CN103819461B - 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 - Google Patents
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 Download PDFInfo
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Abstract
The present invention relates to N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] polymorph of-4-quinazoline amine and preparation method thereof, be specifically related to as tyrosine kinase inhibitor N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine crystal form A or B. The preparation method that the invention still further relates to this polymorph, its pharmaceutical composition and their pharmaceutical applications.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is specifically related to a kind of new N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl with anti-tumor activity] hydrate of-4-quinazoline amine (compound I), the crystal formation of this hydrate, its preparation method, and the application that this hydrate is in the propagation of tumor cell driven as the tumor mediated by receptor tyrosine kinase for treatment or auxiliary treatment mammal (including people) or receptor tyrosine kinase and the medicine of migration.
Background technology
The Chinese patent application that publication number is CN102030742A have studied the propagation of the tumor cell that 4-(substituted anilinic) quinazoline derivant drives as the tumor mediated for treatment or auxiliary treatment mammal (including people) or receptor tyrosine kinase and the application of the medicine aspect of migration by receptor tyrosine kinase. It is disclosed that compound N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] the methyl]-2-furyl with anti-tumor activity]-4-quinazoline amine, there is structural formula shown in formula I:
CN102030742A also discloses the process obtaining compound I, but the yellow solid obtained after column chromatography in this application is not crystal form, but yellow, viscous solid, it is unfavorable for preparation and the preservation of medicine.
4-(substituted anilinic disclosed in prior art) quinazoline derivant is at the prerequisite that advantageous feature pharmacologically is that this compound is applied as pharmaceutical composition; But, as active substance, it is also necessary to meet other requirements and just can serve as pharmaceutical composition. These parameters are largely relevant with the physicochemical properties of this active substance.
The limiting examples of these parameters includes active substance stability under difficult environmental conditions, prepares the stability in pharmaceutical composition process and the stability etc. of pharmaceutical composition terminal storage form.Therefore, should have high stability for the active substance preparing pharmaceutical composition, even if under difficult environmental conditions also it is ensured that this stability.
Owing to the absorption of moisture can cause weight to increase, so hygroscopic effect can reduce the content of medicinal activity material. Therefore, for easy moisture absorption medicine in storage process it should be noted that moistureproof, for instance can pass through add suitable desiccant or be stored in moistureproof environment. Additionally, in process of production, if active substance is exposed in not moistureproof by any way environment, then moisture absorption can reduce its content. Therefore, medicinal activity material preferably should only have slight hygroscopicity.
The polymorphic of active substance is critically important for the content of active substance in preparation, accordingly, it would be desirable to research is known with the presumable polymorphic of active substance that crystal form exists as far as possible. If active substance has different polymorphics, it is necessary to ensure that the crystal formation of this active substance does not change in the preparation process of pharmaceutical preparation, the drug effect of active substance otherwise may be affected.
Another parameter is the resolvability of active substance, and it is all critically important to the selection of the selection of preparation or preparation method under specific circumstances. Such as preparing drug solution (such as venoclysis), it is necessary that active substance should be substantially soluble in physiologically acceptable solvent. The resolvability of active substance is also extremely important for oral drugs.
Accordingly, it would be desirable to the crystal formation of research compound I, meet above-mentioned physicochemical properties and require (such as good stability, resolvability etc.), in order to good Pharmaceutical composition is provided.
Summary of the invention
It is an object of the invention to provide N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl] the novel hydrate of-4-quinazoline amine (compound I) and crystal formation thereof, it has the advantageous use for EGFR Family Tyrosine Kinases inhibitor. The present inventor is through research, it was surprisingly found within the scope that, the polymorph of compound I meets above-mentioned physicochemical properties requirement, is the crystalline solid with favorable property.
For this; first aspect present invention provides N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] the methyl]-2-furyl shown in formula III] polymorphic of-4-quinazoline amine
Wherein, n is 2 or 0.
As n=2, described polymorphic is N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine dihydrate.
As n=0, described polymorphic is N-[the chloro-4-of 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 N-[the chloro-4-of 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 represented 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 °, there is characteristic peak at place.
