CN103819461A - N-[3-chloro-4-(3-fluorobenzyloxy) phenyl]-6-[5-[[2-(methylenesulfonyl) ethyl] amino] methyl]-2-furanyl]-4-quinazolinamine polymorph and preparation method thereof - Google Patents
N-[3-chloro-4-(3-fluorobenzyloxy) phenyl]-6-[5-[[2-(methylenesulfonyl) ethyl] amino] methyl]-2-furanyl]-4-quinazolinamine polymorph and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an N-[3-chloro-4-(3-fluorobenzyloxy) phenyl]-6-[5-[[2-(methylenesulfonyl) ethyl] amino] methyl]-2-furanyl]-4-quinazolinamine polymorph and a preparation method thereof, in particular to an N-[3-chloro-4-(3-fluorobenzyloxy) phenyl]-6-[5-[[2-(methylenesulfonyl) ethyl] amino] methyl]-2-furanyl]-4-quinazolinamine polymorph A or B as a tyrosine kinase inhibitor. The invention further relates to a preparation method of the polymorph, pharmaceutical compositions of the polymorph and pharmaceutical applications of the pharmaceutical compositions.
Description
Technical field
The invention belongs to field of medicine and chemical technology; be specifically related to a kind of new chloro-4-of the N-[3-with anti-tumor activity (3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] hydrate of-4-quinazoline amine (Compound I); the crystal formation of this hydrate; its preparation method, and this hydrate as be used for the treatment of or the propagation of tumour cell and the medicine of migration that tumour that assisting therapy Mammals (comprising people) is mediated by receptor tyrosine kinase or receptor tyrosine kinase drive aspect application.
Background technology
Publication number is that the Chinese patent application of CN102030742A has been studied 4-(substituted anilinic) quinazoline derivant as the tumour or the propagation of tumour cell of receptor tyrosine kinase driving and the application of the medicine aspect of migration that are used for the treatment of or assisting therapy Mammals (comprising people) is mediated by receptor tyrosine kinase.Compound N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl with anti-tumor activity is wherein disclosed] amino] methyl]-2-furyl]-4-quinazoline amine, have suc as formula the structural formula shown in I:
In CN102030742A, disclose the process that obtains Compound I, but the yellow solid obtaining in this application not crystalline form after column chromatography, but yellow thick solid simultaneously, be unfavorable for the Making and banking of medicine.
Disclosed 4-(substituted anilinic in prior art) advantageous feature of quinazoline derivant on pharmacology be this compound as the prerequisite of pharmaceutical composition application; But, as active substance, also must meet other requirements and could be used as pharmaceutical composition.These parameters are relevant with the physicochemical property of this active substance to a great extent.
The limiting examples of these parameters comprises the stability of active substance under varying environment condition, the stability in pharmaceutical compositions process, and the stability of pharmaceutical composition terminal storage form etc.Therefore, should there is high stability for the preparation of the active substance of pharmaceutical composition, even if also should guarantee this stability under varying environment condition.
Hygroscopic effect because can causing weight, the absorption of moisture increases, so can reduce the content of medicinal activity material.Therefore, should guard against damp in storage process for easy moisture absorption medicine, for example can be by adding suitable siccative or being stored in moistureproof environment.In addition, in process of production, if active substance is exposed to not in moistureproof by any way environment, moisture absorption meeting reduces its content.Therefore, medicinal activity material preferably should only have slight water absorbability.
The polymorphic of active substance is very important for the content of active substance in preparation, therefore, needs the clear presumable polymorphic of active substance existing with crystalline form of research as far as possible.If active substance has different polymorphics, must guarantee that the crystal formation of this active substance does not change in the preparation process of pharmaceutical preparation, otherwise may affect the drug effect of active substance.
Another parameter is the resolvability of active substance, and selection to preparation or preparation method's selection is all very important under specific circumstances for it.For example prepare drug solution (for example, for venoclysis), it is necessary that active substance should fully be dissolved in physiologically acceptable solvent.The resolvability of active substance is also extremely important for oral pharmaceutical.
Therefore, need to study the crystal formation of Compound I, meet above-mentioned physicochemical property and require (such as satisfactory stability, resolvability etc.), to good medicinal compositions is provided.
Summary of the invention
The object of the present invention is to provide the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] novel hydrate and the crystal formation thereof of-4-quinazoline amine (Compound I), it has the favourable purposes for EGFR Family Tyrosine Kinases inhibitor.The research of inventor's process, surprising discovery, the polymorphic form of Compound I meets above-mentioned physicochemical property requirement, is the crystalline substance with favourable character.
For this reason, first aspect present invention provides the chloro-4-of the N-[3-shown in formula III (3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] polymorphic of-4-quinazoline amine,
Wherein, n is 2 or 0.
In the time of n=2, described polymorphic is the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine dihydrate.
