WO2013174261A1

WO2013174261A1 - Method for preparing erlotinib hydrochloride crystalline form a

Info

Publication number: WO2013174261A1
Application number: PCT/CN2013/076064
Authority: WO
Inventors: 徐建康; 叶美其; 徐巧巧; 李桂民
Original assignee: 浙江九洲药物科技有限公司
Priority date: 2012-05-25
Filing date: 2013-05-22
Publication date: 2013-11-28
Also published as: CN103420924A; CN103420924B

Abstract

The present invention relates to the field of pharmaceutical synthesis, and more particularly to a method for preparing an erlotinib hydrochloride crystalline form A. The preparation method comprises: performing dissolving by using a mixed solvent of alcohols and any solvent among halogenated hydrocarbons, esters, ethers each containing an oxygen atom, and ketones; upon dissolving completely, mixing the solution with an organic solution of hydrogen chloride, to prepare the erlotinib hydrochloride crystalline form A. The present invention solves the problems such as the crystal-mixing phenomenon occurring in the preparation process, nonconforming regarding the residual solvent, and pollution incurred by the too large quantity of the organic solvent, and the process is stable and applicable to industrial production.

Description

Description: A method for preparing erlotinib hydrochloride crystal form A

The present invention relates to the field of chemical pharmaceutical technology, and more particularly to a method for preparing erlotinib hydrochloride crystal form A. Background technique

Erlotinib hydrochloride, English name: Erlotinib Hydrochloride, Chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride Salt, its structural formula is as shown in formula (I):

I

It is a 4_aminophenylquinazoline oral antineoplastic drug developed by OSI Pharmaceuticals. It was first approved by the US FDA on November 18, 2004 for the treatment of pancreatic cancer and metastatic non-small cells. Lung cancer. The study found that this drug is a small molecule tyrosine kinase epidermal growth factor receptor subtype (EGFR-TK), its mechanism of action is to compete with the substrate in the cell, inhibit EGFR-TK phosphorylation, block tumor cell signal Transduction, thereby inhibiting tumor cell growth and inducing its death.

U.S. Patent No. 5,747,498 (Publication Date: 1998-5-5) and its co-proprietary patents describe the preparation of erlotinib monomers and their hydrochlorides and their hydrochlorides by erlotinib monomers, but The hydrochloride salt is a mixture of Form A polymorph and Form B, and no pure erlotinib hydrochloride Form A is produced.

According to the data given in US Patent US 20040162300 (Publication Date: 2004-8-19),

The differences in melting point, stability, etc. are as follows:

*1 condition: In a hot solution of ethanol/water (45: 55g/g) (temperature 45 ° C) *2 conditions: water

*3 conditions: Water buffer solution (pH=l)

CN101602734 (Publication Date: 2009-12-16) describes a preparation method of erlotinib hydrochloride crystal form A, which is to mix erlotinib free base with an organic solvent, and then add an etheric hydrochloric acid solution at a low temperature. A method of preparing erlotinib hydrochloride Form A is carried out. However, this method has a phenomenon that the ether residual solvent is unacceptable.

201010258627. 9 (Publication Date: 2010-12-15) The erlotinib base FormlV is dissolved in an organic solvent, passed into an isopropanol hydrochloride solution, and dried by filtration to prepare erlotinib hydrochloride crystal form A. Methods. However, some of the mixed crystals were found in the XRPD pattern of the prepared erlotinib hydrochloride Form A.

201010274216. 9 (Publication Date: 2011-1-19) is a method for preparing erlotinib hydrochloride crystal form A by mixing erlotinib free base with an organic solvent and dropwise adding an ester hydrochloric acid solution. In all of the examples of the patent application, the amount of organic solvent reached 30 times the amount of erlotinib free base, which caused excessive contamination.

