CN103664890A - Crystal of quinoline derivative and preparation method of crystal - Google Patents
Crystal of quinoline derivative and preparation method of crystal Download PDFInfo
- Publication number
- CN103664890A CN103664890A CN201310722253.5A CN201310722253A CN103664890A CN 103664890 A CN103664890 A CN 103664890A CN 201310722253 A CN201310722253 A CN 201310722253A CN 103664890 A CN103664890 A CN 103664890A
- Authority
- CN
- China
- Prior art keywords
- crystallization
- crystal
- type
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a crystal of a quinoline derivative, a preparation method of the crystal, a pharmaceutical composition comprising the crystal and application of the pharmaceutical composition in the field of medicine, in particular to three crystalline solid manners of quinoline derivative dihydrochloride, namely an A-type crystal, a B-type crystal and a C-type crystal, wherein the A-type crystal and the B-type crystal are crystals basically not containing crystal water molecules and other solvents, and the C-type crystal is the crystal containing two crystal water molecules.
Description
The application is that application number is 201010245688.1, and the applying date is on August 1st, 2010, and what denomination of invention was " crystallization of quinoline and preparation method thereof " divides an application.
Technical field
The present invention relates to the crystallization of quinoline hydrochloride, the preparation method of described crystallization, containing the pharmaceutical composition of described crystallization and in the purposes of field of medicaments.
Background technology
Tyrosylprotein kinase is the enzyme of one group of catalytic proteins tyrosine residues phosphorylation, in intracellular signal transduction, play an important role, it participates in Normocellular adjusting, signal transmission and growth, also closely related with propagation, differentiation, migration and the apoptosis of tumour cell.Many receptor tyrosine kinases are all relevant to the formation of tumour, according to the difference of its extracellular domain structure, can be divided into EGF-R ELISA (EGFR), platelet derived growth factor acceptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor acceptor (FGFR) etc.
International Patent Application WO 2008112407 discloses compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl in embodiment 24] oxygen base] methyl] cyclopropylamine and preparation method thereof, its structural formula is suc as formula shown in II:
It is the receptor tyrosine kinase inhibitors of target spot more than, can suppress the kinase activities such as vascular endothelial growth factor receptor (VEGFR1, VEGFR2/KDR and VEGFR3), STEM CELL FACTOR acceptor, platelet-derived growth factor receptor, suppress the downstream signal transduction of VEGFR2 mediation, thereby suppress tumor angiogenesis.
The variation of medicinal compound crystal formation causes compound to have different fusing points, solubleness, water absorbability, stability, biological activity etc. conventionally, and these are all the important factors that affect 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 crystal formation has specific thermodynamic property and stability, therefore in the process of preparation, the crystal formation of understanding the compound of applying in each formulation is important, to guarantee the medicine of process application same modality.Therefore, guarantee that compound is single crystal formation or the known miscellany of some crystal formations is necessary.
When judging which kind of polymorphic form is preferred, much character and the preferred polymorphic form that must compare them make one's options based on many physical propertiess.Completely likely a kind of polymorphic in some aspects as the difficulty or ease, stability of preparation etc. to be considered under critical condition be preferred.In other cases, the solubleness that different polymorphic form may Yin Genggao or good pharmacokinetics and preferably.
The discovery of the new polymorphic form of medicinal compound provides the chance of improving medicine physical property, whole character of material have been expanded, therefore thereby can instruct better the research of compound and preparation thereof, the polymorphic form of quinoline hydrochloride provided by the invention has commercial value in the manufacture of medicine and other application.
Summary of the invention
The invention provides formula I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] three kinds of crystalline solid forms of 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 that does not basically contain crystal water and other solvent, uses Cu-K α radiation, and it,, 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 typically exists
there is diffraction peak at place.
Type B crystallization refers to the crystallization that does not basically contain crystal water and other solvent, uses Cu-K α radiation, and it,, 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 typically exists
there is diffraction peak at place.
The crystallization of C type is the crystallization containing two crystal water, uses Cu-K α radiation, and it is about apart from d value at crystal face in X-ray powder diffraction (XRD) collection of illustrative plates
there is diffraction peak at place, typically exists
there is diffraction peak at place, further typically exists
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 approximately 2 moles.
Another aspect of the present invention 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, the A type crystallization of composition Chinese style I compound accounts for the 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 that in said composition, can contain a small amount of formula I compound, include but not limited to Type B crystallization, the crystallization of C type or the amorphous article of formula I compound.
