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Preparation method of sunitinib malate crystal form (I)

A technology of sunitinib malate and its crystal form, which is applied in the field of preparation of crystal form I, and can solve problems such as high vacuum requirements, unsuitability for industrial production applications, and low solvent residue limit

Inactive Publication Date: 2016-06-29
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, due to the low solvent residue limit, the vacuum degree requirements for the equipment for vacuum drying of raw materials are also very high. This crystal conversion process is very unsuitable for industrial production applications.

Method used

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  • Preparation method of sunitinib malate crystal form (I)
  • Preparation method of sunitinib malate crystal form (I)
  • Preparation method of sunitinib malate crystal form (I)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide ( L )- Preparation of malate crystal form Ⅰ

[0018] N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide (75.0g) and methanol (1500ml) were added to the reaction flask, under nitrogen protection, stirred at room temperature for 30 minutes, and L-malic acid (25.0g) was added at one time, the reaction solution dissolved instantly, and then there was a lot of yellow The solid precipitated, and the reaction solution was heated to 50°C and stirred for more than 1 hour, then cooled to room temperature (25°C), concentrated under reduced pressure, and the obtained solid was vacuum-dried at 40°C for more than 4 hours to obtain 100.0 g of an amorphous or slightly crystalline crude product.

[0019] Add 100g of the above crude product and 400ml of dimethyl sulfoxide (DMSO) into the ...

Embodiment 2

[0020] Embodiment 2N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide ( L )- Preparation of malate crystal form Ⅰ

[0021] N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide (75.0g) and methanol (1500ml) were added to the reaction flask, under nitrogen protection, stirred at room temperature for 30 minutes, and L-malic acid (25.0g) was added at one time, the reaction solution dissolved instantly, and then there was a lot of yellow The solid precipitated, and the reaction solution was heated to 50°C and stirred for more than 1 hour, then cooled to room temperature (25°C), concentrated under reduced pressure, and the obtained solid was vacuum-dried at 40°C for more than 4 hours to obtain 100.0 g of an amorphous or slightly crystalline crude product.

[0022] Add 100g of the above crude product and DMSO (400ml) into the reaction flask, and st...

Embodiment 3

[0023] Embodiment 3N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide ( L )- Preparation of malate crystal form Ⅰ

[0024] N-[2-(diethylamino) ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide (75.0g) and methanol (1500ml) were added to the reaction flask, under nitrogen protection, stirred at room temperature for 30 minutes, and L-malic acid (25.0g) was added at one time, the reaction solution dissolved instantly, and then there was a lot of yellow The solid precipitated, and the reaction solution was heated to 50°C and stirred for more than 1 hour, then cooled to room temperature (25°C), concentrated under reduced pressure, and the obtained solid was vacuum-dried at 40°C for more than 4 hours to obtain 100.0 g of an amorphous or slightly crystalline crude product.

[0025] Add 100g of the above crude product and DMSO (400ml) into the reaction flask, and st...

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Abstract

The invention discloses a preparation method of sunitinib malate crystal form (I). The preparation method has the advantages that the reagents are cheap and easily-available, the method is environment-friendly and simple, and the crystals are easy to separate.

Description

technical field [0001] The invention relates to a method for preparing a crystal form of a pharmaceutical compound, in particular to a method for preparing the crystal form I of sunitinib malate, an anticancer drug. Background technique [0002] Sunitinib malate (sunitinibmalate, 1), the chemical name is N-[2-(diethylamino)ethyl]-5-[( Z )-(5-fluoro-1,2-dihydro-2-oxo-indol-3-enyl)methyl]-2,4-dimethyl-1 H -Pyrrole-3-amide ( L )-malate (1:1), the drug is an oral, multi-target receptor tyrosine kinase (receptortyrosinekinases) inhibitor developed by Sugen and Pfizer, which were released in January 2006 and 2007 respectively It was approved for marketing by the US FDA and the European EMEA in January 2019, and is clinically used to treat malignant gastrointestinal stromal tumors or metastatic renal cell carcinomas that are ineffective or intolerable to standard treatments. It can inhibit the phosphorylation of various receptor tyrosine kinases in vivo, especially for tumor-ass...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
Inventor 朱少璇黄小光王健松鲍颖霞叶海鸿余柱明胡海容冯金陈矛
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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