Synthesis method of doravirin intermediate
A synthesis method, the technology of doravirine, is applied in the field of synthesis of chemical drug intermediates, which can solve the problems of difficulty in realizing large-scale production and few reports on synthesis methods, and achieve the effects of lower equipment requirements, low toxicity, and convenient operation
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Embodiment 1
[0049] The synthesis of embodiment 1 compound III
[0050]Add 1000mL of purified water in the reaction flask, and add 4-(trifluoromethyl)nicotinic acid (191.1g, 1.0mol) into the reaction flask under stirring; then add the catalyst molybdenum trioxide (1.5g, 10mmol); be heated to 70 ℃, start to add 30% hydrogen peroxide dropwise, keep warm at 90 ℃ after dropping, stir and react for 12 hours, and track and monitor the complete reaction of raw materials by TLC; cool the reaction solution below 10 ℃, a large amount of solid precipitates, filter, and wash the filter cake with a small amount of purified water, The material was baked at 60°C, and the water content was detected to be less than 0.5%. The material was collected to obtain compound III (182.3g), with a yield of 88%. The mother liquor was directly used in the next batch of reactions.
Embodiment 2
[0051] The synthesis of embodiment two compound V
[0052] Add 700mL of toluene to the reaction flask, add homemade or commercially available Vismeier reagent (128.0g, 1.0mol) into the reaction flask under stirring; add compound III (100.0g, 0.48mol) under stirring; heat up to 100°C, stir React for 14 hours, TLC tracking and monitoring the complete reaction of the raw materials; cool the reaction solution to below 10°C, control the temperature below 10°C, add the reaction solution dropwise to 700mL 25% ammonia water, keep warm and continue to stir for 2h, filter, and filter the cake with purified water After washing and drying, compound V (85.2 g) was obtained with a yield of 79%. The intermediate can also be directly subjected to the next step reaction without drying.
Embodiment 3
[0053] The synthesis of embodiment three compound VI
[0054] Add pre-configured 10% sodium hydroxide solution (540g, 1.35mol) into the reaction flask, control the temperature below 20°C, add amide compound V (100.0g, 0.45mol), then add dropwise 12% sodium hypochlorite solution (350g, 0.56mol); after the drop, the temperature was raised to room temperature, and the stirring reaction was continued for 2 hours, the system was dissolved, and the conversion of compound Ⅴ was followed and monitored by TLC; the oil bath was heated to 80°C, stirred and reacted for 2h, the temperature was lowered to below 20°C, and the pH value was adjusted to 9-10, ethyl acetate was added for extraction, the organic phase was dried and concentrated, and n-heptane was crystallized to obtain compound VI (64.6 g), with a yield of 73%.
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