CN103420924B - A kind of preparation method of Erlotinib hydrochloride crystal form A - Google Patents
A kind of preparation method of Erlotinib hydrochloride crystal form A Download PDFInfo
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- CN103420924B CN103420924B CN201210164053.8A CN201210164053A CN103420924B CN 103420924 B CN103420924 B CN 103420924B CN 201210164053 A CN201210164053 A CN 201210164053A CN 103420924 B CN103420924 B CN 103420924B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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Abstract
The invention belongs to pharmaceutical synthesis field, relate to the preparation method of a kind of Erlotinib hydrochloride crystal form A, described preparation method is to dissolve with the mixed solvent of arbitrary solvent in alcohols and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone, to the most molten clear after, mix with the organic solution of hydrogen chloride, prepare Erlotinib hydrochloride crystal form A.The present invention solves the mixed crystal phenomenon occurred in preparation process, problem, the process stabilizing such as residual solvent is defective, organic solvent too much pollutes, and is suitable for industrialized production.
Description
Technical field
The present invention relates to chemical pharmaceutical technical field, more particularly, to the preparation side of a kind of Erlotinib hydrochloride crystal form A
Method.
Background technology
Erlotinib hydrochloride, English name: Erlotinib Hydrochloride, chemical name: N-(3-ethynyl phenyl)-
6,7-bis-(2-methoxy ethoxy)-4-quinazolinamine hydrochloride, its structural formula is shown below:
。
It is that the 4-aminophenyl quinazoline ditosylate salt that Osi Pharm Inc. of the U.S. (OSI Pharmaceuticals) develops is oral anti-
Tumor medicine, on November 18th, 2004 in U.S. FDA approval listing, is used for treating cancer of pancreas and transitivity non-small cell lung first
Cancer.Research finds, this Department of Pharmacy's small molecule tyrosine kinase EGF-R ELISA hypotype (EGFR-TK), its mechanism of action
It is at intracellular and substrate competition, suppresses EGFR-TK phosphorylation, block the transduction of tumor cell signal, thus suppress tumor thin
Intracellular growth, induces it dead.
United States Patent (USP) US5747498(publication date: 1998-5-5) and patent families describe erlotinib monomer the earliest
And hydrochlorate and prepared the preparation method of its hydrochlorate by erlotinib monomer, but this hydrochlorate is A type polymorph
With the mixture of Type B, do not prepare pure Erlotinib hydrochloride crystal form A.
CN101602734(publication date: 2009-12-16) describe the preparation method of a kind of Erlotinib hydrochloride crystal form A,
Erlotinib free base will mix with organic solvent, then drip the hydrochloric acid solution of ethers, prepare hydrochloric acid angstrom sieve at low temperatures
Method for Buddhist nun crystal formation A.But the method also exists the underproof phenomenon of ethers residual solvent.
201010258627.9(publication date: 2010-12-15) it is that erlotinib base crystal formation Form IV is dissolved in organic solvent
In, it is passed through hydrochloric acid aqueous isopropanol, filtering drying, the method preparing Erlotinib hydrochloride crystal form A.But obtained hydrochloric acid angstrom sieve
XRPD collection of illustrative plates for Buddhist nun crystal formation A is found to have part mixed crystal phenomenon.
201010274216.9(publication date: 2011-1-19) it is that erlotinib free base is mixed with organic solvent, dropping
Esters hydrochloric acid solution, the method preparing Erlotinib hydrochloride crystal form A.In all embodiments of this patent application, organic solvent is used
Amount has reached 30 times of erlotinib free base consumption, can cause too much pollution.
