CN106749222A - Crystal formation A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes - Google Patents
Crystal formation A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes Download PDFInfo
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- CN106749222A CN106749222A CN201611162373.4A CN201611162373A CN106749222A CN 106749222 A CN106749222 A CN 106749222A CN 201611162373 A CN201611162373 A CN 201611162373A CN 106749222 A CN106749222 A CN 106749222A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses one kind Chinese mugwort Saperconazole crystal formation A, using Cu K α radiations, its X ray powder diffraction is obtained, represent that it has following diffraction maximum with 2 θ angles：9.9,13.4,17.5,17.9,20.9,22.0,22.7,25.1,27.3,29.3 and 31.4.Additionally, also disclosing the preparation method of the crystal formation, pharmaceutical composition and purposes.The preparation method of Chinese mugwort Saperconazole crystal formation A of the present invention is simple, process stabilizing, excellent yield, purity are good more than 98.5%, product stability, to temperature and humidity without particular/special requirement, is adapted to preparation technical process and is easy to long term storage and industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, and in particular to a kind of crystal formation A of Chinese mugwort Saperconazole and preparation method thereof and
Pharmaceutical composition, purposes with the compound as active component.
Background technology
In pharmaceutical composition is researched and developed, the crystal habit of pharmaceutical activity molecule is particularly significant for pharmaceutical preparation, activity point
The crystal formation of son directly affects physicochemical property (such as solubility), stability, Clinical efficacy (bioavilability) and the peace of medicine
Quan Xing.Therefore, should as far as possible provide that a kind of stability of crystal form is high, convenient for production when pharmaceutical business metaplasia is produced, can pharmaceutically connect
The bioactive molecule received.
Chinese mugwort Saperconazole, Chinese chemical name：4- [2- [(1R, 2R) -2- (2,5- difluorophenyls) -2- hydroxyl -1- methyl -3-
(1H-1,2,4- triazol-1-yls) propyl group] -4- thiazolyls] benzonitrile；English name：Isavuconazole, No. CAS：241479-
67-4；Molecular formula：C22H17F2N5OS；Molecular weight：437.47, it is the derivative containing triazole and thiazole, its structural formula is as follows：
Chinese mugwort Saperconazole is its prodrug Chinese mugwort Saperconazole sulfuric ester (No. CAS：Bioactive molecule 946075-13-4), the latter is by auspicious
Scholar's Bath rel (Basilea) and Japanese Astellas company (Astellas) are developed jointly, and are eaten by the U.S. in March, 2015
Product Drug Administration (FDA) ratifies the disease for treating aggressive mucor or aspergillin infection, meanwhile, the medicine in
In October, 2015 is ratified to list in European Union.The medicine is made by suppressing the demethylation of 14 α-sterol that fungal cytochrome P450 is mediated
With, so suppress fungal cell membrane ergosterol biosynthesis, promote ergosterol to lack, opposite toxicity intermediate product wool
Sterol increases, and ultimately results in permeability of cell membrane enhancing and growth inhibition.Its pharmacokinetics shows that end Saperconazole clearance rate
Low, long half time, distribution volume are big, central penetrating good, possess the good quality of antifungal；From antibacterial activity,
Chinese mugwort Saperconazole is demonstrated by very strong activity to Aspergillus and mucor, and activity is suitable with voriconazole and posaconazole, better than her
Triaconazole and Fluconazole, the listing of the medicine undoubtedly bring huge good fortune for infecting the patient of the aggressive mould of threat to life
Sound.
United States Patent (USP) US6300353 discloses the synthetic method of Chinese mugwort Saperconazole, but its crystal habit do not reported.Most
Closely, international application for patent (publication No. WO2016055918A1) reports the amorphous state of Chinese mugwort Saperconazole free alkali and a kind of crystallization
Form, its amorphous state is that acquisition is beaten in methyl tertiary butyl ether(MTBE) by the Saperconazole grease that ends, and another crystal habit is
By Chinese mugwort Saperconazole hydrobromate in dichloromethane by the free of sodium carbonate liquor, point liquid gained organic layer is concentrated again
Arrive.But two ways products obtained therefrom purity is not (respectively 92%, 97%) high, stability is unknown, and preparation method is cumbersome, raw
Produce efficiency it is low, be not suitable for as intermediate synthesize its prodrug Chinese mugwort Saperconazole sulfuric ester, be more not suitable as bulk drug develop into it is new
Preparation.Therefore, novel crystal forms of Chinese mugwort Saperconazole and preparation method thereof need to be studied.
