32 (m, 1H), 4.25 (m, 2H), 4.15 (m, 1H), 3.80 (m, 1H), 2.11 (m, 1H), 2.00 (m, 1H), 1.70 (m, 2H), 1.50 (m, 2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.28 (m, 1H), 1.11 (m, 2H), 0.9 (m, 6H),...

example 3

2,3-dihydroxypropyl-(1R,2S,5R)-2-isopropyl-5-methyl cyclohexyl carbonic acid diester

[0034] The compound of Example 2 (3.1 g, 0.01 mol), p-toluene sulfonic acid monohydrate (0.2 g, 0.001 mol) and methanol (20 ml) were added to a reaction flask, and then the mixture was stirred at room temperature for 7 hours, after which, the reaction was stopped and the reaction mixture was washed by saturated sodium carbonate aqueous solution. The solvent was evaporated from the organic layer and the crude product was purified by a silica gel column (eluted by ethyl acetate:petroleum ether=1:6) to give 2.5 g of the title compound, and the yield was 90%. 1H-NMR (CDCl3) δ: 4.50 (m, 1H), 4.32-4.09 (m, 2H), 3.91-4.00 (m, 1H), 3.50-3.75 (m, 2H), 2.11 (m, 1H), 2.00 (m, 1H), 1.70 (m, 2H), 1.50 (m, 2H), 1.28 (m, 1H), 1.11 (m, 2H), 0.9 (m, 6H), 0.82 (d, 3H). Elemental analysis: C14H26O5 found (%): C, 61.32; H, 9.54; O 29.14; calculated (%) C, 61.29; H, 9.55; O 29.16.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention discloses a process for stereoselective synthesis of Lamivudine comprising the following steps: (a) performing a glycosylation-reaction between the compound of formula (I) and cytosine or protected cytosine, and separating the reaction product by recrystallization to obtain the intermediate of formula (II); and (b) deprotecting the intermediate of formula (II) to obtain Lamivudine.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of International Patent Application No. PCT / CN2007 / 002038, filed on Jun. 29, 2007, which claims priority to Chinese Patent Application No. 200710040912.1, filed on May 18, 2007, the entire contents of both of which are incorporated herein by reference.TECHNICAL FIELD [0002] The present application relates to a process for stereoselective synthesis of Lamivudine. BACKGROUND OF THE INVENTION [0003] Lamivudine is a nucleoside reverse transcriptase inhibitor, and is a kind of deoxycytidine analogue, which can inhibit the reproduction of Human immunodeficiency virus (HIV) and hepatitis B virus (HBV), whose chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-1H-pyrimidin-2-one, and structural formula is as follows: [0004] In 1990, Belleau et al firstly reported Lamivudine structure, and BioChem Pharma of Canada firstly developed Lamivudine to be used to treat AIDS (WO91 / 17159) and hepa...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & AuthorityApplications(United States)
IPC IPC(8): C07D239/36
CPCC07D411/04C07D327/04Y02P20/55A61P31/18A61P31/20A61P43/00
InventorLI, JINLIANGLV, FENG
OwnerJIANGSU PUXIN PHARMA CO LTD