CN109206421A - A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof - Google Patents
A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof Download PDFInfo
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- CN109206421A CN109206421A CN201710534510.0A CN201710534510A CN109206421A CN 109206421 A CN109206421 A CN 109206421A CN 201710534510 A CN201710534510 A CN 201710534510A CN 109206421 A CN109206421 A CN 109206421A
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- China
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- chinese mugwort
- crystal form
- saperconazole
- crystal
- mugwort saperconazole
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- HUADITLKOCMHSB-AVQIMAJZSA-N 2-butan-2-yl-4-[4-[4-[4-[[(2s,4r)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 HUADITLKOCMHSB-AVQIMAJZSA-N 0.000 title claims abstract description 100
- 229950005137 saperconazole Drugs 0.000 title claims abstract description 100
- 239000013078 crystal Substances 0.000 title claims abstract description 97
- 235000010894 Artemisia argyi Nutrition 0.000 title claims abstract description 81
- 244000030166 artemisia Species 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 20
- 239000002244 precipitate Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 235000019441 ethanol Nutrition 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- LJANCPRIUMHGJE-UHFFFAOYSA-N 4-(2-bromoacetyl)benzonitrile Chemical compound BrCC(=O)C1=CC=C(C#N)C=C1 LJANCPRIUMHGJE-UHFFFAOYSA-N 0.000 claims description 10
- 150000003556 thioamides Chemical class 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000002798 polar solvent Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 238000000113 differential scanning calorimetry Methods 0.000 abstract description 8
- 238000002411 thermogravimetry Methods 0.000 abstract description 8
- 238000004458 analytical method Methods 0.000 abstract description 4
- 238000002441 X-ray diffraction Methods 0.000 abstract 1
- 238000012512 characterization method Methods 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 15
- 229960000935 dehydrated alcohol Drugs 0.000 description 13
- 238000010792 warming Methods 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 238000005352 clarification Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- -1 2,5- difluorophenyl Chemical group 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012490 blank solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 description 3
- 229960000788 isavuconazole Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 241000235395 Mucor Species 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- LWXUIUUOMSMZKJ-KLFWAVJMSA-M isavuconazonium sulfate Chemical compound OS([O-])(=O)=O.CNCC(=O)OCC1=CC=CN=C1N(C)C(=O)OC(C)[N+]1=CN(C[C@@](O)([C@@H](C)C=2SC=C(N=2)C=2C=CC(=CC=2)C#N)C=2C(=CC=C(F)C=2)F)N=C1 LWXUIUUOMSMZKJ-KLFWAVJMSA-M 0.000 description 2
- 229960003384 isavuconazonium sulfate Drugs 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241001214789 Basilea Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000006202 Sharpless epoxidation reaction Methods 0.000 description 1
- 206010061418 Zygomycosis Diseases 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 201000007524 mucormycosis Diseases 0.000 description 1
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07B2200/07—Optical isomers
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the I crystal of Chinese mugwort Saperconazole, preparation method and application.Comprehensive characterization is carried out with I crystal of the means such as X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, hygroscopicity analysis to Chinese mugwort Saperconazole, discovery I crystal is more amorphous to have more excellent stability.The preparation method of the I crystal of the Chinese mugwort Saperconazole is easy to operate, is easy to control, favorable reproducibility.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, crystal form I and its preparation side in particular to a kind of Saperconazole that ends
Method.
Background technique
Saperconazole (Isavuconazole) is ended by Astellas and Ba Sai Leah (Basilea) drugmaker joint development,
It is the antifungal drug in triazole class of the third generation.Intravenous or oral broad-spectrum antifungal preparation once a day, for aggressive aspergillus
The fungal infection of the threat to life such as bacterium, mucor, candida albicans.Usually occur with the patient of hypoimmunity, in chemotherapy
Tumor patient, the Organ Transplantation Patients for receiving immunosuppressive therapy etc..Wherein end Saperconazole sulfuric ester
(Isavuconazonium sulfate) is included in the Orphan drug (Orphan in the U.S., European Union's invasion Aspergillus, mucormycosis
Medicinal products), FDA ratifies its listing on March 6th, 2015.
Before Saperconazole sulfuric ester (Isavuconazonium sulfate) is ended as Chinese mugwort Saperconazole (Isavuconazole)
Medicine.After the Saperconazole sulfuric ester intravenous administration that ends or oral administration, Ai Shakang can be fully converted to rapidly under the action of esterase
Azoles and a small amount of catabolite.
