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Preparation method of erlotinib hydrochloride crystal form A

A technology of erlotinib hydrochloride and crystal form, which is applied in the field of preparation of erlotinib hydrochloride crystal form A, can solve problems such as easy transformation, achieve cumbersome steps, improve experimental efficiency, and be beneficial to large-scale industrial production

Active Publication Date: 2013-11-20
NANJING YOUKE BIOLOGICAL MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it needs to be carried out at a lower temperature (below 20°C). The patent emphasizes that if the temperature is exceeded, the A crystal form can easily transform into other crystal forms

Method used

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  • Preparation method of erlotinib hydrochloride crystal form A
  • Preparation method of erlotinib hydrochloride crystal form A
  • Preparation method of erlotinib hydrochloride crystal form A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile (compound of formula II, 1Kg, 3.76mol), toluene 5L, acetic acid 20mL and DMF-DMA (492g, 4.13mol, is the formula 1.1 times the molar amount of compound II) mixed and stirred, refluxed in an oil bath, kept at 80-90°C for 3 hours, and then concentrated under reduced pressure at 60-65°C to obtain about 1.3Kg of the intermediate Schiff base oil. Dissolve the oily substance with isopropyl ether / tetrahydrofuran (20:1) (about 10.5L, 8 times the volume of the oily substance) at 35-40°C for clarification, slowly cool down to 10-15°C, and crystallize to obtain 1.09Kg of a white solid , the yield of Schiff's base was 91%, and the HPLC purity was 99.5%.

[0038] Mix the compound of formula III (1.09Kg, 3.39mol), m-aminophenylacetylene (438g, 3.73mol, 1.1 times the molar weight of the compound of formula III), 5L of acetic acid, start heating, control the internal temperature at 95-100°C, and react 2.5-3h, develop with thin-layer chromat...

Embodiment 2

[0042] 2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile (compound of formula II, 1.3Kg, 4.88mol), toluene 6.5L, acetic acid 26mL and DMF-DMA (629g, 5.37mol) Mix and stir, reflux reaction in an oil bath, keep warm at 80-90°C for 3 hours, and then concentrate under reduced pressure at 60-65°C to obtain about 1.6Kg of the intermediate Schiff base oil. Dissolve and clarify the oil with methyl tert-butyl ether / ethyl acetate (25:1) (about 16 L, 10 times the volume of the oil) at 35-40°C, slowly cool down to 10-15°C, and crystallize to obtain White solid 1.39Kg, Schiff base yield 89%, HPLC purity 99.4%.

[0043] Mix the compound of formula III (1.39K, 4.33mol), m-aminophenylacetylene (558g, 4.76mol), and 7L of acetic acid, mix and stir, start heating, control the internal temperature at 95-100°C, react for 2.5-3h, and use thin-layer chromatography Expand the plate (DCM:MeOH=15:1), the reaction is complete, slowly cool down to an internal temperature of 60°C, add 8.4L of water and tetra...

Embodiment 3

[0047] 2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile (compound of formula II, 1.5Kg, 5.64mol), toluene 7.5L, acetic acid 30mL and DMF-DMA (730g, 6.3mol) Mix and stir, reflux in an oil bath for reaction, keep warm at 80-90°C for 3 hours, and then concentrate under reduced pressure at 60-65°C to obtain about 1.9Kg of the intermediate Schiff base oil. The oil was dissolved and clarified with isopropyl ether / tetrahydrofuran (20:1) (about 17 L, 9 times the volume of the oil) at 35-40°C, slowly cooled to 10-15°C, and crystallized to obtain 1.58Kg of a white solid. The yield of Schiff's base was 88%, and the HPLC purity was 99.5%.

[0048] Mix the compound of formula III (1.58Kg, 4.92mol), 7.9L of m-aminophenylacetylene (633g, 5.41mol) acetic acid, mix and stir, start heating, control the internal temperature at 95-100°C, react for 2.5-3h, and use thin-layer chromatography Expand the plate (DCM:MeOH=15:1), the reaction is complete, slowly cool down to an internal temperature of 60°C...

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Abstract

The invention provides a preparation method of an erlotinib hydrochloride crystal form A, which belongs to the technical field of the preparation of a drug compound. The preparation method comprises the following steps: enabling 2-amino-4,5-di(2-methoxy ethyoxyl) cyanophenyl and N, N-dimethyl amide dimethyl acetal to react; re-crystallizing and purifying the obtained Schiff base intermediate, and then synthesizing with aminophenylacetylene to obtain erlotinib free alkali; and adding a hydrochloric acid solution, and recrystallizing to obtain the erlotinib hydrochloride crystal form A. According to the scheme of the invention, the process route is short, the product purity is high, the repeatability is good, and the operation is simple and easy to implement, and therefore, the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of erlotinib hydrochloride crystal form A. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride, compound of formula I), is an innovative drug for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has failed at least one chemotherapy regimen, and is developed by Genetech, OSI and Roche Co-developed and manufactured by Roche. It was approved by the US FDA in November 2004, approved by the European Union for marketing in September 2005, and launched in China in April 2006. In 2005, the FDA also approved the combination of erlotinib and gemcitabine for the treatment of advanced pancreatic cancer, making it the first approved drug for the treatment of advanced pancreatic cancer in the past 10 years. Erlotinib hydrochloride is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK)...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCY02P20/584
Inventor 郭彦飞闵涛车晓明张峰薛峪泉
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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