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A kind of preparation method of sunitinib intermediate

A sunitinib and intermediate technology, applied in the field of medicine, can solve the problems of high synthesis cost, difficult promotion, strong corrosion, etc., and achieve the effects of simplifying the reaction process, reducing the pollution of three wastes, and improving the yield

Inactive Publication Date: 2015-10-28
ZHANGJIAGANG HUACHANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The hydrolytic decarboxylation process is easy to produce by-products such as double decarboxylation, and the materials used in the Vilsmeier-Hacck reaction are highly corrosive, and the market price of tert-butyl acetoacetate used is relatively high, and the synthesis cost is high, so it is not easy to popularize
Generally speaking, this type of synthetic process route is relatively complicated, the reaction time is long, the yield is low, the large-scale production is difficult, and the environmental friendliness is not strong

Method used

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  • A kind of preparation method of sunitinib intermediate
  • A kind of preparation method of sunitinib intermediate
  • A kind of preparation method of sunitinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] This example provides a preparation method of sunitinib intermediate (compound I), which specifically includes the following steps:

[0037] (1) Weigh 84g (1mol) of diketene, add 200ml of purified water, stir at room temperature, then add 139g (1.2mol) of N,N-diethylethylenediamine dropwise for about 1 hour. Stirring was continued for 10 hours at room temperature. Water, unreacted diketene and N,N-diethylethylenediamine were distilled off under reduced pressure, and the residue was viscous.

[0038] (2) Weigh 116g (1mol) of methyl acetoacetate, add 200ml of glacial acetic acid, and stir. Add NaNO dropwise 2 solution (NaNO 2 151g (2.2mol) + 200ml of water], drop it in about 1 hour. Stirring was continued for 3 hours at room temperature, and then 112 g (2 mol) of iron powder was added in batches. Reflux for 3 hours, filter out the insoluble matter while it is hot, add the filtrate to the sticky silk obtained in step (1), stir evenly, heat and reflux for 4 hours, and ...

Embodiment 2

[0043] This example provides a preparation method of sunitinib intermediate (compound I), which specifically includes the following steps:

[0044] (1) Weigh 84g (1mol) of diketene, add 200ml of purified water, stir at room temperature, then add 139g (1.2mol) of N,N-diethylethylenediamine dropwise for about 30 minutes. Stirring was continued for 8 hours at room temperature. Water and unreacted diketene and N,N-diethylethylenediamine were distilled off under reduced pressure. The residue was viscous.

[0045] (2) Weigh 116g (1mol) of methyl acetoacetate, add 250ml of glacial acetic acid, and stir. Add NaNO2 solution [NaNO2137g (2mol) + water 200ml] dropwise, and drop it in about 1 hour. Stirring was continued at room temperature for 3 hours, and then 112 g (2 mol) of iron powder (Fe) was added in batches. Reflux for 3 hours, filter out the insoluble matter while it is hot, add the filtrate to the sticky silk in step (1), stir evenly, heat and reflux for 4 hours, and finally...

Embodiment 3

[0048] This example provides a preparation method of sunitinib intermediate (compound I), which specifically includes the following steps:

[0049] (1) Weigh 84g (1mol) of diketene, add 200ml of purified water, stir at room temperature, then add 139g (1.2mol) of N,N-diethylethylenediamine dropwise, and the dropwise addition time is about 45 minutes. Stirring was continued for 8 hours at room temperature. Water and unreacted diketene and N,N-diethylethylenediamine were distilled off under reduced pressure. The residue was viscous.

[0050] (2) Weigh 116g (1mol) of methyl acetoacetate, add 280ml of glacial acetic acid, and stir. Add NaNO2 solution [NaNO2151g (2.2mol) + water 200ml] dropwise, and drop it in about 45 minutes. Stirring was continued for 4 hours at room temperature, and then 130 g (2 mol) of zinc powder (Zn) was added in batches. Reflux for 3 hours, filter out the insoluble matter while it is hot, add the filtrate to the sticky silk in step (1), stir evenly, hea...

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Abstract

The invention relates to a preparation method of a sunitinib intermediate 2, 4-dimethyl-5-formoxyl-1H-pyrrole-3-formyl (N, N-diethyl ethylenediamine). The method comprises the following steps: (1). carrying out a condensation reaction on ketene dimer and N, N-diethyl ethylenediamine to generate a compound II; (2). sequentially generating a nitrosation reaction and a reduction reaction on methyl acetoacetate to obtain a product, and reacting the product with the compound II obtained in the step (1) to generate a compound III; and (3). generating a reduction reaction on the compound III obtained in the step (2) in the presence of diisobutylaluminum hydride (DIBAL-H) to generate the sunitinib intermediate. Compared with an existing method, the method disclosed by the invention has the advantages of simplifying the reaction process, improving the yield of the intermediate and reducing the three-waste pollution, thereby having an important application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an important intermediate of sunitinib, 2,4-dimethyl-5-formyl-1H-pyrrole-3-formyl (N,N-diethylethanedi ) Preparation method of amine. Background technique [0002] Sunitinib (Sutent) is a new type of multi-targeted oral drug for the treatment of tumors. It is a dual-channel, multi-targeted tyrosine kinase inhibitor that can inhibit cancer cell growth and block tumor growth The required blood and nutrient supply, significantly prolonging the overall survival period, effectively improving subjective and objective symptoms and signs, etc., are widely used in the treatment of solid tumors such as renal cell carcinoma, gastrointestinal stromal tumor, lung cancer, and liver cancer, with good compliance and poor compliance The reaction is light, oral administration is convenient, and the market prospect is good. [0003] 2,4-Dimethyl-5-formyl-1H-pyrrole-3-carboxyl (N,N-di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/34
Inventor 丁敬敏庞宝华李东升叶爱英王平
Owner ZHANGJIAGANG HUACHANG PHARMA
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