WO2001/032652 makes public for the first time structural formula, the Preparation method and use of Chinese mugwort Saperconazole, English name:
Isavuconazole, structural formula are as follows:
The patent reacts to obtain Chinese mugwort Saperconazole by 11 steps, total recovery is 16% using (R)-methyl lactate as starting material
Less than.The route starting material includes a chiral centre, passes through Corey or Sharpless epoxidation methods asymmetric syntheses structure
Second chiral centre is built, however it is selective and not good enough, and obtained isomers is also difficult to purify, and yield is lower.
WO2003/002498 also discloses the specific preparation method of following Chinese mugwort Saperconazole:
The patent is using (R) -3- butyne-2-alcohol as starting material, one under the action of Pd (II) catalyst and diethyl zinc
Step second chiral centre of synthesis, this method can obtain ee value 80% or so substantially, but starting material and Pd (II) catalyst are high
Expensive, production cost greatly increases.
US2182025 discloses new synthetic route, the patent with 1- (2,5- difluorophenyl) -2- (1H-1,2,4- tri-
Azoles -1- base) ethyl ketone is starting material, which is easy to get, but the first step need to react at -78 DEG C, and reaction is more harsh, and selects
Property is not high, it is more difficult to purify.
Therefore, lack in the prior art safety, it is economical, can be extensive and effectively (in high yield, high-purity) is used to prepare
The method of Chinese mugwort Saperconazole.Need to develop a kind of physicochemical property preferably novel crystal forms simultaneously, to improve the stability of Chinese mugwort Saperconazole.
Summary of the invention
One of the objects of the present invention is to provide a kind of novel crystal forms of Saperconazole that ends, and crystal form I are named as, for treating
The fungal infection of the threat to life such as aggressive Aspergillus, mucor, candida albicans.Compare unbodied Chinese mugwort Saperconazole, the Chinese mugwort of crystal form I
Saperconazole has more good stability.
It is a further object to provide the preparation method of the crystal form I of Saperconazole that ends a kind of, the method technique letters
Single, mild condition substantially increases production efficiency, is suitble to the crystal form I of the Chinese mugwort Saperconazole of industrialized production high-purity.
On the one hand, the crystal form I of Chinese mugwort Saperconazole provided by the invention, the crystal form I is in the X-ray powder indicated with 2 θ angles
Last diffracting spectrum (XRPD map) is at about 9.207 ° ± 0.2.,10.177°±0.2.,10.507°±0.2.,13.664°±
0.2。、17.761±0.2。、18.324°±0.2。、21.063°±0.2。、22.290°±0.2。、31.673°±0.2。、
38.538°±0.2.There is characteristic peak at place, and particularly, the characteristic peak relative intensity is greater than 30%.
Particularly, the XRPD map of the crystal form I of the described Chinese mugwort Saperconazole, also 2 angle θ of angle of diffraction be about 21.173 ° ±
0.2。、22.961°±0.2。、23.888°±0.2。、24.608°±0.2。、25.374°±0.2。、25.662°±0.2。、
27.598°±0.2.,28.110°±0.2.,29.518°±0.2.,30.388°±0.2.,37.104°±0.2.There is feature at place
Peak, particularly, the characteristic peak relative intensity are greater than 10%.
Further, the XRPD map of the crystal form I of the Chinese mugwort Saperconazole, is about also 20.286 ° at 2 angle θ of angle of diffraction
±0.2.,26.365°±0.2.,27.080°±0.2.,37.877°±0.2.There is characteristic peak at place, particularly, the characteristic peak
Relative intensity is greater than 5%.
Particularly, the crystal form I of Chinese mugwort Saperconazole of the present invention, has XRPD map substantially as shown in Fig. 1,
In, the XRPD data of the crystal form I are shown in Table 1.
