CN103664892B - The crystallization of quinoline - Google Patents
The crystallization of quinoline Download PDFInfo
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- CN103664892B CN103664892B CN201310723784.6A CN201310723784A CN103664892B CN 103664892 B CN103664892 B CN 103664892B CN 201310723784 A CN201310723784 A CN 201310723784A CN 103664892 B CN103664892 B CN 103664892B
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- 0 Cc1cc(c(F)c(cc2)Oc3c(cc(c(OCC4(*)CC4)c4)OC)c4ncc3)c2[n]1 Chemical compound Cc1cc(c(F)c(cc2)Oc3c(cc(c(OCC4(*)CC4)c4)OC)c4ncc3)c2[n]1 0.000 description 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to the crystallization of quinoline, the preparation method of described crystallization, the pharmaceutical composition containing described crystallization and the purposes at field of medicaments, relate to three kinds of crystalline solid forms of quinoline dihydrochloride specifically, be respectively the crystallization of A type, Type B crystallization and the crystallization of C type, wherein A and Type B crystallization are that the crystallization of C type is the crystallization containing two crystal water not containing the crystallization of crystal water with other solvent on this.
Description
The application is application number is 201010245688.1, and the applying date is on August 1st, 2010, and denomination of invention is the divisional application of " crystallization of quinoline and preparation method thereof ".
Technical field
The present invention relates to the crystallization of quinoline hydrochloride, the preparation method of described crystallization, the pharmaceutical composition containing described crystallization and the purposes at field of medicaments.
Background technology
Tyrosylprotein kinase is the enzyme of one group of catalytic proteins tyrosine residues phosphorylation, play an important role in intracellular signal transduction, it participates in Normocellular adjustment, signal transmission and growth, also closely related with the propagation of tumour cell, differentiation, migration and apoptosis.Many receptor tyrosine kinases are all relevant to the formation of tumour, can be divided into EGF-R ELISA (EGFR), PDGF recepter (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor acceptor (FGFR) etc. according to the difference of its extracellular space structure.
International patent application WO2008112407 discloses compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine and preparation method thereof in embodiment 24, and its structural formula is such as formula shown in II:
It is the receptor tyrosine kinase inhibitors of a Mutiple Targets, the kinase activities such as vascular endothelial growth factor receptor (VEGFR1, VEGFR2/KDR and VEGFR3), stem cell factor receptor, platelet-derived growth factor receptor can be suppressed, suppress the downstream signal transduction of VEGFR2 mediation, thus Tumor suppression new vessel generates.
The change of medicinal compound crystal formation causes compound to have different fusing points, solubleness, water absorbability, stability, biological activity etc. usually, and these are all the important factors affecting difficulty or ease, stability in storage, preparation difficulty or ease and bioavailability etc. prepared by medicine.When there is polymorphic in compound, because specific polymorphic form has specific thermodynamic property and stability, therefore, in the process of preparation, the crystal formation understanding the compound applied in each formulation is important, to ensure the medicine of process application same modality.Therefore, ensure that compound be single crystal formation or the known miscellany of some crystal formations is necessary.
When judging which kind of polymorphic form is preferred, their much character must be compared and preferred polymorphic form makes one's options based on many physical propertiess.Preferred under completely likely the difficulty or ease, stability etc. of a kind of polymorphic in some aspects as preparation are considered to critical condition.In other cases, different polymorphic form may the solubleness of Yin Genggao or excellent pharmacokinetics and preferably.
The discovery of the new polymorphic form of medicinal compound provides the chance improving medicine physical property, namely whole character of material are extended, thus the research of compound and preparation thereof can be instructed better, therefore the polymorphic form of quinoline hydrochloride provided by the invention has commercial value in the manufacture and other application of medicine.
Summary of the invention
The invention provides three kinds of crystalline solid forms of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride, be respectively the crystallization of A type, Type B crystallization and the crystallization of C type.