In the time of n=0, described polymorphic is the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine anhydride.
A second aspect of the present invention provides the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] crystal form A (crystal form A of formula III) of-4-quinazoline amine dihydrate; it is characterized in that; use Cu-K α radiation; the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, and 7.4 ± 0.2 °, 14.6 ± 0.2 °; 16.3 ± 0.2 °; 17.7 ± 0.2 °, 20.5 ± 0.2 °, locate characteristic peak.
Further, described crystal form A, is characterized in that, use Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, 7.4 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 17.7 ± 0.2 °, 20.5 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 25.7 ± 0.2 °, 26.9 ± 0.2 °, locate characteristic peak for 32.2 ± 0.2 °.
Further again, described crystal form A, it is characterized in that, use Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, 7.1 ± 0.2 °, 7.4 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 17.7 ± 0.2 °, 18.0 ± 0.2 °, 18.7 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 21.1 ± 0.2 °, 21.8 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 23.8 ± 0.2 °, 24.6 ± 0.2 °, 25.3 ± 0.2 °, 25.7 ± 0.2 °, 26.9 ± 0.2 °, 27.4 ± 0.2 °, 28.2 ± 0.2 °, 28.6 ± 0.2 °, 32.2 ± 0.2 °, 33.3 ± 0.2 °, locate characteristic peak for 37.8 ± 0.2 °.
Further, described crystal form A, is characterized in that, uses Cu-K α radiation, and the relative intensity I of the characteristic peak of the X-ray powder diffraction representing with 2 θ angles is as follows:
Further, described crystal form A, uses Cu-K α radiation, and the X-ray powder diffraction representing with 2 θ angles is basic consistent with Fig. 1.
Described crystal form A, uses differential scanning calorimeter, and gained DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, and its fusing point is 61 ~ 72 ℃.
Described crystal form A, moisture content scope is 6.0 ~ 6.8%.
The purity of described crystal form A is more than or equal to 95% weight, preferably greater than or equal to 98% weight, more preferably greater than or equal 98.6% weight, most preferably, the purity of described crystal is 98.8% weight, 98.6% weight, 98.9% weight or 99.1% weight.
A third aspect of the present invention provides the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] crystal form B (crystal form B of formula III) of-4-quinazoline amine anhydride; it is characterized in that; use Cu-K α radiation; the X-ray powder diffraction representing with 2 θ angles is at 4.2 ° ± 0.2 °; 16.6 ± 0.2 °, 17.8 ± 0.2 °, 19.3 ± 0.2 °; 19.7 ± 0.2 °, locate characteristic peak for 21.9 ± 0.2 °.
Further, described crystal form B, is characterized in that, use Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.2 ° ± 0.2 °, 16.6 ± 0.2 °, 17.8 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 °, 24.3 ± 0.2 °, 26.3 ± 0.2 °, locate characteristic peak for 26.6 ± 0.2 °.
Further again, described crystal form B, use Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 3.9 ± 0.2 °, 4.2 ° ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 7.8 ± 0.2 °, 9.8 ± 0.2 °, 11.8 ± 0.2 °, 13.0 ± 0.2 °, 13.9 ± 0.2 °, 15.6 ± 0.2 °, 15.8 ± 0.2 °, 16.6 ± 0.2 °, 17.4 ± 0.2 °, 17.8 ± 0.2 °, 18.2 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 °, 23.4 ± 0.2 °, 24.3 ± 0.2 °, 24.7 ± 0.2 °, 24.9 ± 0.2 °, 26.0 ± 0.2 °, 26.3 ± 0.2 °, 26.6 ± 0.2 °, 28.5 ± 0.2 °, 29.4 ± 0.2 °, locate characteristic peak for 37.8 ± 0.2 °.
Further, described crystal form B, is characterized in that, uses Cu-K α radiation, and the relative intensity I of the characteristic peak of the X-ray powder diffraction representing with 2 θ angles is as follows:
Further, described crystal form B, uses Cu-K α radiation, and the X-ray powder diffraction representing with 2 θ angles as shown in Figure 3.
Described crystal form B, uses differential scanning calorimeter, and gained DSC-TGA collection of illustrative plates is basic consistent with Fig. 4, and its fusing point is 93 ~ 103 ℃.
Described crystal form B, moisture content scope is 0 ~ 1.5%.
The purity of described crystal form B is more than or equal to 95% weight, preferably greater than or equal to 98% weight, more preferably greater than or equal 99% weight.
Fourth aspect present invention provides the preparation method of the crystal described in first aspect present invention, second aspect or the third aspect, and described method is as follows:
In the time of n=2, employing method one or method two are prepared described compound.
Method one:
The acid salt of Compound I is joined in inert organic solvents, add alkali aqueous solution, separatory, organic phase stirring and crystallizing, obtains the crystal form A of compound III.