Table 1
| Serial number | 2θ° | Relative intensity | Serial number | 2θ° | Relative intensity |
| 1 | 9.207 | 42.1 | 14 | 25.374 | 13 |
| 2 | 10.177 | 39.5 | 15 | 25.662 | 14 |
| 3 | 10.507 | 46.5 | 16 | 26.365 | 6.2 |
| 4 | 13.664 | 54 | 17 | 27.08 | 8 |
| 5 | 17.761 | 100 | 18 | 27.589 | 29.2 |
| 6 | 18.324 | 53.4 | 19 | 28.11 | 10.5 |
| 7 | 20.286 | 9.6 | 20 | 29.518 | 29 |
| 8 | 21.063 | 32.3 | 21 | 30.388 | 13.8 |
| 9 | 21.173 | 27.1 | 22 | 31.673 | 34.6 |
| 10 | 22.29 | 80.8 | 23 | 37.104 | 10.1 |
| 11 | 22.961 | 26.7 | 24 | 37.877 | 8.3 |
| 12 | 23.888 | 29.6 | 25 | 38.538 | 30.6 |
| 13 | 24.608 | 12.1 |
Due to the difference of measuring condition, each 2 angle θ of peak and relative intensity can be changed on XRPD diffraction pattern, the angle general 2 θ
Variation also can slightly overflow the range within ± 0.2 °, it will be understood by those skilled in the art that the relative intensity of diffraction can depend on
In for example, sample formulation or device therefor.
The fusing point of the crystal form I of the Chinese mugwort Saperconazole is about 121.97 ± 1 DEG C, particularly, the crystal form I of the Chinese mugwort Saperconazole
With basic such as differential scanning calorimetric analysis (DSC) map as shown in Figure 2.
The crystal form I of Chinese mugwort Saperconazole provided by the invention has good fusing point and quality, and quality purity is at least
99.0%, ee value are at least 99.0%.The crystal form I of Chinese mugwort Saperconazole, which has, to be synthesized on a large scale or is configured to needed for therapeutic preparation
Performance, to light, wet, thermostabilization, easy to produce, storage.On the other hand, high-purity Chinese mugwort Saperconazole is prepared the present invention provides a kind of
Crystal form I method, the preparation method includes:
(d) Chinese mugwort Saperconazole crude product is added in intensive polar solvent and is dissolved by heating, obtain solution；
(e) into solution made from step (d), poor solvent is added, is naturally cooling to the temperature precipitated crystal and crystalline substance is precipitated
Body, filtering, the crystal form I of dry Chinese mugwort Saperconazole；
In step (d),
The Chinese mugwort Saperconazole crude product can be the Chinese mugwort Saperconazole crude product that any technique obtains, including Chinese mugwort Saperconazole
The industrial crude product of the various known or unknown crystal form or amorphous forms of anhydrous form, solvate or hydrate form；
The intensive polar solvent is selected from one or more of methanol, ethyl alcohol, isopropanol, tetrahydrofuran, it is preferable that
The intensive polar solvent is ethyl alcohol；
The w/v of the Chinese mugwort Saperconazole crude product and intensive polar solvent is 1Kg:(2~3) L；
The temperature of the dissolution is 40~80 DEG C, it is preferable that the temperature of the dissolution is 60~65 DEG C；
In step (e),
The poor solvent is selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), water, it is preferable that
The poor solvent is water；
The w/v of the Chinese mugwort Saperconazole crude product and poor solvent is 1Kg:(1~3) L；
The temperature precipitated crystal is 0~25 DEG C, it is preferable that the temperature precipitated crystal is 10~25 DEG C.
Inventor has found that increasing temperature can greatly reduce in step (d) needed for Chinese mugwort Saperconazole in the research of Chinese mugwort Saperconazole
Solvent volume, to reduce production cost, and the process cooling that precipitates crystal of step (e) is conducive to precipitate crystal rapidly,
Improve production efficiency.
In addition, excessive in order to solve foreign pigment content in the crystal form I preparation method of Chinese mugwort Saperconazole, related substance is exceeded,
And the problem of precipitating crystal is influenced, a small amount of active carbon is additionally added in preparation method step (d) of the invention and is decolourized, preferably
The weight ratio of ground, the Chinese mugwort Saperconazole crude product and active carbon is 1:0.05.The crystal form product obtained after decolourizing, color are pure
Only, appearance is uniform.
To further increase industrial production efficiency, reducing solvent usage, production cost is reduced, inventor prepares the present invention
Method condition is optimized.
Preferably, the preparation method of the crystal form I of the Chinese mugwort Saperconazole, further includes following steps before step (d):
(a) in a solvent, thioamides II and the bromo- 4'- cyano-acetophenone of 2- are added, condensation reaction occurs for heating, obtains
Reaction solution；
(b) reaction solution of concentration step (a), crystallizes in organic solvent, and filtering, must end Saperconazole hydrobromate；
(c) by step (b) the Saperconazole hydrobromate alkali process obtained that ends, extraction obtains Chinese mugwort Saperconazole crude product.