Further, described crystal form A, it is characterised in that, use Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles 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 °, there is characteristic peak at 32.2 ± 0.2 ° of places.
Further, described crystal form A, it is characterized in that, use Cu-K α radiation, the X-ray powder diffraction represented 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 °, 37.8 there is characteristic peak at ± 0.2 ° of place.
Further, described crystal form A, it is characterised in that using Cu-K α radiation, the relative intensity I of the characteristic peak of the X-ray powder diffraction represented with 2 θ angles is as follows:
Further, described crystal form A, use Cu-K α radiation, basic consistent with Fig. 1 with the X-ray powder diffraction that 2 θ angles represent.
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 DEG C.
Described crystal form A, moisture content range 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, it is more preferably equal to or greater than 98.6% weight, it is most preferred that, 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 N-[the chloro-4-of 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 represented 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 °, there is characteristic peak at 21.9 ± 0.2 ° of places.
Further, described crystal form B, it is characterised in that, use Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles 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 °, there is characteristic peak at 26.6 ± 0.2 ° of places.
Further, described crystal form B, use Cu-K α radiation, the X-ray powder diffraction represented 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 °, 37.8 there is characteristic peak at ± 0.2 ° of place.
Further, described crystal form B, it is characterised in that using Cu-K α radiation, the relative intensity I of the characteristic peak of the X-ray powder diffraction represented with 2 θ angles is as follows:
Further, described crystal form B, use Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles is 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 DEG C.
Described crystal form B, moisture content range is 0 ~ 1.5%.
The purity of described crystal form B is more than or equal to 95% weight, it is preferable that more than or equal to 98% weight, is more preferably equal to or greater than 99% weight.
The preparation method that fourth aspect present invention provides the crystal described in first aspect present invention, second aspect or the third aspect, described method is as follows:
As n=2, employing method one or method two prepare described compound.
Method one:
The acid-addition salts of compound I is joined in inert organic solvents, adds aqueous alkali, separatory, organic facies stirring and crystallizing, obtain the crystal form A of Compound II per I.
Described inert organic solvents is preferably selected from dichloromethane, chloroform, acetonitrile, ether, ethyl acetate the mixture of one or more solvents, and preferred inert organic solvents is dichloromethane or ethyl acetate.
Preferably, described acid-addition salts is selected from hydrochlorate, sulfate, nitrate, xylenesulfonate, mesylate, benzene sulfonate, oxalates, formates, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, citrate, and preferred acid-addition salts is xylenesulfonate.
Preferably, described aqueous alkali be selected from sodium hydrate aqueous solution, sodium bicarbonate aqueous solution, wet chemical, aqueous sodium carbonate, it is preferred that aqueous alkali be sodium hydrate aqueous solution.
Preferably, the concentration of described aqueous alkali 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, it is most preferred that for 3mol/L.
Preferably, the proportioning (g/ml) of described acid-addition salts and inert organic solvents mass/volume is 1:5 ~ 25, it is preferred that 1:10 ~ 25,1:10 ~ 20,1:10 ~ 15,1:5 ~ 15,1:8 ~ 13,1:9 ~ 12; It most preferably is 1:10.
Preferably, the mass/volume proportioning (g/ml) of described acid-addition salts and aqueous alkali is 1:2 ~ 10, more preferably 1:3 ~ 8,1:3 ~ 7,1:4 ~ 7 or 1:4 ~ 6, it is most preferred that for 1:5.
Method two:
Compound I is dissolved in polar organic solvent, is heated to reflux, crystallize of lowering the temperature, and obtains the crystal form A of Compound II per I.
Preferably, described polar organic solvent selected from alcohols (such as methanol, ethanol, isopropanol, butanol, the tert-butyl alcohol), ethers (such as oxolane), alkane (such as dichloromethane, chloroform) or above solvent mixed solvent, it is preferred that polar organic solvent be the tert-butyl alcohol or isopropanol.
Preferably, the proportioning (g/ml) of the mass/volume of described compound I and polar organic solvent is 1:2～10, more preferably 1:2～5,1:2～8,1:2.5～6,1:2～4,1:3～10 or 1:3～5, it is most preferred that for 1:3.
