CN101602734B - Method for preparing Erlotinib hydrochloride crystal form A - Google Patents
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Abstract
The invention belongs to the technical field of chemical pharmacy, and in particular relates to a method for preparing an Erlotinib hydrochloride crystal form A. The method solves the technical problems that the prior art has uncontrollable process conditions, un-quantitative parameters and the like to cause the problems that products of the crystal form A cannot be prepared stably and a crystal form B is easy to generate in the process of preparing the Erlotinib hydrochloride crystal form A. The method comprises the following steps: mixing an Erlotinib free alkali monomer with an organic solvent, then dropping ether chlorine hydride solution, and preparing the Erlotinib hydrochloride crystal form A at a low temperature. The method has the advantages of high process stability, practicable and controllable operation, low cost and high reproducibility, can obtain a pure product of the crystal form A with high yield, is more suitable for the industrial production of preparing the Erlotinib hydrochloride crystal form A, and has high economic benefit.
Description
Technical field
The present invention relates to the chemical pharmaceutical technical field, more specifically, relate to a kind of preparation method of Erlotinib hydrochloride crystal form A.
Background technology
Generating structure, form, the diverse crystalline phenomenon of rerum natura under different condition with a kind of element or compound are called polymorphism.Polymorphism extensively exists in organic drug, and the crystallization of polymorph medicine belongs to molecular lattice more, produces different crystal formations along with the difference of processing condition.Same medicine is because the type of crystal formation and the difference of purity, make the physical properties (as solubleness, dissolution rate, fusing point etc.) and the stability (crystal formation and chemical stability) of medicine may have significant difference, thereby can exert an influence safety, the validity of medicine.
For there being polymorphous bulk drug, preparation technology's emphasis is the preparation (type and purity) of purpose crystal formation and the circulation ratio of crystal formation.Therefore, need in technology, to investigate different crystallization conditions (as the recrystallization solvent of opposed polarity, proportioning, crystallization rate, temperature, time, different processing, drying conditions are as order of addition(of ingredients), stirring velocity etc.) the crystal formation difference of medicine down.Under different conditions, crystal formation easily makes the transition, have Buddhist nun's custard Horizon, method to establish for medicines such as fourth, Cimitidine Type A/ABs such as the medicine that is made the transition by the different solvents recrystallization, what change that envrionment temperature causes making the transition looks sidelong at purine, paraxin, Buddhist nun's custard ground equality as metoclopramide, sulfydryl.This shows that Selection of technological conditions is very important to preparing pure, stable crystal formation, also have very big difficulty, need to consider the difficulty or ease of technology, the height of cost and the stability and the feasibility of technology in the detailed process.
Detecting aspect the whether pure crystal formation, can adopt more convenient relatively, powder x-ray diffraction method (XRPD) accurately.Powder x-ray diffraction method is the method that crystal formation purity was differentiated and measured to crystal formation of carrying out that the most generally adopts at present.Almost the fingerprint with the people is the same for each crystalline powder x-ray diffraction collection of illustrative plates, and the distributing position of its diffraction approach and intensity just have the feature of oneself.When sample comprises the mixture of several crystal formations, the collection of illustrative plates that its powder X-ray-diffractogram is added and obtained by the various crystalline diffraction lines of forming it.Each component diffracted intensity is generally strengthened with the increase of its content, therefore, by the powder x-ray diffraction result, can obtain crystal formation variation, degree of crystallinity, brilliant structure state, whether information such as mixed crystal are arranged, and the discriminating of crystal formation is had the decision meaning.Under collection of illustrative plates evident characteristic situation, use powder x-ray diffraction method to suffice to show that the purity and the type of crystal formation.
Erlotinib hydrochloride, English name: Erlotinib Hydrochloride, chemical name: N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine hydrochlorate, its structural formula is suc as formula shown in (I):
It is the oral antitumour drug of 4-aminophenyl quinazoline ditosylate salt of U.S. Osi Pharm Inc. (OSI Pharmaceuticals) exploitation, and on November 18th, 2004 in the drugs approved by FDA listing, was used for the treatment of carcinoma of the pancreas and transitivity nonsmall-cell lung cancer first.Discover, this Department of Pharmacy's small molecules Tyrosylprotein kinase EGF-R ELISA hypotype (EGFR-TK), its mechanism of action is in cell and substrate competition, suppress the EGFR-TK phosphorylation, the transduction of blocking-up tumour cell signal, thus growth of tumour cell suppressed, induce its death.