The content of the invention
In view of the problem that prior art is present, instant invention overcomes the deficiencies in the prior art, there is provided one kind Chinese mugwort Saperconazole
Crystal formation A and preparation method and application, it is the new crystal habit for being different from disclosed crystal formation, preparation method of the invention
Chinese mugwort Saperconazole crystal formation A is prepared in more economical, easier, reproducible method, the purity of crystal formation obtained by the method is high, product
Excellent in stability, is adapted to industrialized production.
It is an object of the present invention to provide one kind Chinese mugwort Saperconazole crystal formation A.
It is a further object to provide the preparation method of above-mentioned Chinese mugwort Saperconazole crystal formation A.
Third object of the present invention is to provide the pharmaceutical composition comprising above-mentioned Chinese mugwort Saperconazole crystal formation A.
Fourth object of the present invention is to provide the purposes of above-mentioned Chinese mugwort Saperconazole crystal formation A.
In the present embodiment, the invention provides one kind Chinese mugwort Saperconazole crystal formation A, radiated using Cu-K α, obtain it
X-ray powder diffraction collection, represents that it has following diffraction maximum with 2 θ angles：
9.9,13.4,17.5,17.9,20.9,22.0,22.7,25.1,27.3,29.3 and 31.4.
In one embodiment of the present invention, the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, is radiated using Cu-K α, is obtained
X-ray powder diffraction collection, is represented with 2 θ angles, and it has following diffraction maximum of the relative intensity more than 20%：
9.9,13.4,17.5,17.9,20.9,22.0,22.7,25.1,27.3,29.3 and 31.4.
In one embodiment of the present invention, the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, is radiated using Cu-K α, is obtained
Its X-ray powder diffraction collection, represents that it has following diffraction maximum with 2 θ angles：
9.9,10.2,13.4,17.2,17.5,17.9,20.9,22.0,22.4,22.7,23.7,25.1,27.3,29.3,
30.1, and 31.4.
In embodiments of the invention, the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, is radiated using Cu-K α, obtains its X-
Ray powder diffraction, numerical value as 2 θ ± 0.2 is represented with 2 θ angles.
In a preferred embodiment of the invention, the invention provides one kind Chinese mugwort Saperconazole crystal formation A, radiated using Cu-K α,
Its X-ray powder diffraction collection is obtained, is represented with 2 θ angles and interplanar distance (d) value, its specific diffraction maximum parameter is as follows：
In a preferred embodiment of the invention, the invention provides one kind Chinese mugwort Saperconazole crystal formation A, radiated using Cu-K α,
Obtain X-ray powder diffraction collection as shown in Figure 1.
In embodiments of the invention, the invention provides one kind Chinese mugwort Saperconazole crystal formation A, the DSC collection of illustrative plates of the crystal formation A
With three endothermic peaks, it is highly preferred that having peak value to be melted for 126.1 ± 1 DEG C, 231.2 ± 1 DEG C and 327.8 ± 1 DEG C of feature
Melt endothermic peak.
