Preparation method of raw drug suvorexant

A technology for raw materials and intermediates, which is applied in the field of preparation of raw materials Suvorexan, can solve the problems of high reaction temperature, unfavorable guarantee of yield, and amides affecting affinity, etc., and achieves the effect of simple separation operation.

Active Publication Date: 2017-10-27
安徽拜善晟制药有限公司
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Problems solved by technology

[0005] However, the above-mentioned technical solution has the following defects: DMF, methylene chloride and acetone are respectively used as organic solvents in Examples 13-15 of the patent disclosure specification, and the reaction temperature of the condensation acylation reaction in Example 13 is 50 ° C, and the yield is relatively high , the reaction temperature of the condensation acylation reaction in Examples 14-15 is 30°C, and the yield is slightly lower on the basis of Example 13
The carboxylic acid of condensation acylation reaction is a weak acylating agent, and triethylamine reacts with carboxylic acid to generate amide which affects its affinity, which is unfavorable for ensuring the yield of this step; the acylation reaction temperature in the patent publication embodiment 19 is 75°C, the reaction temperature is higher, and the impurities formed by side reactions are more, so the yield is low, which is 93.02%

Method used

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  • Preparation method of raw drug suvorexant
  • Preparation method of raw drug suvorexant
  • Preparation method of raw drug suvorexant

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1 adopts as the synthetic route of background technology, and wherein S1 technological process is:

[0039] Add 48 kg (235 mol) of intermediate I to the reaction kettle, add 300 ml of dichloromethane, start stirring, add 48 kg (235 mol) of intermediate II; after adding alkali and stirring well, add 45 kg of condensing agent EDC.HCL, and control the temperature at 25°C when adding Next, keep warm at 24-27° C. for reaction, monitor by TLC, TLC shows that the reaction is complete, and post-processing to obtain 87 kg (223 mol) of intermediate III, with a yield of 94.9%.

Embodiment 2

[0041] Example 2 uses dimethylformamide as the reaction solvent, uses pyridine as the base, and uses N,N'-carbonyldiimidazole and tris(2,6-dimethoxyphenyl)bismuth composition in a weight ratio of 1:1 as the condensing agent mixed. Insulate at 40-43°C for reaction, monitor by TLC, TLC shows that the reaction is complete, after treatment, 87.4 kg (224 mol) of intermediate III was obtained, with a yield of 95.4%.

Embodiment 3

[0043] The difference between embodiment 3 and embodiment 1 is that a combined condensing agent is adopted, and the combined condensing agent is made of, and the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and three (2 , 6-dimethoxyphenyl) bismuth combined, the weight percentage of tris (2,6-dimethoxyphenyl) bismuth in the condensing agent is 25%, heat preservation 18~22 ℃ reaction, TLC monitoring, after 88 kg (225.6 mol) of intermediate III was obtained with a yield of 96%.

[0044]The N,N'-carbonyldiimidazole in the combined condensing agent can be replaced by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1 Other combinations within the range of -hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, and tris(2,6-dimethoxyphenyl)bismuth, the yields of which are all above 92%; the combination The condensing agent is composed of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and tris(2,6-dimeth...

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Abstract

The invention discloses a preparation method of raw drug suvorexant. The preparation method comprises the following step of generating S1 condensation acylation reaction by virtue of an intermediate I and an intermediate II in the presence of a condensing agent so as to generate an intermediate III, wherein the condensing agent is selected from one or combination of more than two of ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole and tri(2,6-dimethoxyphenyl)bismuth. By adopting the proper condensing agent or condensing agent combination in the S1 condensation acylation reaction in the preparation method, and the yield in the prior art can be achieved at a reaction temperature of about 25 DEG C, and the condensing agent and intermediate products are simply separated, so that the energy saving and the consumption reduction in the large-scale industrial production are promoted.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a raw material drug Suvorexan. Background technique [0002] Suvorexant, English name Suvorexant, also known as MK-4305, is a dual orexin receptor antagonist newly developed by Merck, which can help patients improve sleep by blocking orexin that makes it difficult to fall asleep. At present, Phase III clinical research has been completed, and the research found that it can reduce the sleep initiation time, improve the sleep quality of patients, have few side effects, and is suitable for long-term treatment. [0003] The background technology section of CN103923068A describes in detail the preparation route and corresponding technical defects of Suwo Leisheng, and further discloses the following synthesis route: [0004] [0005] However, the above-mentioned technical solution has the following defects: DMF, methylene chloride and acetone are resp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 常松王喆明魏勇慕龙治吴章栓范征
Owner 安徽拜善晟制药有限公司
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