As n=0, following methods is adopted to prepare described compound,
Compound I is dissolved in the tert-butyl alcohol and in the mixed system of water, heats and all dissolve to solid, crystallize of lowering the temperature, obtain the crystal form B of Compound II per I; Or
Compound I is dissolved in the tert-butyl alcohol, is heated to reflux, molten clear after add water, crystallize of lowering the temperature, obtain the crystal form B of Compound II per I.
Preferably, the mass/volume proportioning (g/ml) of described compound I and the tert-butyl alcohol is 1:5 ~ 20, it is preferred to 1:10 ~ 20, more preferably 1:10 ~ 15,1:8 ~ 18,1:10 ~ 18,1:9 ~ 12, it is most preferred that for 1:10;The volume ratio of the described tert-butyl alcohol and water is 1:1 ~ 10, it is preferred to 1:1.5 ~ 5,1:1.1.2 ~ 8,1:1.4～8,1:1.5～6 or 1:1.5～3, more preferably 1:1.5 ~ 2.5, it is most preferred that for 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 is referred to document CN102030742A to be prepared.
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 any one of the third aspect, and one or more optional pharmaceutically acceptable carriers or excipient. The pharmaceutical carrier that those skilled in the art are familiar with is used to can be prepared as the pharmaceutical composition of the compounds of this invention containing effective dose. Described pharmaceutical composition can become for oral administration with solid or liquid form, supply parental injection or for rectally etc. by particular formulation especially.
Sixth aspect present invention relates to crystal described in first aspect present invention, second aspect or any one of the third aspect in preparation for treating and/or prevent the purposes in the medicine of disease that mammal (including people) is relevant to receptor tyrosine kinase or disease.
Sixth aspect present invention further relates to the purposes in tumor that crystal described in first aspect present invention, second aspect or any one of the third aspect mediates by receptor tyrosine kinase in preparation or cancer or the propagation of tumor cell driven by receptor tyrosine kinase and the medicine of migration for treatment or auxiliary treatment and/or prevention mammal (including people).
Seventh aspect present invention relates to a kind of method for the treatment of and/or the prevention disease relevant to receptor tyrosine kinase or disease in mammal in need, and the method includes to the crystal described in the first aspect present invention of administration therapeutically effective amount in need, second aspect or any one of the third aspect.
Seventh aspect present invention further relates to a kind of tumor that treatment or auxiliary treatment and/or prevention mammal (including people) are mediated in mammal in need or cancer or the method for the propagation of tumor cell driven by receptor tyrosine kinase and migration by receptor tyrosine kinase, and the method includes to the crystal described in the first aspect present invention of administration therapeutically effective amount in need, second aspect or any one of the third aspect.
Seventh aspect present invention treats further to one and/or prevents the tumor of mammal (including people) or the method for cancer in mammal in need, and the method includes to the crystal described in the first aspect present invention of administration therapeutically effective amount in need, second aspect or any one of the third aspect.
Tumor of the present invention or cancer include erbB receptor tyrosine kinase cancer susceptible, such as the tumor that EGFR or Her2 high expressed and EGF drive, including the cancer of entity tumor such as bile duct, bone, bladder, brain/central nervous system, breast, Colon and rectum, endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neuron, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and pudendum etc., and non-solid tumors such as leukemia, multiple myeloma or lymphoma etc.
All documents that the present invention is recited, their full content is incorporated herein by, and if when implication expressed by these documents is inconsistent with the present invention, it is as the criterion with the statement of the present invention.In addition, various terms and phrase that the present invention uses have and well known to a person skilled in the art general sense, nonetheless, the present invention remains desirable at this, these terms and phrase are described in more detail and explained, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
The X-ray powder diffraction characteristic peak that the crystal formation of the compound I of the present invention represents with 2 θ angles, wherein " ± 0.2 ° " is the measurement error scope allowed.
The polymorph of the compound I of the present invention can use with other active ingredient combinations, as long as it does not produce other detrimental effects, for instance anaphylaxis.
