A kind of heterogeneous synthesis method and application of ritonavir intermediate

A technology for ritonavir and intermediates, which is applied in the field of pharmaceutical synthesis, can solve problems such as increasing production cost and technological difficulty, and achieves the effects of improving production safety, reducing harm and reducing water content.

Active Publication Date: 2018-06-05
厦门蔚嘉制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All these factors greatly increase the production cost and process difficulty

Method used

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  • A kind of heterogeneous synthesis method and application of ritonavir intermediate
  • A kind of heterogeneous synthesis method and application of ritonavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In a 1000ml four-necked bottle, dissolve 30g (0.18mol) of L-valine methyl ester hydrochloride and 18-21.2g of triphosgene in 270ml of dichloromethane, and add it dropwise under nitrogen protection at 5-10°C Add 480ml of 1.2M sodium bicarbonate aqueous solution (0.57mol) and finish adding in about 1h and 10min; then raise the temperature to 35-40°C, keep stirring for 1h to react and generate isocyanate compound (S)-(-)-2-isocyanate Acyl-3-methylbutyric acid methyl ester; Then add 32g of 2-isopropyl-4-(methylaminomethyl)thiazole hydrochloride in batches at 35~40°C, during the addition process use 50g of 10% sodium hydroxide solution was used to adjust the pH value to be stable at 6; after the dropwise addition was completed, the temperature was kept at 35-40°C for 1 hour; after the reaction was monitored by HPLC, the liquid was separated, and the aqueous phase was extracted with 100g of dichloromethane, and the extract was mixed with the organic phase Combined, then washe...

Embodiment 2

[0033] In a 1000ml four-necked bottle, dissolve 30g (0.18mol) of L-valine methyl ester hydrochloride and 18-21.2g of triphosgene in 270ml of dichloromethane, and add it dropwise under nitrogen protection at 10-20°C Add 480ml of 1.2M sodium bicarbonate aqueous solution (0.57mol) and finish adding in about 1 hour; then raise the temperature to 30°C, keep stirring for 1 hour to react to generate isocyanate compound (S)-(-)-2-isocyanato-3 - methyl methyl butyrate; then add 32 g of 2-isopropyl-4- (methylaminomethyl) thiazole hydrochloride in batches at 30°C, use 50 g of 10% hydrogen during the addition The sodium oxide solution was used to adjust the pH value to be stable at 6; after the dropwise addition was completed, the temperature was kept at 30°C for 1 hour; after the reaction was monitored by HPLC, the liquid was separated, and the aqueous phase was extracted with 100g of dichloromethane, the extract was combined with the organic phase, and then 200g of 15 Wash once with % s...

Embodiment 3

[0035] In a 1000ml four-neck flask, dissolve 30g (0.18mol) of L-valine methyl ester hydrochloride and 21g of triphosgene in 270ml of dichloromethane, and add 480ml of it dropwise under nitrogen protection at 20-28°C It is 1.2M sodium bicarbonate aqueous solution (0.57mol), about 1h to add; then keep stirring for 1h to react to generate isocyanate compound (S)-(-)-2-isocyanato-3-methylbutyric acid methyl ester; Then add 32g of 2-isopropyl-4-(methylaminomethyl)thiazole hydrochloride in batches at 20~28°C, adjust the pH value with 10% sodium hydroxide solution of 50g in the process of adding Stable at 6; after the dropwise addition, keep warm at 20-28°C for 1 hour; after the reaction is monitored by HPLC, separate the liquids, extract the aqueous phase with 100g of dichloromethane, combine the extract with the organic phase, and then use 200g of 15% sodium chloride The solution was washed once; the liquid was separated, and the organic phase was evaporated to dryness under reduce...

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Abstract

The invention discloses a heterogeneous synthetic method and application of a Ritonavir intermediate. The heterogeneous synthetic method comprises the following steps: dissolving L-valine methyl ester hydrochloride and triphosgene in dichloromethane by utilizing a heterogeneous method; adding inorganic alkali liquor dropwise at a low temperature to generate isocyanate compounds; adding 2-isopropyl- 4-(methyl amino methyl) thiazole into a pot without separating to obtain N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)formyl)methyl-L-valine. According to the heterogeneous synthetic method, one-pot synthesis of the Ritonavir intermediate MTV methyl ester is realized; all products can be purified through pulping and crystallizing; the purity of the products is higher than 98 percent. The pollution in a production process is low; the heterogeneous synthetic method has low harm to an operator, and is beneficial to environment, easy to operate, and particularly suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a heterogeneous synthesis method of a ritonavir intermediate and an application thereof. Background technique [0002] N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)formyl)-L-valeryl, an important intermediate of anti-AIDS drug Ritonavir Amino acid methyl ester, a large number of reports are under anhydrous conditions, react with excess phosgene and primary amine, use organic base (pyridine (Py), triethylamine) under the environment that methylene chloride (DCM) or toluene (Toluene) exist amine, diisopropylethylamine, etc.) to prepare isocyanate compound (S)-(-)-2-isocyanato-3-methylbutyric acid methyl ester; then the purified isocyanate compound is mixed with 2 -Isopropyl-4-(methylaminomethyl)thiazole reacts to generate N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)formyl)- L-valine methyl ester, the reaction formula is as follows: [0003] [0004...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/28
CPCC07D277/28
Inventor 侯鹏翼李泽敏
Owner 厦门蔚嘉制药有限公司
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