CN103664890B - The crystallization of quinoline and preparation method - Google Patents
The crystallization of quinoline and preparation method Download PDFInfo
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- CN103664890B CN103664890B CN201310722253.5A CN201310722253A CN103664890B CN 103664890 B CN103664890 B CN 103664890B CN 201310722253 A CN201310722253 A CN 201310722253A CN 103664890 B CN103664890 B CN 103664890B
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 133
- 230000008025 crystallization Effects 0.000 title claims abstract description 133
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 57
- 239000013078 crystal Substances 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 52
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- 238000001914 filtration Methods 0.000 claims description 25
- 238000007605 air drying Methods 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 17
- 150000002118 epoxides Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- 238000001228 spectrum Methods 0.000 claims description 11
- 229910017488 Cu K Inorganic materials 0.000 claims description 9
- 229910017541 Cu-K Inorganic materials 0.000 claims description 9
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- 230000005855 radiation Effects 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 8
- QJBXPIZGUYIVKB-UHFFFAOYSA-N cyclopropanamine;dihydrochloride Chemical compound Cl.Cl.NC1CC1 QJBXPIZGUYIVKB-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
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- 239000002904 solvent Substances 0.000 abstract description 6
- BTUQCUPQFZHMNS-UHFFFAOYSA-N quinoline;dihydrochloride Chemical compound Cl.Cl.N1=CC=CC2=CC=CC=C21 BTUQCUPQFZHMNS-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 28
- 238000000034 method Methods 0.000 description 26
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- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
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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 present invention relates to crystallization and preparation method, the pharmaceutical composition containing described crystallization and the purposes at field of medicaments of quinoline, three kinds of crystalline solid forms more particularly to quinoline dihydrochloride, it is respectively the crystallization of A type, Type B crystallization and c-type crystallization, wherein A and Type B crystallization are this upper crystallization not containing water of crystallization and other solvent, and c-type crystallization is the crystallization containing two water of crystallization.
Description
The application is Application No. 201010245688.1, filing date on August 1st, 2010, and invention entitled " quinoline spreads out
Biological crystallization and preparation method thereof " divisional application.
Technical field
The present invention relates to the crystallization of quinoline hydrochlorate, the preparation method of described crystallization, medicine containing described crystallization
Compositions and in the purposes of field of medicaments.
Background technology
Tyrosine kinase is the enzyme of one group of catalytic proteins tyrosine residue phosphorylation, rises in intracellular signal transduction
Important effect, it participates in Normocellular regulation, signal transmission and grows, also with the propagation of tumor cell, break up, migrate
Closely related with apoptosis.Many receptor tyrosine kinases are all relevant to the formation of tumor, according to its extracellular space structure not
With being divided into EGF-R ELISA (EGFR), PDGF recepter (PDGFR), vascular endothelial cell growth
Factor acceptor (VEGFR), fibroblast growth factor acceptor (FGFR) etc..
International patent application WO2008112407 disclose in embodiment 24 compound 1-[[[4-(4-fluoro-2-methyl-
1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl] cyclopropylamine and preparation method thereof, its structural formula is such as
Shown in formula II:
It is the receptor tyrosine kinase inhibitors of a Mutiple Targets, can suppress vascular endothelial growth factor receptor
The kinase activity such as (VEGFR1, VEGFR2/KDR and VEGFR3), stem cell factor receptor, platelet-derived growth factor receptor, presses down
The downstream signal transduction of VEGFR2 processed mediation, thus suppress tumor angiogenesis.
The change of medicinal compound crystal formation typically results in compound and has different fusing point, dissolubility, hygroscopicity, stable
Property, biological activity etc., these are all to affect difficulty or ease, storage stability, preparation difficulty or ease and bioavailability etc. prepared by medicine
Key factor.When compound exists polymorphic, owing to specific polymorphic form has specific macroscopic property with steady
Qualitative, therefore during preparation, it is important for understanding the crystal formation of the compound of application in each dosage form, to ensure to produce
The medicine of process application same modality.Thus it is guaranteed that compound is single crystal formation or the known mixture of some crystal formations is
Necessary.