In step (a),
The reaction temperature of the condensation reaction is 30~65 DEG C, and preferably 40~45 DEG C, the reaction time is generally 20~24
Hour；Reaction end is detected with HPLC；
The solvent is selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), ethyl alcohol, preferably
Ethyl alcohol；
The molar ratio of the thioamides II and the bromo- 4'- cyano-acetophenone of 2- is 1:0.95~1:1.3, preferably 1:
1.05~1:1.1.
In step (b),
The organic solvent be selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), ethyl acetate,
Preferably ethyl acetate；
The crystallization is two sections of crystallizations, first precipitates crystal at 40~55 DEG C, is then cooled to 15~25 DEG C again and continues to be precipitated
Crystal；
The time of the crystallization is 3~24 hours；
Preferably, the crystallization is at 40~55 DEG C, and stirring precipitates crystal 1~4h, is down to 15~25 DEG C naturally, is continued
Precipitate crystal 2~6h；
In step (c),
The alkali be selected from one or more of sodium bicarbonate, sodium carbonate, sodium hydroxide, preferably sodium bicarbonate,
Sodium carbonate.
Beneficial effect
Due to the implementation of above technical scheme, the invention has the following advantages over the prior art:
The present invention provides a kind of new Chinese mugwort Saperconazole crystal form I, the application for Chinese mugwort Saperconazole in medical industry is provided newly
Selection, the present invention also provides it is a kind of prepare Chinese mugwort Saperconazole crystal form I method, this method is easy to operate, mild condition, examination used
Agent is cheap and easy to get, is suitable for industrialization existence, gained crystal form I purity is high, high income, impurity content, ee value meet medicinal requirements.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction XRPD map of the Chinese mugwort Saperconazole crystal form I prepared in embodiment 6；
Fig. 2 is the thermogravimetric analysis TGA map of the Chinese mugwort Saperconazole crystal form I prepared in embodiment 6；
Fig. 3 is the differential scanning calorimetric analysis DSC map of the Chinese mugwort Saperconazole crystal form I prepared in embodiment 6；
Fig. 4 is the X-ray powder diffraction XRPD map of the Chinese mugwort Saperconazole amorphous article prepared in comparative example.
Specific embodiment
The present invention with further reference to following embodiment, the preparation of the embodiment detailed description of the present invention salt and crystal form and
Using.It will be apparent for a person skilled in the art that changes many of these for both material and method can not depart from
Implement in the case where the scope of the invention.
Detecting instrument and method:
Instrument used in X-ray powder diffraction (XRPD) is Bruker D8 Advance diffractometer, is adopted
The K α X-ray for being 1.54nm with copper target wavelength, under the operating condition of 40kV and 40mA, θ -2 θ angular instrument, Mo monochromator,
Lynxeye detector.Instrument is correcting peak position using the preceding standard sample carried with instrument.Acquisition software is Diffrac Plus
XRD Commander, analysis software is MDIJade5.0.Sample is tested at room temperature, and the sample that needs are detected is placed on
On organic slide.Detailed testing conditions are as follows: angular range: 3~40 ° of 2 θ；Step-length: 0.02 ° of 2 θ；Speed: 0.2 second/step.Unless
It illustrates, sample is not ground before detection.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.It usually takes the sample of 5~15mg to be placed in platinum crucible, adopts
With the mode of segmentation high resolution detection, N is dried in 50mL/min with the heating rate of 10 DEG C/min2Protection under by sample from room
Temperature rise is to 300 DEG C, while weight change of the TA software records sample in temperature-rise period.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.It usually takes 1~10 milligram of sample to be placed in capping punching (to remove
Non-specifically illustrate) aluminium crucible in, with the heating rate of 10 DEG C/min in the dry N of 50mL/min2Protection under by sample from room
Temperature rise is to 200 DEG C or 300 DEG C, while thermal change of the TA software records sample in temperature-rise period.In this application, fusing point is
It is reported by initial temperature.All temperature indicate that room temperature refers to 20~25 DEG C with DEG C (degree Celsius).