U.S. Pat 5747498 (patentee: Pfizer, authorization date: on May 5th, 1998) described N-(3-ethynyl phenyl)-6 the earliest, 7-two (2-methoxy ethoxy)-4-quinazoline amine (erlotinib) and hydrochloride form thereof, and in embodiment (embodiment 20), the synthetic method of erlotinib hydrochloride has been described, wherein as follows about the detailed process for preparing its hydrochloride by the erlotinib monomer:
The erlotinib free base monomer is dissolved in the CHCl of certain volume
3In the solution, dilute, use the hydrochloric acid diethyl ether solution of 1 mole (1M) to carry out titration then, obtain precipitate: erlotinib hydrochloride, yield 71%, fusing point: 228-230 ℃ with the ether of number volume.
Though it is the form medicinal, the acceptable salt of human body that can be used as that Pfizer's this piece patent is pointed out the erlotinib hydrochloride, and which kind of crystal formation the salt of unspecified its preparation is.According to another piece U.S. Pat 6900221 (patentee: Osi Pharm Inc., date of publication: description May 17 calendar year 2001): in fact disclosed hydrochloride contains the mixture of A type polymorphic form and Type B in the U.S. Pat 5747498, because the part of its stability reduces the Chinese patent families CN100351241 of US6900221 correspondence (see the 22nd page).
Further, U.S. Pat 20040162300 (date of publication: on August 19th, 2004) embodiment (embodiment 4-6) has provided the data of fusing point, stability and the solubleness aspect of crystal form A, B, and is specific as follows:
| Rerum natura | Crystal form A | Crystal form B |
| Fusing point (℃) | 205-208 | 227-231 |
| Stability (solution heat KJ/mol) * 1 | 50.0-55.6 | 61.2-62.4 |
| Solvability * 2 | 0.194％ | 0.098％ |
| Solvability * 3 | 0.017％ | 0.003％ |
* condition
1: in the solution of ethanol/water (45:55g/g) heat (temperature: 45 ℃)
* condition
2: water
* condition
3: the buffered soln of water (pH=1)
Can judge in conjunction with above data, erlotinib hydrochloride genomorph described in the patent US5747498 is in A, B mixed crystal, reason is: products therefrom fusing point (228-230 ℃) is close with the fusing point (227-231 ℃) of crystal form B, but its stability is not as pure crystal form B (promptly causing owing to A type polymorphic form composition).
Thereafter a series of patents, provided the form of other crystal formations of erlotinib hydrochloride as US 2004/0162300, US 2006/0154941 etc., as crystal formation E, amorphous forms, though wherein also provided some data relevant for crystal form A, but, do not provide concrete method with regard to how synthesizing pure crystal form A.
Summary of the invention
The present invention has carried out process modification on the basis of prior art described in the background technology (US5747498), solved because prior art exists that processing condition are uncontrollable, parameter can't quantitatively wait technical problem, and cause stably to make A crystal formation product, in the process of preparation Erlotinib hydrochloride crystal form A, produce the problem of crystal form B easily, propose a kind of preparation method of Erlotinib hydrochloride crystal form A, can make pure A crystal formation product.This method technology stability height, operation feasible is controlled, and cost is low, the circulation ratio height, the yield height is more suitable for being used to prepare the suitability for industrialized production of Erlotinib hydrochloride, has very high economic benefit.
The reaction formula that the present invention relates to is as follows:
The technical scheme that adopts is:
Erlotinib free base monomer and organic solvent are mixed, drip the hydrogen chloride solution of ethers then, make Erlotinib hydrochloride crystal form A at low temperatures.
Further, concrete scheme is as follows:
Described erlotinib free base monomer and described organic solvent are mixed, temperature reaches-50～20 ℃ in making, drip the hydrogen chloride solution of described ethers, dropwised in 0～5 hour, dripped follow-up continuation of insurance temperature 0～12 hour, filter, wet product are dried at normal temperatures, promptly obtain described Erlotinib hydrochloride crystal form A.
