A kind of synthetic method of lamivudine intermediate

A synthesis method and cytosine technology, applied in the field of synthesis of lamivudine intermediates, can solve problems affecting the health and safety of operators, polluting the environment, and high toxicity of raw materials, achieving low production costs, simplified reaction steps, The effect of saving production cost

Inactive Publication Date: 2011-12-28
浙江教育学院 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this reaction, due to the use of thionyl chloride as the chlorination reagent, the raw materials are highly toxic. At the same time, a large amount of sulfur dioxide waste gas is generated during the reaction process, which seriously corrodes the equipment and seriously pollutes the environment, affecting the health and safety of operators.

Method used

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  • A kind of synthetic method of lamivudine intermediate
  • A kind of synthetic method of lamivudine intermediate
  • A kind of synthetic method of lamivudine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]Preparation of chlorinated compounds: in a 250mL three-necked flask, add (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol), N,N-dimethylformamide 7.3g, 100mL dichloromethane, and keep stirring until compound III dissolves. Cool to about 0°C, control the temperature at 5-10°C, add dropwise a mixed solution of 11.9 grams (0.04mol) of bis(trichloromethyl)carbonate in 50mL of dichloromethane, and slowly heat up to 30-35°C, keep warm for 2 hours. The resulting reaction solution is a chloride (compound IV) solution, ready for use.

[0028] Preparation of N,O-bis(trimethylsilyl)cytosine: In a 500mL three-necked flask, add 11.1 grams (0.1mol) of cytosine, 24.5 grams of hexamethyldisilazane, 100mL of toluene, 3 drops of methanesulfonic acid, Heated to reflux for 3 hours until the solution was clear and cooled slightly. This was a toluene solution of N,O-bis(trimethylsilyl)cytosine.

[0029] Preparation of (2R, 5S)-5-(cytos...

Embodiment 2

[0032] Preparation of chlorinated compounds: in a 250mL three-necked flask, add (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol), N,N-dimethylformamide 7.3g, 100mL dichloromethane, and keep stirring until compound III dissolves. Cool to about 0°C, control the temperature at 5-10°C, add dropwise a mixed solution of 14.9 grams (0.05mol) of bis(trichloromethyl)carbonate in 50mL of dichloromethane, and slowly heat up to 30-35°C, keep warm for 2 hours. The resulting reaction solution is a chloride (compound IV) solution, ready for use.

[0033] Preparation of N, O-bis(trimethylsilyl)cytosine: Same as Example 1.

[0034] Preparation of (2R, 5S)-5-(cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester: same as Example 1

[0035] Post-treatment: Same as Example 1, to obtain 26.8 g of white solid product, HPLC purity: 99.02%, chiral purity: 99.15%, melting point: 218.0-218.9°C, yield: 70.34%.

Embodiment 3 1

[0036] Embodiment 3 one pot method

[0037] In a 500mL three-neck flask, add 11.1g (0.1mol) of cytosine, 24.5g of hexamethyldisilazane, 100mL of toluene, and 3 drops of methanesulfonic acid, and heat to reflux for 3 hours until the solution is clear. This is N,O- Bis(trimethylsilyl)cytosine in toluene. Cool slightly, add 7.3g (0.1mol) of N,N-dimethylformamide, 12g of triethylamine, at a temperature of about 15-20°C, slowly add the (2R,5R)-5-hydroxy -1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and bis(trichloromethyl)carbonate 11.9 grams (0.04mol) were dissolved in 150mL of dichloromethane mixed solution, after dripping, keep warm for 3 hours, then slowly raise the temperature to 40-45°C, and react for 8 hours. Stop responding.

[0038] Post-processing: Pour the reaction solution into a mixed solution containing 100 g of water, 12 g of triethylamine, and 60 g of n-hexane, stir for 8 hours, filter, and rinse the resulting solid with 10...

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Abstract

The invention discloses a lamivudine intermediate, that is, (2R,5S)-5-(5-cytosine-1-yl)-1,3-oxothioheterocycle with the structure shown in formula (VI) The synthetic method of pentane-2-carboxylic acid-L-menthyl ester is based on (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2 as shown in formula (III) -Carboxylic acid-L-menthyl ester is raw material, obtains structure as the chlorinated product shown in formula (IV) by chlorination reaction, chlorinated product (IV) and structure as shown in the N of formula (V), O-bis( Trimethylsilyl) 5-cytosine condensation, hydrolysis in the system. The present invention uses bis(trichloromethyl)carbonate instead of thionyl chloride in the prior art as the chlorination reagent, and has the advantages of safe and reliable operation, and environmental protection.

Description

(1) Technical field [0001] The present invention relates to a synthetic method of a lamivudine intermediate, in particular to (2R, 5S)-5-(cytosine-1-yl)-1,3-oxathiolane-2-carboxylic acid- Synthetic method of L-menthyl ester. (2) Background technology [0002] Lamivudine (compound I) is a drug raw material with good antiviral activity, mainly used for hepatitis B and anti-AIDS virus, and is the main active ingredient in the current cocktail therapy for hepatitis B and AIDS. [0003] Lamivudine has two chiral carbons, and its synthesis process involves stereoselective synthesis. There are many reports on its synthesis, and the main routes are: [0004] (1) take L-gulose as the synthetic route of raw material (Beach, J. et al, J.Org. Chem., 57 (8), 2217-19 (1992); Humber, David C. et al Tetrahedron Lett. , 33(32), 4625-28(1992)); (2) the synthetic route (David C., et al, Tetrahedron Lett., 33( 32), 4625-28(1992)); (3) take glyoxylic acid, 1,4-dithiane-2,5-diol as the synthet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D411/04
Inventor 游金宗蒋善会
Owner 浙江教育学院
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