The bromo- 4 '-cyano-acetophenone of 2-, ethyl alcohol, the reagents such as ethyl acetate are that analysis is pure, are had by Chinese medicines group chemical reagent
Limit company provides, and agents useful for same and solvent unless otherwise indicated, are not specially treated.Thioamides II refers to CN1223564C
The preparation method of middle embodiment 14.Saperconazole end purchased from the Shanghai medical limited liability company of white member, purity: 98.9%.
HPLC purity testing condition
Instrument: high performance liquid chromatograph is equipped with UV detector
Chromatographic column: Waters XbridgeC18150 × 4.6mm, 3.5 μm
Mobile phase A: 0.01mol/L potassium dihydrogen phosphate (pH2.8): acetonitrile=100:10, v:v
Mobile phase B: acetonitrile
Detection wavelength: 266nm/210nm
Flow velocity: 0.7mL/min
Sample volume: 10 μ L
Column temperature: 40 DEG C
Runing time: 40min
Gradient table:
Dilution: acetonitrile: water=50:50, v:v
Test solution: precision weighs that test sample is appropriate, is dissolved and is diluted in every 1mL containing about 0.5mg's with dilution
Solution.
Contrast solution: precision measurement test solution is appropriate, with diluted at the solution in every 1mL containing about 5ug
Procedures/systems applicability requirement: molten according to chromatographic condition difference sample introduction blank solution, contrast solution and test sample
Liquid records chromatographic process.It is required that blank solution is noiseless, repeat into 6 needle contrast solutions, in the map obtained by 6 needle contrast solutions,
RSD≤2.0% of main peak peak area meter.
Impurity content calculates: calculating impurity content in sample with principal component Self-control method
HPLC chiral determination condition:
Instrument: high performance liquid chromatograph is equipped with UV detector
Chromatographic column: CHIRALPAK IC250 × 4.6mm, 5 μm
Mobile phase: 0.1% n-butylamine [n-hexane: ethyl alcohol: methanol=20:4:1, v:v:v]
Detection wavelength: 266nm
Flow velocity: 1.0mL/min
Sample volume: 20 μ L
Column temperature: 30 DEG C
Runing time: 40min
Dilution: isopropanol
Test solution: precision weighs that test sample is appropriate, is dissolved and is diluted in every 1mL containing about 1.0mg's with dilution
Solution.
Contrast solution: precision measure test solution it is appropriate, with diluted in every 1mL containing about the solution of 10 μ g.
Separating degree solution: precision weighs Chinese mugwort Saperconazole bulk pharmaceutical chemicals, and end Saperconazole enantiomter 3C (4- [2- [(2S, 3S)-
3- (2,5- difluorophenyl) -3- hydroxyl -4- (1,2,4- triazol-1-yl] -1,3- thiazole-4-yl] benzonitrile) and diastereo-isomerism
Body 3B (4- [2- [(2R, 3S) -3- (2,5- difluorophenyl) -3- hydroxyl -4- (1,2,4- triazol-1-yl] -1,3- thiazole-4-yl]
Benzonitrile), 3D (4- [2- [(2S, 3R) -3- (2,5- difluorophenyl) -3- hydroxyl -4- (1,2,4- triazol-1-yl] -1,3- thiophene
Azoles -4- base] benzonitrile) (three above isomers standard items are purchased from the limited public affairs of Shenzhen's Hengfeng Wanda's biotechnology to standard items
Department) in right amount, dissolved with dilution and be made in every 1mL be containing about each component 10 μ g mixed solution.
The requirement of procedures/systems applicability: sample introduction blank solution, separating degree solution, control are successively distinguished according to chromatographic condition
Solution and test solution record chromatographic process.It is required that blank solution is noiseless, separating degree solution each component separating degree must not be small
In 3.0,5 needle contrast solution of sample introduction is repeated, in the map obtained by 5 needle contrast solutions, RSD≤2.0% of main peak peak area meter.
