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Process for synthesizing sunitinib

A synthesis method, sunitinib technology, applied in the direction of organic chemistry, can solve the problems of increasing the difficulty of purification, and achieve the effect of easy crystallization and purification, simplified purification method, and easy reaction

Active Publication Date: 2012-11-28
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the introduction of amide in advance, the intermediates are basically liquid, which increases the difficulty of purification

Method used

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  • Process for synthesizing sunitinib
  • Process for synthesizing sunitinib
  • Process for synthesizing sunitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] Add 7.5 liters of acetic acid and 5.0 kg of tert-butyl acetoacetate into a 25-liter plastic bucket, add dropwise a solution of 2.24 kg of sodium nitrite dissolved in 3.5 liters of water at 0 degrees, control the temperature not to exceed 5 degrees, add 3 liters of water after dropping, and keep warm for reaction After 30 minutes, remove the cold bath, and slowly heat up the reaction. After the reaction, add 5 liters of water, carefully neutralize it with solid sodium bicarbonate until it is nearly neutral, and finally adjust the pH to 7-8 with a small amount of 4N sodium hydroxide solution. Extracted with ethyl ester, dried and concentrated to obtain about 5.6kg of liquid, which was directly used in the next reaction.

[0029] In 25 liters of plastic barrels, add 2.8kg of the product of the previous step, 3kg of ethyl acetoacetate and 10 liters of acetic acid, add the mixture of 3.4kg of zinc powder and 3.4kg of sodium acetate in batches, control the feeding ...

Embodiment 2

[0046]

[0047] Add 1.5 liters of acetic acid and 1.0 kg of tert-butyl acetoacetate to a 5-liter four-neck bottle, add dropwise a solution of 0.5 kg of sodium nitrite dissolved in 2 liters of water at 0 degrees, control the temperature not to exceed 5 degrees, add 1 liter of water after dropping, and keep warm React for 30 minutes, remove the cold bath, and slowly heat up the reaction. After the reaction, add 2 liters of water, carefully neutralize it with solid sodium bicarbonate to near neutrality, and finally adjust the pH to 7-8 with a small amount of 4N sodium hydroxide solution. Extracted with ethyl acetate, dried and concentrated to obtain about 1.2kg of liquid, which was directly used in the next reaction.

[0048] In a 5-liter four-necked bottle, add 1.2kg of the product from the previous step, 1kg of propyl acetoacetate and 2 liters of acetic acid, add a mixture of 0.8kg of zinc powder and 0.8kg of sodium acetate in batches, and control the feeding speed so that th...

Embodiment 3

[0055]

[0056] Add 100 liters of acetic acid and 50 kg of tert-butyl acetoacetate to a 250-liter kettle, add dropwise a solution of 25 kg of sodium nitrite dissolved in 35 liters of water at 0°C, control the temperature not to exceed 5°C, add 30 liters of water after dropping, and keep the temperature for 30 minutes. Remove the cold bath, slowly heat up the reaction, after the reaction, add 50 liters of water, carefully neutralize to near neutral with solid sodium bicarbonate, finally adjust the pH to 7-8 with a small amount of 4N sodium hydroxide solution, and extract with ethyl acetate , dried, and concentrated to obtain about 56kg of liquid, which was directly used in the next reaction.

[0057] In the 250 liter kettle, add 30kg of the product of the previous step, 3kg of methyl acetoacetate and 150 liters of acetic acid, add the mixture of 50kg of zinc powder and 50kg of sodium acetate in batches, control the feed rate, so that the temperature is no more than 85 degrees...

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Abstract

The invention discloses a method for synthesizing sunitinib, which comprises the following steps that: tert-butyl acetoacetate and acetylacetic ester are taken as initial raw materials, and tetra-substituted pyrrole is obtained through a nitrosification reduction reaction; then 2,4-dimethyl pyrrole-3-formic acid is obtained through the hydrolysis and is amidated; then an aldehyde group is utilized on position 5 of pyrrole through a Vilsmeier-Hacck reaction; and finally the obtained product and 5-fluorooxindole react to obtain the sunitinib. The method has low cost and simple operation, and isfavorable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a synthesis method of sunitinib. Background technique [0002] Sunitinib (Sunitinib, SU011248, structural formula I) is a new oral small molecule tyrosine kinase inhibitor, which has the potential of inhibiting angiogenesis and antitumor effect. Sunitinib is a newly developed drug with good bioavailability and to some extent also antagonizes receptor tyrosine kinases (RTKs) that promote angiogenesis. Sunitinib can also inhibit some other tyrosine kinase receptor family proteins, which are related to a variety of malignant tumors, such as small cell lung cancer, gastrointestinal tumors (GISTs), breast cancer, acute non-lymphatic leukemia, etc. Sunitinib has a good effect in the treatment of neuroendocrine tumors, colon cancer and breast cancer in phase II clinical trials. Sunitinib also showed good results when used in kidney cancer and imatinib-resistant gas...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
Inventor 沈鑫廖立新林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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