Described inert organic solvents is preferably the mixture that is selected from one or more solvents in methylene dichloride, trichloromethane, acetonitrile, ether, ethyl acetate, and preferred inert organic solvents is methylene dichloride or ethyl acetate.
Preferably, described acid salt is selected from hydrochloride, vitriol, nitrate, xylenesulfonate, mesylate, benzene sulfonate, oxalate, formate, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, Citrate trianion, and preferred acid salt is xylenesulfonate.
Preferably, described alkali aqueous solution is selected from aqueous sodium hydroxide solution, sodium bicarbonate aqueous solution, wet chemical, aqueous sodium carbonate, and further preferred alkali aqueous solution is aqueous sodium hydroxide solution.
Preferably, the concentration of described alkali aqueous solution is 0.1～5mol/L, more preferably 0.5～1mol/L, 0.1～3mol/L, 1～3.5mol/L, 0.8～4.5mol/L, 2 ~ 4mol/L, 0.5 ~ 4.5mol/L or 2.5～3.5mol/L, most preferably be 3mol/L.
Preferably, the proportioning (g/ml) of described acid salt and inert organic solvents mass/volume is 1:5 ~ 25, further preferred 1:10 ~ 25,1:10 ~ 20,1:10 ~ 15,1:5 ~ 15,1:8 ~ 13,1:9 ~ 12; Most preferably be 1:10.
Preferably, the mass/volume proportioning (g/ml) of described acid salt and alkali aqueous solution is 1:2 ~ 10, and more preferably 1:3 ~ 8,1:3 ~ 7,1:4 ~ 7 or 1:4 ~ 6, most preferably be 1:5.
Method two:
Compound I is dissolved in polar organic solvent, reflux, and cooling crystallization, obtains the crystal form A of compound III.
Preferably, described polar organic solvent is selected from the mixed solvent of alcohols (for example methyl alcohol, ethanol, Virahol, butanols, the trimethyl carbinol), ethers (for example tetrahydrofuran (THF)), alkane (for example methylene dichloride, trichloromethane) or above solvent, and further preferred polar organic solvent is the trimethyl carbinol or Virahol.
Preferably, the proportioning of the mass/volume of described Compound I and polar organic solvent (g/ml) is 1:2～10, and more preferably 1:2～5,1:2～8,1:2.5～6,1:2～4,1:3～10 or 1:3～5, most preferably be 1:3.
In the time of n=0, adopt following methods to prepare described compound,
Compound I is dissolved in the mixed system of the trimethyl carbinol and water, is heated to solid and all dissolves, cooling crystallization, obtains the crystal form B of compound III; Or
Compound I is dissolved in the trimethyl carbinol, and reflux, moltenly adds water after clear, and cooling crystallization obtains the crystal form B of compound III.
Preferably, the mass/volume proportioning (g/ml) of described Compound I and the trimethyl carbinol is 1:5 ~ 20, is preferably 1:10 ~ 20, and more preferably 1:10 ~ 15,1:8 ~ 18,1:10 ~ 18,1:9 ~ 12, most preferably be 1:10; The described trimethyl carbinol and the volume ratio of water are 1:1 ~ 10, are preferably 1:1.5 ~ 5,1:1.1.2 ~ 8,1:1.4～8,1:1.5～6 or 1:1.5～3, and more preferably 1:1.5 ~ 2.5, most preferably are 1:1.5.
In the preparation method of fourth aspect present invention, wherein said Compound I is that those skilled in the art can prepare according to prior art, and in an exemplary method, Compound I can reference literature CN102030742A preparation.
Fifth aspect present invention relates to a kind of pharmaceutical composition, and it comprises the crystal described in first aspect present invention, second aspect or third aspect any one, and optional one or more pharmaceutically acceptable carriers or vehicle.Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectal administration etc.
Sixth aspect present invention relates to crystal described in first aspect present invention, second aspect or third aspect any one in the purposes for the preparation for the treatment of and/or preventing in the medicine of disease that Mammals (comprising people) is relevant to receptor tyrosine kinase or illness.
Sixth aspect present invention also relates to crystal described in first aspect present invention, second aspect or the third aspect any one purposes in the tumour or cancer or the propagation of tumour cell being driven by receptor tyrosine kinase and the medicine of migration that are mediated by receptor tyrosine kinase for the preparation for the treatment of or assisting therapy and/or prevention Mammals (comprising people).
Seventh aspect present invention relates to a kind of disease relevant to receptor tyrosine kinase or method of illness for the treatment of and/or preventing in the Mammals that has needs, and the method comprises to the crystal having described in first aspect present invention, second aspect or the third aspect any one of administration treatment significant quantity of needs.