WO2009025873(publication date: 2009-2-16) describe and a kind of erlotinib free base is mixed into solvent
Suspension, the mixed solution being passed through hydrogen chloride gas or addition concentrated hydrochloric acid or hydrochloric acid and esters prepares Erlotinib hydrochloride crystalline substance
The method of type A.This preparation method uses erlotinib free base and methanol and the mixed solution of toluene, or methanol and 1,3-bis-
The mixed solution of oxygen pentane is mixed into suspension and prepares Erlotinib hydrochloride crystal form A, need to be by erlotinib free base and solvent
It is mixed into suspension, so operates, poor repeatability, it is easily formed mixed crystal.
The mixed crystal phenomenon that exists in view of prior art, the problem such as residual solvent is defective, organic solvent too much pollutes,
Being necessary further to be improved the preparation method of Erlotinib hydrochloride crystal form A, development yield is high, process stabilizing, suitable
Close the preparation method of the Erlotinib hydrochloride crystal form A of industrialized production.
Summary of the invention
The invention provides the preparation method of a kind of Erlotinib hydrochloride crystal form A, the method well solves to be prepared
The problems such as the mixed crystal phenomenon, the residual solvent that occur in journey are defective, organic solvent too much pollutes, have process control, weight
Existing property is good and process stabilizing.Such preparation method is suitable for industrialized production, has important economic worth.
The reaction equation that the present invention relates to is as follows:
。
The invention provides one to be dissolved with one group of solvent by erlotinib free base monomer, prepare Erlotinib hydrochloride brilliant
The method of type A；This group of solvent is alcohols and arbitrary solvent in halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone
Mixed solvent.
Inventor find above-mentioned one group of dissolution solvent through simple agitation operation can by molten for erlotinib free base monomer clearly.
Described alcohols solvent can be C1～C6Fatty alcohol.Described halogenated hydrocarbon solvent can be dichloromethane, three chloromethanes
Alkane or 1,2-dichloroethylene；Described esters solvent can be ethyl acetate, Ethyl formate, methyl acetate, isopropyl acetate, acetic acid
Propyl ester, butyl acetate or isobutyl acetate；Described ketones solvent can be acetone, methyl iso-butyl ketone (MIBK), butanone, methyl butyl ketone
Or methyl isopropyl Ketone；The described ether solvent containing an oxygen atom can be oxolane, methyltetrahydrofuran, ether, different
Propyl ether, methyl phenyl ethers anisole or methyl tertiary butyl ether(MTBE).
Described alcohols solvent is preferably methanol, ethanol, isopropanol；Described halogenated hydrocarbon solvent is preferably dichloromethane；Institute
State esters solvent and be preferably ethyl acetate；Described ketones solvent is preferably acetone；The described ether solvent containing an oxygen atom is excellent
Elect methyl tertiary butyl ether(MTBE) as.
Preferably, this group of solvent is the mixed solvent of alcohols and alkyl chloride kind solvent.
It is highly preferred that described alcohols solvent is methanol；Described alkyl chloride kind solvent is dichloromethane, chloroform.
In described alcohols solvent and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone, arbitrary solvent volume ratio is little
In 1.
Preferably, the body of arbitrary solvent in described alcohols and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone
Long-pending ratio is 1:1.01～10.
It is highly preferred that arbitrary solvent in described alcohols and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone
Volume ratio is 1:3～10.
A kind of embodiment that the present invention provides is: dissolved with one group of solvent by erlotinib free base monomer, with chlorination
Erlotinib hydrochloride crystal form A is prepared after the organic solution mixing of hydrogen.
The preferred hydrogen chloride of organic solution of described hydrogen chloride and alcohols, esters, the mixed solution of ethers.