Impurity calculates: calculating content of isomer with 1% Self-control method
The preparation of the Chinese mugwort Saperconazole hydrobromate of embodiment 1
190mL dehydrated alcohol and 19.0g thioamides II are added in 500mL reaction flask, is warming up to 40~45 DEG C, stirring
After dissolved clarification, be added the bromo- 4 '-cyano-acetophenone of 12.95g2-, at this temperature react 20~for 24 hours.It is depressurized at 40~50 DEG C dense
It is reduced to dry, rises to 50~55 DEG C after 190mL ethyl acetate is added, after stirring precipitates crystal 2h, be down to 15~25 DEG C naturally, continue
Stirring precipitates crystal 4h.Filtering, dry 21.1g end Saperconazole hydrobromate, yield: 67.1%, HPLC:98.72%.1HNMR(400MHZ,DMSO-d6) δ: 8.74 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=8.4Hz, 2H), 8.01 (s, 1H),
7.94 (d, J=8.4Hz, 2H), 7.63 (br, 2H), 7.26-7.33 (m, 1H), 7.17-7.22 (m, 1H), 7.04-7.09 (m,
1H), 4.96 (d, J=14.48Hz, 1H), 4.51 (d, J=14.48Hz, 1H), 4.15 (dd, J1=14.48Hz, J2=
7.12Hz, 1H), 1.19 (d, J=7.12Hz, 3H)
The preparation of the Chinese mugwort Saperconazole hydrobromate of embodiment 2
190mL dehydrated alcohol and 19.0g thioamides II are added in 500mL reaction flask, is warming up to 60~65 DEG C, stirring
After dissolved clarification, be added the bromo- 4 '-cyano-acetophenone of 14.99g2-, at this temperature react 20~for 24 hours.It is depressurized at 40~50 DEG C dense
It is reduced to dry, rises to 50~55 DEG C after 190mL ethyl acetate is added, after stirring precipitates crystal 2h, be down to 15~25 DEG C naturally, continue
Stirring precipitates crystal 4h.Filtering, dry 19.0g end Saperconazole hydrobromate, yield: 60.5%, HPLC:97.37%.
The preparation of the Chinese mugwort Saperconazole hydrobromate of embodiment 3
190mL dehydrated alcohol and 19.0g thioamides II are added in 500mL reaction flask, is warming up to 40~45 DEG C, stirring
After dissolved clarification, be added the bromo- 4 '-cyano-acetophenone of 14.25g2-, at this temperature react 20~for 24 hours.It is depressurized at 40~50 DEG C dense
It is reduced to dry, rises to 50~55 DEG C after 190mL ethyl acetate is added, after stirring precipitates crystal 2h, be down to 15~25 DEG C naturally, continue
Stirring precipitates crystal 4h.Filtering, dry 22.0g end Saperconazole hydrobromate, yield: 69.8%, HPLC:98.07%.
The preparation of the crystal form I of the Chinese mugwort Saperconazole of embodiment 4
The 21.0g Chinese mugwort Saperconazole hydrobromate of 220mL ethyl acetate and the preparation of embodiment 1 is added in 500mL reaction flask,
It is neutralized with 210mL saturated sodium bicarbonate, layering, organic phase 210mL saturated common salt water washing, anhydrous sodium sulfate is dry.
Filtering, filtrate are concentrated to dryness at 40~50 DEG C, and 42mL dehydrated alcohol is added, is warming up to 60~65 DEG C of stirrings
1.05g active carbon is added after dissolved clarification, keeps the temperature 1h, heat filtering, filter cake is washed with 10mL dehydrated alcohol.
Filtrate is warming up to 60~65 DEG C, 26mL purified water is slowly added dropwise at this temperature, continues to keep the temperature 1h, it is then natural
Be down to 15~25 DEG C continue stirring precipitate crystal for 24 hours, filtering, filter cake 21mL ethyl alcohol: water (2:1, v/v) washing, obtained filter
Cake is dried under reduced pressure 8h at 40~50 DEG C, obtains 14.0g off-white powder, and XRPD is confirmed as Chinese mugwort Saperconazole crystal form I.Yield: 75.4%,
HPLC purity: 99.89%, ee value: 99.92%.1HNMR(400MHZ,DMSO-d6)δ:8.41(s,1H),8.25(s,1H),
8.20 (d, J=8.52Hz, 2H), 7.92 (d, J=8.52Hz, 2H), 7.65 (s, 1H), 7.22-7.28 (m, 1H), 7.13-
7.18 (m, 1H), 7.04-7.09 (m, 1H), 6.15 (s, 1H), 4.92 (d, J=14.48Hz, 1H), 4.41 (d, J=
14.48Hz,1H),4.14(dd,J1=14.48Hz, J2=7.2Hz, 1H), 1.17 (d, J=7.2Hz, 3H)
The preparation of the crystal form I of the Chinese mugwort Saperconazole of embodiment 5
The 19.0g Chinese mugwort Saperconazole hydrobromate of 190mL ethyl acetate and the preparation of embodiment 2 is added in 500mL reaction flask,
It is neutralized with 190mL saturated sodium bicarbonate, layering, organic phase 190mL saturated common salt water washing, anhydrous sodium sulfate is dry.