W02009025873 (Publication Date: 2009-2-16) describes a method of preparing erlotidine hydrochloride by mixing erlotinib free base with a solvent into a suspension, introducing hydrogen chloride gas or adding concentrated hydrochloric acid or a mixed solution of hydrochloric acid and ester. The method of the nanoform A. The preparation method uses a mixed solution of erlotinib free base with methanol and toluene, or a mixed solution of methanol and 1,3-dioxolane to form a suspension to prepare erlotinib hydrochloride crystal form A, which is required to be angstrom Rotinib free base is mixed with a solvent to form a suspension, so that the operation is poor in repeatability and easy to form a mixed crystal.

In view of the problems of mixed crystals in the prior art, unqualified residual solvents, and excessive contamination of organic solvents, it is necessary to further improve the preparation method of erlotinib hydrochloride Form A, and the yield of the developed product is high. Stable, suitable for the industrial production of erlotinib hydrochloride crystal form A preparation method. Summary of the invention

The object of the present invention is to provide a preparation method of erlotinib hydrochloride crystal form A, which solves the problems of mixed crystal phenomenon, unqualified residual solvent and excessive organic solvent pollution in the preparation process. Process controllable, reproducible and stable process. Such a preparation method is suitable for industrial production and has important economic value.

The reaction involved is as follows:

The invention provides a method for preparing erlotinib hydrochloride crystal form A by dissolving erlotinib free base monomer in a solvent; the group of solvents is an alcohol and a halogenated hydrocarbon, an ester, and a A mixed solvent of an oxygen atom or a solvent of any one of the ketones.

The inventors have found that the above-mentioned group of dissolved solvents can be used to dissolve the erlotinib free base monomer by a simple stirring operation.

The alcohol solvent may be a fatty alcohol of ( ₆ ). The halogenated hydrocarbon solvent may be dichloromethane, chloroform or 1,2-dichloroethylene; the ester solvent may be acetic acid B. Ester, ethyl formate, methyl acetate, isopropyl acetate, propyl acetate, butyl acetate or isobutyl acetate; the ketone solvent may be acetone, methyl isobutyl ketone, butanone, methyl butyl The ketone or methyl isopropyl ketone; the ether solvent containing one oxygen atom may be tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, anisole or methyl tert-butyl ether.

The alcohol solvent is preferably methanol, ethanol or isopropanol; the halogenated hydrocarbon solvent is preferably dichloromethane; the ester solvent is preferably ethyl acetate; and the ketone solvent is preferably acetone; The ether solvent containing one oxygen atom is preferably methyl tert-butyl ether.

Preferably, the set of solvents is a mixed solvent of an alcohol and a chlorinated alkane solvent.

More preferably, the alcohol solvent is methanol; and the chlorinated solvent is dichloromethane or chloroform.

The volume ratio of the alcohol solvent to any of the halogenated hydrocarbons, esters, ethers containing one oxygen atom, and ketone is less than 1. Preferably, the volume ratio of the alcohol to any of the halogenated hydrocarbons, esters, ethers containing one oxygen atom, and ketone is from 1:3 to 10.

One embodiment provided by the present invention is:

The erlotinib free base monomer is dissolved in a solvent and mixed with an organic solution of hydrogen chloride to prepare erlotinib hydrochloride Form A.

The organic solution of hydrogen chloride is preferably a mixed solution of hydrogen chloride and an alcohol, an ester or an ether.

The mixed solution of hydrogen chloride and alcohol may be methanol hydrogen chloride solution, ethanol hydrogen chloride solution, isopropanol hydrogen chloride solution, n-propanol hydrogen chloride solution, n-butanol hydrogen chloride solution, sec-butanol hydrogen chloride solution, isobutanol hydrogen chloride solution or uncle Butanol hydrogen chloride solution; the mixed solution of hydrogen chloride and ester may be ethyl formate hydrogen chloride solution, methyl acetate hydrogen chloride solution, ethyl acetate hydrogen chloride solution, isopropyl acetate hydrogen chloride solution, propyl acetate hydrogen chloride solution, butyl acetate A hydrogen chloride solution or an isobutyl acetate hydrogen chloride solution; the mixed solution of hydrogen chloride and ether may be an ether hydrogen chloride solution, an anisole hydrogen chloride solution, a diisopropyl ether hydrogen chloride solution or a methyl tert-butyl ether hydrogen chloride solution.