Further, warm preferred temperature is-50～0 ℃ in the described reaction.
Further, drip preferred 0～1 hour of the time of the hydrogen chloride solution of described ethers.
Further, dripped behind the hydrogen chloride solution of described ethers soaking time preferred 0～2 hour.
Further, described erlotinib free base monomer: the molar ratio of described hydrogenchloride is 1.0: (1.0～2.0); Be preferably 1: (1.01～1.5); More preferably 1: (1.01～1.2).
Further, described organic solvent contains one of following: 1. benzene class: toluene or dimethylbenzene; 2. ethers: tetrahydrofuran (THF), ether, isopropyl ether, methyl-phenoxide or methyl tertiary butyl ether; 3. ketone: acetone, methyl iso-butyl ketone (MIBK), butanone or methyl butyl ketone; 4. alkanes: normal heptane, Skellysolve A, hexane, hexanaphthene or methylcyclohexane; 5. chlorinated hydrocarbon: methylene dichloride, chloroform or 1,2-dichloroethene; 6. ester class: ethyl acetate, isobutyl acetate, butylacetate or isopropyl acetate; 7. mixed solvent: the mixed solvent of methylene dichloride and methyl tertiary butyl ether, the perhaps mixed solvent of chloroform and ether.
Further, described organic solvent preferably contains one of following: 1. single solvent: toluene, tetrahydrofuran (THF), acetone, normal heptane, methylene dichloride, chloroform or ethyl acetate; 2. mixed solvent: chloroform and ether volume ratio are that 5: 1 mixed solvent or methylene dichloride and methyl tertiary butyl ether volume ratio are 5: 1 mixed solvent; More preferably methylene dichloride and methyl tertiary butyl ether volume ratio are 5: 1 mixed solvent or acetone single solvent.
Further, the hydrogen chloride solution of described ethers is one of following: ether hydrogen chloride solution, methyl-phenoxide hydrogen chloride solution, isopropyl ether hydrogen chloride solution or methyl tertbutyl ether solution of hydrogen chloride.
Further, the hydrogen chloride solution of described ethers is preferably one of following: ether hydrogen chloride solution or methyl tertbutyl ether solution of hydrogen chloride; Methyl tertbutyl ether solution of hydrogen chloride more preferably.
Further, optimized technical scheme is as follows:
With described erlotinib free base monomer and described methylene dichloride and methyl tertiary butyl ether volume ratio is that 5: 1 mixed solvent or acetone single solvent mixes, be cooled to-50～0 ℃, drip described methyl tertbutyl ether solution of hydrogen chloride, dropwised in 0～1 hour, dripped follow-up continuation of insurance temperature 0～2 hour, filter, wet product are dried at normal temperatures, promptly obtain pure described Erlotinib hydrochloride crystal form A.
The present invention through a large amount of experiment, has overcome and has been easy to generate the difficulty that mixed crystal and crystal formation easily change aspect the processing condition selection.In experimentation, follow the tracks of, find to be put into room temperature (25～30 ℃) stirring for some time behind the low-temp reaction, measuring the existing a large amount of crystal form B of discovery through powder x-ray diffraction method (XRPD) generates, promptly produce a large amount of A, B mixed crystal, when temperature is heated to backflow, just become crystal form B after backflow for some time fully, therefore in the selection of temperature, grope just to obtain scope of the present invention through a large amount of experiments, and only be controlled in the temperature range of the present invention, just can make pure A crystal formation.
In addition, the time that drips and be incubated also is influential to the preparation of crystal form A.Grope on time selected, in the insulating process that drips after finishing, the phenomenon that just has mixed crystal after time lengthening occurs.Therefore the control of order of addition(of ingredients), institute's solubilizing agent, the control of feed rate, time is also very important for making pure crystal form A.
The Erlotinib hydrochloride A crystal formation that makes, A, B mixed crystal, the B crystal formation has obtained affirmation through powder x-ray diffraction method (XRPD) check and analysis.