Reactive compound shown in the polymorph of the compounds of this invention I can use as unique cancer therapy drug, or can be used in combination with one or more other antitumor drug. Therapeutic alliance by by each therapeutic component simultaneously, order or separate administration and realize.
Term used herein " compositions " means to include comprising each product specifying composition of specified amount and any product directly or indirectly produced from each combination specifying composition of specified amount.
Heretofore described " % weight " refers to percentage ratio (w/w) by weight.
The unit of heretofore described " proportioning of mass/volume " is g/ml, the proportioning (g/ml) of example acid-addition salts as mentioned and inert organic solvents is 1:1.5, its implication refers to, when the quality of acid-addition salts is 1 gram, the consumption of inert organic solvents is 1.5ml.
Formula III compound of the present invention, as n=2, described polymorphic is dihydrate, and theoretical water content is 6.0%, and as n=0, described polymorphic is anhydride, and theoretical water content is 0. As well known to those skilled in the art, the product prepared is likely to be completely dried, so the dihydrate of formula III compound and the crystal formation of anhydride with micro free water still comprise within the scope of the present invention.
The beneficial effect of the invention
N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl shown in the formula III that the present invention relates to] hydrate of-4-quinazoline amine and crystal form A thereof or B, there is good stability. Due to good stability so that the final preparation (pharmaceutical composition) of compounding pharmaceutical active component (API) is more suitable, and making the storage of API convenient, the effect duration of storage is longer; In preparation, it is easy to preparation, purification, more convenient to operate simply, be more suitable for industrialized great 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.
Detailed description of the invention
The present invention is further illustrated below by concrete preparation embodiment and biological test example, it should be understood, however, that, these embodiments and test example are only used for the use specifically described in more detail, and are not to be construed as limiting in any form the present invention.
The material that used and test method in test are carried out generality and/or concrete description by the present invention. Although for realize many materials that the object of the invention uses and operational approach is to it is known in the art that but the present invention remains in this to be described in detail as far as possible. It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art. Unreceipted actual conditions person in embodiment, conventionally the condition of condition or manufacturer's suggestion carries out. Agents useful for same or the unreceipted production firm person of instrument, be can pass through city available from conventional products.
Instrument of the present invention and method:
(1) high resolution mass spectrum
INSTRUMENT MODEL: Q-Tofmicro mass spectrograph.
Test condition: ESI(electron spray).
(2) X-ray powder diffraction analysis
INSTRUMENT MODEL: D/max-rB (Rigaku motor)
Method of testing: the sample (100mg) after finely ground is filled out in glass plate groove, after its plane being flushed with glass surface extension with microscope slide, sample is placed in D/max-rB (Rigaku motor), use the copper X-ray source of 40kV, 100mA, sweep limits is 3～50 ° (2 θ), scanning speed 4 °/minute, 12 minutes sweep times. Scanning error is generally ± 0.2 degree (2 θ).
(3) differential scanning calorimeter
INSTRUMENT MODEL: TGA/DSC1(METTLER) thermal analyzer.
Method of testing: be placed in the sealed aluminum pan with little pin hole by the sample of weight 10mg, keeps balance at 25 DEG C, then heats to 110 DEG C with the sweep speed of 10 DEG C/min. Drying nitrogen is used as purging gas.
Method described in CN102030742A can prepare compound I, as shown in example 1 below.
Embodiment 1:N-[the chloro-4-of 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:
Reaction bulb adds under Bis(tert-butoxycarbonyl)oxide 25g, 2-MEA hydrochlorate 14.4g and 140ml dichloromethane condition of ice bath and be dividedly in some parts triethylamine 18ml; reaction is stirred at room temperature overnight; add the hydrochloric acid solution washing of excessive 0.5M; organic layer saturated nacl aqueous solution washs; anhydrous sodium sulfate dries; solvent evaporated obtains the 2-MEA 5.7g(oily liquids of Boc protection), productivity 87%.