Seventh aspect present invention also relates to a kind for the treatment of or assisting therapy and/or prevention Mammals (comprising people) are mediated by receptor tyrosine kinase in the Mammals that has needs tumour or cancer or the propagation of tumour cell being driven by receptor tyrosine kinase and the method for migration, and the method comprises to the administration that has needs treats the crystal described in first aspect present invention, second aspect or the third aspect any one of significant quantity.
Seventh aspect present invention further relates to a kind of tumour of Mammals (comprising people) or method of cancer for the treatment of and/or preventing in the Mammals that has needs, and the method comprises to the crystal having described in first aspect present invention, second aspect or the third aspect any one of administration treatment significant quantity of needs.
Tumour of the present invention or cancer comprise the responsive cancer of erbB receptor tyrosine kinase, as the tumour of EGFR or Her2 high expression level and EGF driving, comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour is as leukemia, multiple myeloma or lymphoma etc.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
The X-ray powder diffraction characteristic peak that the crystal formation of Compound I of the present invention represents with 2 θ angles, wherein " ± 0.2 ° " measuring error scope for allowing.
The polymorphic form of Compound I of the present invention can be used in combination with other activeconstituents, for example, as long as it does not produce other detrimental actions, anaphylaxis.
Active compound shown in the polymorphic form of the compounds of this invention I can be used as unique cancer therapy drug and uses, or can combine use with one or more other antitumor drugs.Combination therapy realizes by each being treated to component while, order or separating administration.
Term used herein " composition " means to comprise the product of the each appointment composition that comprises specified amount, and any product of the combination results of direct or indirect each appointment composition from specified amount.
" % weight " described in the present invention refers to per-cent (w/w) by weight.
The unit of " proportioning of mass/volume " described in the present invention is g/ml, for example described acid salt and the proportioning (g/ml) of inert organic solvents are 1:1.5, its implication refers to, when the quality of acid salt is 1 gram, the consumption of inert organic solvents is 1.5ml.
Formula III compound of the present invention, in the time of n=2, described polymorphic is dihydrate, and theoretical water content is 6.0%, and in the time of n=0, described polymorphic is anhydride, and theoretical water content is 0.As well known to those skilled in the art, the product preparing probably can complete drying, so still comprise within the scope of the present invention with the dihydrate of formula III compound and the crystal formation of anhydride of micro free water.
The beneficial effect of the invention
The chloro-4-of N-[3-shown in the formula III the present invention relates to (3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] hydrate and crystal form A or the B of-4-quinazoline amine, there is satisfactory stability.Due to good stability, make the final preparation (pharmaceutical composition) of compounding pharmaceutical activeconstituents (API) more suitable, and make the storage of API convenient, the validity period of storage is longer; Aspect preparation, easily preparation, purifying, more convenient to operate simple, be more suitable for industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction of Fig. 1 formula III compound crystal form A.
The DSC/TGA collection of illustrative plates of Fig. 2 formula III compound crystal form A.
The X-ray powder diffraction of Fig. 3 formula III compound crystal form B.
The DSC/TGA collection of illustrative plates of Fig. 4 formula III compound crystal form B.
Embodiment
Further illustrate the present invention below by concrete Preparation Example and biological test example, still, should be understood to, these embodiment and test example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Instrument of the present invention and method:
(1) high resolution mass spectrum
Instrument model: Q-Tof micro mass spectrograph.
Test condition: ESI(electron spray(ES)).
(2) X-ray powder diffraction is analyzed
Instrument model: D/max-rB (Rigaku motor)
Testing method: the sample after porphyrize (100mg) is filled out in sheet glass groove, after its plane and glass surface being hung and are flushed with slide glass, sample is placed in to D/max-rB (Rigaku motor), use the copper X-ray source of 40kV, 100mA, sweep limit is 3～50 ° (2 θ), 4 °/minute of sweep velocitys, 12 minutes sweep times.Be generally ± 0.2 degree (2 θ) of scanning errors.
(3) differential scanning calorimeter
Instrument model: TGA/DSC1(METTLER) thermal analyzer.
Testing method: the sample of heavy 10mg is placed in to the sealed aluminum pan with little pin hole, keeps balance at 25 ℃, be then heated to 110 ℃ with the scanning speed of 10 ℃/min.Drying nitrogen is used as sweeping gas.