Filtering, filtrate are concentrated to dryness at 40~50 DEG C, and 38mL dehydrated alcohol is added, it is molten to rise to 60~65 DEG C of stirrings
0.95g active carbon is added after clear, keeps the temperature 1h, heat filtering, filter cake is washed with 9mL dehydrated alcohol.
Filtrate is warming up to 60~65 DEG C, 47mL purified water is slowly added dropwise at this temperature, continues to keep the temperature 1h, it is then natural
Be down to 10~15 DEG C continue stirring precipitate crystal for 24 hours, filtering, filter cake 19mL ethyl alcohol: water (1:1, v/v) washing, obtained filter
Cake is dried under reduced pressure 8h at 40~50 DEG C, obtains 14.85g off-white powder, and XRPD is confirmed as Chinese mugwort Saperconazole crystal form I.Yield:
92.6%, HPLC purity: 99.80%, ee value: 99.90%.
The preparation of the crystal form I of the Chinese mugwort Saperconazole of embodiment 6
The 22.0g Chinese mugwort Saperconazole hydrobromate of 220mL ethyl acetate and the preparation of embodiment 3 is added in 500mL reaction flask,
It is neutralized with 220mL saturated sodium bicarbonate, layering, organic phase 220mL saturated common salt water washing, anhydrous sodium sulfate is dry.
Filtering, filtrate are concentrated to dryness at 40~50 DEG C, and 44mL dehydrated alcohol is added, is warming up to 60~65 DEG C of stirrings
1.1g active carbon is added after dissolved clarification, keeps the temperature 1h, heat filtering, filter cake is washed with 11mL dehydrated alcohol.
Filtrate is warming up to 60~65 DEG C, 55mL purified water is slowly added dropwise at this temperature, continues to keep the temperature 1h, it is then natural
Be down to 15~25 DEG C continue stirring precipitate crystal for 24 hours, filtering, filter cake 22mL ethyl alcohol: water (1:1, v/v) washing, obtained filter
Cake is dried under reduced pressure 8h at 40~50 DEG C, obtains 17.0g off-white powder, i.e. Chinese mugwort Saperconazole crystal form I.Yield: 91.6%, HPLC are pure
Degree: 99.95%, ee value: 99.91%.The XRPD map, TGA map and DSC map for measuring it, are shown in Fig. 1, Fig. 2 and Fig. 3 respectively,
It is almost the same with the XRPD map, TGA map and DSC map of the Chinese mugwort Saperconazole crystal form I in embodiment 4 and 5, it can be seen that,
It is really Chinese mugwort Saperconazole crystal form I.Wherein, the specific data of the XRPD map of Fig. 1 are as shown in table 2.
Table 2
Embodiment 7
190mL dehydrated alcohol and 19.0g thioamides II are added in 500mL reaction flask, is warming up to 40~45 DEG C, stirring
After dissolved clarification, be added the bromo- 4 '-cyano-acetophenone of 14.25g2-, at this temperature react 20~for 24 hours.It is depressurized at 40~50 DEG C dense
It is reduced to dry, rises to 50~55 DEG C after 190mL ethyl acetate is added, after stirring precipitates crystal 2h, be down to room temperature naturally, continue to stir
Precipitate crystal 4h.Filtering, obtained filter cake is added into the reaction flask for having 220mL ethyl acetate, with 220mL saturated sodium bicarbonate
It neutralizes, layering, organic phase 220mL saturated common salt water washing, anhydrous sodium sulfate is dry.
Filtering, filtrate are concentrated to dryness at 40~50 DEG C, and 44mL dehydrated alcohol is added, is warming up to 60~65 DEG C of stirrings
1.1g active carbon is added after dissolved clarification, keeps the temperature 1h, heat filtering, filter cake is washed with 11mL dehydrated alcohol.