When judging which kind of polymorph is preferred, it is necessary to compare their many character and preferred polymorphic
Thing makes one's options based on many physical propertys.Entirely possible is a kind of polymorphic in some aspects as preparation difficulty or ease,
Stability etc. be considered as critical under the conditions of be preferred.In other cases, different polymorphs may Yin Genggao
Dissolubility or excellent pharmacokinetics and preferred.
The discovery of the new polymorph of medicinal compound provides the chance improving medicine physical characteristic, i.e. extends thing
Whole character of matter, such that it is able to preferably instruct the research of compound and preparation thereof, the quinoline derivatives that therefore present invention provides
The polymorph of thing hydrochlorate is commercially valuable in the manufacture and other application of medicine.
Summary of the invention
The invention provides type I compound 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxyl group quinoline
Quinoline-7-base] epoxide] methyl] three kinds of crystalline solid forms of cyclopropylamine dihydrochloride, the crystallization of respectively A type, Type B crystallization and c-type
Crystallization.
Wherein the crystallization of A type refers to be substantially free of the crystallization of water of crystallization and other solvent, uses Cu-K α radiation, and it is penetrated at X-
In line powder diffraction (XRD) collection of illustrative plates, it is about away from d value at crystal face There is diffraction maximum at place, typically exists There is diffraction maximum at place, the most typically exists There is diffraction maximum at place.
Type B crystallization refers to be substantially free of the crystallization of water of crystallization and other solvent, uses Cu-K α radiation, and it is in X-ray
In powder diffraction (XRD) collection of illustrative plates, it is about away from d value at crystal facePlace has
Diffraction maximum, typically exists
There is diffraction maximum at place, the most typically exists There is diffraction maximum at place.
C-type crystallization is the crystallization containing two water of crystallization, uses Cu-K α radiation, and it is at X-ray powder diffraction (XRD) collection of illustrative plates
In, it is about away from d value at crystal faceThere is diffraction maximum at place, typically existsThere is diffraction at place
Peak, the most typically exists There is diffraction maximum at place.Its thermogravimetric analysis (TGA) collection of illustrative plates (Fig. 8) understands, and weight is lost
It is 7%, the water of about 2 moles.
Another aspect of the invention provides the crystallization of above-mentioned A type, Type B crystallization or the crystal composition of c-type crystallization.Wherein A
The crystal composition of type crystallization refers to, in compositions, the A type crystallization of type I compound accounts for more than the 50% of composition weight, preferably
More than 70%, more preferably more than 90%, most preferably more than 95%, can be containing a small amount of type I compound in said composition
Other crystallization or amorphous article, include but not limited to the Type B crystallization of type I compound, c-type crystallization or amorphous article.
The crystal composition of Type B crystallization refers to, the Type B crystallization of the type I compound in compositions accounts for composition weight
More than 50%, preferably more than 70%, more preferably more than 90%, most preferably more than 95%, can be containing few in said composition
Other crystallization or amorphous article of amount type I compound, includes but not limited to that the A type crystallization of type I compound, c-type crystallization or nothing are fixed
Type thing.
The crystal composition of c-type crystallization refers to, the c-type crystallization of the type I compound in compositions accounts for composition weight
More than 50%, preferably more than 70%, more preferably more than 90%, most preferably more than 95%, can be containing few in said composition
Other crystallization or amorphous article of amount type I compound, includes but not limited to that the A type crystallization of type I compound, Type B crystallization or nothing are fixed
Type thing.
Another aspect of the invention there are provided the preparation method of above-mentioned crystallization or crystal composition, and the method includes
By type I compound 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl]
Cyclopropylamine dihydrochloride crystallizes under certain conditions, thus obtains above-mentioned three kinds of crystallizations or crystal composition.Need explanation
It is, during preparing formula I compound crystal, due to the restriction of crystallization condition, can not obtain the purest formula I chemical combination
The specific crystallization of certain of thing (crystallization of such as A type), it is true that under the condition of laboratory or industrialized production, often
Crystal composition (such as A type knot to the crystal composition based on certain specific crystallization (crystallization of such as A type), the i.e. present invention
Brilliant crystal composition).