The crystal composition of Type B crystallization refers to, the Type B crystallization of the formula I compound in composition accounts for the 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 that in said composition, can contain a small amount of formula I compound, include but not limited to the crystallization of A type, the crystallization of C type or the amorphous article of formula I compound.
The crystal composition of C type crystallization refers to, the C type crystallization of the formula I compound in composition accounts for the 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 that in said composition, can contain a small amount of formula I compound, include but not limited to the crystallization of A type, Type B crystallization or the amorphous article of formula I compound.
Another aspect of the present invention has been to provide the preparation method of above-mentioned crystallization or crystal composition, the method comprises oxygen base-6-methoxy quinoline-7-yl by formula I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl)] oxygen base] methyl] crystallization under certain conditions of cyclopropylamine dihydrochloride, thus obtain above-mentioned three kinds of crystallizations or crystal composition.It should be noted that, in preparationⅠcompound crystallisation process, restriction due to crystallization condition, can not obtain substantially certain specific crystallization (for example A type crystallization) of pure formula I compound, in fact, under the condition of laboratory or suitability for industrialized production, tend to for example obtain take certain specific crystallization (for example A type crystallization), as main crystal composition, i.e. crystal composition of the present invention (crystal composition of A type crystallization).
Wherein, the method for the preparation of formula I compound described in can reference literature, or carry out as follows.Formula II compound is dissolved in the organic solvent of 1-20 times of weight, and the temperature of reaction solution is controlled at-15～120 ℃, and with the solution reaction of a certain amount of hydrogen chloride gas or hydrogenchloride, the solid of separating out is through dihydrochloride separated, that be drying to obtain 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 the solution with hydrogenchloride reacts, such as concentrated hydrochloric acid, hydrogenchloride alcohol saturated solution, the methanol solution of hydrogenchloride, the dichloromethane solution of the diethyl ether solution of hydrogenchloride or hydrogenchloride etc.Preferably, the solution of hydrogenchloride is slowly added drop-wise in reaction solution, after being added dropwise to complete, reaction mixture is remained on to-10～5 ℃, continue reaction 0.5～3 hour, until separate out solid, filter, in 50-90 ℃ of vacuum-drying, spend the night, obtain.
Wherein, formula II compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] preparation of the cyclopropylamine method described in can reference literature 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, and the formula I compound dissolution preparing according to the method described above, in methyl alcohol, optionally, can be heated, and obtains saturated or approaches the solution of the formula I compound of state of saturation.Then, solution is placed in to crystallization under low temperature.If gained crystallization, after 50-100 ℃ of vacuum-drying, then in 50-100 ℃ of normal pressure forced air drying, is obtained to the crystal composition of the crystallization of A type or the crystallization of A type of formula I compound; If gained crystallization, in 40 ℃ of-100 ℃ of normal pressure forced air dryings, is obtained to the crystal composition of the crystallization of C type or the crystallization of C type of formula I compound.
In mixed solvent method, can first formula I compound be dissolved in the water of 1-5 times of weight, by the aqueous solution under 0-100 ℃ of stirring, the methyl alcohol, ethanol or the acetone that slowly add 1-20 times of volume, finish and keep its state 30 minutes, optionally, by solution filter, filtrate is put-18～40 ℃ of standing crystallizatioies of environment, leaches crystallization.Or directly by formula I compound dissolution in the aqueous solution of methyl alcohol, ethanol or acetone, optionally, can heat and obtain saturated or approach the solution of saturated formula I compound, then, selectable, by solution filter, filtrate is put-18～40 ℃ of standing crystallizatioies of environment, leaches crystallization.
The crystallization of gained, after 50 ℃ of-100 ℃ of vacuum-dryings, then in 50 ℃ of-100 ℃ of normal pressure forced air dryings, obtains the A type crystallization of formula I compound, the crystal composition of crystal composition, Type B crystallization or the Type B crystallization of the crystallization of A type; If gained crystallization, in 40 ℃ of-100 ℃ of normal pressure forced air dryings, is obtained to the crystal composition of the crystallization of C type or the crystallization of C type of formula I compound.
