Preparation process of aprepitant

A preparation process and aprepitant technology, applied in the field of aprepitant preparation technology, can solve the problems of unsatisfactory purity, low yield, and high impurity content, and achieve an optimized formula, low impurity content, and high purity. Effect

Inactive Publication Date: 2019-03-15
成都晶富医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The technical problem to be solved by the present invention is: there are technical problems such as low yield, high impurity content, and unsatisfac...

Method used

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  • Preparation process of aprepitant
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  • Preparation process of aprepitant

Examples

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Embodiment 1

[0039] This embodiment provides a preparation process of aprepitant, comprising the following steps:

[0040] Setp1, first add compound A and compound B to a mixed solvent of N,N-dimethylformamide and triethylamine and stir to dissolve to obtain a mixed solution; wherein, the mass ratio of compound A to compound B is 1.3; in the mixed solvent, N , The mass ratio of the mixed solvent of N-dimethylformamide and triethylamine is 1:0.3, and the solute mass fraction of the mixed solution is 45%.

[0041] Setp2, under a nitrogen atmosphere, add lithium diisopropylamide to the mixed solution for uniform mixing; wherein, the added mass of lithium diisopropylamide is 1 / 3 of the sum of the mass of compound A and compound B.

[0042] Setp3, under nitrogen protection and stirring conditions, add dropwise a solution of diethyl sulfate in xylene; the quality of adding diethyl sulfate is 0.05% of the mass sum of compound A and compound B, the solution of diethyl sulfate in xylene The mass p...

Embodiment 2

[0058] This embodiment provides a preparation process of aprepitant, comprising the following steps:

[0059] Setp1, first add compound A and compound B to a mixed solvent of N,N-dimethylformamide and triethylamine and stir to dissolve to obtain a mixed solution; wherein, the mass ratio of compound A to compound B is 2.0; in the mixed solvent, N , The mass ratio of the mixed solvent of N-dimethylformamide and triethylamine is 1:0.3, and the mass fraction of solute in the mixed solution is 20%.

[0060] Setp2, under a nitrogen atmosphere, add lithium diisopropylamide to the mixed solution for uniform mixing; wherein, the added mass of lithium diisopropylamide is 1 / 3 of the sum of the mass of compound A and compound B.

[0061]Setp3, under nitrogen protection and stirring conditions, add dropwise the solution of diethyl sulfate in xylene; the quality of adding diethyl sulfate is 0.10% of the mass sum of compound A and compound B, the solution of diethyl sulfate in xylene The ma...

Embodiment 3

[0077] This embodiment provides a preparation process of aprepitant, comprising the following steps:

[0078] Setp1, first add compound A and compound B to a mixed solvent of N,N-dimethylformamide and triethylamine and stir to dissolve to obtain a mixed solution; wherein, the mass ratio of compound A to compound B is 1.6; in the mixed solvent, N , The mass ratio of the mixed solvent of N-dimethylformamide and triethylamine is 1:0.3, and the solute mass fraction of the mixed solution is 34%.

[0079] Setp2, under a nitrogen atmosphere, add lithium diisopropylamide to the mixed solution for uniform mixing; wherein, the added mass of lithium diisopropylamide is 1 / 3 of the sum of the mass of compound A and compound B.

[0080] Setp3, under nitrogen protection and stirring conditions, add dropwise the xylene solution of diethyl sulfate; the added quality of diethyl sulfate is 0.07% of the mass sum of compound A and compound B, the xylene solution of diethyl sulfate The mass percen...

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Abstract

The invention discloses a preparation process of aprepitant. The process comprises the steps as follows: Step 1, a compound A and a compound B are firstly added to a mixed solvent of N,N-dimethylformamide and triethylamine to be stirred and dissolved to obtain a mixed solution; Step2, adding lithium diisopropylamide to the mixed solution in a nitrogen atmosphere and performing uniform mixing; Step3, dropwise adding a diethyl sulfate xylene solution under conditions of nitrogen shielding and stirring; Step 4, after addition, conducting a stirring reaction at 30-35 DEG C for 12-15 h under shielding of nitrogen; Step 5, separating and purifying a reaction product in Step 4 to obtain a final aprepitant product. By process improvement and formula optimization, the aprepitant synthesis processhas the characteristics of mild reaction condition, low cost and the like and is suitable for large-scale industrial production; the synthesized aprepitant product has low impurity content and high purity, and the yield of aprepitant is greatly increased.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation process of aprepitant. Background technique [0002] Aprepitant is a selective high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. Low affinity for serotonin receptor 3 (5-HT3), dopamine receptor, and glucocorticoid receptor targets of other existing drugs for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) or no affinity. Aprepitant inhibits cisplatin-induced emesis in the acute and delayed phases, and enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the glucocorticoid dexamethasone on cisplatin-induced emesis. The structural formula of aprepitant is as follows: [0003] [0004] The synthesis method of the most important API in the prior art is: [0005] [0006] The impurity removal method reported in the literature includes recrystalliz...

Claims

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Application Information

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IPC IPC(8): C07D413/06
CPCC07D413/06
Inventor 杨眉赵永龙
Owner 成都晶富医药科技有限公司
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