Lamivudine diastereoselective synthesis method

A technology of lamivudine and synthetic method, which is applied in the direction of drug combination, digestive system, organic chemistry, etc., can solve the problems that are not conducive to the health of operators, strong triethylamine, expensive raw materials, etc.

Active Publication Date: 2009-09-30
湖南千金湘江药业股份有限公司
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  • Claims
  • Application Information

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Problems solved by technology

Then use iodotrimethylsilane as a Lewis acid to couple cytosine through a carbon-nitrogen bond, and use the reducing agent lithium aluminum hydride to reduce the final product lamivudine. The total yield of this method is not high, and the chemical raw materials used more expensive
[0006] Chinese patent CN03135330.4 discloses titled "the diastereoselective preparation method of lamivudine", which introduces the photoactive alcohol ester of glyoxylic acid as the starting material and 2,5-dihydroxy-1,4- Dithiothiane is condensed to obtain trans-5-hydroxyl-1,3-oxathiolane-2-carboxylate, which is condensed with silanized N-acetylcytosine under the action of alkali after halogenation, Then obtain lamivudine by reduction, ammonia solution, etc., the raw materials used are expensive, and lamivudine has high solubility in water, making it difficult to effectively separate them in water
[0010] The patent discloses a diastereoselective synthetic method of nucleoside analogs, but does not directly provide a diastereoselective synthetic method of lamivudine. Those skilled in the art know based on common knowledge that nucleoside analogs include lamivudine. A large class of macromolecular compounds including vudine, on its basis, the main problem to be solved in the industrialize

Method used

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Embodiment 1

[0050] A preparation method of lamivudine. Its production method is:

[0051] step 1:

[0052] Preparation of trans 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester (i.e. intermediate III):

[0053]

[0054] In a 500mL three-necked flask, add 17.5mL (0.1mol) L(-) menthol, 50% 18.4g (0.1mol) glyoxylic acid monohydrate, 200mL isopropyl ether and 3mL concentrated sulfuric acid, reflux reaction under vigorous stirring After 10 hours, change the condenser tube to a water separator, and slowly separate a certain amount of water. After cooling slightly, add 15.2g (0.1mol) of 2,5-dihydroxy-1,4-dithiane, and the mixture is refluxed for 3 hours , cooled, filtered with suction, the filtrate was concentrated under reduced pressure to 100mL and then cooled at 0-5°C, slowly added 2mL of triethanolamine in 200mL n-heptane solution, stirred at the same temperature for 8h, filtered with suction, and the filter cake was washed with a small amount of isopropyl Was...

Embodiment 2

[0072] The other steps of Example 2 are the same as in Example 1, except that 4-amino-1-(2R-hydroxymethyl-[1,3]oxathiolane-5S-yl)-1H-pyrimidine in step 4 The preparation of -2-ketone monoaspirin salt (i.e. intermediate VI) is as follows:

[0073] Add 38.1g (0.1mol) 5S-cytosine-1'-yl-1,3-oxathiolane-2-carboxylic acid-(1'R, 2'S, 5'R) to a 500mL three-necked flask Menthyl ester (i.e. intermediate V), 200mL tetrahydrofuran, under stirring, add 5.4g (0.1mol) potassium borohydride and 4.2g (0.1mol) lithium chloride, stir at room temperature for 15h, and slowly add 10mL of 10% dilute Hydrochloric acid, stirred for 10 min, filtered, the filtrate was evaporated to dryness under reduced pressure, the residue was added to 200 mL of water, the aqueous layer was extracted with isopropyl ether (100 mL x 3) to remove menthol, 19.8 g (0.11 mol) of aspirin was added, and heated to 70 ° C to obtain The solution was clarified, placed in the refrigerator for crystallization, filtered, and dried ...

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Abstract

A lamivudine diastereoselective synthesis method, which takes chiral auxiliary agent L-menthol as the initial material, synthesizes trans-5-hydroxyl-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester under the action of concentrated sulfuric acid, choose triethanolamine to obtain trans-isomer trans-5-hydroxyl-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester, and let the trans-isomer to react with acylating agent to obtain trans-5-acetoxy-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthol ester, glycosidate with cytosine under the action of alkali to obtain 5S-cytosine-1'-radical-1, 3-oxygen thiacyclopentane-2-carboxylic acid-(1'R, 2'S, 5'R) menthyl ester, and then deoxidize with a deoxidizer, and salifying with aspirin, to ionize and liberate lamivudine. Since triethanolamine is added as in the course of reaction interconverting agent, the yield of lamivudine is increased greatly. Aspirin is added in the course of reaction, so that the lamivudine forms an aspirin salt that has poor water solubility, and therefore can effectively separate and liberate lamivudine from the medium.

Description

Technical field: [0001] The invention relates to a production method of nucleoside analogs, in particular to a diastereoselective synthesis production method of lamivudine. Background technique: [0002] Lamivudine (lamivudine, Zeffix, chemical name: 2,3-dideoxy-3-thiocytosine, referred to as 3TC) is a nucleoside analog and a viral DNA reverse transcriptase inhibitor. For chronic hepatitis B, the treatment of patients with proven decompensated liver disease or histologically confirmed active and (or) fibrosis. Its chemical structure is: [0003] [0004] Lamivudine, a novel deoxynucleoside analog, is (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl )-2(1H)-Pyrimidinone is one of the four optical isomers of the cis left-handed optical enantiomer, which is a new generation of nucleoside antiviral drugs superior to the anti-HIV drug AZT. It has obvious effects on human immunodeficiency virus HIV and has been approved by dozens of countries to treat AIDS. Since 199...

Claims

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Application Information

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IPC IPC(8): C07D411/04A61P31/20A61P1/16A61P31/18
Inventor 张瑞华袁秀菊刘友先王朝磊姚亮元徐义权王雪姣
Owner 湖南千金湘江药业股份有限公司
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