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Preparation method of lamivudine

A technology of lamivudine and reaction time, which is applied in the direction of organic chemistry, etc., can solve the problems such as the optical purity of the product does not meet the medicinal standard, the raw materials and reagents are expensive, and are not suitable for industrial production, etc. Short, high atom utilization effect

Active Publication Date: 2019-03-08
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw materials and reagents used in this method are expensive, high in cost, poor in repeatability, low in total yield, and the optical purity of the obtained product cannot reach the pharmaceutical standard, so it is not suitable for industrial production

Method used

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  • Preparation method of lamivudine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of (1R,2S,5R)-2-isopropyl-5-R-methyl-1-cyclohexyl chloroformate 2:

[0048] Add 15.60g (0.1mol) L-menthol and 156ml dichloromethane to a round-bottomed three-necked flask equipped with mechanical stirring, a thermometer, a constant-pressure feeding funnel and an exhaust gas absorption device, stir to fully dissolve, and cool to -5°C , add 14.84g (0.05mol) triphosgene and continue stirring to make it fully dissolved, then dropwise add a solution of 37.44g triethylamine and 78ml dichloromethane, and the dropwise addition is completed in about 1.5 hours. Incubate the reaction for 2 hours, enter the second reaction stage, be warming up to 25 ° C, and stir the reaction for about 6 hours. After the reaction is completed, the precipitate is separated by filtration. Washed with brine, dried with anhydrous sodium sulfate, and finally rectified under reduced pressure to collect 95-96°C, 5 mmHg fractions to obtain 19.73 g of colorless oily compound 2, with a yield of 9...

Embodiment 2

[0050] Preparation of but-2-ene-1,4-diylbis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)bis(carbonate)4:

[0051] In a round-bottomed three-necked flask equipped with a mechanical stirring, a thermometer, and a constant-pressure feeding funnel, add 4.93g (0.052mol) butenediol, 30ml dichloromethane, stir well, cool to 0°C in an ice-water bath, add 6.48g triethyl ether amine, stir evenly, dissolve the obtained 21.88g (0.10mol) of compound 2 in 45ml of dichloromethane and slowly add it dropwise to the three-necked flask, stir and react for 1 hour, separate out the precipitate by filtration, and wash the mother liquor with saturated sodium bicarbonate solution, It was then dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 18.98 g of compound 4 with a yield of 84%. 1 H-NMR (CDCl 3 )δ: 5.88(t, 2H), 4.77(d, 4H), 4.51(m, 2H), 1.83(m, 2H), 1.75-1.50(t, 4H), 1.63-1.38(m, 8H), 1.54 (m, 2H), 1.41 (m, 2H), 0.86 (d, 6H), 0.83 (d, 12H). Elemental Analysis C 26 O...

Embodiment 3

[0053] Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(2-oxoethyl)carbonate:

[0054] Add 2.52g (0.01mol) tungstic acid, 17.41ml (0.30mol) 50% H to a round-bottomed three-necked flask equipped with mechanical stirring and a thermometer in turn 2 0 2 Aqueous solution, 83ml of n-butanol solution, stirred for half an hour, then added 22.59g (0.05mol) of compound (4) obtained, stirred evenly, heated to 80°C, reacted for 5 hours, removed the catalyst by centrifugation, extracted, and the organic phase was dried with anhydrous After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 18.83 g of compound 5 in a yield of 79%. 1 H-NMR (CDCl 3 ) δ: 9.65(s, 2H), 4.67(s, 2H), 4.51(m, 1H), 2.10(m, 1H), 2.00(m, 1H), 1,70(m, 2H), 1.51(m , 2H), 1.28 (m, 1H), 1.12 (m, 2H), 0.9 (m, 6H), 0.81 (d, 3H). Elemental Analysis C 13 H 22 O 4 Measured value (%): C65.48, H9.15, 026.40; Theoretical value (%) C64.44, H9.15, O26.41.

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Abstract

The invention discloses a preparation method of lamivudine. The method comprises the steps of obtaining pure 5S-(cytosinyl-1')-1,3-oxathiolane-2-ethoxycarbonyl-(1'R,2'S,3'R)-menthyl ester through refining; removing chiral aid L-menthol in the presence of a weak base and a solvent to obtain a lamivudine product. The raw materials are cheap and readily available, the reagents used are environmentally friendly, the steps are short, the reaction conditions are mild, the atomic utilization rate is high, the yield is high, the obtained product has high chemical purity and meets the medicinal standards, and the preparation method is suitable for large-scale production of lamivudine.

Description

technical field [0001] The invention relates to the technical field of drug synthesis. Specifically relates to a preparation method of lamivudine. Background technique [0002] Lamivudine (Lamivudine, 3TC) is a nucleoside reverse transcriptase inhibitor developed by Canadian Biochem Pharma company, and its chemical name is: (2R)-hydroxymethyl-(5S)-(cytosine-1'- Base)-1,3-oxathiolane was approved by the US FDA in November 1995 for the treatment of human immunodeficiency virus (HIV). In 1998, it was approved for the treatment of hepatitis B virus (HBV). Its mechanism of action is to inhibit the activity of HIV-1 reverse transcriptase by phosphorylating it into 5'-triphosphate by cellular enzymes and then competing with the deoxy 5'-triphosphate substrate, and binding to viral DNA to cause chain termination, thereby achieving inhibition The role of the virus. Combining lamivudine with other antiviral drugs has a synergistic effect, which can increase sensitivity and reduce ...

Claims

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Application Information

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IPC IPC(8): C07D411/04
CPCC07D411/04
Inventor 刘生鹏顾继山吴晓宇许莉莉熊芸孙国锋丁一刚
Owner WUHAN INSTITUTE OF TECHNOLOGY
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