Described hydrogen chloride can be methanolic hydrogen chloride solution, ethanolic hydrogen chloride solution, isopropanol with the mixed solution of alcohols
Hydrogen chloride solution, normal propyl alcohol hydrogen chloride solution, n-butyl alcohol hydrogen chloride solution, sec-butyl alcohol hydrogen chloride solution, isobutanol hydrogen chloride are molten
Liquid or tert-butyl alcohol hydrogen chloride solution；Described hydrogen chloride can be Ethyl formate hydrogen chloride solution, acetic acid with the mixed solution of esters
Methyl ester hydrogen chloride solution, ethyl acetate hydrogen chloride solution, isopropyl acetate hydrogen chloride solution, propyl acetate hydrogen chloride solution, second
Acid butyl ester hydrogen chloride solution or isobutyl acetate hydrogen chloride solution；Described hydrogen chloride can be ether chlorine with the mixed solution of ethers
Change hydrogen solution, methyl phenyl ethers anisole hydrogen chloride solution, diisopropyl ether hydrogen chloride solution or methyl tertbutyl ether solution of hydrogen chloride.
Described hydrogen chloride and the mixed solution preferred methanolic hydrogen chloride solution of alcohols, ethanolic hydrogen chloride solution, isopropanol chlorine
Change hydrogen solution；Described hydrogen chloride and the mixed solution ethyl acetate hydrogen chloride solution of esters, isopropyl acetate hydrogen chloride are molten
Liquid；Described hydrogen chloride and the mixed solution preferred diisopropyl ether hydrogen chloride solution of ethers, methyl tertbutyl ether solution of hydrogen chloride.
After erlotinib free base monomer is molten clearly, filtration treatment can be increased, then mix with the organic solution of hydrogen chloride
Reaction, to remove the most insoluble impurity.
The one that the present invention provides is preferred embodiment: dissolved with one group of solvent by erlotinib free base monomer,
Until molten clear after, filter, filtrate mix with the organic solution of hydrogen chloride, and controlling the interior temperature of reaction is-50～50 DEG C, is incubated 0～12 little
Time prepare Erlotinib hydrochloride crystal form A.
In described reaction, temperature is preferably-10～45 DEG C, and described temperature retention time is preferably 0～6 hour.
Described erlotinib free base monomer is 1.0:(1.0～2.0 with the molar ratio of described hydrogen chloride)；It is preferably
1:(1.01～1.5)；More preferably 1:(1.01～1.2).
C described herein1～C6Fatty alcohol includes but not limited to: methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol,
Sec-butyl alcohol, isobutanol, the tert-butyl alcohol, 1-amylalcohol, 2-amylalcohol, 3-amylalcohol, 2-methyl-1-butene alcohol, 2-methyl-2 butanol, 3-methyl-
2-butanol, 3-methyl-1-butanol, 2,2-dimethyl-1-propanol, 1-hexanol, 2-hexanol, 3-hexanol.
What the present invention provided be dissolved to one group of solvent of erlotinib free base molten clearly, such as alcohols and halogenated hydrocarbon, ester
In class, ethers containing an oxygen atom, ketone the mixed solution of arbitrary solvent be dissolved to molten clearly, prepare Erlotinib hydrochloride crystal form
The method of A, solve preparation process occurs mixed crystal phenomenon, residual solvent is defective, organic solvent too much pollutes
Problem, process stabilizing, it is suitable for industrialized production.
Detailed description of the invention
In order to be further appreciated by the present invention, below in conjunction with embodiment to the Erlotinib hydrochloride crystal form A that the present invention provides
Preparation method is described in detail.It is to be appreciated that these embodiments describe simply for further describing the present invention's
Feature rather than to the scope of the invention or the restriction of right.
