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A kind of preparation technology of emtricitabine intermediate

An organic solvent and flucytosine technology, which is applied in the field of preparation of emtricitabine intermediates, can solve problems such as easy hydrolysis of menthyl, poor selectivity of amide hydrolysis, and poor applicability, and achieve production costs Low, high product yield, the effect of improving selectivity

Active Publication Date: 2019-11-12
ZHEJIANG INT STUDIES UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is cumbersome, and the process is complicated, and the hydrolysis selectivity of the obtained amide is not good, which easily causes the hydrolysis of menthyl, thereby affecting the yield, so the applicability is not strong, and the process is as follows:

Method used

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  • A kind of preparation technology of emtricitabine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0059] Embodiment 1: preparation compound 22

[0060] A, the preparation of chlorinated compound: with reference to relevant literature, in the there-necked flask of 250mL, by (2R,5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester ( Compound 5) 28.8 g (0.1 mol), using dichloromethane as a solvent, prepared by thionyl chloride or bis(trichloromethyl)carbonate to obtain a dichloromethane solvent for chlorinated compounds, ready to use.

[0061] B. Preparation of Compound 21: In a 250mL three-necked flask, add 12.9 grams (0.1mol) of 5-fluorocytosine, 24.2 grams (0.15mol) of hexamethyldisilazane, 100mL toluene, N,N-dimethylformaldehyde Amide 8.8 g (0.12 mol), 2 drops of methanesulfonic acid, heat and reflux for 2 hours, until the solution is clear, cool slightly, evaporate toluene and excess hexamethyldisilazane under reduced pressure, add 80 mL of dichloromethane, triethyl 11 g (0.11 mol) of amine was heated up to dissolve, cooled to 35-40°C for use, and a dichloro...

Embodiment 2-8

[0065] In Example 1, compound 21 was prepared, 12.9 grams (0.1mol) of 5-fluorocytosine, when the amount of hexamethyldisilazane and N,N-dimethylformamide used was changed, the yield of compound 22 and purity results.

[0066] Table 1

[0067]

[0068]

Embodiment 9

[0069] Embodiment 9: Preparation of compound 22

[0070] A, the preparation of chlorinated compound: with reference to relevant literature, in the there-necked flask of 250mL, by (2R,5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester ( Compound 5) 28.8 g (0.1 mol), using dichloromethane as a solvent, prepared by thionyl chloride or bis(trichloromethyl)carbonate to obtain a dichloromethane solvent for chlorinated compounds, ready to use.

[0071] B. Preparation of Compound 21: In a 250mL three-necked flask, add 12.9 grams (0.1mol) of 5-fluorocytosine, 24.2 grams (0.15mol) of hexamethyldisilazane, 100mL toluene, N,N-dimethylformaldehyde Amide 8.8 g (0.12 mol), ammonium sulfate 0.13 g, heat to reflux for 2 hours, until the solution is clear, cool slightly, evaporate toluene and excess hexamethyldisilazane under reduced pressure, add dichloromethane 80mL, triethylamine 11 g (0.11 mol) was heated up to dissolve, cooled to 35-40°C for use, and a dichloromethane soluti...

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Abstract

The invention discloses a preparation process of an emtricitabine intermediate, namely (2R,5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-dioxathiolane-2-carboxylic acid-L-menthyl ester shown as a structural formula (I). The preparation process comprises the following steps: (A) taking 5-fluorocytosine shown as a structural formula 7 as a raw material, and enabling the 5-fluorocytosine to react with N,N-dimethylformamide shown as a structural formula 20 and hexamethyldisilazane shown as a structural formula 8 to prepare 2-O-trimethylsilyl-4-N-[(N',N'-dimethyl)amino]methylene-5-fluorocytosine shown as a structural formula 21; (B) condensing the compound 21 and a chlorine substitute shown as a structural formula 6 to generate (2R,5S)-5-(4'-N-((N',' dimethyl)amino)methylene-5'-fluoro-cytosine-1-yl)-1,3-dioxathiolane-2-carboxylic acid-L-menthyl ester shown as a structural formula 22; and (C) hydrolyzing the compound 22 in an acidic solution to prepare the compound I. According to the preparation process, side reaction can be reduced so that the purity of a product is improved and the consumption of raw materials is reduced. The formula (I) is as shown in the specification.

Description

[0001] (1) Technical field [0002] The invention relates to a preparation process of an emtricitabine intermediate, in particular to (2R,5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-oxathiolane- Synthetic method of 2-carboxylate-L-menthyl ester (ie, compound 1 hereinafter). [0003] (2) Background technology [0004] (2R,5S)-5-(5'-fluoro-cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound 1, referred to as: F -CME) is the key intermediate for the preparation of emtricitabine (compound 2). [0005] Emtricitabine (compound 2), chemical name: (2R,5S)-5-fluoro-1-[2-hydroxymethyl-1,3-oxathiolan-5-yl]cytosine, the earliest It was successfully developed by Gilead Sciences in the United States, and was approved in the United States in July 2003 for the treatment of HIV-1 infection in adults in combination with other antiretroviral drugs. It is a new nucleoside reverse transcriptase inhibitor , a highly efficient and selective inhibitor of AIDS virus HIV and hepatitis ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D411/04
CPCC07D411/04
Inventor 游金宗齐德强王学杰
Owner ZHEJIANG INT STUDIES UNIV
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