A kind of preparation method of 1-malate sunitinib e-form isomer

A sunitinib malate and isomer technology, which is applied in the field of preparation of the E-isomer of sunitinib malate, can solve problems such as the E-isomer of sunitinib that is not mentioned , to achieve the effect of high product yield, mild reaction conditions and high purity

Active Publication Date: 2022-07-08
NANJING HUAWE MEDICINE TECH DEV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] ChemMedChem2016, 11, 72-80 reported that sunitinib and its analogues are prone to cis-trans conversion when exposed to light, but did not mention how to prepare higher purity sunitinib E formula from sunitinib Isomers, after investigation, it was found that no other literature or patents have reported the synthesis of E-type sunitinib isomers

Method used

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  • A kind of preparation method of 1-malate sunitinib e-form isomer
  • A kind of preparation method of 1-malate sunitinib e-form isomer
  • A kind of preparation method of 1-malate sunitinib e-form isomer

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preparation example Construction

[0022] The preparation of L-malate sunitinib E-form isomer is obtained by the following technical route:

[0023] The raw material drug L-malate sunitinib ((Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1, 2-Dihydro-3H-indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate) was synthesized by using existing technology.

Embodiment 1

[0029] Example 1: (E)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3 -subunit)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate preparation

[0030] (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene ) methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate (0.5 g, 0.89 mmol) was dissolved in 300 mL of water, 5.3 mg of anthracene was added, and after mixing evenly, it was placed in In the photoreactor, turn on a 500W medium pressure mercury lamp, control the temperature at 0-5°C and react for 16-18h, stop the reaction when the liquid phase monitoring conversion rate is greater than 90%, filter, and store the filtrate in a freeze dryer at -50°C in the dark. Lyophilized at ~-60℃ for 24h to obtain (E)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H -Indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate 0.32g, yield 64%, HPLC purity 91% (as figure 1 ).

Embodiment 2

[0031] Example 2: (E)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3 -subunit)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate preparation

[0032] (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene ) methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate (0.5 g, 0.89 mmol) was dissolved in 200 mL of ethanol, 5 mg of anthracene was added, and after mixing uniformly, set In the light-incident reactor, turn on a 500W medium-pressure mercury lamp, control the temperature at 0-5°C and react for 16-18h, stop the reaction when the liquid phase monitoring conversion rate is greater than 90%, and store the filtrate in a freeze dryer at -50°C~ -60°C lyophilization for 24h to obtain (E)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H- Indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole L-malate 0.22 g, yield 44%, HPLC purity 90%.

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Abstract

The invention discloses a preparation method of L-malate sunitinib E-form isomer, comprising the following steps: (1) using L-malate sunitinib as a starting material, preparing L-malate sunitinib Nitinib and the organic photosensitizer are dissolved in a solvent and mixed uniformly; (2) the mixture obtained in step (1) is subjected to a photocatalytic reaction under the irradiation of a light source; (3) the product obtained in step (2) is lyophilized in the dark. obtain the target product. The method has simple steps, mild reaction conditions, high yield and high purity. The E-isomer of L-sunitinib malate prepared by the method of the invention provides effective guarantee for the process research and quality control of L-sunitinib malate raw materials and related preparations, and has great significance and practical value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of the E-form isomer of L-malate sunitinib. Background technique [0002] Sunitinib Malate, chemical name (Z)-N-[2-(diethylamino)ethyl-5-[(5-fluoro-2-oxo-1,2-di) Hydrogen-3H-indole-3-ylidene)methyl]-2,4-dimethyl-3-carbamoyl-1H-pyrrole malate, the structural formula is [0003] [0004] Sunitinib malate capsules are produced by Pfizer and are an oral small molecule multi-target receptor tyrosine kinase inhibitor (rTKI). The indications of the drug in China are: 1. Gastrointestinal stromal tumor (GIST) that fails or cannot tolerate imatinib mesylate; 2. Inoperable advanced renal cell carcinoma (RCC); 3. Inoperable Resected, metastatic, well-differentiated advanced pancreatic neuroendocrine tumor (pNET) in adult patients. [0005] Impurities are easily generated in the process of drug synthesis and drug degradation, which have a serious impact on the qual...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
CPCC07D403/06C07B2200/09
Inventor 施路王晶徐峰黄辉张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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