Wherein the crystallization of A type refers to the crystallization being substantially free of crystal water and other solvent, and use Cu-K α radiation, it is in X-ray powder diffraction (XRD) collection of illustrative plates, is about apart from d value at crystal face
there is diffraction peak at place, typically exists
there is diffraction peak at place, further typical
there is diffraction peak at place.
Type B crystallization refers to the crystallization being substantially free of crystal water and other solvent, and use Cu-K α radiation, it is in X-ray powder diffraction (XRD) collection of illustrative plates, is about apart from d value at crystal face
there is diffraction peak at place, typically exists
there is diffraction peak at place, further typical
there is diffraction peak at place.
The crystallization of C type is the crystallization containing two crystal water, and use Cu-K α radiation, it is in X-ray powder diffraction (XRD) collection of illustrative plates, is about apart from d value at crystal face
there is diffraction peak at place, typically exists
there is diffraction peak at place, further typical
there is diffraction peak at place.Its thermogravimetric analysis (TGA) collection of illustrative plates (Fig. 8) is known, and weight loss is 7%, the water of about 2 moles.
The present invention another aspect provides the crystal composition of the crystallization of above-mentioned A type, Type B crystallization or the crystallization of C type.Wherein the crystal composition of A type crystallization refers to, in composition, the A type crystallization of type I compound accounts for more than 50% of composition weight, preferably more than 70%, more preferably more than 90%, most preferably more than 95%, other crystallization or the amorphous article of a small amount of type I compound can be contained in said composition, include but not limited to the Type B crystallization of type I compound, the crystallization of C type or amorphous article.
The crystal composition of Type B crystallization refers to, the Type B crystallization of the type I compound in composition accounts for more than 50% of composition weight, preferably more than 70%, more preferably more than 90%, most preferably more than 95%, other crystallization or the amorphous article of a small amount of type I compound can be contained in said composition, include but not limited to the A type crystallization of type I compound, the crystallization of C type or amorphous article.
The crystal composition of C type crystallization refers to, the C type crystallization of the type I compound in composition accounts for more than 50% of composition weight, preferably more than 70%, more preferably more than 90%, most preferably more than 95%, other crystallization or the amorphous article of a small amount of type I compound can be contained in said composition, include but not limited to the A type crystallization of type I compound, Type B crystallization or amorphous article.
Another aspect of the invention there are provided the preparation method of above-mentioned crystallization or crystal composition, the method comprises type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride crystallization under certain conditions, thus obtains above-mentioned three kinds of crystallizations or crystal composition.It should be noted that, in preparationⅠcompound crystallisation process, due to the restriction of crystallization condition, can not obtain certain specific crystallization (such as the crystallization of A type) of substantially pure type I compound, in fact, under the condition of laboratory or suitability for industrialized production, often obtain based on the crystal composition of certain specific crystallization (such as the crystallization of A type), i.e. crystal composition of the present invention (crystal composition of such as A type crystallization).
Wherein, the preparation of type I compound can refer to the method described in document, or carries out as follows.Be dissolved in the organic solvent of 1-20 times of weight by formula II compound, the temperature of reaction solution controls at-15 ~ 120 DEG C, and with the solution reaction of a certain amount of hydrogen chloride gas or hydrogenchloride, the solid of precipitation is through being separated, being drying to obtain the dihydrochloride of formula II compound.Wherein, described organic solvent comprises ethyl acetate, ether, tetrahydrofuran (THF), Virahol, isopropyl ether, methylene dichloride, trichloromethane, tetracol phenixin, DMF, DMSO, benzene, toluene, methyl alcohol, ethanol, acetone etc., particular methanol, ethanol, acetone.The mol ratio of hydrogenchloride and formula II compound is preferably 2 ~ 10:1, is more preferably 3:1.For the ease of controlling the amount of hydrogenchloride, preferably react with the solution of hydrogenchloride, such as the dichloromethane solution etc. of concentrated hydrochloric acid, ethanolic hydrogen chloride saturated solution, the methanol solution of hydrogenchloride, the diethyl ether solution of hydrogenchloride or hydrogenchloride.Preferably, the solution of hydrogenchloride is slowly added drop-wise in reaction solution, after being added dropwise to complete, reaction mixture is remained on-10 ~ 5 DEG C, continue reaction 0.5 ~ 3 hour, until separate out solid, filter, in 50-90 DEG C of dried in vacuo overnight, to obtain final product.