The mixed solution of hydrogen chloride and an alcohol is preferably a methanol hydrogen chloride solution, an ethanol hydrogen chloride solution, or an isopropanol hydrogen chloride solution; the mixed solution of hydrogen chloride and an ester is preferably an ethyl acetate hydrogen chloride solution or an isopropyl acetate hydrogen chloride solution; A mixed solution of hydrogen chloride and an ether is preferably a isopropyl ether hydrogen chloride solution or a methyl t-butyl ether hydrogen chloride solution.

After the erlotinib free base monomer is dissolved, the filtration treatment may be increased, and then mixed with an organic solution of hydrogen chloride to remove insoluble impurities.

A preferred embodiment provided by the present invention is: dissolving erlotinib free base monomer in a group of solvents, after being dissolved, filtering, and mixing the filtrate with an organic solution of hydrogen chloride to control the reaction internal temperature to be -50~ Preparation of erlotinib hydrochloride Form A at 50 ° C for 0 to 12 hours.

The internal temperature of the reaction is preferably _10 to 45 ° C, and the heat retention time is preferably 0 to 6 hours.

The molar ratio of the erlotinib free base monomer to the hydrogen chloride is 1.0: (1. 0~2. 0); preferably 1: (1·01~1·5) _; more preferably 1 : (1·01~1· 2).

(^~( ₆ fatty alcohols described in the present application include but are not limited to: methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, 1-pentanol , 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 3-methyl-1-butanol, 2,2-Dimethyl-1-propanol, 1-hexanol, 2-hexanol, 3-hexanol.

The invention provides the erlotinib free base dissolved in a solvent by a group of solvents, such as a mixed solution of an alcohol with a halogenated hydrocarbon, an ester, an ether containing an oxygen atom, or a solvent of any one of the ketones. The method for preparing erlotinib hydrochloride crystal form to dissolve the solution, solves the problems of mixed crystal phenomenon, unqualified residual solvent and excessive organic solvent pollution in the preparation process, and has stable process and is suitable for industrial production. DRAWINGS

Figure 1 : Powder X-ray diffraction pattern of erlotinib hydrochloride Form A prepared in Example 1. detailed description

In order to further understand the present invention, the preparation method of erlotinib hydrochloride Form A provided by the present invention will be described in detail below with reference to the examples. It is to be understood that the description of the embodiments of the invention is not intended to limit the scope of the invention.

Example 1

In a clean and dry 100 ml four-necked flask, 10 g (2.5 4 mmol) of erlotinib free base monomer, 10 ml of methanol, and 30 ml of dichloromethane were added, and the mixture was stirred and filtered, and the filtrate was added dropwise for use. The dried 250 ml four-necked flask was added with 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6. 5 g (26. 7 mmol), and ice water was cooled to -10 to -5 ° C. The above-mentioned erlotinib free base monomer in methanol dichloromethane solution was added dropwise, added dropwise, and then incubated at _10 to -5 ° C for 6 hours, filtered, and the wet product was dried in a vacuum oven at 40 ° C. , dry product: 10. 6g, yield: 97. 0%. Example 2

In a clean and dry 100 ml four-necked flask, 10 g (25. 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 40 ml of dichloromethane were added, and the mixture was stirred and dissolved, and the filtrate was added dropwise. A clean and dry 250 ml four-necked flask, adding 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6. 5 g (26. 7 mmol), and cooling to -10 to -5 ° with ice water. C, start to add the above erlotinib free base monomer in methanol dichloromethane solution, add dropwise, then incubated at _10~ -5 °C for 2 hours, filter, wet product into 40 ° C vacuum oven Dry in the middle, dry product: 10. 6g, yield: 97. 0%.