Embodiment 1
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), methanol
10ml, dichloromethane 30ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-mouthfuls of one clean dried of another preparation
Flask, addition 50ml methyl tertiary butyl ether(MTBE) and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%), ice
Being water-cooled to-10～-5 DEG C, start to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, dropping is finished, then
Being incubated 6 hours-10～-5 DEG C, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.6g, yield:
97.0%。
Embodiment 2
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, dichloromethane 40ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-of one clean dried of another preparation
Mouth flask, addition 50ml methyl tertiary butyl ether(MTBE) and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%),
Frozen water is cooled to-10～-5 DEG C, starts to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, and dropping is finished,
Being incubated 2 hours-10～-5 DEG C again, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.6g, yield:
97.0%。
Embodiment 3
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, oxolane 50ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-of one clean dried of another preparation
Mouth flask, addition 50ml methyl tertiary butyl ether(MTBE) and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%),
Frozen water is cooled to-10～-5 DEG C, starts to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, and dropping is finished,
Being incubated 6 hours-10～-5 DEG C again, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.5g, yield:
96.1%。
Embodiment 4
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, ethyl acetate 100ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml of one clean dried of another preparation
Four-hole boiling flask, addition 50ml methyl tertiary butyl ether(MTBE) and the methyl tertbutyl ether solution of hydrogen chloride 6.5g that content is 15%
(26.7mmol), frozen water is cooled to-10～-5 DEG C, and the methanol dichloromethane starting to drip above-mentioned erlotinib free base monomer is molten
Liquid, dropping finishes, then is incubated 2 hours-10～-5 DEG C, filter, and wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product:
10.5g, yield: 96.1%.
Embodiment 5
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, acetone 100ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-mouthfuls of one clean dried of another preparation
Flask, addition 50ml methyl tertiary butyl ether(MTBE) and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%), ice
Being water-cooled to-10～-5 DEG C, start to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, dropping is finished, then
Being incubated 3 hours-10～-5 DEG C, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.8g, yield:
98.8%。
Embodiment 6
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, dichloromethane 50ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-of one clean dried of another preparation
Mouth flask, addition 50ml isopropanol and the isopropanol hydrogen chloride solution 7.9g(26.8mmol that content is 12.4%), frozen water cools down
To-10～-5 DEG C, starting to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, dropping is finished, then-10
～-5 DEG C be incubated 3 hours, filter, wet product put in 40 DEG C of vacuum drying ovens be dried, obtain dry product: 10.8g, yield: 98.8%.
Embodiment 7
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, ethyl acetate 100ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml of one clean dried of another preparation
Four-hole boiling flask, addition 100ml ethyl acetate and the ethyl acetate hydrogen chloride solution 8.7g(26.7mmol that content is 11.2%), ice
Being water-cooled to-10～-5 DEG C, start to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, dropping is finished, then
Being incubated 12 hours-10～-5 DEG C, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.6g, yield:
97%。
Embodiment 8
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, dichloromethane 50ml, stir molten clear rear filtration, and filtrate treats that dropping uses, the 250ml tetra-of one clean dried of another preparation
Mouth flask, addition 50ml dichloromethane and the isopropanol hydrogen chloride solution 7.9g(26.8mmol that content is 12.4%), frozen water cools down
To-10～-5 DEG C, starting to drip the methanol dichloromethane solution of above-mentioned erlotinib free base monomer, dropping is finished, then-10
～-5 DEG C be incubated 12 hours, filter, wet product put in 40 DEG C of vacuum drying ovens be dried, obtain dry product: 10.4g, yield: 95.2%.
Embodiment 9
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), methanol
10ml, dichloromethane 80ml, stir molten clear rear filtration, and filtrate keeps 20～30 DEG C, drips 50ml methyl-tert in above-mentioned filtrate
Butyl ether and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%) mixed liquor that forms, interior temperature keeps
20～30 DEG C, dropping is finished, then is incubated 2 hours at 20～30 DEG C, filters, and wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry
Product: 10.7g, yield: 97.9%.
Embodiment 10
In the 100ml four-hole boiling flask of clean dried, put into erlotinib free base monomer 10g(25.4mmol), isopropyl
Alcohol 10ml, dichloromethane 80ml, stir molten clear rear filtration, and filtrate keeps 10～20 DEG C, drips 50ml methyl in above-mentioned filtrate
Tertbutyl ether and the methyl tertbutyl ether solution of hydrogen chloride 6.5g(26.7mmol that content is 15%), interior temperature keeps 10～20 DEG C, drips
Finishing, then be incubated 2 hours at 10～20 DEG C, filter, wet product is put in 40 DEG C of vacuum drying ovens and is dried, and obtains dry product: 10.7g, receives
Rate: 97.9%.