Wherein, the preparation of formula II compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine can refer to the method described in document and carries out.
The preparation of crystallization of the present invention or crystal composition can adopt single-solvent process or mixed solvent method.Wherein in single-solvent process, methyl alcohol is good solvent, is dissolved in methyl alcohol by the type I compound prepared according to the method described above, optionally, can heat, and obtains solution that is saturated or type I compound close to state of saturation.Then, solution is placed in crystallization under low temperature.If by gained crystallization after 50-100 DEG C of vacuum-drying, then in 50-100 DEG C of normal pressure forced air drying, obtain the A type crystallization of type I compound or the crystal composition of A type crystallization; If by gained crystallization in 40 DEG C-100 DEG C normal pressure forced air dryings, obtain the C type crystallization of type I compound or the crystal composition of C type crystallization.
In mixed solvent method, can first type I compound be dissolved in the water of 1-5 times of weight, under the aqueous solution is stirred at 0-100 DEG C, slowly add the methyl alcohol of 1-20 times of volume, ethanol or acetone, finish and keep its state 30 minutes, optionally, solution is filtered, filtrate is put-18 ~ 40 DEG C of environment and is left standstill crystallization, leaches crystallization.Or directly type I compound is dissolved in the aqueous solution of methyl alcohol, ethanol or acetone, optionally, can carry out heating obtain saturated or close to the solution of saturated type I compound, then, selectable, solution is filtered, filtrate is put-18 ~ 40 DEG C of environment and is left standstill crystallization, leaches crystallization.
The crystallization of gained, after 50 DEG C of-100 DEG C of vacuum-dryings, then in 50 DEG C-100 DEG C normal pressure forced air dryings, obtains the crystal composition of the A type crystallization of type I compound, the crystal composition of A type crystallization, Type B crystallization or Type B crystallization; If by gained crystallization in 40 DEG C-100 DEG C normal pressure forced air dryings, obtain the C type crystallization of type I compound or the crystal composition of C type crystallization.
Preferably, the preparation method of the crystal composition of the crystallization of A type or the crystallization of A type is: methyl alcohol type I compound being dissolved in 2-20 times of weight, in 60-95% aqueous ethanolic solution or 60-95% aqueous acetone solution, stirring heating 60-100 DEG C molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred to refrigerated overnight under-18 ~ 4 DEG C of conditions, separate out light yellow to off-white color crystalline solid, suction filtration, filtrate is with after methyl alcohol cold on a small quantity or 60-95% aqueous ethanolic solution or the washing of 60-95% aqueous acetone solution, filter cake is after 80-85 DEG C of vacuum-drying, in 80-85 DEG C of normal pressure forced air drying, obtain.
The preparation method of the crystal composition of the crystallization of A type or the crystallization of A type also comprises dry obtained for the crystal composition of the crystallization of C type or the crystallization of C type under certain condition, in one embodiment of the invention, drying conditions is after 85 DEG C of vacuum-dryings, then in 90-100 DEG C of normal pressure forced air drying.
Preferably, the preparation method of the crystal composition of Type B crystallization or Type B crystallization is: type I compound be dissolved in 3-20 times of weight 80-90% aqueous ethanolic solution or 60-70% aqueous acetone solution, stirring heating 60-100 DEG C molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred to refrigerated overnight under-18 ~ 4 DEG C of conditions, separate out light yellow to off-white color crystalline solid, suction filtration, filtrate is with after methyl alcohol cold on a small quantity or 80-90% aqueous ethanolic solution or the washing of 60-70% aqueous acetone solution, filter cake is after 80-85 DEG C of vacuum-drying, in 80-85 DEG C of normal pressure forced air drying, obtain.