Can prepare Compound I according to the method for describing in CN102030742A, as shown in embodiment 1 below.
the chloro-4-of embodiment 1:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] preparation of-4-quinazoline amine (Compound I):
the preparation of the 2-MEA of a.Boc protection:
In reaction flask, add under tert-Butyl dicarbonate 25g, 2-MEA hydrochloride 14.4g and 140ml methylene dichloride condition of ice bath and add triethylamine 18ml in batches; stirring at room temperature reaction is spent the night; add the hydrochloric acid soln washing of excessive 0.5M; organic layer washs with saturated nacl aqueous solution; anhydrous sodium sulfate drying; solvent evaporated obtains the 2-MEA 5.7g(oily liquids of Boc protection), productive rate 87%.
the preparation of the 2-methylthio group ethamine of b.Boc protection:
Under ice bath, nitrogen protection condition; NaH1.2g is added in batches in anhydrous tetrahydro furan (250ml) solution of 2-MEA 7g of Boc protection; rise to room temperature reaction 1h, under condition of ice bath, drip the tetrahydrofuran solution of 3ml methyl iodide, drip and finish the rear about 1h of room temperature reaction; add saturated sodium carbonate solution cancellation reaction; by in reaction solution impouring water, ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution; anhydrous sodium sulfate drying, solvent evaporated obtains oily liquids.Column chromatography obtains the 2-methylthio group ethamine 3.6g of Boc protection, productive rate 47%.
the preparation of the 2-first sulfoxide group ethamine of c.Boc protection:
Under condition of ice bath; the 2-methylthio group ethamine 3.6g of Boc protection is dissolved in methyl alcohol, drips the aqueous solution of sodium periodate, finish rear stirring at room temperature reaction and spend the night; filter; washed with dichloromethane filter cake, removes the organic reagent in filtrate under reduced pressure, adds saturated nacl aqueous solution; ethyl acetate extraction; anhydrous magnesium sulfate drying, filtration removes solvent under reduced pressure and obtains the 2-first sulfoxide group ethamine 3.4g(oily matter that Boc protects), productive rate 87%.
the preparation of the 2-first sulfoxide group ethylamine hydrochloride of d.Boc protection:
The 2-first sulfoxide group ethamine 3.4g of Boc protection is dissolved in anhydrous diethyl ether, passes into hydrochloric acid gas, it is complete that TLC detects raw material reaction, removes solvent under reduced pressure and obtain the 2-first sulfoxide group ethylamine hydrochloride 1.9g(oily matter that Boc protects), productive rate 82%.
the chloro-4-of e.N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] first base]-2-furyl] preparation of-4-quinazoline amine:
Compound 5-(4-(4-(3-fluorine benzyloxy)-3-chloroanilino)-6-quinazolyl) furans-2-formaldehyde tosilate 15g is dissolved in the mixing solutions of methylene chloride/methanol (3:1), add 15ml triethylamine stirring reaction 10min, add 2-first sulfoxide ethylamine hydrochloride 7.5g, stirring at room temperature reaction, it is complete that TLC detects raw material reaction, under ice bath, add sodium borohydride 2.5g in batches, TLC detection reaction is complete, add appropriate methylene dichloride, saturated ammonium chloride solution washing, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, column chromatography obtains yellow thick solid 9.1g, be the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine (Compound I), productive rate 69%.
the chloro-4-of embodiment 2:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] preparation of-4-quinazoline amino acid additive salt
For example: the preparation of Compound I xylenesulfonate (Compound I I)
The Compound I 5g(8.88mmol that embodiment 1 is made) add in 25ml ethanol; stirring and dissolving; add tosic acid 4.58g(26.5mmol); separate out yellow solid; suction filtration, dries, and obtains the chloro-4-of 7.75g N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine xylenesulfonate (yellow thick solid); yield 93.5%, purity 95.3%.
MS(m/z):[M-H]907.1713。
Other acid salt example hydrochloric acid salt, vitriol, nitrate, mesylate, benzene sulfonate, oxalate, formate, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, Citrate trianion etc. can adopt with the similar method of aforesaid method to be prepared.
the chloro-4-of embodiment 3:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I I2g that embodiment 2 is prepared joins in the mixed system of 20ml methylene dichloride and 10ml3mol/L aqueous sodium hydroxide solution, and stirring and dissolving leaves standstill separatory, organic layer stirring and crystallizing, suction filtration, dries, obtain 1.2g faint yellow solid, yield 90%, purity 99.1%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and XRPD collection of illustrative plates as shown in Figure 1.
Above-mentioned product uses differential scanning calorimeter; its DSC-TGA collection of illustrative plates as shown in Figure 2; its fusing point is 93 ~ 103 ℃; determine that by weight-loss curve products therefrom is the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine dihydrate; lose first crystal water when being heated to 48 ~ 83 ℃; be heated to 84 ~ 108 ℃ and lose second crystal water, the ratio of twice weight loss is added and obtains moisture content is 6.8%.Show to contain in formula products therefrom two crystal water.
the chloro-4-of embodiment 4:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I I2g that embodiment 2 is prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L aqueous sodium hydroxide solution, and stirring and dissolving leaves standstill separatory, organic layer stirring and crystallizing, suction filtration, dries, obtain 1.3g faint yellow solid, yield 100%, purity 99.1%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.6%.