In a word, beneficial effect of the present invention is: make Erlotinib hydrochloride A crystal formation product by the erlotinib free base monomer, used feasible process is controlled, simple to operate, easy handling, and cost is low, the technology circulation ratio is high and more stable, can access pure A crystal formation product, the yield height reaches as high as 100% level, be more suitable for being used to prepare the suitability for industrialized production of Erlotinib hydrochloride, have very high economic benefit.
Description of drawings
The powder x-ray diffraction collection of illustrative plates of the Erlotinib hydrochloride crystal form A that accompanying drawing 1: embodiment 1 makes.
The Erlotinib hydrochloride A that accompanying drawing 2: embodiment 15 makes, the powder x-ray diffraction collection of illustrative plates of B mixed crystal.
The powder x-ray diffraction collection of illustrative plates of the Erlotinib hydrochloride crystal form B that accompanying drawing 3: embodiment 16 makes.
Embodiment
In order to understand content of the present invention better, be described further below in conjunction with specific embodiment.
Embodiment 1 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, methylene dichloride 100mL and methyl tertiary butyl ether 20mL, start and stir, frozen water is cooled to-20～-15 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl tertbutyl ether solution of hydrogen chloride 14.0mL, dripped off in 0～1 hour, drip to finish, be incubated 0.1～1 hour again, insulation is finished, and filters, with the wet product of 10mL methyl tertiary butyl ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 2 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, acetone 100mL, start and stir, frozen water is cooled to-20～-15 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl tertbutyl ether solution of hydrogen chloride 14.0mL, dripped off in 0～1 hour, drip to finish, be incubated 0.1～1 hour again, insulation is finished, and filters, with the wet product of 10mL methyl tertiary butyl ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 3 (preparation of Erlotinib hydrochloride crystal form A)
In the 500mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, toluene 18.5mL and start stirring, frozen water is cooled to-5～0 ℃, and it is 0.1mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl-phenoxide hydrogen chloride solution 254mL, dripped off in 1.5～2.5 hours, drip to finish, be incubated 1.5～2.5 hours again, insulation is finished, and filters, with the wet product of 10ml methyl-phenoxide drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.7g, yield: 99.1%.
Embodiment 4 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, dimethylbenzene 50mL and start stirring, frozen water is cooled to-15～-10 ℃, and it is 1.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 26.69mL, dripped off in 1.5～2.5 hours, drip to finish, be incubated 1.5～2.5 hours again, insulation is finished, and filters, with the wet product of 10mL methyl-phenoxide drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.8g, yield: 99.7%.
Embodiment 5 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, ether 120mL and start stirring, frozen water is cooled to-20～-15 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 14mL, dripped off in 0.1～0.5 hour, drip to finish, be incubated 10 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 6 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, tetrahydrofuran (THF) 100mL and start stirring, frozen water is cooled to-25～-20 ℃, it is the methyl tertbutyl ether solution of hydrogen chloride 16.95mL of 3.0mol.L-1 that beginning slowly drips hydrogen cloride concentration, drips off in 4～6 hours, drips and finishes, be incubated 0.1～1 hour again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.7g, yield: 97.9%.
Embodiment 7 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, hexanaphthene 80mL and start stirring, frozen water is cooled to-15～-10 ℃, and it is 5.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl tertbutyl ether solution of hydrogen chloride 6.1mL, dripped off in 0.5～1.5 hour, drip to finish, be incubated 2 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 8 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, Skellysolve A 80mL and start stirring, frozen water is cooled to-20～-15 ℃, and it is 3.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl-phenoxide hydrogen chloride solution 10.18mL, dripped off in 1 hour, drip to finish, be incubated 2 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 9 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, ethyl acetate 100mL and start stirring, frozen water is cooled to-20～-15 ℃, and it is 3.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 11.02mL, dripped off in 1.5 hours, drip to finish, be incubated 3 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.5g, yield: 97.8%.
Embodiment 10 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, normal heptane 100mL, start and stir, frozen water is cooled to-25～-20 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 16.53mL, dripped off in 1 hour, drip to finish, be incubated 2 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.3g, yield: 97.9%.