Preferably, the preparation method of the crystal composition of the crystallization of C type or the crystallization of C type is: 50-99.9% methanol aqueous solution type I compound being dissolved in 2-20 times of weight, in 60-95% aqueous ethanolic solution or 60-95% aqueous acetone solution, stirring heating 60-100 DEG C molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred to refrigerated overnight under-18 ~ 4 DEG C of conditions, separate out light yellow to off-white color crystalline solid, suction filtration, filtrate is with after methyl alcohol cold on a small quantity or 80-90% ethanol or the washing of 60-70% aqueous acetone solution, filter cake is in 40-55 DEG C of normal pressure forced air drying, obtain.
Use Cu-K α radiation, as shown in Figure 1, it has following feature to the spectrogram of the typical XRD of A type crystallization:
Use Cu-K α radiation, as shown in Figure 4, it has following feature to the spectrogram of the typical XRD of Type B crystallization:
Use Cu-K α radiation, as shown in Figure 5, it has following feature to the spectrogram of the typical XRD of C type crystallization:
Another aspect of the present invention there are provided the pharmaceutical composition of above-mentioned crystallization or crystal composition.
The crystal composition of the crystal composition of the A type crystallization of 1-of the present invention [[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride (type I compound) or the crystal composition of A type crystallization, Type B crystallization or Type B crystallization, the crystallization of C type or the crystallization of C type, is generically and collectively referred to as " active substance of the present invention " hereinafter.
Active substance of the present invention can by the administration of any applicable institute disease therapy, comprises by oral, the locally administration such as (as oral cavity, sublingual etc.), parenteral (as in subcutaneous, muscle, intravenously, spinal cord, intracutaneous, sheath etc.), rectum, vagina.Preferred administering mode is oral administration.
Although active substance of the present invention can with the form administration of pure substance, usually with the form administration of pharmaceutical composition.The pharmaceutical composition of active substance of the present invention also comprises one or more pharmaceutical excipients, optionally, also can comprise other therapeutic activity composition.Also can with chemotherapy, radiotherapy, these therapy Combined Preparation of surgical operation.
Be applicable to oral pharmaceutical composition and comprise tablet, capsule, pulvis, granule, dripping pill, paste, powder, tincture etc., preferred tablet and capsule.Wherein tablet can be conventional tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet, and capsule can be conventional capsule, slow releasing capsule, controlled release capsule or enteric coated capsule.
Pharmaceutical composition of the present invention can use conventional pharmaceutical adjuvants well known in the art to be obtained by ordinary method.Conventional pharmaceutical excipient comprises weighting agent, absorption agent, wetting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent comprises starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose etc.; Absorption agent comprises calcium sulfate, secondary calcium phosphate, calcium carbonate, magnesium oxide etc.; Wetting agent comprises water, ethanol etc.; Tackiness agent comprises hypromellose, polyvidone, Microcrystalline Cellulose etc.; Disintegrating agent comprises croscarmellose sodium, polyvinylpolypyrrolidone, tensio-active agent, low-substituted hydroxypropyl cellulose etc.; Lubricant comprises Magnesium Stearate, talcum powder, polyoxyethylene glycol, Stepanol MG, micropowder silica gel, talcum powder etc.Pharmaceutical excipient is also comprising toner, sweeting agent etc.
Consumption for active substance of the present invention in the unit formulation of oral Tablet and Capsula agent must change according to the treatment situation of patient and concrete route of administration.Such as, unit formulation for oral administration can contain the active substance of such as 1mg ~ 100mg easily, preferably comprises the active substance of 3mg ~ 30mg.
Active substance of the present invention and pharmaceutical composition thereof have the activity suppressing receptor tyrosine kinase, can be used for treating tumour, as liver cancer, kidney, colorectal carcinoma or gastrointestinal stromal tumor etc.