the chloro-4-of embodiment 5:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I I2g that embodiment 2 is prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L aqueous sodium hydroxide solution, stirring and dissolving, leaves standstill separatory, organic layer stirring and crystallizing, suction filtration, dry, obtain 1.3g faint yellow solid, yield 10%, purity 98.9%, the product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.5%.
the chloro-4-of embodiment 6:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I crude product 2g that embodiment 1 is prepared joins in the 6ml trimethyl carbinol, and reflux is molten clear, and cooling crystallization, obtains 1.6g faint yellow solid, yield 80%, purity 98.6%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.7%.
the chloro-4-of embodiment 7:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I crude product 2g that embodiment 1 is prepared joins in 6ml Virahol, and reflux is molten clear, and cooling crystallization, obtains 1.7g faint yellow solid, yield 85%, purity 98.8%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.5%.
the chloro-4-of embodiment 8:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The Compound I I2g that embodiment 2 is prepared joins in the mixed system of 20ml methylene dichloride and 10ml3mol/L aqueous sodium carbonate, and stirring and dissolving leaves standstill separatory, organic layer stirring and crystallizing, suction filtration, dries, obtain 1.2g faint yellow solid, yield 90%, purity 99.3%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.5%.
the chloro-4-of embodiment 9:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form A (crystalline substance of formula III compound of-4-quinazoline amine dihydrate
type A) preparation
The dimethanesulfonate 2g of the Compound I that embodiment 2 is prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L sodium bicarbonate aqueous solution, and stirring and dissolving leaves standstill separatory, organic layer stirring and crystallizing, suction filtration, dries, obtain 1.4g faint yellow solid, yield 93.8%, purity 99.1%.The product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the crystal form A of compound III, and XRPD collection of illustrative plates as shown in Figure 1.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture content 6.6%.
the chloro-4-of embodiment 10:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form B (crystal formation of formula III compound of-4-quinazoline amine anhydride
b) preparation
The Compound I crude product 2g that embodiment 1 is prepared joins in the 20ml trimethyl carbinol; reflux is molten clear; under reflux conditions, add 30ml water; cooling crystallization; suction filtration; dry; obtain 1.7g yellow crystalline powder; yield 85%; purity 99.0%; the product obtaining is carried out to X-ray powder diffraction, and result shows that this product is the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] crystal form B (crystal form B of formula III compound) of-4-quinazoline amine anhydride, XRPD collection of illustrative plates is as shown in Figure 3.
The DSC-TGA collection of illustrative plates that the crystal form B use differential scanning calorimeter of formula III compound obtains as shown in Figure 4; its fusing point is 93 ~ 103 ℃; and determine that by weight-loss curve described compound is the chloro-4-of N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine anhydride, moisture content 1.4%.Endotherm(ic)peak when endotherm(ic)peak on weight-loss curve is crystal form B fusing.
the chloro-4-of embodiment 11:N-[3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
amino] methyl]-2-furyl] crystal form B (crystal formation of formula III compound of-4-quinazoline amine anhydride
b) preparation
The Compound I crude product 2g that embodiment 1 is prepared joins in the mixed solvent of the 20ml trimethyl carbinol and 10ml water, being heated to solid dissolves completely, cooling crystallization, suction filtration, dries, and obtains 1.6g yellow crystalline powder, yield 80%, purity 99.3%, carries out X-ray powder diffraction by the product obtaining, and its XRPD collection of illustrative plates is basic consistent with Fig. 3.
Use differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 4, moisture content 0.8%.
Embodiment 12: crystal form A, B prepared by the embodiment of the present invention investigate result in 45 ℃ of vacuum-dryings 5 hours and 7 hours rear stabilities, and the method for concrete study on the stability can be with reference to the method for 2010 editions second appendix XIX C of Chinese Pharmacopoeia; Purity detecting HPLC method, can be with reference to the method for 2010 editions second appendix VD of Chinese Pharmacopoeia.
Table 1 crystal form A, B study on the stability result
As can be seen from the above table, crystal form A of the present invention, the purity of B after 45 ℃ of vacuum-drying do not change, and have satisfactory stability.
Claims (21)
1. the chloro-4-of the N-[3-shown in formula III (3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] polymorphic of-4-quinazoline amine,
Wherein, n is 2 or 0.
2. polymorphic claimed in claim 1, wherein n is 2.
3. polymorphic claimed in claim 2, it is crystal form A, it is characterized in that, uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, and 7.4 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 18.0 ± 0.2 °, locate characteristic peak for 20.5 ± 0.2 °.
4. polymorphic according to claim 2, is characterized in that, uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, and 7.4 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 17.7 ± 0.2 °, 20.5 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 25.7 ± 0.2 °, 26.9 ± 0.2 °, locate characteristic peak for 32.2 ± 0.2 °.