Preferably, the preparation method of the crystal composition of the crystallization of A type or the crystallization of A type is: the methyl alcohol that formula I compound is dissolved in to 2-20 times of weight, in 60-95% aqueous ethanolic solution or 60-95% aqueous acetone solution, stirring heating 60-100 ℃ molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred under-18～4 ℃ of conditions and refrigerate and spend the night, separate out light yellow to off-white color crystalloid solid, suction filtration, filtrate is with after a small amount of cold methyl alcohol or 60-95% aqueous ethanolic solution or the washing of 60-95% aqueous acetone solution, filter cake is after 80-85 ℃ of vacuum-drying, in 80-85 ℃ 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 the crystal composition of the crystallization of C type or the crystallization of C type dry making under certain condition, in one embodiment of the invention, after drying conditions is 85 ℃ of vacuum-dryings, then in 90-100 ℃ of normal pressure forced air drying.
Preferably, the preparation method of the crystal composition of Type B crystallization or Type B crystallization is: formula I compound is dissolved in 3-20 times of weight 80-90% aqueous ethanolic solution or 60-70% aqueous acetone solution, stirring heating 60-100 ℃ molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred under-18～4 ℃ of conditions and refrigerate and spend the night, separate out light yellow to off-white color crystalloid solid, suction filtration, filtrate is with after a small amount of cold methyl alcohol or 80-90% aqueous ethanolic solution or the washing of 60-70% aqueous acetone solution, filter cake is after 80-85 ℃ of vacuum-drying, in 80-85 ℃ 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: the 50-99.9% methanol aqueous solution that formula I compound is dissolved in to 2-20 times of weight, in 60-95% aqueous ethanolic solution or 60-95% aqueous acetone solution, stirring heating 60-100 ℃ molten clear after, suction filtration while hot, filtrate is put to room temperature, be transferred under-18～4 ℃ of conditions and refrigerate and spend the night, separate out light yellow to off-white color crystalloid solid, suction filtration, filtrate is with after a small amount of cold methyl alcohol or 80-90% ethanol or the washing of 60-70% aqueous acetone solution, filter cake is in 40-55 ℃ 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 has been to provide the pharmaceutical composition of above-mentioned crystallization or crystal composition.
1-[[[4-of the present invention (the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] crystal composition of crystal composition, the crystallization of C type or the crystallization of C type of the A type crystallization of cyclopropylamine dihydrochloride (formula I compound) or crystal composition, Type B crystallization or the Type B crystallization of A type crystallization, be generically and collectively referred to as hereinafter " active substance of the present invention ".
Active substance of the present invention can be by the administration of any applicable treated disease, comprises by administrations such as oral, local (as oral cavity, hypogloeeis etc.), non-stomach and intestine (as in subcutaneous, muscle, intravenously, spinal cord, intracutaneous, sheath etc.), rectum, vaginas.Preferred administering mode is oral administration.
Although active substance of the present invention can be with the form administration of pure substance, conventionally 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 be used conventional pharmaceutical excipient well known in the art to make 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 also comprises tinting material, sweeting agent etc.
The consumption that is used for the unit formulation active substance of the present invention of oral Tablet and Capsula agent must change according to patient's treatment situation and concrete route of administration.For example, unit formulation for oral administration can contain for example active substance of 1mg～100mg easily, preferably comprises the active substance of 3mg～30mg.
Active substance of the present invention and pharmaceutical composition thereof have the activity that suppresses 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 being obtained by crystalline compounds is distinctive often for specific crystal formation, the advantage orientation effect that wherein relative intensity of bands of a spectrum (especially at low angle) 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, judge whether when identical with known crystal formation, to should be noted that the relative position at peak rather than their relative intensity.In XRD figure spectrum, conventionally with 2 θ angles or crystal face, apart from d, represent peak position, because 2 θ angles are relevant with the wavelength of incident X-rays, therefore with crystal face, apart from d, represent to have more representativeness.There is 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 compound of the same race, its XRD spectra has similarity on the whole, and the d value error that characterizes peak position is generally within ± 2%, and most of error is no more than ± 1%; Relative intensity error can be larger, but variation tendency is consistent.In addition, judge when whether crystal formation is the same and should note keeping organic conception, 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 evaluation of mixture, because degradation factor under content can cause the disappearance of part diffracted ray, now, without relying on whole bands of a spectrum of observing in high-purity sample, even several bands of a spectrum may be also distinctive to given crystallization.