It should be noted that, in XRD, the diffraction spectrogram obtained by crystalline compounds is distinctive often for specific crystal formation, wherein the relative intensity of bands of a spectrum (especially at low angle) the advantage orientation effect that may produce because of the difference of crystallization condition, particle diameter and other condition determination and changing.Therefore, the relative intensity of diffraction peak to for crystal formation be not distinctive, when judging whether identical with known crystal formation, should be noted that relative position instead of their relative intensity at peak.In XRD figure spectrum, usually represent peak position with 2 θ angles or crystal face apart from d, because 2 θ angles are relevant with the wavelength of incident X-rays, therefore represent with crystal face distance d and have more representativeness.Have simple conversion relation between the two: d=λ/2sin θ, wherein d represents crystal face distance, λ represent incident X-rays wavelength (for Cu-Ka,
), θ is diffraction angle.For the crystal formation of the same race of same compound, its XRD spectra has similarity on the whole, characterizes the d value error of peak position generally within ± 2%, and most of error is no more than ± and 1%; Relative intensity error can be comparatively large, but variation tendency is consistent.In addition, should note keeping organic conception when judging that whether crystal formation is the same, because be not that a diffracted ray represents a thing phase, but a set of specific " d-I/I1 " data just represent a certain thing phase.Should be noted also that in the qualification of mixture, because under content, degradation factor can cause the disappearance of portion diffracts line, now, without the need to relying in high-purity sample the whole bands of a spectrum observed, even several bands of a spectrum may be also distinctive to given crystallization.
DSC measure when crystallization due to its crystalline structure change or crystal melt and absorb or rejected heat time transition temperature.For the crystal formation of the same race of same compound, continuous print analyze in, thermal transition temperature and fusing point error typically within about 5 DEG C, usually within about 3 DEG C, when we say that a compound has a given DSC peak or fusing point, this refers to this DSC peak or fusing point ± 5 DEG C.DSC provides a kind of householder method distinguishing different crystal forms.Different crystal habits can be identified according to its different transition temperature feature.It is to be noted for mixture, its DSC peak or fusing point may change in the larger context.In addition, due in the process of material melts with decomposition, therefore temperature of fusion and temperature rise rate closely related.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum 1 of A type crystallization
Fig. 2 is the XRD figure spectrum 2 of A type crystallization
Fig. 3 is the XRD figure spectrum 3 of A type crystallization
Fig. 4 is the XRD figure spectrum of Type B crystallization
Fig. 5 is the XRD figure spectrum of C type crystallization
Fig. 6 is thermogravimetric analysis (TGA) collection of illustrative plates of A type crystallization
Fig. 7 is the DSC collection of illustrative plates of A type crystallization
Fig. 8 is thermogravimetric analysis (TGA) collection of illustrative plates of C type crystallization
Fig. 9 is the DSC collection of illustrative plates of C type crystallization
Embodiment
Embodiment 1
The preparation of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride (type I compound)
Method a:
1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine (formula II compound) 80g is added in 2L reaction flask, 800ml dehydrated alcohol, suspension is made in stirring, ice-water bath cools, temperature control is in less than 10 DEG C, fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL in 15 minutes, reaction solution by suspension, become clarification gradually, be added dropwise to complete 3-5 minute, reaction solution is orange red settled solution, this solution separates out rapidly a large amount of off-white color solid, react 1 hour at continuing maintenance 10 DEG C, suction filtration, the a small amount of absolute ethanol washing of filter cake, 80 DEG C of vacuum-dryings are after 6 hours, obtain off-white color 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride 86.2g, yield 91%.