Wherein, the preparation of type I compound can refer to the method described in document, or carries out as follows.By formula
II compound is dissolved in the organic solvent of 1-20 times of weight, and the temperature of reactant liquor controls at-15～120 DEG C, with a certain amount of
Hydrogen chloride gas or the solution reaction of hydrogen chloride, the solid of precipitation is separated, be drying to obtain the dihydrochloride of formula II compound.Its
In, described organic solvent include ethyl acetate, ether, oxolane, isopropanol, diisopropyl ether, dichloromethane, chloroform,
Carbon tetrachloride, DMF, DMSO, benzene, toluene, methanol, ethanol, acetone etc., preferably methanol, ethanol, acetone.Hydrogen chloride and formula II
The mol ratio of compound is preferably 2～10:1, is more preferably 3:1.For the ease of controlling the amount of hydrogen chloride, preferably molten with hydrogen chloride
Liquid reacts, such as concentrated hydrochloric acid, ethanolic hydrogen chloride saturated solution, the methanol solution of hydrogen chloride, the diethyl ether solution of hydrogen chloride or
The dichloromethane solution etc. of hydrogen chloride.Preferably, the solution of hydrogen chloride is slowly dropped in reactant liquor, after being added dropwise to complete, will
Reactant mixture is maintained at-10～5 DEG C, continues reaction 0.5～3 hour, until separating out solid, filters, in 50-90 DEG C of vacuum
It is dried overnight, to obtain final product.
Wherein, formula II compound 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-
Base] epoxide] methyl] preparation of cyclopropylamine can refer to the method described in document and carries out.
The preparation of crystallization of the present invention or crystal composition can use single-solvent process or mixed solvent method.Wherein
In single-solvent process, methanol is good solvent, the type I compound prepared according to the method described above is dissolved in methanol, depending on needing
Want, can heat, obtain the saturated or solution of type I compound close to saturation.Then, solution is placed under low temperature
Crystallization.If being crystallized by gained after being vacuum dried in 50-100 DEG C, then at 50-100 DEG C of normal pressure forced air drying, obtain formula I chemical combination
The A type crystallization of thing or the crystal composition of A type crystallization；If being crystallized by gained in 40 DEG C-100 DEG C normal pressure forced air dryings, obtain formula
The c-type crystallization of I compound or the crystal composition of c-type crystallization.
In mixed solvent method, first type I compound can be dissolved in the water of 1-5 times of weight, aqueous solution is stirred at 0-100 DEG C
Mix down, be slowly added to the methanol of 1-20 times of volume, ethanol or acetone, finish its state of holding 30 minutes, optionally, by molten
Liquid filters, and filtrate is put-18～40 DEG C of environment and stood crystallize, leaches crystallization.Or directly type I compound is dissolved in methanol, second
In the aqueous solution of alcohol or acetone, optionally, can carry out heating and obtain saturated or close to saturated type I compound solution,
Then, selectable, solution to be filtered, filtrate is put-18～40 DEG C of environment and is stood crystallize, leaches crystallization.
After the crystallization of gained is vacuum dried in 50 DEG C-100 DEG C, then at 50 DEG C-100 DEG C normal pressure forced air dryings, obtain formula I
The A type crystallization of compound, the crystal composition of A type crystallization, Type B crystallization or the crystal composition of Type B crystallization；If gained is crystallized
In 40 DEG C-100 DEG C normal pressure forced air dryings, obtain c-type crystallization or the crystal composition of c-type crystallization of type I compound.
Preferably, the preparation method of the crystal composition of the crystallization of A type or the crystallization of A type is: type I compound is dissolved in 2-20
In times methanol of weight, 60-95% ethanol water or 60-95% aqueous acetone solution, agitating heating 60-100 DEG C is molten clearly
After, sucking filtration while hot, filtrate puts to room temperature, refrigerated overnight under the conditions of being transferred to-18～4 DEG C, separates out and light yellow ties to off-white color
Crystalline solid, sucking filtration, filtrate is washed with the coldest methanol or 60-95% ethanol water or 60-95% aqueous acetone solution
After, after filter cake is vacuum dried in 80-85 DEG C, in 80-85 DEG C of normal pressure forced air drying, to obtain final product.