In embodiments of the invention, the invention provides one kind Chinese mugwort Saperconazole crystal formation A, the parameter of its infrared light spectral peak
It is 3363,2968,2931,2227,1605,1486,1274,1243,1179,1132,855,766 (units：cm-1)。
Second aspect, In one embodiment of the present invention, the invention provides the preparation of above-mentioned Chinese mugwort Saperconazole crystal formation A
Method, comprises the following steps：
Chinese mugwort Saperconazole is dissolved in Chinese mugwort Saperconazole solution is obtained in the solvent I for be heated to uniform temperature, then at such a temperature
Stirring, the solid that stirring is cooled to precipitation is not further added by, or stirs at such a temperature and solvent II is added dropwise, and is stirred after being added dropwise to complete
Mix and be cooled to the solid of precipitation and be not further added by, then filter, be dried to obtain Chinese mugwort Saperconazole crystal formation A.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, it is described molten
Agent I can effectively dissolve the Chinese mugwort Saperconazole of any form, and the solvent II can analyse the Chinese mugwort Saperconazole being dissolved in solvent I
Go out, the purpose of Chinese mugwort Saperconazole crystal formation A is prepared so as to reach.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, it is described molten
Agent I is one or two the mixed solvent in methyl alcohol, ethanol, isopropanol, ethyl acetate, acetone, acetic acid.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, it is described molten
Agent II is the one kind in water, n-hexane, normal heptane, hexamethylene, petroleum ether, methyl tertiary butyl ether(MTBE).
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, the Chinese mugwort
Saperconazole is 1g with the mass/volume ratio of solvent I:2~50ml.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, it is described molten
The volume of agent II is 0~5.0 times of the volume of solvent I.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, described one
Constant temperature degree is 40~80 DEG C, it is preferable that be 42~70 DEG C.
In embodiments of the invention, the preparation method of the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, wherein, it is described to stir
The temperature for mixing cooling is -5~30 DEG C, more preferably 0~5 DEG C.
In the method for preparing the Chinese mugwort Saperconazole crystal formation A that the present invention is provided, the Chinese mugwort Saperconazole can be using this
The Chinese mugwort Saperconazole that existing any means are obtained in field, such as by the preparation side described in patent US6300353 specifications
The Chinese mugwort Saperconazole that method is obtained.
The third aspect, present invention also offers a kind of pharmaceutical composition, comprising Chinese mugwort Saperconazole crystal formation A and as described above
Kind or more plants pharmaceutically acceptable carrier.
Fourth aspect, present invention also offers the medicine that the Chinese mugwort Saperconazole crystal formation A can be used as anti-invasion fungi in preparation
Purposes in thing.
In embodiments of the invention, it is true that the Chinese mugwort Saperconazole crystal formation A that the present invention is provided can be used as anti-invasion in preparation
Purposes in the medicine of bacterium, wherein, the invasive fungi is Aspergillus or mucor.
The method for preparing Chinese mugwort Saperconazole crystal formation A of the present invention is easy to operate, reproducible, and the crystal formation obtained by the method
A purity is high, product quality stabilization, had both been adapted to development in laboratory and also has been adapted for industrialized production.Reported with patent WO2016055918A1
The unformed shape of the Chinese mugwort Saperconazole in road is compared with crystalline state, and the Chinese mugwort Saperconazole crystal formation A purity in the present invention is higher, and stability is more
It is good, can be directly used for preparation research and production.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 1.
Fig. 2 is the means of differential scanning calorimetry figure (DSC) of the crystal formation A of Chinese mugwort Saperconazole prepared by the embodiment of the present invention 1.
Fig. 3 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 2.
Fig. 4 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 3.
Fig. 5 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 4.
Fig. 6 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 5.
Fig. 7 is the X-ray powder diffraction figure (XRPD) of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 6.
Fig. 8 is that Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 1 accelerates the X-ray powder diffraction figure after June
(XRPD)。
Fig. 9 is the infared spectrum (IR) that the embodiment of the present invention 1 prepares Chinese mugwort Saperconazole crystal formation A.
Specific embodiment
Below in conjunction with the embodiment of the present invention and accompanying drawing, the present invention is described in further detail.It should be appreciated that herein
Described specific embodiment is only used to explain the present invention, does not constitute and limit the scope of protection of the invention.
