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Novel preparation method of Erlotinib hydrochloride with crystal form A

A technology of hydrochloride and crystal form, which is applied in the field of preparation of polymorphic drugs, can solve the problems of easy conversion of crystal form into other crystal forms and restrictions, and achieve the effects of good reproducibility, low cost, and increased reaction temperature

Active Publication Date: 2012-07-25
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mentioned reaction temperature is -50°C to 20°C, and crystal form A is easily transformed into other crystal forms beyond this temperature range
The above two methods must be carried out at low temperature, resulting in limitations in the industrial preparation process

Method used

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  • Novel preparation method of Erlotinib hydrochloride with crystal form A
  • Novel preparation method of Erlotinib hydrochloride with crystal form A
  • Novel preparation method of Erlotinib hydrochloride with crystal form A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of Erlotinib Hydrochloride A Crystal Form

[0029] Weigh Erlotinib free base (393mg, 1mmol), then add it to the reaction flask, add 12mL ethyl acetate, control the temperature at 20°C, stir magnetically, start to add 1.1mL HCl ethyl acetate solution (1M) dropwise, drop after 5min After the addition was complete, the mixture was stirred for 20 min, filtered, washed with ethyl acetate (3×2 mL), and dried in vacuo at 30° C. to obtain 428 mg of crystalline form A of Erlotinib hydrochloride with a yield of 100%.

Embodiment 2

[0030] Embodiment 2: Preparation of Erlotinib Hydrochloride A Crystal Form

[0031] Weigh Erlotinib free base (393mg, 1mmol), then add it to the reaction flask, add 12mL ethyl acetate, control the temperature at 40°C, stir magnetically, start to add 1.1mL HCl ethyl acetate solution (1M) dropwise, drop after 5min After the addition was complete, the mixture was stirred for 20 min, filtered, washed with ethyl acetate (3×2 mL), and dried in vacuo at 30° C. to obtain 427 mg of crystalline form A of Erlotinib hydrochloride with a yield of 100%.

Embodiment 3

[0032] Embodiment 3: Preparation of Erlotinib Hydrochloride A Crystal Form

[0033] Weigh Erlotinib free base (393mg, 1mmol), then add it to the reaction flask, add 12mL acetone, control the temperature at 30°C, stir magnetically, start to add 1.1mL HCl isopropyl acetate solution (1M) dropwise, and add dropwise after 5min After completion, continue to stir for 20 min, filter, wash with acetone (3×2 mL), and dry in vacuo at 30° C. to obtain 426 mg of Erlotinib hydrochloride Form A with a yield of 99%.

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Abstract

The invention provides a preparation method of Erlotinib hydrochloride with the crystal form A. The method comprises the following steps: mixing Erlotinib free alkali with organic solvent, and then dropping the hydrochloric acid solution of ester to obtain the Erlotinib hydrochloride with the crystal form A.

Description

technical field [0001] The present invention relates to the technical field of preparation of polymorphic drugs, more specifically to a preparation method of Erlotinib hydrochloride A crystal form Background technique [0002] Erlotinib hydrochloride, also known as [6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride, its structural formula As shown in Formula 1, it is a 4-aminophenylquinazoline oral antineoplastic drug developed by OSI Pharmaceuticals in the United States. It was approved by the FDA in 2004 for the treatment of pancreatic cancer and metastatic non-small cell lung cancer. [0003] [0004] So far, according to literature reports, Erlotinib hydrochloride has A crystal form, B crystal form, E crystal form, M crystal form, N crystal form, P crystal form and amorphous form. There are many literatures about the preparation of crystal form A. In US Patent No. 5,747,498, Erlotinib free base was dissolved in chloroform at the earlie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 叶建胜黄常康
Owner HAINAN SIMCERE PHARMA CO LTD
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