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Preparation method of lamivudine and intermediate thereof

A technology for lamivudine and intermediates, applied in the directions of organic chemistry, antiviral agents, etc., can solve the problems of introduction, corrosion of equipment, complicated operation, etc., and achieve the effects of simplified process steps, low production cost, and safe and reliable operation.

Active Publication Date: 2012-09-05
SHANDONG WEIFANG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses thionyl chloride to synthesize chlorinated compounds, and the raw material is highly toxic. At the same time, a large amount of sulfur dioxide waste gas is produced in the reaction process, which seriously corrodes equipment and pollutes the environment; the reaction yield of chlorinated compounds and cytosine is not high, and the operation is complicated, and salicylic acid is introduced Impurities

Method used

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  • Preparation method of lamivudine and intermediate thereof
  • Preparation method of lamivudine and intermediate thereof
  • Preparation method of lamivudine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] (1) Synthesis of (2R, 5R)-5-acetyl-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl) ester

[0021]

[0022] 28.8g (2R, 5R)-5-hydroxyl-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl) ester, 12.2g Acetic anhydride, 0.1g DMAP, 8.2g pyridine, and 57.6g dichloromethane were added to a 100ml reaction bottle, stirred at 40°C until the raw materials were completely reacted, the reaction solution was concentrated to dryness, and the residue was crystallized with petroleum ether to obtain 29.7g of white needle-like solid. Yield 90.0%.

[0023] (2) Synthesis of (2R, 5R)-5-acetyl-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl) ester

[0024]

[0025] 28.8g (2R,5R)-5-hydroxyl-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl)ester, 9.4g Add acetyl chloride, 8.2g pyridine, 0.1g DMAP, and 57.6g dichloromethane into a 100ml reaction bottle, stir at 10°C until the raw materials ar...

Embodiment 2

[0036] (2R,5S)-5-(4-Amino-2-oxopyridin-1-yl)-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl Synthesis of 1R-cyclohexyl) ester

[0037]

[0038] (1) Heat 13.3g of cytosine, 27.9ml of hexamethylaziasilane, 0.08ml of methanesulfonic acid, and 33.0ml of toluene to reflux. After complete dissolution, nitrogen protection is used to cool down, and 33g of (2R, 5R)-5-acetyl- [1,3] Oxathiolane-2-carboxylic acid (2S-isopropyl-5R-methyl-1R-cyclohexyl) ester and 84ml methylene chloride solution, add 40g iodotrimethylsilane dropwise, After the drop is completed, lower the temperature at 35-40°C until the reaction of the raw materials is complete, then add hydrochloric acid dropwise to pH ≈ 2.5, and keep at 30-35°C. After dripping, stir for 1 hour, filter, the filter cake becomes granular, wash the filter cake with saturated sodium bicarbonate, and dry to obtain 33.5 g of white solid, yield 88.0%, melting point: 219°C (decomposition).

[0039] (2) Heat 13.3g of cytosine, 27....

Embodiment 3

[0043] Synthesis of Lamivudine

[0044] 38.1g (2R, 5S)-5-(4-amino-2-oxopyridin-1-yl)-[1,3]oxathiolane-2-carboxylic acid (2S-isopropyl-5R -Methyl-1R-cyclohexyl) ester and 250ml of absolute ethanol mixture were stirred at 15-20°C, and 7.6g of sodium borohydride was added in batches, and the temperature was kept at 15-20°C and stirred for 2 hours, and the reaction was completed by TLC monitoring, 40 Concentrate the reaction solution at ℃ to dryness, add 10 ml of water and 100 ml of n-hexane, stir for 30 minutes at 20-25 °C, separate the n-hexane, filter to obtain crude lamivudine, recrystallize from absolute ethanol to obtain lamivudine 16.1, and obtain rate 70.3%, 1 H-NMR (600MHz, DMSO): δ3.055(1H, dd), δ3.409(1H, dd), δ3.704(2H, m), δ5.174(1H, t), δ5.321(1H , t), δ5.739(1H, d), δ6.209(1H, t), δ7.244(2H, s), δ7.823(1H, d), 13 C-NMR (600MHz, DMSO): δ36.967, δ63.523, δ86.508, δ87.217, δ94.621, δ141.656, δ155.390, δ166.337.

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Abstract

The invention discloses a preparation method of lamivudine and an intermediate thereof; (2R,5R)-5-hydroxyl-[1,3]oxathiolane-2-carboxylicacid(2S-isopropyl-5R-methyl-1R-cyclohexyl)ester, the structure of which is shown in formula (II) is used as a raw material; acyl compound, the structure of which is shown in formula (III) is obtained by the acylation reaction of acyl; acyl compound (III) reacts with cytimidine, the structure of which is shown in formula (IV) by condensation reaction to prepare the intermediate of lamivudine (V) and the intermediate is reducted to obtain lamivudine (I). The invention is characterized by safe and reliable operation, simplified process, low production cost and the like, thus being suitable for industrialized production.

Description

(1) Technical field [0001] The invention relates to a preparation method of lamivudine and its intermediate. (2) Background technology [0002] Lamivudine is a pharmaceutical raw material with good antiviral activity. It is mainly used for hepatitis B and anti-AIDS virus. It is the main active ingredient in the current treatment of hepatitis B and AIDS cocktail therapy. Its synthesis needs to pass through the synthesis transition of intermediates. [0003] US5047407 discloses entitled "2-substituted-5-substituted-1,3-oxathiolaneswith antiviral properties", the method uses 2-bromodiethoxyethane as raw material, reacts with thiobenzoic acid and hydrolyzes sodium hydroxide Obtain 2-mercaptodiethoxyethane, react with benzoyloxyacetaldehyde to obtain 2-benzoyloxymethyl-5-ethoxyl-1,3-oxathiolane, and then in trifluoro Under the catalysis of trimethylsilyl methanesulfonate, react with cytosine protected with trimethylsilane, acetylate, remove the trans-form by column chromatograph...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D411/04A61P31/20A61P31/18
Inventor 邓兵刘云峰公维国林吉茂
Owner SHANDONG WEIFANG PHARMA FACTORY
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