Claims (4)
1. the preparation method of an Erlotinib hydrochloride crystal form A, it is characterised in that erlotinib free base monomer is molten with a group
Agent is dissolved, and mixes with the organic solution of hydrogen chloride, and controlling the interior temperature of reaction is-50～50 DEG C, is incubated 0～12 hour, prepares hydrochloric acid
Erlotinib crystal formation A, described one group of solvent be alcohols solvent with in halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone
The mixed solvent of arbitrary solvent, described halogenated hydrocarbon solvent is dichloromethane；Described esters solvent is ethyl acetate；Described contain one
The ether solvent of individual oxygen atom is oxolane；Described ketones solvent is acetone；Described alcohols solvent is methanol or isopropanol；Institute
State the methyl tertiary butyl ether(MTBE) that organic solution is hydrogen chloride of hydrogen chloride, isopropanol or ethyl acetate solution；Described alcohols solvent with
In halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone, the volume ratio of arbitrary solvent is less than 1.
Preparation method the most according to claim 1, it is characterised in that described one group of solvent is molten by erlotinib free base
Solution is the most molten clearly.
Preparation method the most according to claim 1, it is characterised in that erlotinib free base monomer is molten with one group of solvent
Solve, until molten clear after, filter, mix with the organic solution of hydrogen chloride, controlling temperature in reaction is-50～50 DEG C, is incubated 0～12 little
Time, prepare Erlotinib hydrochloride crystal form A；Described one group of solvent be alcohols solvent with halogenated hydrocarbon, esters, containing an oxygen atom
The mixed solvent of arbitrary solvent in ethers, ketone, described halogenated hydrocarbon solvent is dichloromethane；Described esters solvent is acetic acid second
Ester；The described ether solvent containing an oxygen atom is oxolane；Described ketones solvent is acetone；Described alcohols solvent is methanol
Or isopropanol；The organic solution of described hydrogen chloride is the methyl tertiary butyl ether(MTBE) of hydrogen chloride, isopropanol or ethyl acetate solution；Described
In alcohols solvent and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone, the volume ratio of arbitrary solvent is less than 1.
Preparation method the most according to claim 1, it is characterised in that erlotinib free base monomer is molten with one group of solvent
Solve, until molten clear after, filter, mix with the organic solution of hydrogen chloride, controlling temperature in reaction is-50～50 DEG C, is incubated 0～12 little
Time, prepare Erlotinib hydrochloride crystal form A；Described one group of solvent be alcohols solvent with halogenated hydrocarbon, esters, containing an oxygen atom
The mixed solvent of arbitrary solvent in ethers, ketone, described halogenated hydrocarbon solvent is dichloromethane；Described esters solvent is acetic acid second
Ester；The described ether solvent containing an oxygen atom is oxolane；Described ketones solvent is acetone；Described alcohols solvent is methanol
Or isopropanol；The organic solution of described hydrogen chloride is the methyl tertiary butyl ether(MTBE) of hydrogen chloride, isopropanol or ethyl acetate solution；Described
In alcohols solvent and halogenated hydrocarbon, esters, ethers containing an oxygen atom, ketone the volume ratio of arbitrary solvent be 1:1.01～
10。
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| CN201210164053.8A CN103420924B (en) | 2012-05-25 | 2012-05-25 | A kind of preparation method of Erlotinib hydrochloride crystal form A |
| PCT/CN2013/076064 WO2013174261A1 (en) | 2012-05-25 | 2013-05-22 | Method for preparing erlotinib hydrochloride crystalline form a |
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| WO2013174261A1 (en) | 2013-11-28 |
| CN103420924A (en) | 2013-12-04 |
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