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Method for preparing emtricitabine

A technology of emtricitabine and reaction time, applied in organic chemistry methods, organic chemistry and other directions, can solve the problems of expensive raw materials and reagents, low total yield and high cost, and achieves green environmental protection reagents, mild reaction conditions, and easy operation. The effect of simple process

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

However, this method has the disadvantages of expensive raw materials and reagents, high cost, poor repeatability, low overall 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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  • Method for preparing emtricitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0048] Add 15.60g (0.1mol) L-menthol and 156ml dichloromethane into a round-bottomed three-necked flask equipped with mechanical stirring, thermometer, constant pressure addition funnel and exhaust gas absorption device, stir to make it fully dissolve, and cool to -5°C , add 14.84g (0.05mol) triphosgene and continue to stir to make it fully dissolved, then add dropwise a solution of 37.44g triethylamine and 78ml dichloromethane, and the dropwise addition is completed in about 1.5 hours. Insulate and react for 2 hours, enter the second reaction stage, raise the temperature to 25°C, stir and react for about 6 hours, after the reaction, filter and separate the precipitate, the mother liquor is sequentially passed through distilled water, 5% dilute hydrochloric acid, 5% sodium carbonate, saturated Washed with brine, dried with anhydrous sodium sulfate, finally rectified under reduced pressure, c...

Embodiment 2

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

[0051] Add 4.93g (0.052mol) butylene glycol and 30ml dichloromethane into a round-bottomed three-necked flask equipped with mechanical stirring, a thermometer, and a constant-pressure addition funnel, stir well, cool to 0°C in an ice-water bath, add 6.48g triethylene glycol Amine, stirred evenly, dissolved 21.88g (0.10mol) of compound 2 obtained in 45ml of dichloromethane and slowly added dropwise to a three-necked flask, stirred and reacted for 1 hour, filtered to separate the precipitate, and the mother liquor was washed with saturated sodium bicarbonate solution. Then it was dried with anhydrous sodium sulfate, and the solvent was distilled off 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). Elementa...

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 2 0 2 Aqueous solution, 83ml n-butanol solution, stirred for half an hour, then added 22.59g (0.05mol) of the obtained compound (4), stirred evenly, raised the temperature to 80°C, reacted for 5 hours, removed the catalyst by centrifugation, extracted, and used anhydrous After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 18.83 g of compound 5, with 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 method for preparing emtricitabine. The method comprises the following steps: refining so as to obtain 5S-(5'-flucytosine-1')-1,3-oxythiacyclopentane-2-carbethoxy-(1'R,2'S,3'R)-menthyl lactate; under a weak alkali and solvent condition, removing a chiral aid L-menthol, thereby obtaining a product of emtricitabine. The initial raw material used in the method is low in price, easy to obtain, mild in reaction condition, high in atom utilization rate and simple and convenient in operation process, the reagent is environmentally friendly, the obtained product is high in chemical purity, meets medicine standards, and is applicable to industrial production of emtricitabine.

Description

technical field [0001] The invention relates to the technical field of drug synthesis. Specifically relates to a preparation method of emtricitabine. Background technique [0002] Emtricitabine (FTC) was developed by Gilead Science of the United States and was first launched in the United States in July 2003. Its chemical name is: (2R,5S)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-2(1H)-pyrimidine ketone. It is a nucleoside reverse transcriptase inhibitor, which has good curative effect on the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Its mechanism of action is that after oral administration, it is phosphorylated into 5'-triphosphate with cell activity, and 5'-triphosphate enters the main chain of viral DNA and binds to the main chain, leading to chain termination, thereby inhibiting HIV-1 reverse transcription Enzyme and HBV DNA polymerase activity to achieve the effect of inhibiting the virus. [0003] At present, many ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D411/04
CPCC07D411/04C07B2200/07
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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