Industrial preparation method for lamivudine

Abstract

The invention discloses an industrial preparation method for lamivudine (3TC). The method is characterized in that: 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1<,>R, 2<,>S, 5<,>R)-5<,>-methyl-2<,>-(1-methylethyl) cyclohexyl] ester reacts with a acylating agent to obtain a acylate; the acylate and monosilylated acyl cytosine or monosilylated cytosine schiff's base are subjected to a glycosylation through a catalysis of lewis acid to obtain a 3TC intermediate, followed by reducing and deacylating or hydrolyzing and reducing to obtain the 3TC. The method provided by the present invention has advantages of simple, available and cheap raw materials, simple operation, safe production, high yield, less waste pollution, and is applicable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemistry or pharmaceutical chemistry, and in particular relates to an industrialized preparation method of anti-hepatitis B virus drug lamivudine. Background technique [0002] Lamivudine (Lamivudine, 3TC) is shown in formula (I), and its chemical name is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane -5-yl)-1H-pyrimidin-2-one is a nucleoside analog antiviral drug. Nucleotides are the raw materials for the synthesis of human genetic material DNA and RNA. Lamivudine mimics the structure of nucleotides in structure, but it does not have the function of nucleotides. Its mechanism of action is to inhibit viral DNA polymerase and reverse transcriptase activity, and has a competitive inhibitory effect on the synthesis and elongation of viral DNA chains. Therefore, in the process of DNA synthesis, nucleoside analogs can be incorporated, but they cannot synthesize nucleic acid chains with normal functions, so that ...

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Problems solved by technology

The method prepares 5-chloro-1, and the chlorination reaction process of 3-oxathiolane-2-carboxylic acid-(-)-bornyl ester has used the thionyl chloride which is very corrosive to equipment; the reaction process Sulfur dioxide waste gas is produced, which seriously pollutes the environment; the reaction yield of chlorides and N-acetylcytosine is not high, only 66%, and the above factors are not conducive to industrial production

[0007] CN101597281A discloses a kind of preparation method of lamivudine and its intermediate, the method is in the preparation of (2R, 5R)-5-acetyl-[1,3]oxathiolane-2-carboxylic acid (2S -Use acetic anhydride, acetyl chloride in the process of -isopropyl-5R-methyl-1R-cyclohexyl) ester, although yield reaches 90% or 88.5%, the product purity that obtains is low; In preparation (2R, 5R )-5-propionyl-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl) ester using propionic anhydride, the yield 86%, in the preparation of (2R,5S)-5-(4-amino-2-oxopyridin-1-yl)-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl In the process of base-5R-methyl-1R-cyclohexyl) ester, silane reagent is used to react with cytosine to form silane double-protected cytosine, and the double-protected cytosine of disilane participates in condensation reaction, although the yield is improved, but The purity of the obtained product is relatively low, and the purity of the lamivudine prepared in this way is also low. It must be recrystallized and purified many times to meet the medicinal requirements. The operation process is cumbersome and it is difficult to realize industrial production.

[0008] The preparation method of lamivudine disclosed above still has some deficiencies. It is necessary to find a method that is simple to operate, safe and environmentally friendly, has high yield and purity, and is suitable for industrial production.

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