DSC measures when crystallization is because its crystalline structure changes or crystal melting absorbs or transition temperature during rejected heat.Crystal formation of the same race for compound of the same race, in continuous analysis, thermal transition temperature and fusing point error are typically within approximately 5 ℃, conventionally within approximately 3 ℃, when we say that a compound has a given DSC peak or fusing point, this refers to this DSC peak or fusing point ± 5 ℃.DSC provides a kind of householder method of 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 fusing with decomposition, so 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
1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] preparation of cyclopropylamine dihydrochloride (formula I compound)
Method a:
In 2L reaction flask, add 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] cyclopropylamine (formula II compound) 80g, 800ml dehydrated alcohol, suspension is made in stirring, ice-water bath is cooling, temperature control is in below 10 ℃, in 15 minutes, drip fast self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reaction solution is by the suspension starting, become gradually clarification, be added dropwise to complete 3-5 minute, reaction solution is orange red settled solution, this solution is separated out rapidly a large amount of off-white color solids, at continuing to keep 10 ℃, react 1 hour, suction filtration, the a small amount of absolute ethanol washing of filter cake, 80 ℃ of vacuum-dryings are after 6 hours, obtain off-white color 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] cyclopropylamine dihydrochloride 86.2g, yield 91%.
Mp:240～255 ℃ (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:
In 1L reaction flask, add 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] cyclopropylamine 80g, 400ml methyl alcohol, suspension is made in stirring, ice-water bath is cooling, temperature control is in below 10 ℃, in 15 minutes, drip fast self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reaction solution is by the suspension starting, become gradually clarification, 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 solids, at continuing to keep 10 ℃, react 1 hour, suction filtration, filter cake washs with a small amount of cold methanol, 80 ℃ of vacuum-dryings are after 6 hours, obtain off-white color title compound 51.3g, yield 54%.
Method c:
In 2L reaction flask, add 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] cyclopropylamine 80g, in 1200mL90% aqueous acetone solution, suspension is made in stirring, ice-water bath is cooling, temperature control is in below 10 ℃, in 15 minutes, drip fast self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reaction solution is by the suspension starting, become gradually clarification, 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 solids, at continuing to keep 10 ℃, react 1 hour, suction filtration, filter cake washs with a small amount of cold methanol, 80 ℃ of vacuum-dryings are after 6 hours, obtain off-white color title compound 44.6g, yield 47%.
1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] preparation of cyclopropylamine dihydrochloride A type crystallization
Method a:
Get the formula I compound 20g that embodiment 1 prepares, methyl alcohol 100mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to 4 ℃ of refrigerations and spend the night, separate out light yellow crystalloid solid next day, suction filtration, with a small amount of cold methanol washing leaching cake, in 80-85 ℃ of vacuum-drying after 6 hours, in 85 ℃ of normal pressure forced air dryings 6 hours, obtain A type crystallization 16.8g, its XRD figure spectrum is as shown in Figure 1.
Method b:
Get the formula I compound 20g that embodiment 1 prepares, 90% aqueous ethanolic solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to 4 ℃ of refrigerations and spend the night, separate out off-white color crystalloid solid next day, suction filtration, with a small amount of absolute ethanol washing filter cake, in 80-85 ℃ of vacuum-drying after 6 hours, in 85 ℃ of normal pressure forced air dryings 6 hours, obtain A type crystallization 10.7g, its XRD figure spectrum is as shown in Figure 2.
Method c:
Get the formula I compound 20g that embodiment 1 prepares, 80% aqueous acetone solution 90mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to 4 ℃ of refrigerations and spend the night, separate out off-white color crystalloid solid next day, suction filtration, with a small amount of washing with acetone filter cake, in 80-85 ℃ of vacuum-drying after 6 hours, in 85 ℃ of normal pressure forced air dryings 6 hours, obtain A type crystallization 12.3g, its XRD figure spectrum is 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 basic identical on peak shape, peak position and peak intensity, determines that thus three samples are identical crystallization.The XRD figure spectrum of three samples difference slightly in some details may be that the difference due to the difference in sample preparation process and test causes.
1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] preparation of cyclopropylamine dihydrochloride Type B crystallization
Get the formula I compound 20g that embodiment 1 prepares, 70% aqueous acetone solution 100mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to 4 ℃ of refrigerations and spend the night, separate out off-white color crystalloid solid next day, suction filtration, with a small amount of washing with acetone filter cake, in 80-85 ℃ of vacuum-drying after 6 hours, in 85 ℃ of normal pressure forced air dryings 6 hours, obtain Type B crystallization 13.0g, its XRD figure spectrum is as shown in Figure 4.