Experiment tester used
1st, X-ray powder diffraction spectrum
INSTRUMENT MODEL：SHIMADZU LabX XRD-6000X- ray powder diffractometers
Ray：Monochromatic Cu-K alpha rays
Scan mode：Q/2q, sweep limits：2~50
Voltage：40KV, electric current：30mA
2nd, DSC spectrums
INSTRUMENT MODEL：NETZSCH DSC 204F1Phoenix
Purge gass：Nitrogen
Heating rate：10.0K/min
Temperature range：20~400 DEG C
3rd, infrared spectrum
INSTRUMENT MODEL：ThermoFisher Nicolet 6700
Compressing tablet：KBr compressing tablets
4th, high performance liquid chromatography (HPLC)
INSTRUMENT MODEL：SHIMADZU LC-20A
Chromatographic column：Welchrom C18 4.6*250mm 5um
Column temperature：40℃
Flow velocity：1.0ml/min
Sampling volume：20ul
Wavelength：252nm
Solvent：Methyl alcohol
Mobile phase A：3.5ml acetic acid is dissolved in water and is diluted to 1000ml, and pH is adjusted with triethylamine.
Mobile phase B：Methyl alcohol
Embodiment 1
To 100g Chinese mugworts Saperconazole, 200ml ethyl acetate is added in 2L reaction bulbs, 50 DEG C of Saperconazoles that will end are heated under stirring
Dissolving is complete, keeps the temperature, instills 600ml n-hexanes, continues to stir 1h, is stirred for cooling to 0~5 DEG C, until analysis
The solid for going out is not further added by.Suction filtration, filter cake is washed with 100ml n-hexanes, and filter cake, to constant weight, is obtained in forced air drying at 50 DEG C
White solid Chinese mugwort Saperconazole crystal formation A, yield 88%, HPLC detection purity 99.2%, fusing point：120~121 DEG C.X-ray powder
Diffracting spectrum and DSC collection of illustrative plates are shown in Fig. 1 and Fig. 2 respectively.
Embodiment 2
To 100g Chinese mugworts Saperconazole, 400ml isopropanols is added in 1L reaction bulbs, 60 DEG C of Saperconazoles that will end are heated under stirring molten
Solution is complete, is incubated and stirs 1h, is stirred for cooling to 0~5 DEG C, until the solid for separating out is not further added by.Suction filtration obtains filter cake,
And by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid Chinese mugwort Saperconazole crystal formation A, yield 81%, HPLC detection purity
99.0%, fusing point：119~120 DEG C.X-ray powder diffraction collection is shown in Fig. 3.
Embodiment 3
To 100g Chinese mugworts Saperconazole, 300ml acetic acid is added in 2L reaction bulbs, 50 DEG C are heated under stirring will Chinese mugwort Saperconazole dissolving
Completely, it is kept at this temperature, instills 800ml purified waters, continue to stir 1h, be stirred for cooling to 0~5 DEG C, until analysis
The solid for going out is not further added by.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid Chinese mugwort Saperconazole
Crystal formation A, yield 79%, HPLC detection purity 98.8%, fusing point：120~122 DEG C.X-ray powder diffraction collection is shown in Fig. 4.
Embodiment 4
To 50g Chinese mugworts Saperconazole, 150ml acetone is added in 1L reaction bulbs, 45 DEG C are heated under stirring will Chinese mugwort Saperconazole dissolving
Completely, it is kept at this temperature, instills 350ml purified waters, continue to stir 1h, be stirred for cooling to 0~5 DEG C, until analysis
Go out solid not to be further added by.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid Chinese mugwort Saperconazole brilliant
Type A, yield 89%, HPLC detection purity 99.1%, fusing point：121~122 DEG C.X-ray powder diffraction collection is shown in Fig. 5.
Embodiment 5
To 40g Chinese mugworts Saperconazole, 240ml methyl alcohol is added in 1L reaction bulbs, 55 DEG C are heated under stirring will Chinese mugwort Saperconazole dissolving
Completely, it is kept at this temperature, instills 120ml purified waters, continue to stir 1h, be stirred for cooling to 0~5 DEG C, until analysis
Go out solid not to be further added by.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain faint yellow solid Chinese mugwort Saperconazole
Crystal formation A, yield 82%, HPLC detection purity 99.5%, fusing point：121~122 DEG C.X-ray powder diffraction collection is shown in Fig. 6.
