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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 chemical pharmaceuticals, and can solve problems such as not being suitable for industrial production, difficult to complete the reaction, and cumbersome preparation methods

Inactive Publication Date: 2013-10-23
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is greatly affected by the production conditions. If it is necessary to strictly control the rate of dripping hydrochloric acid and the cooling rate, otherwise it is not easy to obtain crystal A, but it is easier to become stable crystal B. Therefore, this method is not easy to control in industrialized production. Very suitable for industrial production
[0009]WO2010040212A1 discloses a method for preparing erlotinib hydrochloride crystal form A, in which hydrogen chloride gas is fed into or Dissolve hydrogen chloride in isopropanol and spray erlotinib free base solid containing 15% isopropanol to form erlotinib hydrochloride crystal form A. Solid, which makes the reaction difficult to complete, and the environment is more polluted
[0010] WO2011058525 discloses a method for preparing erlotinib hydrochloride crystal form A, dissolving the A erlotinib free base in acetone, dichloromethane, diethyl ether, Clarify in ethyl acetate or their mixed solvents, then lower the temperature to 25℃~300C, pass through anhydrous hydrogen chloride gas or ether solution of hydrogen chloride, keep warm or heat up 40℃~600C for 4 hours, the erlotinib hydrochloride crystal form A was separated. This method uses hydrogen chloride gas or hydrogen chloride ether solution, which increases the risk of inflammability and explosion in the production process, and is more environmentally polluting. big

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

[0035] Add 1 g of erlotinib free base monomer and 10 ml of acetone into a clean 50 ml reaction bottle, start stirring, cool to an internal temperature of -20°C to -15°C, and slowly add 1.4 ml of 2mol / L hydrogen chloride acetone solution dropwise, To pH = 5, the dropwise addition was completed in 1 hour, kept stirring for 1 hour, filtered, drained, and dried in a vacuum oven at 20°C to 30°C to obtain 1.07g of dry crystal form, yield 99.1%, purity (HPLC: 99.7%) .

[0036] The obtained crystal form was tested by X powder diffractometer, CuKα source (α = 1.5406?) of Shimadzu XRD-6000 X-ray diffractometer, at 40kv, 30mA, scanning range 5 ~ 40 (deg), scanning speed, 4deg / min, get as figure 1 The diffraction pattern (XRPD) shows that the crystal form is erlotinib hydrochloride crystal form A.

Embodiment 2

[0038] Add 1 g of erlotinib free base monomer and 12 ml of acetone into a clean 50 ml reaction bottle, start stirring, cool to the inner temperature of -20 ° C ~ -15 ° C, and start slowly adding 2 mol / L of hydrogen chloride ethyl acetate solution 1.4 ml, until pH=5, the dropwise addition was completed in 0.5 hours, kept stirring for 1 hour, filtered, drained, and dried in a vacuum oven at 20-30°C to obtain 1.08 g of dry product, with a yield of 99.7%. After testing its XRPD, it was shown to be erlotinib hydrochloride crystal form A with a purity (HPLC: 99.6%).

Embodiment 3

[0040] Add 1 g of erlotinib free base monomer and 10 ml of acetone into a clean 50 ml reaction bottle, start stirring, cool to an internal temperature of -20°C to -15°C, and slowly add 1.4 ml of 2mol / L hydrogen chloride ethanol solution dropwise, To pH = 1, the dropwise addition was completed in 2 hours, kept stirring for 6 hours, filtered, pumped dry, and dried in a vacuum oven at 20-30°C to obtain 1.07 g of dry product, with a yield of 99.1%. After testing its XRPD, it was shown to be erlotinib hydrochloride crystal form A with a purity (HPLC: 99.7%).

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Abstract

The invention specifically relates to a preparation method of an erlotinib hydrochloride crystal form A. The preparation method comprises the following steps of: mixing erlotinib hydrochloride free alkaline monomer with an organic solvent; and dropwise adding a non-ether hydrogen chloride solution or a hydrogen chloride solution for reacting to obtain the erlotinib hydrochloride crystal form A under low-temperature reaction condition. The preparation method of the erlotinib hydrochloride crystal form A is incapable of affecting industrial production due to weather temperature changes, simple and convenient to operate, very good in safety, high in stability, good in repeatability and more suitable for the industrial production of the erlotinib hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of a new crystal form A of erlotinib hydrochloride. Background technique [0002] Erlotinib Hydrochloride, English name: Erlotinib Hydrochloride, chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride Salt, see shown in structural formula (1): [0003] [0004] Erlotinib hydrochloride is a 4-aminophenylquinazoline oral antineoplastic drug developed by OSI Pharmaceuticals (OSI Pharmaceuticals), which is suitable for pancreatic cancer and metastatic non-small cell lung cancer. It was approved for listing for the first time. Its mechanism of action is to compete with the substrate of the small molecule tyrosine kinase epidermal growth factor receptor subtype (EGFR-TK) in the cell, inhibit the phosphorylation of EGFR-TK, block the signal transduction of tumor cells, and thus inhibit the growth of tum...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 周兴国罗君来叶文润邓杰蔡中文何伟
Owner CHONGQING PHARMA RES INST
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