1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] preparation of cyclopropylamine dihydrochloride C type crystallization
Method a:
Get the formula I compound 20g that embodiment 1 prepares, 90% aqueous ethanolic solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to-4 ℃ of refrigerations and spend the night, separate out off-white color crystalloid solid next day, suction filtration, with a small amount of absolute ethanol washing filter cake, in 45-50 ℃ 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:
Get the formula I compound 20g that embodiment 1 prepares, 95% methanol aqueous solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to-18 ℃ of refrigerations and spend the night, separate out light yellow crystalloid solid next day, suction filtration, with a small amount of cold methanol washing leaching cake, in 45-50 ℃ of normal pressure forced air drying 8 hours, obtain C type crystallization 7.3g.
Method c:
Get the formula I compound 20g that embodiment 1 prepares, 85% aqueous acetone solution 80mL, stirring heating refluxes, question response liquid molten clear after, insulation reaction 15 minutes, while hot suction filtration, obtain orange red filtrate, put to room temperature, be transferred to-18 ℃ of refrigerations and spend the night, separate out off-white color crystalloid solid next day, suction filtration, with a small amount of cold acetone washing leaching cake, in 45-50 ℃ of normal pressure forced air drying 8 hours, obtain C type crystallization 8.9g.
Get the C type crystallization 5.2g of the formula I compound that embodiment 4 method a prepare, in 85 ℃ of vacuum-dryings after 6 hours, then in 90-100 ℃ of normal pressure forced air drying 6 hours, obtain the A type crystallization 4.7g of off-white color formula I compound.
With reference to the method for the appendix XI X C Raw medicine influence factor test of Chinese Pharmacopoeia 2005 version (two), high temperature test and strong illumination test (4500 ± 500Lx) are carried out respectively in the A type crystallization of the formula I compound that the method a of embodiment 2 is prepared, the Type B crystallization that the method for embodiment 3 prepares, the C type crystallization preparing according to the method a of embodiment 4.Wherein, the condition of high temperature test is: 40 ℃ ± 2 ℃, and 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, preliminary influence factor test-results was as shown in table 1.
Table 1
Claims (10)
1. formula I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] crystallization of cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is about apart from d value at crystal face in X-ray powder diffraction
there is diffraction peak at place.
2. the crystallization of claim 1,
there is diffraction peak at place.
3. crystal composition, wherein claim 1 or 2 crystallization account for the more than 50% of crystal composition weight.
4. formula I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] crystallization of cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is about apart from d value at crystal face in X-ray powder diffraction
there is diffraction peak at place.
5. the crystallization of claim 4,
there is diffraction peak at place.
6. crystal composition, wherein claim 4 or 5 crystallization account for the more than 50% of crystal composition weight.
7. formula I compound 1-[[[4-(the fluoro-2-Methyl-1H-indole-5-of 4-yl) oxygen base-6-methoxy quinoline-7-yl] oxygen base] methyl] crystallization of cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is about apart from d value at crystal face in X-ray powder diffraction
there is diffraction peak at place.
8. the crystallization of claim 7, its
there is diffraction peak at place.
9. crystal composition, wherein claim 7 or 8 crystallization account for the more than 50% of crystal composition weight.