Mp:240 ~ 255 DEG C (decomposition); MS (M+H)
+: 408.2;
1HNMR（DMSO-d6）δ(ppm)：1.10(2H,-CH
2-CH
2-),1.23(2H,-CH
2-CH
2-),2.50(3H,-CH
3),4.08(3H,-OCH
3),4.43(2H,-OCH
2-),6.31(1H,ArH),6.77(1H,ArH),7.10(1H,ArH),7.29(1H,ArH),7.80(1H,ArH),8.73(1H,ArH),8.88(3H,-NH
3 +),11.66(1H,-NH-)，16.62(1H,HCl)。
Method b:
1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine 80g is added in 1L reaction flask, 400ml methyl alcohol, suspension is made in stirring, ice-water bath cools, temperature control is in less than 10 DEG C, fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL in 15 minutes, reaction solution by suspension, become clarification gradually, be added dropwise to complete 3-5 minute, reaction solution is orange red settled solution, after this solution separate out rapidly a large amount of off-white color solid, react 1 hour at continuing maintenance 10 DEG C, suction filtration, the a small amount of cold methanol of filter cake washs, 80 DEG C of vacuum-dryings are after 6 hours, obtain off-white color title compound 51.3g, yield 54%.
Method c:
1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine 80g is added in 2L reaction flask, in 1200mL90% aqueous acetone solution, suspension is made in stirring, ice-water bath cools, temperature control is in less than 10 DEG C, fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL in 15 minutes, reaction solution by suspension, become clarification gradually, be added dropwise to complete 3-5 minute, reaction solution is orange red settled solution, after this solution separate out rapidly a large amount of off-white color solid, react 1 hour at continuing maintenance 10 DEG C, suction filtration, the a small amount of cold methanol of filter cake washs, 80 DEG C of vacuum-dryings are after 6 hours,
Obtain off-white color title compound 44.6g, yield 47%.
Embodiment 2
The preparation of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride A type crystallization
Method a:
The type I compound 20g that Example 1 prepares, methyl alcohol 100mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, separate out light yellow crystals solid next day, suction filtration, with a small amount of cold methanol washing leaching cake, in 80-85 DEG C of vacuum-drying after 6 hours, in 85 DEG C of normal pressure forced air dryings 6 hours, obtain A type crystallization 16.8g, its XRD figure spectrum as shown in Figure 1.
Method b:
The type I compound 20g that Example 1 prepares, 90% aqueous ethanolic solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, separate out off-white color crystalline solid next day, suction filtration, with a small amount of absolute ethanol washing filter cake, in 80-85 DEG C of vacuum-drying after 6 hours, in 85 DEG C of normal pressure forced air dryings 6 hours, obtain A type crystallization 10.7g, its XRD figure spectrum as shown in Figure 2.
Method c:
The type I compound 20g that Example 1 prepares, 80% aqueous acetone solution 90mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, separate out off-white color crystalline solid next day, suction filtration, with a small amount of washing with acetone filter cake, in 80-85 DEG C of vacuum-drying after 6 hours, in 85 DEG C of normal pressure forced air dryings 6 hours, obtain A type crystallization 12.3g, its XRD figure spectrum as shown in Figure 3.
The crystallization that relatively in the present embodiment, method a, b and c prepare, the XRD figure spectrum of three samples is substantially identical on peak shape, peak position and peak intensity, determines that three samples are identical crystallization thus.XRD figure spectrum slightly difference in some details of three samples may be caused by the difference due to the difference in Sample Preparation Procedure and test.
Embodiment 3
The preparation of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride Type B crystallization
The type I compound 20g that Example 1 prepares, 70% aqueous acetone solution 100mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, separate out off-white color crystalline solid next day, suction filtration, with a small amount of washing with acetone filter cake, in 80-85 DEG C of vacuum-drying after 6 hours, in 85 DEG C of normal pressure forced air dryings 6 hours, obtain Type B crystallization 13.0g, its XRD figure spectrum as shown in Figure 4.