The preparation method of the crystal composition of the crystallization of A type or the crystallization of A type also includes c-type crystallization or the crystallization of c-type crystallization
Compositions is dried under certain condition and prepares, in one embodiment of the invention, after drying condition is 85 DEG C of vacuum drying, 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 is dissolved in 3-20
In times weight 80-90% ethanol water or 60-70% aqueous acetone solution, agitating heating 60-100 DEG C molten clear after, take out while hot
Filtering, filtrate is put to room temperature, and refrigerated overnight under the conditions of being transferred to-18～4 DEG C separates out light yellow to off-white color crystalline solid,
Sucking filtration, filtrate with after the coldest methanol or 80-90% ethanol water or the washing of 60-70% aqueous acetone solution, filter cake in
After 80-85 DEG C of vacuum drying, in 80-85 DEG C of normal pressure forced air drying, to obtain final product.
Preferably, the preparation method of the crystal composition of c-type crystallization or c-type crystallization is: type I compound is dissolved in 2-20
In times 50-99.9% methanol aqueous solution of weight, 60-95% ethanol water or 60-95% aqueous acetone solution, agitating heating
60-100 DEG C molten clear after, sucking filtration while hot, filtrate puts to room temperature, refrigerated overnight under the conditions of being transferred to-18～4 DEG C, separates out shallow
Yellow uses the coldest methanol or 80-90% ethanol or 60-70% acetone water to off-white color crystalline solid, sucking filtration, filtrate
After solution washing, filter cake, in 40-55 DEG C of normal pressure forced air drying, to obtain final product.
Using Cu-K α radiation, as shown in Figure 1, it has the feature that the spectrogram of the typical XRD of A type crystallization
Using Cu-K α radiation, as shown in Figure 4, it has the feature that the spectrogram of the typical XRD of Type B crystallization
Using Cu-K α radiation, as shown in Figure 5, it has the feature that 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.
1-of the present invention [[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base]
Epoxide] methyl] cyclopropylamine dihydrochloride (type I compound) A type crystallization or A type crystallization crystal composition, Type B crystallization or B
The crystal composition of type crystallization, c-type crystallization or the crystal composition of c-type crystallization, collectively referenced hereinafter as " active matter of the present invention
Matter ".
Active substance of the present invention can be by the administration of any applicable treated disease, including by oral, locally
The approach such as (such as oral cavity, Sublingual etc.), parenteral (as in subcutaneous, muscle, intravenous, spinal cord, Intradermal, sheath etc.), rectum, vagina is given
Medicine.Preferably administering mode is oral administration.
Although active substance of the present invention can be administered with the form of pure material, but generally gives with the form of pharmaceutical composition
Medicine.The pharmaceutical composition of active substance of the present invention also comprises one or more pharmaceutic adjuvants, optionally, also can comprise other treatment
Active component.Can also be with chemotherapy, radiotherapy, these therapy administering drug combinations of surgical operation.
It is suitable for oral pharmaceutical composition and includes tablet, capsule, powder, granule, drop pill, paste, powder, tincture
Deng, preferred tablet and capsule.Wherein tablet can be conventional tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric
Sheet, capsule can be conventional capsule, slow releasing capsule, controlled release capsule or enteric coated capsule.
The pharmaceutical composition of the present invention can use conventional pharmaceutical adjuvants well known in the art to be prepared by conventional method.Conventional
Pharmaceutic adjuvant include filler, absorbent, wetting agent, binding agent, disintegrating agent, lubricant etc..Filler includes starch, breast
Sugar, mannitol, microcrystalline Cellulose etc.；Absorbent includes calcium sulfate, calcium hydrogen phosphate, calcium carbonate, magnesium oxide etc.；Wetting agent includes
Water, ethanol etc.；Binding agent includes hypromellose, polyvidone, microcrystalline Cellulose etc.；Disintegrating agent includes cross-linked carboxymethyl fiber
Element sodium, polyvinylpolypyrrolidone, surfactant, low-substituted hydroxypropyl cellulose etc.；Lubricant includes magnesium stearate, Pulvis Talci, gathers
Ethylene glycol, Stepanol MG, micropowder silica gel, Pulvis Talci etc..Pharmaceutic adjuvant also includes coloring agent, sweeting agent etc..
In the unit formulation of tablet for oral administration and capsule, the consumption of active substance of the present invention must be according to patient's
Treatment situation and concrete route of administration change.Such as, unit formulation for oral administration can contain easily such as 1mg～
The active substance of 100mg, preferably comprises the active substance of 3mg～30mg.