Embodiment 6
To 100g Chinese mugworts Saperconazole, 300ml methyl alcohol and 300ml ethanol is added in 2L reaction bulbs, 50 DEG C are heated under stirring will
Chinese mugwort Saperconazole dissolving is complete, is kept at this temperature, and instills 300ml purified waters, continues to stir 1h, is stirred for cooling to 0
~5 DEG C, until separate out solid not being further added by.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid
Body Chinese mugwort Saperconazole crystal formation A, yield 85%, HPLC detection purity 99.4%, fusing point：120~121 DEG C.X-ray powder diffraction figure
Spectrum is shown in Fig. 7.
Embodiment 7
To 50g Chinese mugworts Saperconazole, 400ml ethyl acetate is added in 2L reaction bulbs, 50 DEG C of Saperconazoles that will end are heated under stirring
Dissolving is complete, is kept at this temperature, and instills 1000ml normal heptanes, continues to stir 1h, is stirred for cooling to 0~5 DEG C, directly
It is not further added by solid is separated out.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid Ai Shakang
Azoles crystal formation A, yield 81%, HPLC detection purity 99.0%, fusing point：120~121 DEG C.
Embodiment 8
To 50g Chinese mugworts Saperconazole, 250ml ethyl acetate is added in 3L reaction bulbs, 50 DEG C of Saperconazoles that will end are heated under stirring
Dissolving is complete, is kept at this temperature, and instills 1750ml petroleum ethers, continues to stir 1h, is stirred for cooling to 0~5 DEG C, directly
It is not further added by solid is separated out.Suction filtration obtains filter cake, and by filter cake in forced air drying at 50 DEG C to constant weight, obtain white solid Ai Shakang
Azoles crystal formation A, yield 87%, HPLC detection purity 98.8%, fusing point：121~122 DEG C.
Embodiment 9
Chinese mugwort Saperconazole crystal formation A about 20mg, polyethylene glycol-polylactic acid diblock copolymer (mPEG-PLA) 100mg are weighed, is put
In beaker, add appropriate dimethylformamide to make its molten clear, be subsequently adding 30ml dichloromethane；The solution is transferred to bag filter
In (retention relative molecular weight is 3500), sealing；Dialysed into 2L ultra-pure waters, a water was changed every 2 hours, dialyse 24h.Dialysis
Complete, the solution in removal bag filter, centrifugation takes supernatant, with 0.45 micron of filtering with microporous membrane, obtain final product Chinese mugwort Saperconazole glue
Beam solution.The micellar solution of preparation is acted on into mucor or Aspergillus, as a result shows the pharmaceutical composition to mucor or song
Mould is respectively provided with good inhibiting effect.
Comparative example
The embodiment of the present invention prepares the Chinese mugwort Saperconazole free alkali of Chinese mugwort Saperconazole crystal formation A and patent WO2016055918A1 reports
Amorphous state and crystalline state purity data contrast it is as shown in table 1：
The embodiment of the present invention of table 1 gained Chinese mugwort Saperconazole crystal formation A and patent WO2016055918A1 report gained Ai Shakang
The purity data contrast of the amorphous state and crystalline state of azoles free alkali
Note：Impurity A is the quaternary ammonium salt impurities of Chinese mugwort Saperconazole and 4- cyano group -2 '-bromoacetophenone generation, and impurity B is Ai Shakang
The diastereoisomer of azoles.
Result shows, the purity of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention is apparently higher than the pure of disclosed crystal formation
Degree.
Additionally, the present invention has also investigated the quality of Chinese mugwort Saperconazole crystal formation A of the invention and the stability and and patent of crystal formation
The crystal formation of WO2016055918A1 reports is compared, and embodiment of the present invention 1 and patent WO2016055918A1 are implemented
The crystal formation product of the gained of example 2 has carried out acceleration June (temperature：40 DEG C ± 2 DEG C, humidity：75% ± 5%) stability experiment.
The crystal formation product of the gained of the embodiment of the present invention 1 and the crystal formation product of the gained of patent WO2016055918A1 examples 2 enter
Row accelerates the stability experiment result after June as shown in table 2：
The crystal formation of the gained of 2 embodiment of the present invention of table 1 Chinese mugwort Saperconazole crystal formation A and the gained of patent WO2016055918A1 examples 2
The stability experiment result accelerated after June of product
Result shows that after the accelerated June experiment of Chinese mugwort Saperconazole crystal formation A prepared by the embodiment of the present invention 1, X-ray powder spreads out
Penetrate spectrum data basically identical (see Fig. 1 and Fig. 8), proterties, fusing point, purity and enantiomter content almost do not change；
And after the accelerated June experiment of crystal formation product of the gained of patent WO2016055918A1 examples 2, purity decreases.Therefore it is of the invention
The quality and stability of crystal form of Chinese mugwort Saperconazole crystal formation A prepared by embodiment 1 are good.
