Novel method for synthesizing ritonavir

A technology of ritonavir and a new method, which is applied in the field of medicinal chemistry, can solve the problems of increasing the difficulty of industrialized large-scale production, harsh reaction conditions, cumbersome operation, etc., and achieve the advantages of large production capacity, production cost and reaction conditions simple effect

Pending Publication Date: 2020-09-11
厦门蔚嘉制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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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,

Method used

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  • Novel method for synthesizing ritonavir
  • Novel method for synthesizing ritonavir
  • Novel method for synthesizing ritonavir

Examples

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Example Embodiment

[0025] Example 1 A new method for synthesizing ritonavir

[0026] The reaction kettle R101 is evacuated, the nitrogen is broken, 1500kg of dichloromethane and 165kg of intermediate V are added to the kettle under the protection of nitrogen, and the stirring is turned on to cool down to 5±5°C; 58.0kg of pivaloyl chloride is added to the kettle; Keep the temperature of the reactor R101 at 5±5°C, and add 50.0g of triethylamine dropwise to the kettle through the high-level tank V101-I; after the dripping, the temperature in the reactor is kept at 5±5°C, and the reaction kettle is stirred for 1 to 2 hours; Add 12.0kg of 4-dimethylaminopyridine (DMAP), stir for 30 minutes, then add the dichloromethane solution of Intermediate VI (183.0g dissolved in 500kg); after the addition, raise the temperature in the kettle to 30±5°C, The reaction was stirred for 8-10 hours; samples were taken, and the reaction of intermediate VI was determined to be complete by HPLC.

[0027] Post-treatment method...

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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...

Claims

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Application Information

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IPC IPC(8): C07D277/28
CPCC07D277/28
Inventor 侯鹏翼涂福荣
Owner 厦门蔚嘉制药有限公司
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