The preparation of the 2-methyl mercapto ethamine of b.Boc protection:
When ice bath, nitrogen protection; NaH1.2g is dividedly in some parts 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 iodomethane, drip room temperature reaction after finishing and be about 1h; add saturated sodium carbonate solution cancellation reaction; reactant liquor is poured in water, extraction into ethyl acetate, organic facies saturated nacl aqueous solution washs; anhydrous sodium sulfate dries, and solvent evaporated obtains oily liquids. Column chromatography obtains the 2-methyl mercapto ethamine 3.6g of Boc protection, productivity 47%.
The preparation of the 2-first sulfoxide group ethamine of c.Boc protection:
Under condition of ice bath; the 2-methyl mercapto ethamine 3.6g that Boc protects is dissolved in methanol, the aqueous solution of dropping sodium metaperiodate, finish rear room temperature stirring reaction overnight; filter; washed with dichloromethane filter cake, removes the organic reagent in filtrate under reduced pressure, adds saturated nacl aqueous solution; extraction into ethyl acetate; anhydrous magnesium sulfate dries, and filtration removes solvent under reduced pressure and obtains the 2-first sulfoxide group ethamine 3.4g(grease of Boc protection), productivity 87%.
The preparation of the 2-first sulfoxide group ethylamine hydrochloride of d.Boc protection:
Being dissolved in absolute ether by the 2-first sulfoxide group ethamine 3.4g that Boc protects, pass into HCl gas, it is complete that TLC detects raw material reaction, removes solvent under reduced pressure and obtains the 2-first sulfoxide group ethylamine hydrochloride 1.9g(grease of Boc protection), productivity 82%.
E.N-[the chloro-4-of 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) furan-2-formaldehyde tosilate 15g is dissolved in the mixed solution of methylene chloride/methanol (3:1), add 15ml triethylamine stirring reaction 10min, add 2-first sulfoxide ethylamine hydrochloride 7.5g, reaction is stirred at room temperature, it is complete that TLC detects raw material reaction, sodium borohydride 2.5g it is dividedly in some parts under ice bath, TLC detection reaction is complete, add q. s. methylene chloride, saturated ammonium chloride solution washs, saturated nacl aqueous solution washs, anhydrous sodium sulfate dries, column chromatography obtains yellow, viscous solid 9.1g, it is N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine (compound I), productivity 69%.
Embodiment 2:N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl]
Amino] methyl]-2-furyl] preparation of-4-quinazoline amino acid addition salts
Such as: the preparation of compound I xylenesulfonate (Compound II per)
The compound I5g(8.88mmol that embodiment 1 is prepared) add in 25ml ethanol; stirring and dissolving; add p-methyl benzenesulfonic acid 4.58g(26.5mmol); precipitate out yellow solid; sucking filtration, dries, and obtains 7.75gN-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine xylenesulfonate (yellow, viscous solid); yield 93.5%, purity 95.3%.
MS(m/z):[M-H]907.1713。
Other acid-addition salts example hydrochloric acid salt, sulfate, nitrate, mesylate, benzene sulfonate, oxalates, formates, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, citrates etc. can adopt the method similar with said method to prepare.
Embodiment 3:N-[the chloro-4-of 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
Compound II per 2g embodiment 2 prepared joins in the mixed system of 20ml dichloromethane and 10ml3mol/L sodium hydrate aqueous solution, stirring and dissolving, stands separatory, organic layer stirring and crystallizing, sucking filtration, dries, obtain 1.2g faint yellow solid, yield 90%, purity 99.1%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and XRPD collection of illustrative plates is as shown in Figure 1.
Above-mentioned product uses differential scanning calorimeter; its DSC-TGA collection of illustrative plates is as shown in Figure 2; its fusing point is 93 ~ 103 DEG C; determine that products therefrom is N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl by weight-loss curve]-4-quinazoline amine dihydrate; when heating loses first water of crystallization to 48 ~ 83 DEG C; heating loses second water of crystallization to 84 ~ 108 DEG C, and namely the ratio addition of twice loss in weight obtains moisture is 6.8%. Show in formula products therefrom containing two water of crystallization.