Embodiment 11 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, methylene dichloride 120mL, start and stir, frozen water is cooled to-20～-15 ℃, and it is 1.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl tertbutyl ether solution of hydrogen chloride 15.25mL, dripped off in 1～1.5 hour, drip to finish, be incubated 2 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 12 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, trichloromethane 100mL, start and stir, frozen water is cooled to-20～-15 ℃, and it is 2.5mol.L that beginning slowly drips hydrogen cloride concentration
-1Isopropyl ether hydrogen chloride solution 12.2mL, dripped off in 1～1.5 hour, drip to finish, be incubated 3 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.1g, yield: 98.3%.
Embodiment 13 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, trichloromethane 100mL and ether 20mL, start and stir, frozen water is cooled to-50～0 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 14.0mL, dripped off in 0.5～1 hour, drip to finish, be incubated 0.3～1 hour again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.9g, yield: 100%.
Embodiment 14 (preparation of Erlotinib hydrochloride crystal form A)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, butanone 100mL, start and stir, frozen water is cooled to-20～-15 ℃, and it is 2.0mol.L that beginning slowly drips hydrogen cloride concentration
-1Methyl-phenoxide hydrogen chloride solution 15.3mL, dripped off in 0.5～1.5 hour, drip to finish, be incubated 3 hours again, insulation is finished, and filters, with the wet product of 10mL methyl-phenoxide drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10.5g, yield: 96.1%.
The comparative example
Embodiment 15 (preparation of Erlotinib hydrochloride A, B mixed crystal)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, trichloromethane 100mL, start and stir, under room temperature (30 ℃), it is 2.5mol.L that beginning slowly drips hydrogen cloride concentration
-1Ether hydrogen chloride solution 12.2mL, dripped off in 0.5～1.5 hour, drip to finish, be incubated 3 hours again, insulation is finished, and filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 9.8g, yield: 92.1%.
Embodiment 16 (preparation of Erlotinib hydrochloride crystal form B)
In the 250mL of clean dried four-hole boiling flask, drop into erlotinib free base monomer 10g, methylene dichloride 100mL and methyl tertiary butyl ether 20mL, start and stir, beginning to drip hydrogen cloride concentration is 2.0mol.L
-1Ether hydrogen chloride solution 14.0mL, dripped off in 0～1 hour, drip to finish, be heated to backflow, and be incubated 1 hour, insulation is finished, and is cooled to room temperature, filters, with the wet product of 10mL ether drip washing, after draining, it is dry to put into 20～30 ℃ of vacuum drying ovens, gets dry product: 10g, yield: 91.5%.
In sum, the preparation method of Erlotinib hydrochloride crystal form A of the present invention, this method technology stability height, operation feasible is controlled, and cost is low, the circulation ratio height, can access pure A crystal formation product, the yield height is more suitable for being used to prepare the suitability for industrialized production of Erlotinib hydrochloride, has very high economic benefit.
Need to prove that all documents of mentioning are in the present invention quoted as a reference in this application, are just quoted as a reference separately as each piece document.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (5)
1. the preparation method of an Erlotinib hydrochloride crystal form A, it is characterized in that may further comprise the steps: erlotinib free base monomer and organic solvent are mixed, temperature reaches more than or equal to-50 ℃ extremely less than 0 ℃ in making, drip the hydrogen chloride solution of ethers, dropwised in 0～5 hour, dripped follow-up continuation of insurance temperature 0～12 hour, filter, wet product are dried at normal temperatures, promptly obtain described Erlotinib hydrochloride crystal form A; Wherein, described organic solvent is selected from: 1. single solvent: toluene, dimethylbenzene, ether, tetrahydrofuran (THF), acetone, butanone, Skellysolve A, hexanaphthene, normal heptane, methylene dichloride, chloroform or ethyl acetate, 2. mixed solvent: the mixed solvent of methylene dichloride and methyl tertiary butyl ether, the perhaps mixed solvent of chloroform and ether; The hydrogen chloride solution of described ethers is selected from: ether hydrogen chloride solution, isopropyl ether hydrogen chloride solution, methyl tertbutyl ether solution of hydrogen chloride or methyl-phenoxide hydrogen chloride solution, described erlotinib free base monomer: the molar ratio of described hydrogenchloride is 1.0: (1.0～2.0).