Embodiment 4
The preparation of 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride C type crystallization
Method a:
The type I compound 20g that Example 1 prepares, 90% aqueous ethanolic solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-4 DEG C of refrigerated overnight, separate out off-white color crystalline solid next day, suction filtration, with a small amount of absolute ethanol washing filter cake, in 45-50 DEG C of normal pressure forced air drying 8 hours, obtain C type crystallization 8.6g, its XRD figure spectrum as shown in Figure 5.
Method b:
The type I compound 20g that Example 1 prepares, 95% methanol aqueous solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-18 DEG C of refrigerated overnight, separate out light yellow crystals solid next day, suction filtration, with a small amount of cold methanol washing leaching cake, in 45-50 DEG C of normal pressure forced air drying 8 hours, obtain C type crystallization 7.3g.
Method c:
The type I compound 20g that Example 1 prepares, 85% aqueous acetone solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, suction filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-18 DEG C of refrigerated overnight, separate out off-white color crystalline solid next day, suction filtration, with a small amount of cold acetone washing leaching cake, in 45-50 DEG C of normal pressure forced air drying 8 hours, obtain C type crystallization 8.9g.
Embodiment 5 prepares the crystallization of A type by the crystallization of C type
The C type crystallization 5.2g of the type I compound that Example 4 method a prepares, in 85 DEG C of vacuum-dryings after 6 hours, then in 90-100 DEG C of normal pressure forced air drying 6 hours, obtains the A type crystallization 4.7g of off-white color type I compound.
Embodiment 6 stability test
With reference to the method for the annex Ⅺ Ⅹ C Raw medicine influence factor test of China's coastal port (two), high temperature test and strong illumination test (4500 ± 500Lx) are carried out in the Type B crystallization that the A type crystallization of the type I compound prepared by the method a of embodiment 2, the method for embodiment 3 prepare, the C type crystallization prepared according to the method a of embodiment 4 respectively.Wherein, the condition of high temperature test is: 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.The investigation time is 10 days, and respectively at the 0th day, the 10th day sampling checked for impurities total amount, to investigate its stability, primary contributions factorial experiments result was as shown in table 1.
Table 1
Claims (17)
1. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is in X-ray powder diffraction, and being about 7.48,8.48,9.92,14.24,18.34,19.04,19.86,22.02,22.60,24.26,25.32,27.06,29.56 places at the 2 θ number of degrees has diffraction peak.
2. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride,
Use Cu-K α radiation, its X-ray powder diffraction has following feature:
3. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride, it has X-ray powder diffraction as described in Figure 1 substantially
。
4. crystal composition, the crystallization wherein according to any one of claim 1-3 accounts for more than 50% of crystal composition weight.
5. crystal composition, the crystallization wherein according to any one of claim 1-3 accounts for more than 70% of crystal composition weight.
6. crystal composition, the crystallization wherein according to any one of claim 1-3 accounts for more than 90% of crystal composition weight.
7. crystal composition, the crystallization wherein according to any one of claim 1-3 accounts for more than 95% of crystal composition weight.
8. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is in X-ray powder diffraction, and being about 8.12,8.96,13.72,14.72,18.76,19.10,19.60,21.30,23.74,24.56,24.86,27.00,29.58 places at the 2 θ number of degrees has diffraction peak.
9. the crystallization of claim 8, its 2 θ number of degrees about 8.12,8.96,11.96,12.40,13.72,14.12,14.72,15.20,18.76,19.10,19.60,21.30,22.98,23.74,24.56,24.86,26.30,27.00,27.64,28.60,29.58, there is diffraction peak at 31.04 places.
10. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride,
Use Cu-K α radiation, its X-ray powder diffraction has following feature:
11. the crystallization of type I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole of 4--5-base) oxygen base-6-methoxy quinoline-7-base] oxygen base] methyl] cyclopropylamine dihydrochloride, it has X-ray powder diffraction as described in Figure 4 substantially
。
12. crystal compositions, the crystallization wherein according to any one of claim 8-11 accounts for more than 50% of crystal composition weight.
13. crystal compositions, the crystallization wherein according to any one of claim 8-11 accounts for more than 70% of crystal composition weight.