Example 3

In a clean and dry 100 ml four-necked flask, 10 g (2.5 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 50 ml of tetrahydrofuran were added, and the mixture was stirred and filtered, and the filtrate was added dropwise for use. The dried 250 ml four-necked flask was added with 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6. 5 g (26. 7 mmol), and ice water was cooled to -10 to -5 ° C. The above-mentioned erlotinib free base monomer in methanol dichloromethane solution was added dropwise, added dropwise, and then incubated at _10 to -5 ° C for 6 hours, filtered, and the wet product was dried in a vacuum oven at 40 ° C. , dry product: 10. 5g, yield: 96. 1%.

Example 4

In a clean and dry 100 ml four-necked flask, 10 g (2.5 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 100 ml of ethyl acetate were added, and the mixture was stirred and dissolved, and the filtrate was added dropwise, and the preparation was further prepared. A clean and dry 250 ml four-necked flask, adding 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6. 5 g (26. 7 mmol), and cooling to -10 to -5 ° with ice water. C, start to add the above erlotinib free base monomer in methanol dichloromethane solution, add dropwise, then incubated at _10~ -5 °C for 2 hours, filter, wet product into 40 ° C vacuum oven Dry in the middle, dry product: 10. 5g, yield: 96. 1%.

Example 5

In a clean and dry 100 ml four-necked flask, 10 g (2.5 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 100 ml of acetone were added, and the mixture was stirred and filtered, and the filtrate was added dropwise for use. The dried 250 ml four-necked flask was added with 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6. 5 g (26. 7 mmol), and ice water was cooled to -10 to -5 ° C. The above-mentioned erlotinib free base monomer in methanol dichloromethane solution was added dropwise, and the mixture was added dropwise, and then kept at _10 to -5 ° C for 3 hours, filtered, and the wet product was dried in a vacuum oven at 40 ° C. , dry product: 10. 8g, yield: 98. 8%.

Example 6

In a clean and dry 100 ml four-necked flask, 10 g (25. 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 50 ml of dichloromethane were added, and the mixture was stirred and dissolved, and the filtrate was added dropwise. A clean and dry 250 ml four-necked flask, adding 50 ml of isopropyl alcohol and a content of 12. 4% of isopropanol hydrogen chloride solution 7. 9 g (26. 8 mmol), cooling with ice water to _10~ -5 °C, starting to add dropwise The above-mentioned erlotinib free base monomer in methanol dichloromethane solution is added dropwise, and then kept at -10 to -5 ° C for 3 hours, filtered, and the wet product is dried in a vacuum oven at 40 ° C to obtain a dry Product: 10. 8g, Yield: 98.8%. Example 7

In a clean and dry 100 ml four-necked flask, 10 g (2.5 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 100 ml of ethyl acetate were added, and the mixture was stirred and dissolved, and the filtrate was added dropwise, and the preparation was further prepared. a clean and dry 250 ml four-necked flask, adding 100 ml of ethyl acetate and a content of 11.2% ethyl acetate hydrogen chloride solution of 8. 7 g (26. 7 mmol), cooling with ice water to -10 to -5 ° C, starting to drip Add the above erlotinib free base monomer in methanol dichloromethane solution, add dropwise, then keep at -10~- 5 °C for 12 hours, filter, wet product into 40 ° C vacuum oven to dry, get Dry product: 10. 6g, yield: 97%.

Example 8

In a clean and dry 100 ml four-necked flask, 10 g (25. 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 50 ml of dichloromethane were added, and the mixture was stirred and dissolved, and the filtrate was added dropwise. A clean and dry 250 ml four-necked flask, adding 50 ml of dichloromethane and a content of 12. 4% of isopropanol hydrogen chloride solution 7. 9 g (26. 8 mmol), cooling with ice water to _10~ -5 °C, starting to drip Add the above erlotinib free base monomer in methanol dichloromethane solution, add dropwise, then keep at -10~- 5 °C for 12 hours, filter, wet product into 40 ° C vacuum oven to dry, get Dry product: 10. 4g, Yield: 95. 2%.

