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Process for synthesizing ritonavir

A technology of ritonavir and amino group, which is applied in the field of synthesizing ritonavir, can solve the problems affecting thiazole methylamine group, difficult control of hydrogenolysis debenzyl group selectivity, selectivity problems, etc., to achieve reaction specificity Strong, improved atomic utilization, and cost-reducing effects

Inactive Publication Date: 2004-12-15
XIAMEN UNIV
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Problems solved by technology

[0011] The limitation of method 1 is the selectivity problem during the monoacylation of diaminoalcohol under the protection of boron reagent and the trouble of purification of the product
However, since the hydrogenolysis of compound 11 will affect the thiazole methylamine group at the other end, the selectivity conditions for hydrogenolysis to benzylation are not easy to control

Method used

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  • Process for synthesizing ritonavir
  • Process for synthesizing ritonavir
  • Process for synthesizing ritonavir

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Embodiment Construction

[0022] Below by embodiment the present invention will be further described.

[0023] Step 1 Benzylaminoalcohol 1 (696mg, 1.5mmol) was dissolved in anhydrous dichloromethane (30ml). Cool to -20°C. A solution of N-carboxylic acid internal anhydride 8 in dichloromethane (2.25ml, 2.25mmol) was slowly added dropwise. After the addition was complete, 30 ml of a dichloromethane solution of triethylamine (0.27 ml, 1.92 mmol) was slowly added dropwise over 10 min. React at -13~-17°C for 2 hours. Adjust the pH to 4 with concentrated hydrochloric acid. Adjust the pH to 8-9 with saturated sodium bicarbonate solution. wash. Dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 991 mg of valyl ampicillin.

[0024] 1 H NMR (CDCl 3 , 500MHz) δ7.05-7.35(m, 20H), 4.12(m, 1H), 3.90(d, J=13.3Hz, 2H), 3.57(dt, J=2.2×8.1Hz, 1H), 3.38(d , J=14.2Hz, 2H), 3.10(d, J=4.1Hz, 1H), 3.04(dd, J=14.2×5.8Hz, 1H), 2.62-2.82(m, 4H), 2.15(m, 1H) , 1.57(m, 2H), 1.53(m, 2H), 1.3...

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Abstract

The present invention relates to the synthesis process of Ritonavir as one proteinase inhibitor for resisting AIDS. The synthesis process includes the condensation between benzylamino alcohol and valine NCA to obtain valyl benzylamino alcohol, the reaction between valyl benzylamino alcohol and ditert-butyl dicarbonate to obtain tert-butoxy acyl valyl benzylamino alcohol, the hydrogenolysis and debenzylation of tert-butoxy acyl valyl benzylamino alcohol in ammonium formate and Pd-C to obtain tert-butoxy acyl valyl amino alcohol, the active esterification reaction between tert-butoxy acyl valyl amino alcohol and 5-methylol thiazole, subsequent hydrolysis to obtain thiazolyl-5-methoxycarbonyl valyl amino alcohol, and the reaction of thiazolyl-5-methoxycarbonyl valyl amino alcohol and isopropyl thiazolyl methylamine under the action of BTC to obtain final product Ritonavir. The present invention has lowered cost and raised atomic utilization.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing ritonavir, an anti-AIDS protease inhibitor. (2) Background technology [0002] Ritonavir, chemical name: (5S, 8S, 10S, 11S)-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4- Thiazolyl]-3,6-dioxo-8,11-bis(benzyl)-2,4,7,12-tetraazatridecyl-13-carboxylic acid, 5-thiazole methyl ester (CAS No. 155213-67-5) is a protease inhibitor against AIDS HIV-1 and HIV-2 (Proc. Natl. Acad. Sci. USA, 1995, 92, 2484). The structural formula of ritonavir is as follows: [0003] [0004] From the structural analysis of ritonavir, it can be divided into four fragments. I is a fragment of 5-hydroxythiazole, IV is a fragment of isopropylthiazole methylamine, III is a fragment of valine, and II is a fragment of chiral aminoalcohol. According to patents and literature reports, the synthesis of ritonavir includes the following processes: (a) synthesis of two thiazole fragments (I and IV), (b) synthesis of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P31/18C07D277/28
Inventor 靳立人许志杰蒋洪平
Owner XIAMEN UNIV