5. polymorphic claimed in claim 2, it is characterized in that, use Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 4.7 ± 0.2 °, 7.1 ° ± 0.2 °, 7.4 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 17.7 ± 0.2 °, 18.0 ± 0.2 °, 18.7 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 21.1 ± 0.2 °, 21.8 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 23.8 ± 0.2 °, 24.6 ± 0.2 °, 25.3 ± 0.2 °, 25.7 ± 0.2 °, 26.9 ± 0.2 °, 27.4 ± 0.2 °, 28.2 ± 0.2 °, 28.6 ± 0.2 °, 32.2 ± 0.2 °, 33.3 ± 0.2 °, locate characteristic peak for 37.8 ± 0.2 °.
6. polymorphic claimed in claim 2, is characterized in that, uses Cu-K α radiation, and the X-ray powder diffraction representing with 2 θ angles is basic consistent with Fig. 1.
7. polymorphic claimed in claim 2, is characterized in that, uses differential scanning calorimeter, and gained DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, and its fusing point is 61 ~ 72 ℃;
Preferably, polymorphic claimed in claim 2, its moisture content scope is in 6.0 ~ 6.8% weight.
8. the polymorphic described in claim 2 to 7 any one, the purity of wherein said crystal is more than or equal to 95% weight, preferably greater than or equal to 98% weight, more preferably greater than or equal 98.6% weight, most preferably, the purity of described crystal is 98.8% weight, 98.6% weight, 98.9% weight or 99.1% weight.
9. polymorphic claimed in claim 1, wherein n is 0.
10. polymorphic claimed in claim 9, it is crystal form B, it is characterized in that, use Cu-K α radiation, the X-ray powder diffraction that 2 θ angles represent is at 4.2 ° ± 0.2 °, and 5.9 ± 0.2 °, 11.8 ± 0.2 °, 13.0 ± 0.2 °, 16.6 ± 0.2 °, 17.8 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, locate characteristic peak for 21.9 ± 0.2 °.
11. polymorphics claimed in claim 9, is characterized in that, use Cu-K α radiation,
The X-ray powder diffraction that 2 θ angles represent is at 4.2 ° ± 0.2 °, and 16.6 ± 0.2 °, 17.8 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 °, 24.3 ± 0.2 °, 26.3 ± 0.2 °, locate characteristic peak for 26.6 ± 0.2 °.
12. polymorphics claimed in claim 9, is characterized in that, use Cu-K α radiation,
The X-ray powder diffraction that 2 θ angles represent is at 3.9 ± 0.2 °, 4.2 ° ± 0.2 °, 5.9 ± 0.2 °, 6.4 ± 0.2 °, 7.8 ± 0.2 °, 9.8 ± 0.2 °, 11.8 ± 0.2 °, 13.0 ± 0.2 °, 13.9 ± 0.2 °, 15.6 ± 0.2 °, 15.8 ± 0.2 °, 16.6 ± 0.2 °, 17.4 ± 0.2 °, 17.8 ± 0.2 °, 18.2 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, 20.8 ± 0.2 °, 21.9 ± 0.2 °, 22.5 ± 0.2 °, 23.4 ± 0.2 °, 24.3 ± 0.2 °, 24.7 ± 0.2 °, 24.9 ± 0.2 °, 26.0 ± 0.2 °, 26.3 ± 0.2 °, 26.6 ± 0.2 °, 28.5 ± 0.2 °, 29.4 ± 0.2 °, locate characteristic peak for 37.8 ± 0.2 °.
13. polymorphics claimed in claim 9, is characterized in that, use Cu-K α radiation, and the X-ray powder diffraction that 2 θ angles represent is basic consistent with Fig. 3.
14. polymorphics claimed in claim 9, is characterized in that, use differential scanning calorimeter, and gained DSC-TGA collection of illustrative plates is basic consistent with Fig. 4, and its fusing point is 93 ~ 103 ℃;
Preferably, polymorphic claimed in claim 9, its moisture content scope is 0 ~ 1.5%.
Polymorphic described in 15. claim 9 to 14 any one, the purity of wherein said crystal is more than or equal to 95% weight, preferably greater than or equal to 98% weight, more preferably greater than or equal 99% weight.
Polymorphous method described in 16. preparation claim 1 to 15 any one, the method is as follows:
In the time of n=2, employing method one or method two are prepared described polymorphic,
Method one:
The acid salt of Compound I is joined in inert organic solvents, add alkali aqueous solution, separatory, organic phase stirring and crystallizing, obtains the crystal form A of compound III;
Method two:
Compound I is dissolved in polar organic solvent, reflux, and cooling crystallization, obtains the crystal form A of compound III;
In the time of n=0, adopt following methods to prepare described polymorphic,
Compound I is dissolved in the mixed system of the trimethyl carbinol and water, heat solid is dissolved completely, and cooling crystallization, obtains the crystal form B of compound III; Or
Compound I is dissolved in the trimethyl carbinol, and reflux, moltenly adds water after clear, and cooling crystallization obtains the crystal form B of compound III.