14. crystal compositions, the crystallization wherein according to any one of claim 8-11 accounts for more than 90% of crystal composition weight.
15. crystal compositions, the crystallization wherein according to any one of claim 8-11 accounts for more than 95% of crystal composition weight.
16. pharmaceutical compositions, containing the crystallization according to any one of claim 1-3,8-11.
Crystallization according to any one of 17. claim 1-3,8-11 suppresses the application in the medicine of receptor tyrosine kinase activity in preparation.
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| CN105311029A (en) | 2014-06-06 | 2016-02-10 | 正大天晴药业集团股份有限公司 | Antineoplastic-activity quinoline derivative |
| CN105311030B (en) * | 2014-06-06 | 2020-03-24 | 正大天晴药业集团股份有限公司 | Anti-tumor spiro-substituted compound |
| CN105213394B (en) * | 2014-06-06 | 2019-04-09 | 正大天晴药业集团股份有限公司 | Quinoline with anti-tumor activity |
| AU2015290007B2 (en) | 2014-07-14 | 2019-11-21 | Advenchen Pharmaceuticals, Nanjing Ltd. | Fused quinoline compunds as pi3k, mTor inhibitors |
| AU2015360095B2 (en) * | 2014-12-09 | 2020-02-27 | Advenchen Laboratories Nanjing Ltd | Quinoline derivative against non-small cell lung cancer |
| CN106999485B (en) * | 2014-12-09 | 2020-04-14 | 正大天晴药业集团股份有限公司 | Anti-squamous cell lung carcinoma quinoline derivatives |
| US9751859B2 (en) * | 2015-05-04 | 2017-09-05 | Advenchen Pharmaceuticals, LLC | Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts |
| CN108601773A (en) | 2015-07-11 | 2018-09-28 | 南京爱德程医药科技有限公司 | Fused quinoline compound as PI3K/MTOR inhibitor |
| JP6855488B2 (en) * | 2016-01-08 | 2021-04-07 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. | Use of quinoline derivatives for the treatment of esophageal cancer and methods of treatment thereof, pharmaceutical compositions and kits |
| CN107296811B (en) * | 2016-04-15 | 2022-12-30 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treating gastric cancer |
| WO2018214925A1 (en) * | 2017-05-26 | 2018-11-29 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treatment of colorectal cancer |
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| CN114716410A (en) * | 2018-02-11 | 2022-07-08 | 正大天晴药业集团股份有限公司 | Crystal of quinoline derivative |
| EP3766870B1 (en) | 2018-03-02 | 2023-09-27 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Crystal of compound as c-met kinase inhibitor and preparation method therefor and use thereof |
| WO2019174508A1 (en) * | 2018-03-14 | 2019-09-19 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treatment of nasopharyngeal carcinoma |
| WO2019174590A1 (en) | 2018-03-14 | 2019-09-19 | 正大天晴药业集团股份有限公司 | Quinoline derivative for treatment of triple-negative breast cancer |
| CN110357856B (en) * | 2018-04-09 | 2021-02-26 | 新发药业有限公司 | Arotinib hydrochloride intermediate and preparation method of Arotinib hydrochloride |
| CN112368273A (en) * | 2018-06-25 | 2021-02-12 | 正大天晴药业集团股份有限公司 | Crystal habit of quinoline derivative and preparation method of crystal powder thereof |
| EP3854396A4 (en) | 2018-09-18 | 2022-06-29 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Quinoline derivative used for treating small cell lung cancer |
| CN109748904A (en) * | 2019-01-31 | 2019-05-14 | 正大天晴药业集团股份有限公司 | The crystallization of quinoline |
| CA3137204A1 (en) | 2019-04-19 | 2020-10-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma |
| CN113116895B (en) * | 2020-12-31 | 2023-08-18 | 天津医科大学肿瘤医院 | Quinoline derivatives for the treatment of neuroblastoma |
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