Novel method for synthesizing ritonavir

Abstract

The invention discloses a novel method for synthesizing ritonavir, and relates to the field of pharmaceutical chemistry. The method comprises the following steps: at -5 to 10 DEG C, adding pivaloyl chloride into an intermediate V, dropwise adding an organic alkali, keeping the temperature in the reaction kettle at -5 to 10 DEG C after dropwise adding, stirring for reacting for T1, adding 4-dimethylaminopyridine, stirring for T2 time, finally adding a dichloromethane solution of an intermediate VI, raising the reaction temperature to 25 to 35 DEG C after adding, and stirring until the reactionis finished. Common industrial raw materials and reagents are used, so the method is suitable for industrial mass production, and through simple purification002C the yield is 85% or above, and the purity is 99.5% or above.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for synthesizing ritonavir. Background technique [0002] There are few synthetic methods of ritonavir reported so far, and the main synthetic method is through two key intermediate structures, N-((N-methyl-N-((2-isopropyl-4-thiazolyl) Methyl)amino)formyl)-L-valine and (2S,3S,5S)-5-(tert-butoxycarboxamido)-2-(N-5-thiazolyl-methoxycarbonyl)amino -1,6-diphenyl-3-hydroxyhexane for condensation preparation. The two fragment structures are as follows: [0003] 1.1N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)formyl)-L-valine methyl ester (carboxylic acid intermediate) and 1.2( 2S, 3S, 5S)-5-amino-2-(N-5-thiazolyl-methoxycarbonyl)amino-1,6-diphenyl-3-hydroxyhexane (amino intermediate), two fragments The existing process report of the condensation method is as follows: [0004] 1) Abbott WO9414436 patent of the original research company, which uses 1-ethyl-(3...

AI Technical Summary

Problems solved by technology

The reaction solvent chloroform is highly toxic, which is not conducive to the safety of production; the reagents butanone and butyl acetate are not commonly used solvents, which increases the difficulty of industrialized large-scale production

Reaction by-products such as tetramethylurea and phosphorus-containing salts, etc., post-treatment and purification are cumbersome, which is not conducive to ensuring product quality

[0007] In a word, the process of synthesizing ritonavir has expensive reaction reagents and low reaction yield, which is not conducive to the control of large production costs of the process; the reaction conditions are relatively harsh, the operation is cumbersome, and it is not conducive to the control of product quality.

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