10. pharmaceutical composition, contains the crystallization described in claim 1,2,4,5,7 or 8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310722253.5A CN103664890B (en) | 2010-08-01 | 2010-08-01 | The crystallization of quinoline and preparation method |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010245688.1A CN102344438B (en) | 2010-08-01 | 2010-08-01 | Crystals of quinoline derivative and preparation methods thereof |
| CN201310722253.5A CN103664890B (en) | 2010-08-01 | 2010-08-01 | The crystallization of quinoline and preparation method |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010245688.1A Division CN102344438B (en) | 2010-08-01 | 2010-08-01 | Crystals of quinoline derivative and preparation methods thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664890A true CN103664890A (en) | 2014-03-26 |
| CN103664890B CN103664890B (en) | 2016-10-05 |
Family
ID=50303761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310722253.5A Active CN103664890B (en) | 2010-08-01 | 2010-08-01 | The crystallization of quinoline and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664890B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292580A (en) * | 2015-05-04 | 2019-10-01 | 杭州爱德程医药科技有限公司 | The method for being used to prepare anticancer agent AL3818, its crystal form and its salt |
| WO2020001406A1 (en) * | 2018-06-25 | 2020-01-02 | 正大天晴药业集团股份有限公司 | Crystal habit of quinoline derivative and preparation method for crystalline powder thereof |
| WO2020156501A1 (en) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | Crystals of quinolone derivatives |
| CN112294813A (en) * | 2019-07-30 | 2021-02-02 | 正大天晴药业集团股份有限公司 | Use of quinoline derivatives for the treatment of chordoma |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008112407A1 (en) * | 2007-03-14 | 2008-09-18 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
-
2010
- 2010-08-01 CN CN201310722253.5A patent/CN103664890B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008112407A1 (en) * | 2007-03-14 | 2008-09-18 | Advenchen Laboratories, Llc | Spiro substituted compounds as angiogenesis inhibitors |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292580A (en) * | 2015-05-04 | 2019-10-01 | 杭州爱德程医药科技有限公司 | The method for being used to prepare anticancer agent AL3818, its crystal form and its salt |
| CN110292580B (en) * | 2015-05-04 | 2023-08-04 | 杭州爱德程医药科技有限公司 | Process for preparing anticancer agent AL3818, crystalline form thereof and salt thereof |
| WO2020001406A1 (en) * | 2018-06-25 | 2020-01-02 | 正大天晴药业集团股份有限公司 | Crystal habit of quinoline derivative and preparation method for crystalline powder thereof |
| 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 |
| US11731955B2 (en) | 2018-06-25 | 2023-08-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Crystal habit of quinoline derivative and preparation method for crystalline powder thereof |
| WO2020156501A1 (en) * | 2019-01-31 | 2020-08-06 | 正大天晴药业集团股份有限公司 | Crystals of quinolone derivatives |
| CN112294813A (en) * | 2019-07-30 | 2021-02-02 | 正大天晴药业集团股份有限公司 | Use of quinoline derivatives for the treatment of chordoma |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664890B (en) | 2016-10-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102344438B (en) | Crystals of quinoline derivative and preparation methods thereof | |
| ES2904646T3 (en) | Pharmaceutical compositions modulating c-Met | |
| CN101868465B (en) | Solid forms comprising N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, compositions thereof, and uses therewith | |
| JP6971390B2 (en) | Crystal form, manufacturing method and use of deuterated AZD9291 | |
| WO2017016463A1 (en) | Egfr inhibitor and pharmaceutically acceptable salt and polymorph thereof, and use thereof | |
| KR20220008273A (en) | N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2 (trifluoromethyl)isonicotine as RAF inhibitor for the treatment of cancer New crystalline form of amide | |
| CN101821255A (en) | 2-morpholin-4-yl-pyrimidines as PI3K inhibitors | |
| JP6717947B2 (en) | Crystals of quinazoline derivative and preparation method thereof | |
| CN102070618B (en) | Compound and crystals thereof | |
| CN104284897B (en) | Brilliant type of ADZ6140 and its production and use | |
| JP5460689B2 (en) | Polymorphs of 4-phenylaminoquinazoline derivatives, methods for their preparation and uses thereof | |
| US7166722B2 (en) | N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n′-(5-methyl-3-isoxazolyl)urea salt in crystalline form | |
| CN103664890A (en) | Crystal of quinoline derivative and preparation method of crystal | |
| KR20240000540A (en) | (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3- Solid state forms of (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof | |
| WO2020061996A1 (en) | Novel crystal forms of deuterated azd9291 compound and use thereof | |
| CN104341343B (en) | Crystal form of betrixaban and its preparation method and application | |
| CN109748904A (en) | The crystallization of quinoline | |
| JP7036798B2 (en) | Quinazoline derivative salt crystals | |
| JP2020526593A (en) | Crystal form, salt form and production method of N-phenyl-2-aminopyrimidine compounds | |
| WO2017107986A1 (en) | Crystals of quinazoline derivative and preparation method therefor | |
| CN102558159A (en) | 4-subsittution m sulfonylurea amide aniline-quinazoline derivate and preparation method and application thereof | |
| WO2019149090A1 (en) | Crystal form of urate transporter 1 inhibitor and preparation method and use thereof | |
| CN106995452B (en) | Double target spot inhibitor of a kind of thieno [3,2 d] miazines EGFR/ErbB2 and its production and use | |
| CN111630045A (en) | Crystal of quinoline derivative | |
| TW201829398A (en) | Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: 222062 Lianyungang, Jiangsu Province, Yu Road, Haizhou District No. 369 Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. |