Active substance of the present invention and pharmaceutical composition thereof have the activity of suppression receptor tyrosine kinase, can be used for treatment swollen
Tumor, such as hepatocarcinoma, renal carcinoma, colon cancer or gastrointestinal stromal tumor etc..
It should be noted that in XRD, crystalline compounds the diffraction spectrogram obtained is for specific crystal formation spy often
Levying property, wherein the relative intensity of bands of a spectrum (especially at low angle) may be because of crystallization condition, particle diameter and other mensuration bar
The difference of part and the advantage orientation effect that produces and change.Therefore, targeted crystal formation is not by the relative intensity of diffraction maximum
Distinctive, it may be judged whether time identical with known crystal formation, should be noted that relative position rather than their phase at peak
To intensity.Generally peak position is represented with 2 θ angles or crystal face away from d, owing to the wavelength at 2 θ angles with incident X-rays has in XRD figure is composed
Close, therefore represent away from d with crystal face and have more representativeness.There is simple conversion relation: d=λ/2sin θ, wherein d between the two
Represent crystal face away from, λ represent incident X-rays wavelength (for Cu-Ka,), θ is the angle of diffraction.For chemical combination of the same race
The crystal formation of the same race of thing, its XRD spectra has similarity on the whole, characterizes the d value error of peak position typically within ± 2%,
Major part error is less than ± 1%；Relative intensity error can be relatively big, but variation tendency is consistent.It addition, as judging that crystal formation is whether
Time it should be noted that keep organic conception because being 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, owing under content, degradation factor can cause part
The disappearance of diffracted ray, now, it is not necessary to rely on the whole bands of a spectrum observed in high-purity sample, even several bands of a spectrum are likely to given
Crystallization be distinctive.
DSC measures when crystallization owing to its crystal structure changes or crystal melt and transformation temperature when absorbing or discharge heat
Degree.For the crystal formation of the same race of same compound, in continuous print is analyzed, thermal transition temperature and fusing point error are typically at about 5 DEG C
Within, generally 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 different according to it
Transition temperature feature and identified.It is to be noted for mixture, its DSC peak or fusing point may be bigger
In the range of change.Additionally, due to decomposition during material melts, therefore fusion temperature phase close with heating rate
Close.
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
Detailed description of the invention
Embodiment 1
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl] ring
The preparation of propylamine dihydrochloride (type I compound)
Method a:
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-is added in 2L reaction bulb
Base] epoxide] methyl] cyclopropylamine (formula II compound) 80g, 800ml dehydrated alcohol, suspension, ice-water bath cooling, control are made in stirring
Temperature in less than 10 DEG C, in 15 minutes fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reactant liquor by
Suspension, gradually becomes clarification, is added dropwise to complete 3-5 minute, and reactant liquor is orange red settled solution, and this solution separates out rapidly greatly
Amount off-white color solid, reacts 1 hour at continuing to keep 10 DEG C, sucking filtration, a small amount of absolute ethanol washing of filter cake, 80 DEG C of vacuum drying
After 6 hours, obtain off-white color 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide]
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 ,-CH2-CH2-),1.23(2H,-CH2-CH2-),2.50(3H,-
CH3),4.08(3H,-OCH3),4.43(2H,-OCH2-),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,-NH3 +), 11.66 (1H ,-NH-), 16.62 (1H,
HCl)。
Method b:
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-is added in 1L reaction bulb
Base] epoxide] methyl] cyclopropylamine 80g, 400ml methanol, stirring makes suspension, and ice-water bath cools down, temperature control in less than 10 DEG C, 15
In minute fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reactant liquor by suspension, gradually become
Clarification, be added dropwise to complete 3-5 minute, reactant liquor is orange red settled solution, after this solution separate out rapidly a large amount of off-white color solid,
Reacting 1 hour at continuing to keep 10 DEG C, sucking filtration, filter cake washs with a small amount of cold methanol, after 80 DEG C are vacuum dried 6 hours, obtains class white
Color title compound 51.3g, yield 54%.