2. according to the preparation method of the described Erlotinib hydrochloride crystal form A of claim 1, it is characterized in that the time that drips the hydrogen chloride solution of ethers is 0～1 hour; Soaking time is 0～2 hour behind the hydrogen chloride solution of dropping ethers.
3. according to the preparation method of the described Erlotinib hydrochloride crystal form A of claim 1, it is characterized in that, described organic solvent is selected from 1. single solvent: toluene, tetrahydrofuran (THF), acetone, normal heptane, methylene dichloride, chloroform or ethyl acetate, 2. mixed solvent: chloroform and ether volume ratio are that 5: 1 mixed solvent or methylene dichloride and methyl tertiary butyl ether volume ratio are 5: 1 mixed solvent.
4. according to the preparation method of the described Erlotinib hydrochloride crystal form A of claim 1, it is characterized in that the hydrogen chloride solution of described ethers is ether hydrogen chloride solution or methyl tertbutyl ether solution of hydrogen chloride.
5. according to the preparation method of the described Erlotinib hydrochloride crystal form A of claim 1, it is characterized in that may further comprise the steps: with described erlotinib free base monomer and methylene dichloride and methyl tertiary butyl ether volume ratio is that 5: 1 mixed solvent or acetone single solvent mixes, be cooled to more than or equal to-50 ℃ extremely less than 0 ℃, drip the methyl tertbutyl ether solution of hydrogen chloride, dropwised in 0～1 hour, dripped follow-up continuation of insurance temperature 0～2 hour, filter, wet product are dried at normal temperatures, promptly obtain pure described Erlotinib hydrochloride crystal form A.
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| EP2499118A2 (en) * | 2009-11-12 | 2012-09-19 | Ranbaxy Laboratories Limited | Processes for the preparation of erlotinib hydrochloride form a and erlotinib hydrochloride form b |
| CN101914068A (en) * | 2010-08-14 | 2010-12-15 | 浙江华海药业股份有限公司 | Novel crystal form of erlotinib alkali and preparation method thereof |
| CN101948441B (en) * | 2010-09-07 | 2012-07-25 | 江苏先声药物研究有限公司 | Novel preparation method of Erlotinib hydrochloride with crystal form A |
| CN103130760B (en) * | 2011-11-29 | 2015-06-17 | 中国科学院大连化学物理研究所 | Novel targeting antineoplastic drug and manufacture method thereof and application thereof |
| CN103360325A (en) * | 2012-03-26 | 2013-10-23 | 重庆医药工业研究院有限责任公司 | Preparation method of erlotinib hydrochloride crystal form A |
| CN103420924B (en) * | 2012-05-25 | 2016-08-31 | 浙江九洲药业股份有限公司 | A kind of preparation method of Erlotinib hydrochloride crystal form A |
| WO2014136126A2 (en) * | 2013-03-08 | 2014-09-12 | Laurus Labs Private Limited | A process for preparing erlotinib hydrochloride form a |
| CN104072427B (en) * | 2013-03-29 | 2019-05-28 | 江苏豪森药业集团有限公司 | The preparation method of Eriotinib Hydrochloride form |
| CN103333124B (en) * | 2013-05-28 | 2015-03-25 | 埃斯特维华义制药有限公司 | Preparation method of hydrochloric acid erlotinib crystal form F |
| CN103333125B (en) * | 2013-06-19 | 2015-11-11 | 扬子江药业集团有限公司 | A kind of preparation method of quinazoline amine hydrochloride stable polymorphic substance |
| CN103508962B (en) * | 2013-07-03 | 2016-04-13 | 山东金城医药化工股份有限公司 | The preparation method of erlotinib hydrochloride form B |
| CN103450097A (en) * | 2013-08-08 | 2013-12-18 | 江南大学 | Preparation method of high-purity crystal-form-A erlotinib hydrochloride |
| CN103641786A (en) * | 2013-12-26 | 2014-03-19 | 山东博迈康药物研究有限公司 | Preparation method of erlotinib hydrochloride crystal form A |
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