Although reference be made herein to invention has been described for multiple explanatory embodiments of the invention, it should be appreciated that,
Those skilled in the art can carry out a lot of other modification and implementation methods, and these modifications and implementation method will fall in the application
Within disclosed spirit and spirit, to those skilled in the art, these modifications or improvements will be apparent from.
Claims (10)
1. a kind of Chinese mugwort Saperconazole crystal formation A, it is characterised in that radiated using Cu-K α, its X-ray powder diffraction collection is obtained, with 2
θ angles represent that the collection of illustrative plates has following diffraction maximum：
9.9,13.4,17.5,17.9,20.9,22.0,22.7,25.1,27.3,29.3 and 31.4.
2. end Saperconazole crystal formation A as claimed in claim 1, wherein, the relative intensity of the diffraction maximum is both greater than 20%.
3. end Saperconazole crystal formation A as claimed in claim 1, wherein, the collection of illustrative plates has following diffraction maximum：
9.9,10.2,13.4,17.2,17.5,17.9,20.9,22.0,22.4,22.7,23.7,25.1,27.3,29.3,
30.1, and 31.4.
4. end Saperconazole A crystal formations as claimed in claim 1, and the collection of illustrative plates has diffraction maximum as described below：
5. end Saperconazole crystal formation A as claimed in claim 1, and its DSC collection of illustrative plates has three endothermic peaks, it is highly preferred that having peak
It is worth the endothermic peak for 126.1 ± 1 DEG C, 231.2 ± 1 DEG C of endothermic peak and 327.8 ± 1 DEG C of endothermic peak.
6. the preparation method of the Chinese mugwort Saperconazole crystal formation A as any one of claim 1 to 5, comprises the following steps：By Ai Sha
Health azoles obtains Chinese mugwort Saperconazole solution in being dissolved in the solvent I for be heated to uniform temperature, then stirs at such a temperature, and stirring is cooled to
The solid of precipitation is not further added by, or stirs at such a temperature and solvent II is added dropwise, and stirring is cooled to precipitation after being added dropwise to complete
Solid is not further added by, and then filters, is dried to obtain Chinese mugwort Saperconazole crystal formation A.
7. preparation method as claimed in claim 6, wherein, the solvent I is methyl alcohol, ethanol, isopropanol, ethyl acetate, third
One or two mixed solvent in ketone, acetic acid；The solvent II is water, n-hexane, normal heptane, hexamethylene, petroleum ether, first
One kind in base tertbutyl ether.
8. preparation method according to claim 6, wherein, the Chinese mugwort Saperconazole is 1g with the mass/volume ratio of solvent I:2
~50ml；
The volume of the solvent II is 0~5.0 times of the volume of solvent I.
9. preparation method according to claim 6, wherein, the uniform temperature is 40~80 DEG C, it is preferable that be 42~70
℃；
The temperature of the stirring cooling is -5~30 DEG C, more preferably 0~5 DEG C.
10. a kind of pharmaceutical composition, it contains Chinese mugwort Saperconazole crystal formation A and the pharmaceutically acceptable load described in claim 1
Body.
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| CN109206421A (en) * | 2017-07-03 | 2019-01-15 | 上海医药集团股份有限公司 | A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof |
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| WO2016055918A1 (en) * | 2014-10-08 | 2016-04-14 | Wockhardt Limited | Novel stable polymorphs of isavuconazole or its salt thereof |
| CN105732605A (en) * | 2014-12-06 | 2016-07-06 | 山东亨利医药科技有限责任公司 | Preparation method of isavuconazole intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109206421A (en) * | 2017-07-03 | 2019-01-15 | 上海医药集团股份有限公司 | A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof |
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