Method c:
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-is added in 2L reaction bulb
Base] epoxide] methyl] cyclopropylamine 80g, in 1200mL90% aqueous acetone solution, suspension is made in stirring, and ice-water bath cools down, temperature control in
Less than 10 DEG C, in 15 minutes fast drop self-control saturated (10%) ethanol solution of hydrogen chloride 200mL, reactant liquor by suspendible
State, gradually becomes clarification, is added dropwise to complete 3-5 minute, and reactant liquor is orange red settled solution, after this solution separate out rapidly in a large number
Off-white color solid, reacts 1 hour at continuing to keep 10 DEG C, sucking filtration, and filter cake washs with a small amount of cold methanol, and 80 DEG C of vacuum drying 6 are little
Shi Hou, obtains off-white color title compound 44.6g, yield 47%.
Embodiment 2
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl] ring
The preparation of propylamine dihydrochloride A type crystallization
Method a:
Type I compound 20g that Example 1 prepares, methanol 100mL, agitating heating refluxes, and question response liquid is molten clearly
After, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, next day separates out shallow
Yellow crystalline solid, sucking filtration, washs filter cake with a small amount of cold methanol, after 80-85 DEG C of vacuum drying 6 hours, in 85 DEG C of normal pressures
Forced air drying 6 hours, obtains A type crystallization 16.8g, and its XRD figure is composed as shown in Figure 1.
Method b:
Type I compound 20g that Example 1 prepares, 90% ethanol water 80mL, agitating heating refluxes, and treats anti-
Answer liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, secondary
Day precipitation off-white color crystalline solid, sucking filtration, with a small amount of absolute ethanol washing filter cake, after 80-85 DEG C of vacuum drying 6 hours,
In 85 DEG C of normal pressure forced air dryings 6 hours, obtaining A type crystallization 10.7g, its XRD figure is composed as shown in Figure 2.
Method c:
Type I compound 20g that Example 1 prepares, 80% aqueous acetone solution 90mL, agitating heating refluxes, question response
Liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, next day
Separating out off-white color crystalline solid, sucking filtration, with a small amount of washing with acetone filter cake, after 80-85 DEG C of vacuum drying 6 hours, in 85 DEG C
Normal pressure forced air drying 6 hours, obtains A type crystallization 12.3g, and its XRD figure is composed as shown in Figure 3.
The crystallization that relatively in the present embodiment, method a, b and c prepare, the XRD figure of three samples is composed in peak shape, peak position
Essentially identical with on peak intensity, thereby determine that three samples are identical crystallization.The XRD figure of three samples is composed in some details
Slightly difference, it may be possible to caused by the difference of the difference in Sample Preparation Procedure and test.
Embodiment 3
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl] ring
The preparation of propylamine dihydrochloride Type B crystallization
Type I compound 20g that Example 1 prepares, 70% aqueous acetone solution 100mL, agitating heating refluxes, and treats anti-
Answer liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to 4 DEG C of refrigerated overnight, secondary
Separating out off-white color crystalline solid day, sucking filtration, with a small amount of washing with acetone filter cake, after 80-85 DEG C of vacuum drying 6 hours, in 85
DEG C normal pressure forced air drying 6 hours, obtains Type B crystallization 13.0g, and its XRD figure is composed as shown in Figure 4.
Embodiment 4
1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide] methyl] ring
The preparation of propylamine dihydrochloride c-type crystallization
Method a:
Type I compound 20g that Example 1 prepares, 90% ethanol water 80mL, agitating heating refluxes, and treats anti-
Answer liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-4 DEG C of refrigerated overnight,
Separating out off-white color crystalline solid next day, sucking filtration, with a small amount of absolute ethanol washing filter cake, in 45-50 DEG C of normal pressure forced air drying 8
Hour, obtaining c-type crystallization 8.6g, its XRD figure is composed as shown in Figure 5.
Method b:
Type I compound 20g that Example 1 prepares, 95% methanol aqueous solution 80mL, agitating heating refluxes, and treats anti-
Answer liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-18 DEG C of cold preservations
At night, separate out light yellow crystals solid, sucking filtration next day, wash filter cake with a small amount of cold methanol, in 45-50 DEG C of normal pressure forced air drying 8
Hour, obtain c-type crystallization 7.3g.