Embodiment 4:N-[the chloro-4-of 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
Compound II per 2g embodiment 2 prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L sodium hydrate aqueous solution, stirring and dissolving, stands separatory, organic layer stirring and crystallizing, sucking filtration, dries, obtain 1.3g faint yellow solid, yield 100%, purity 99.1%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.6%.
Embodiment 5:N-[the chloro-4-of 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
Compound II per 2g embodiment 2 prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L sodium hydrate aqueous solution, stirring and dissolving, stands separatory, organic layer stirring and crystallizing, sucking filtration, dry, obtain 1.3g faint yellow solid, yield 10%, purity 98.9%, the product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.5%.
Embodiment 6:N-[the chloro-4-of 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
Compound I crude product 2g embodiment 1 prepared joins in the 6ml tert-butyl alcohol, be heated to reflux molten clearly, lower the temperature crystallize, obtain 1.6g faint yellow solid, yield 80%, purity 98.6%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.7%.
Embodiment 7:N-[the chloro-4-of 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
Compound I crude product 2g embodiment 1 prepared joins in 6ml isopropanol, be heated to reflux molten clearly, lower the temperature crystallize, obtain 1.7g faint yellow solid, yield 85%, purity 98.8%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.5%.
Embodiment 8:N-[the chloro-4-of 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
Compound II per 2g embodiment 2 prepared joins in the mixed system of 20ml dichloromethane and 10ml3mol/L aqueous sodium carbonate, stirring and dissolving, stands separatory, organic layer stirring and crystallizing, sucking filtration, dries, obtain 1.2g faint yellow solid, yield 90%, purity 99.3%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and its XRPD collection of illustrative plates is basic consistent with Fig. 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.5%.
Embodiment 9:N-[the chloro-4-of 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 compound I embodiment 2 prepared joins in the mixed system of 20ml ethyl acetate and 10ml3mol/L sodium bicarbonate aqueous solution, stirring and dissolving, stands separatory, organic layer stirring and crystallizing, sucking filtration, dries, obtain 1.4g faint yellow solid, yield 93.8%, purity 99.1%. The product obtained is carried out X-ray powder diffraction, and result shows the crystal form A that this product is Compound II per I, and XRPD collection of illustrative plates is as shown in Figure 1.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, moisture 6.6%.
Embodiment 10:N-[the chloro-4-of 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
Compound I crude product 2g embodiment 1 prepared joins in the 20ml tert-butyl alcohol, be heated to reflux molten clearly, 30ml water is added under counterflow condition, cooling crystallize, sucking filtration, dry, obtain 1.7g yellow crystalline powder, yield 85%, purity 99.0%, the product obtained is carried out X-ray powder diffraction, result shows that this product is N-[the chloro-4-of 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 is as shown in Figure 4; its fusing point is 93 ~ 103 DEG C; and determine that described compound is N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl by weight-loss curve] and-4-quinazoline amine anhydride, moisture 1.4%. Endothermic peak on weight-loss curve is endothermic peak during crystal form B fusing.
Embodiment 11:N-[the chloro-4-of 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
Compound I crude product 2g embodiment 1 prepared joins in the mixed solvent of the 20ml tert-butyl alcohol and 10ml water, heating to solid is completely dissolved, cooling crystallize, sucking filtration, dries, and obtains 1.6g yellow crystalline powder, yield 80%, purity 99.3%, carries out X-ray powder diffraction by the product obtained, and its XRPD collection of illustrative plates is basic consistent with Fig. 3.
Using differential scanning calorimeter product obtained above, its DSC-TGA collection of illustrative plates is basic consistent with Fig. 4, moisture 0.8%.
Embodiment 12: crystal form A, B prepared by the embodiment of the present invention investigate result at 45 DEG C of vacuum dryings 5 hours and 7 hours rear stabilities, and the method for concrete study on the stability is referred to the method for 2010 editions second annex XIXC of Chinese Pharmacopoeia; Purity detecting HPLC method, it is possible to reference to the method for 2010 editions second annex 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 B purity after 45 DEG C of vacuum dryings does not change, and has good stability.