Example 9

In a clean and dry 100 ml four-necked flask, 10 g (25. 4 mmol) of erlotinib free base monomer, 10 ml of methanol, and 80 ml of dichloromethane were added, and the mixture was stirred and dissolved, and the filtrate was kept at 20 to 30 ° C. A mixture of 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution of 6.5 g (26. 7 mmol) was added dropwise to the filtrate, and the internal temperature was maintained at 20 to 30 ° C. Then, it was kept at 20 to 30 ° C for 2 hours, filtered, and the wet product was dried in a vacuum oven at 40 ° C to obtain a dry product: 10.7 g, yield: 97.9%.

Example 10

In a clean and dry 100 ml four-necked flask, 10 g (25. 4 mmol) of erlotinib free base monomer, 10 ml of isopropyl alcohol, and 80 ml of dichloromethane were added, and the mixture was stirred and filtered, and the filtrate was kept at 10 to 20 ° C. To the above filtrate, 50 ml of methyl tert-butyl ether and a 15% methyl tert-butyl ether hydrogen chloride solution were added dropwise to a solution of 6. 5 g (26. 7 mmol), and the internal temperature was maintained at 10 to 20 ° C, and the mixture was added dropwise. The mixture was kept at 10 to 20 ° C for 2 hours, filtered, and the wet product was dried in a vacuum oven at 40 ° C to obtain a dry product: 10.7 g, yield: 97.9%.

Claims

A method for preparing erlotinib hydrochloride crystal form A, which comprises dissolving erlotinib free base monomer in a solvent to prepare erlotinib hydrochloride crystal form A, characterized in that the group of solvents It is a mixed solvent of an alcohol solvent and a solvent of a halogenated hydrocarbon, an ester, an ether containing one oxygen atom, or a ketone.

2. The preparation method according to claim 1, wherein the group of solvents dissolves erlotinib free base to dissolve.

The method according to claim 1, wherein the group of solvents is a mixed solvent of an alcohol and a chlorinated alkane solvent.

The method according to claim 1, wherein the alcohol solvent is ( _{6 to 6} fatty alcohol).

The method according to claim 4, wherein the alcohol solvent is methanol, ethanol or isopropanol.

The preparation method according to claim 1, wherein the halogenated hydrocarbon solvent is dichloromethane, chloroform or 1,2-dichloroethylene; and the ester solvent is ethyl acetate. Ethyl formate, methyl acetate, isopropyl acetate, propyl acetate, butyl acetate or isobutyl acetate; the ether solvent containing one oxygen atom is tetrahydrofuran, methyltetrahydrofuran, diethyl ether, diisopropyl ether, benzene Methyl ether or methyl tert-butyl ether; the ketone solvent is acetone, methyl isobutyl ketone, butanone, methyl butyl ketone or methyl isopropyl ketone.

The method according to claim 1, wherein a volume ratio of the alcohol solvent to any of a halogenated hydrocarbon, an ester, an oxygen atom-containing ether, and a ketone is less than 1.

The preparation method according to claim 1, wherein the erlotinib free base monomer is dissolved in a solvent, and after being dissolved, the erlotinib hydrochloride crystal form is prepared by mixing with an organic solution of hydrogen chloride. A.

The method according to claim 9, wherein the organic solution of hydrogen chloride is an alcohol, ester or ether solution of hydrogen chloride.

The preparation method according to claim 1, wherein the erlotinib free base monomer is dissolved in a solvent, and after being dissolved, it is filtered and mixed with an organic solution of hydrogen chloride to control the reaction internal temperature. -50~50 ° C, keeping warm for 0~12 hours, preparing erlotinib hydrochloride crystal form.