Method c:
Type I compound 20g that Example 1 prepares, 85% aqueous acetone solution 80mL, agitating heating refluxes, and treats anti-
Answer liquid molten clear after, insulation reaction 15 minutes, sucking filtration while hot, obtain orange red filtrate, put to room temperature, be transferred to-18 DEG C of cold preservations
At night, separate out off-white color crystalline solid, sucking filtration next day, wash filter cake with a small amount of cold acetone, in 45-50 DEG C of normal pressure forced air drying 8
Hour, obtain c-type crystallization 8.9g.
Embodiment 5 is crystallized by c-type prepares the crystallization of A type
The c-type crystallization 5.2g of the type I compound that Example 4 method a prepares, after 85 DEG C of vacuum drying 6 hours,
Then at 90-100 DEG C of normal pressure forced air drying 6 hours, obtain the A type crystallization 4.7g of off-white color type I compound.
Embodiment 6 stability test
With reference to the method for crude drug influence factor test in annex Ⅺ Ⅹ C of China's coastal port (two), will be real
Execute the A type crystallization of the type I compound that method a of example 2 prepares, Type B crystallization that the method for embodiment 3 prepares, according to
The c-type crystallization that method a of embodiment 4 prepares carries out hot test and strong illumination test (4500 ± 500Lx) respectively.Its
In, the condition of hot test is: 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%.The investigation time is 10 days, respectively at the 0th day,
10 days sampling checked for impurities total amounts, to investigate its stability, primary contributions factorial experiments result is as shown in table 1.
Table 1
Claims (10)
1. type I compound 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide]
Methyl] crystallization of cyclopropylamine dihydrochloride,
It is characterized in that using Cu-K α radiation, it is in X-ray powder diffraction spectrum, be about 7.48 at the 2 θ number of degrees, 8.48,
9.92, there is diffraction maximum at 14.24,18.34,19.04,19.86,22.02,22.60,24.26,25.32,27.06,29.56.
2. type I compound 1-[[[4-(4-fluoro-2-Methyl-1H-indole-5-base) epoxide-6-methoxy quinoline-7-base] epoxide]
Methyl] crystallization of cyclopropylamine dihydrochloride,
Using Cu-K α radiation, its X-ray powder diffraction spectrum has the feature that
3. crystal composition, wherein the crystallization described in claim 1 or 2 accounts for more than the 50% of crystal composition weight.
4. crystal composition, wherein the crystallization described in claim 1 or 2 accounts for more than the 70% of crystal composition weight.
5. crystal composition, wherein the crystallization described in claim 1 or 2 accounts for more than the 90% of crystal composition weight.
6. crystal composition, wherein the crystallization described in claim 1 or 2 accounts for more than the 95% of crystal composition weight.
7. the preparation method of the crystallization described in claim 1 or 2 or the crystal composition described in any one of claim 3-6 is:
Type I compound is dissolved in the methanol of 2-20 times of weight, 60-95% ethanol water or 60-95% aqueous acetone solution, stirs
Mix heating 60-100 DEG C molten clear after, sucking filtration while hot, filtrate puts to room temperature, refrigerated overnight under the conditions of being transferred to-18～4 DEG C,
Separate out light yellow to off-white color crystalline solid, sucking filtration, filtrate with the coldest methanol or 60-95% ethanol water or
After the washing of 60-95% aqueous acetone solution, after filter cake is vacuum dried in 80-85 DEG C, in 80-85 DEG C of normal pressure forced air drying, i.e.
?.
8. the preparation method of the crystallization described in claim 1 or 2 or the crystal composition described in any one of claim 3-6 is:
Being dried under certain condition by the crystal composition of c-type crystallization or c-type crystallization and prepare, described drying condition is that 85 DEG C of vacuum are done
After dry, then at 90-100 DEG C of normal pressure forced air drying, wherein said c-type crystallization, it is characterised in that use Cu-K α radiation, its
In X-ray powder diffraction spectrum, the 2 θ number of degrees about 5.38,6.38,6.92,11.70,14.42,14.98,16.24,17.56,
18.10, there is diffraction maximum at 20.44,21.56,23.80,24.24,25.28,25.70,26.44.
9. pharmaceutical composition, containing the crystallization described in claim 1 or 2.
10. the application in the medicine of preparation suppression receptor tyrosine kinase activity of the crystallization described in claim 1 or 2.
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