17. preparation methods according to claim 16, wherein, in the time of n=2, described inert organic solvents is preferably the mixture that is selected from one or more solvents in methylene dichloride, trichloromethane, acetonitrile, ether, ethyl acetate, and preferred inert organic solvents is methylene dichloride or ethyl acetate;
Preferably, described acid salt is selected from hydrochloride, vitriol, nitrate, xylenesulfonate, mesylate, benzene sulfonate, oxalate, formate, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, Citrate trianion, and preferred acid salt is xylenesulfonate;
Preferably, described alkali aqueous solution is selected from aqueous sodium hydroxide solution, sodium bicarbonate aqueous solution, wet chemical, aqueous sodium carbonate, and further preferred alkali aqueous solution is aqueous sodium hydroxide solution;
Preferably, the concentration of described alkali aqueous solution is 0.1～5mol/L, more preferably 0.5～1mol/L, 0.1～3mol/L, 1～3.5mol/L, 0.8～4.5mol/L, 2～4mol/L, 0.5～4.5mol/L or 2.5～3.5mol/L, most preferably be 3mol/L;
Preferably, the proportioning (g/ml) of described acid salt and inert organic solvents mass/volume is 1:5 ~ 25, further preferred 1:10 ~ 25,1:10 ~ 20,1:10 ~ 15,1:5 ~ 15,1:8 ~ 13,1:9 ~ 12; Most preferably be 1:10;
Preferably, the mass/volume proportioning (g/ml) of described acid salt and alkali aqueous solution is 1:2 ~ 10, and more preferably 1:3 ~ 8,1:3 ~ 7,1:4 ~ 7 or 1:4 ~ 6, most preferably be 1:5;
Preferably, described polar organic solvent is selected from the mixed solvent of alcohols (for example methyl alcohol, ethanol, Virahol, butanols, the trimethyl carbinol), ethers (for example tetrahydrofuran (THF)), alkane (for example methylene dichloride, trichloromethane) or above solvent, and further preferred polar organic solvent is the trimethyl carbinol or Virahol;
Preferably, the proportioning of the mass/volume of described Compound I and polar organic solvent (g/ml) is 1:2～10, and more preferably 1:2～5,1:2～8,1:2.5～6,1:2～4,1:3～10 or 1:3～5, most preferably be 1:3.
Preparation method described in 18. claims 16, wherein, in the time of n=0, the mass/volume proportioning (g/ml) of Compound I and the trimethyl carbinol is 1:5 ~ 20, be preferably 1:10 ~ 20, more preferably 1:10 ~ 15,1:8 ~ 18,1:10 ~ 18,1:9 ~ 12, most preferably be 1:10; The described trimethyl carbinol and the volume ratio of water are 1:1 ~ 10, are preferably 1:1.5 ~ 5,1:1.1.2 ~ 8,1:1.4～8,1:1.5～6 or 1:1.5～3, and more preferably 1:1.5 ~ 2.5, most preferably are 1:1.5.
19. 1 kinds of pharmaceutical compositions, it comprises the compound described in claim 1 to 15 any one, and optional one or more pharmaceutically acceptable carriers or vehicle.
Compound described in 20. claim 1 to 15 any one is in the purposes for the preparation for the treatment of and/or preventing in the medicine of disease that Mammals (comprising people) is relevant to receptor tyrosine kinase or illness.
The purposes of compound described in 21. claim 1 to 15 any one in the tumour or cancer or the propagation of tumour cell being driven by receptor tyrosine kinase and the medicine of migration that are mediated by receptor tyrosine kinase for the preparation for the treatment of or assisting therapy and/or prevention Mammals;
Preferably, described tumour or cancer comprise the responsive cancer of erbB receptor tyrosine kinase, as the tumour (comprise that noumenal tumour is as the cancer of bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour being as leukemia, multiple myeloma or lymphoma etc.) of EGFR or Her2 high expression level and EGF driving.
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| CN201610255798.3A CN105732596B (en) | 2012-11-19 | 2012-11-19 | N- [the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl] -6- [5- [[2- (methanesulfinyl) ethyl] amino] methyl] -2- furyl] -4- quinazoline amine polymorph and preparation method thereof |
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| CN112645932A (en) * | 2016-03-22 | 2021-04-13 | 江苏豪森药业集团有限公司 | Polymorphic forms of an EGFR inhibitor free base or an acid salt thereof, methods of making and uses thereof |
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Effective date of registration: 20201109 Address after: 570314 -A, Nanhai Avenue, national hi tech Development Zone, Hainan, Haikou, 273 Patentee after: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd. Patentee after: Qilu Pharmaceutical Co.,Ltd. Address before: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 317 250100 Patentee before: Qilu Pharmaceutical Co.,Ltd. |