Claims (52)
1. N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] the methyl]-2-furyl shown in formula III] polymorphic of-4-quinazoline amine,
Wherein, n is 2,
It is characterized in that, use Cu-K α radiation, the X-ray powder diffraction represented 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 °, 37.8 there is characteristic peak at ± 0.2 ° of place.
2. the polymorphic described in claim 1, it is characterised in that use Cu-K α radiation, basic consistent with Fig. 1 with the X-ray powder diffraction that 2 θ angles represent.
3. the polymorphic described in claim 1, it is characterised in that use differential scanning calorimeter, gained DSC-TGA collection of illustrative plates is basic consistent with Fig. 2, and its fusing point is 61～72 DEG C.
4. the polymorphic described in claim 1, its moisture content range is in 6.0～6.8% weight.
5. the polymorphic described in any one of Claims 1-4, the purity of wherein said crystal is more than or equal to 95% weight.
6. the polymorphic described in any one of Claims 1-4, the purity of wherein said crystal is more than or equal to 98% weight.
7. the polymorphic described in any one of Claims 1-4, the purity of wherein said crystal is more than or equal to 98.6% weight.
8. the polymorphic described in any one of Claims 1-4, the purity of wherein said crystal is 98.8% weight, 98.6% weight, 98.9% weight or 99.1% weight.
9. the preparation polymorphous method described in any one of claim 1 to 8, the method adopts method one or method two to prepare described polymorphic,
Method one:
Joining in inert organic solvents by the acid-addition salts of compound I, add aqueous alkali, separatory, organic facies stirring and crystallizing, obtain the polymorphic of Compound II per I, wherein said inert organic solvents is dichloromethane or ethyl acetate,
Described acid-addition salts is selected from hydrochlorate, sulfate, nitrate, xylenesulfonate, mesylate, benzene sulfonate, oxalates, formates, acetate, benzoate, maleate, fumarate, malate, tartrate, dibenzoyl tartaric acid salt, citrate
Described aqueous alkali is selected from sodium hydrate aqueous solution, sodium bicarbonate aqueous solution, wet chemical and aqueous sodium carbonate,
The concentration of described aqueous alkali is 0.1～5mol/L,
Described acid-addition salts and inert organic solvents mass/volume proportioning are 1:5～25, and the unit of mass/volume proportioning is g/ml,
The mass/volume proportioning of wherein said acid-addition salts and aqueous alkali is 1:2～10, and the unit of mass/volume proportioning is g/ml;
Method two:
Compound I is dissolved in polar organic solvent, is heated to reflux, crystallize of lowering the temperature, and obtains the polymorphic of Compound II per I, and wherein said polar organic solvent is the tert-butyl alcohol or isopropanol,
The mass/volume proportioning of wherein said compound I and polar organic solvent is 1:2～10, and the unit of mass/volume proportioning is g/ml.
10. method according to claim 9, wherein, described acid-addition salts is xylenesulfonate or mesylate.
11. method according to claim 9, wherein, described acid-addition salts is xylenesulfonate.
12. method according to claim 9, wherein said aqueous alkali is sodium hydrate aqueous solution.
13. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 0.5～1mol/L.
14. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 0.1～3mol/L.
15. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 1～3.5mol/L.
16. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 0.8～4.5mol/L.
17. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 2～4mol/L.
18. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 0.5～4.5mol/L.
19. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 2.5～3.5mol/L.
20. according to the method described in any one of claim 9 to 12, the concentration of wherein said aqueous alkali is 3mol/L.
21. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:10～25, and the unit of mass/volume proportioning is g/ml.
22. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:10～20, and the unit of mass/volume proportioning is g/ml.
23. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:10～15, and the unit of mass/volume proportioning is g/ml.
24. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:5～15, and the unit of mass/volume proportioning is g/ml.
25. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:8～13, and the unit of mass/volume proportioning is g/ml.
26. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:9～12, and the unit of mass/volume proportioning is g/ml.
27. method according to claim 9, wherein said acid-addition salts and inert organic solvents mass/volume proportioning are 1:10, and the unit of mass/volume proportioning is g/ml.
