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Novel process for preparing emtricitabine intermediate

A technology of emtricitabine and intermediates, which is applied in the field of drug synthesis, can solve the problems of high corrosiveness of reagents, low silanization yield, and low purity of compounds, and achieve the effects of low corrosiveness, high purity, and extended service life

Inactive Publication Date: 2016-12-07
XIAMEN CITY WEI JIA CHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the process conditions reported in the current literature are harsh, the reagents are highly corrosive, and the low yield of 5-fluorocytosine (4) through silanization leads to an extremely low total yield; Recrystallization to obtain qualified products

Method used

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  • Novel process for preparing emtricitabine intermediate
  • Novel process for preparing emtricitabine intermediate
  • Novel process for preparing emtricitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053]

[0054] Add DMF (33.5kg, 444.5mol) in reactor, methylene dichloride 725kg, N 2The temperature was lowered to 0°C under protection, and a solution of triphosgene (46kg, 155mol) in dichloromethane (325kg) was added dropwise within about 2.5 hours. After the addition was completed, (2R,5R)-5-hydroxyl-1 was added in batches within 1 hour , 3-Oxathiolane-2-carboxyl-menthyl ester (2) (125kg, 433.5mol), after the addition was completed, it was stirred at 18°C ​​to 20°C for 1 hour, and the feed liquid was a light yellow solution.

Embodiment 2

[0056]

[0057] Add 56.25kg (403.5mol) of 5-fluorocytosine to the reactor, 30.3kg (201.7mol) of sodium iodide, ammonium sulfate (0.75kg, 5.65mol), hexamethyldisiloxane (75kg, 464.7mol) , 300kg of dichloromethane, the suspension was heated to reflux, and after 6 hours, a light yellow clear liquid was obtained.

Embodiment 3

[0058] The preparation technology of the compound described in embodiment 3 formula (1)

[0059]

[0060] 1. Add DMF (33.5kg, 444.5mol), dichloromethane 725kg, N 2 The temperature was lowered to 0°C under protection, and a solution of triphosgene (46kg, 155mol) in dichloromethane (325kg) was added dropwise within about 2.5 hours. After the addition was completed, (2R,5R)-5-hydroxyl-1 was added in batches within 1 hour , 3-oxathiolane-2-carboxyl-menthyl ester (2) (125kg, 433.5mol), after the addition was completed, it was kept stirring at 18°C ​​to 20°C for 1 hour, and the feed liquid was a light yellow solution.

[0061] 2. Add 56.25kg (403.5mol) of 5-fluorocytosine, 30.3kg (201.7mol) of sodium iodide, ammonium sulfate (0.75kg, 5.65mol), hexamethyldisiloxane (75kg , 464.7mol), dichloromethane 300kg, the suspension was heated to reflux, and after 6 hours, a pale yellow clear liquid;

[0062] 3. Cool down to 25°C, add the second-step feed solution below 30°C, a lot of white...

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Abstract

The invention provides a novel process for preparing an emtricitabine intermediate, namely, a compound shown in the formula (1) in the description, and relates to the field of medicine synthesis. The novel process includes the steps that (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxy l-menthyl ester is subjected to triphosgene chlorination and reacts with 5-flucytosine protected with silane, and then the fine compound in the formula (1) is obtained through hydrolysis and crystallization with acetonitrile. The total yield reaches 85% or above, the purity is 99.7% or above, andany individual impurity is 0.2% or below; triphosgene replaces thionyl chloride for chlorination of (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxy l-menthyl ester, operation is convenient, corrosivity is small, and the service life of equipment can be prolonged; sodium iodide is added into a silanization reaction of 5-flucytosine, and the yield is greatly increased.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a new process for preparing an emtricitabine intermediate. Background technique [0002] Emtricitabine (emtricitabine), the chemical name is 4-amino-5-fluoro-1-[(2R,5S)-2-hydroxymethyl-1,3-oxathiolan-5-yl]-2 (1H)-pyrimidinone, its structural formula is as shown in formula (a), [0003] It is an HIV reverse transcriptase inhibitor developed by Gilead Sciences of the United States. It was first launched in the United States in July 2003 and is clinically used to treat AIDS and hepatitis B. [0004] Emtricitabine is generally prepared by reduction of formula (1) [0005] [0006] At present, there are reports in the literature that route 1 is used to synthesize the compound shown in formula (1): (2R,5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid l-mentyl ester (2) Halogenation to obtain (2R,5R)-5-hydroxy-1,3-oxathiolane-2-carboxylic acid l-mentyl ester (3); 5-fluorocytosine (...

Claims

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Application Information

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IPC IPC(8): C07D327/04C07F7/18C07D411/04
CPCC07D327/04C07D411/04C07F7/18
Inventor 侯鹏翼
Owner XIAMEN CITY WEI JIA CHEM TECH CO LTD
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