28. the mass/volume proportioning of method according to claim 9, wherein said acid-addition salts and aqueous alkali is 1:3～8, the unit of mass/volume proportioning is g/ml.
29. the mass/volume proportioning of method according to claim 9, wherein said acid-addition salts and aqueous alkali is 1:3～7, the unit of mass/volume proportioning is g/ml.
30. the mass/volume proportioning of method according to claim 9, wherein said acid-addition salts and aqueous alkali is 1:4～7, the unit of mass/volume proportioning is g/ml.
31. the mass/volume proportioning of method according to claim 9, wherein said acid-addition salts and aqueous alkali is 1:4～6, the unit of mass/volume proportioning is g/ml.
32. the mass/volume proportioning of method according to claim 9, wherein said acid-addition salts and aqueous alkali is 1:5, the unit of mass/volume proportioning is g/ml.
33. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:2～5, and the unit of mass/volume proportioning is g/ml.
34. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:2～8, and the unit of mass/volume proportioning is g/ml.
35. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:2.5～6, and the unit of mass/volume proportioning is g/ml.
36. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:2～4, and the unit of mass/volume proportioning is g/ml.
37. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:3～10, and the unit of mass/volume proportioning is g/ml.
38. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:3～5, and the unit of mass/volume proportioning is g/ml.
39. method according to claim 9, the mass/volume proportioning of wherein said compound I and polar organic solvent is 1:3, and the unit of mass/volume proportioning is g/ml.
40. a pharmaceutical composition, it comprises the polymorphic described in any one of claim 1 to 8, and one or more optional pharmaceutically acceptable carriers or excipient.
41. the purposes that the polymorphic described in any one of claim 1 to 8 is in the medicine of the disease prepared for treating and/or prevent mammal relevant to receptor tyrosine kinase or disease.
42. purposes according to claim 41, wherein said mammal is behaved.
43. the polymorphic described in any one of claim 1 to 8 is in the preparation purposes for treating or in auxiliary treatment and/or the prevention tumor that mediated by receptor tyrosine kinase of mammal or cancer or the propagation of tumor cell driven by receptor tyrosine kinase and the medicine of migration.
44. purposes according to claim 43, wherein said tumor or cancer are erbB receptor tyrosine kinase cancer susceptible.
45. purposes according to claim 44, wherein said erbB receptor tyrosine kinase cancer susceptible is EGFR or Her2 high expressed and the tumor of EGF driving.
46. the tumor that purposes according to claim 45, wherein said EGFR or Her2 high expressed and EGF drive is entity tumor or non-solid tumors.
47. purposes according to claim 46, wherein said entity tumor is selected from the cancer of bile duct, bone, bladder, central nervous system, breast, Colon and rectum, stomach, head and neck, liver, lung, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and pudendum.
48. purposes according to claim 47, wherein said central nervous system is neuron.
49. purposes according to claim 47, wherein said central nervous system is brain.
50. purposes according to claim 46, wherein said entity tumor is carcinoma of endometrium.
51. purposes according to claim 46, wherein said entity tumor is nonsmall-cell lung cancer.
52. purposes according to claim 46, wherein said non-solid tumors is leukemia, multiple myeloma or lymphoma.
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| CN201210464607.6A CN103819461B (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 |
| 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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| CN201210464607.6A CN103819461B (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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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1636992A (en) * | 2000-06-30 | 2005-07-13 | 葛兰素集团有限公司 | Process for producing quinazoline ditosylate salt compounds |
| CN102030742A (en) * | 2009-09-28 | 2011-04-27 | 齐鲁制药有限公司 | 4-(substituent phenylamino group) quinazoline derivatives used as tyrosine kinase inhibitor |
| WO2011116634A1 (en) * | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1636992A (en) * | 2000-06-30 | 2005-07-13 | 葛兰素集团有限公司 | Process for producing quinazoline ditosylate salt compounds |
| CN102030742A (en) * | 2009-09-28 | 2011-04-27 | 齐鲁制药有限公司 | 4-(substituent phenylamino group) quinazoline derivatives used as tyrosine kinase inhibitor |
| WO2011116634A1 (en) * | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
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