Filtrate is warming up to 60~65 DEG C, 55mL purified water is slowly added dropwise at this temperature, continues to keep the temperature 1h, it is then natural
Be down to 15~25 DEG C continue stirring precipitate crystal for 24 hours, filtering, filter cake 22mL ethyl alcohol: water (1:1, v/v) washing, obtained filter
Cake is dried under reduced pressure 8h at 40~50 DEG C, obtains 17.2g off-white powder, i.e. Chinese mugwort Saperconazole crystal form I.Yield: 61.9%, HPLC are pure
Degree: 99.96%, ee value: 99.93%.
Embodiment 8
Be added in 500mL reaction flask Chinese mugwort Saperconazole crude product of the 20.0g purchased from the white medical limited liability company of member in Shanghai and
60mL purified water is slowly added dropwise at this temperature, continues to keep the temperature after being warming up to 60~65 DEG C of stirring dissolved clarifications for 60mL dehydrated alcohol
1h, be then down to naturally 15~25 DEG C continue stirring precipitate crystal for 24 hours, filtering, filter cake 22mL ethyl alcohol: water (1:1, v/v) is washed
It washs, obtained filter cake is dried under reduced pressure 8h at 40~50 DEG C, obtains 18.2g off-white powder, i.e. Chinese mugwort Saperconazole crystal form I.Yield:
91.0%, HPLC purity: 99.96%, ee value: 99.98%.
Comparative example
10g Chinese mugwort Saperconazole crystal form I prepared by Example 6, is dissolved in 100mL dichloromethane solution, 35~40
It is concentrated to dryness at DEG C, the amorphous article for the Saperconazole that must end.The XRPD map for measuring it, is shown in Fig. 4.
Test case
In addition, Chinese mugwort Saperconazole crystal form I in order to better illustrate the present invention is with good stability, embodiment 4 is made
The amorphous article of standby Chinese mugwort Saperconazole crystal form I and the homemade Chinese mugwort Saperconazole of comparative example has carried out comparative experiments.Stability test side
Method:
Draw moist: being tested according to Chinese Pharmacopoeia four 9103 drug draws moist test guidelines of version in 2015；
High humidity test: taking sample to be placed in weighing bottle in right amount, and opening is placed under the conditions of 25 DEG C/90% ± 5%RH, detects
5th day and 10 days purity, chirality and content, compared with the 0th day sample；
Hot test: taking sample to be placed in weighing bottle in right amount, and opening is placed in 60 DEG C of insulating boxs, detects the 5th day and 10
It purity, chirality and content, compared with the 0th day sample；
Exposure experiments to light: taking sample to be placed in weighing bottle in right amount, and opening is placed in the lighting box of illumination 4500Lx ± 500Lx
In, purity, chirality and the content of detection the 5th day and 10 days, compared with the 0th day sample.
Accelerated test: taking sample to be placed in weighing bottle in right amount, and opening is placed under the conditions of 40 ± 2 DEG C/75% ± 5%RH,
Detect purity, chirality and the content of 1M, 2M and 3M.
Saperconazole amorphous article is ended with Chinese mugwort Saperconazole crystal form I of the invention by Experimental Comparison, and obtained result is as follows:
Table 3
Table 4
By upper table 3 and table 4 as it can be seen that Chinese mugwort Saperconazole crystal form I of the invention high temperature, high humidity, illumination condition stability inferior compared with
The Saperconazole that ends is unformed more preferable, and also has more good stability in the accelerated test of 3M.
Claims (10)
1. a kind of crystal form I for the Saperconazole that ends, which is characterized in that the crystal form I is in the X-ray powder diffraction indicated with 2 θ angles
Map is at about 9.207 ° ± 0.2.,10.177°±0.2.,10.507°±0.2.,13.664°±0.2.,17.761±0.2.,
18.324°±0.2.,21.063°±0.2.,22.290°±0.2.,31.673°±0.2.,38.538°±0.2.There is feature at place
Peak.
2. the crystal form I of Chinese mugwort Saperconazole as described in claim 1, which is characterized in that the X-ray powder diffraction of the crystal form I
Map is about also 21.173 ° ± 0.2 at 2 angle θ of angle of diffraction.,22.961°±0.2.,23.888°±0.2.,24.608°±
0.2。、25.374°±0.2。、25.662°±0.2。、27.598°±0.2。、28.110°±0.2。、29.518°±0.2。、
30.388°±0.2.,37.104°±0.2.There is characteristic peak at place.
3. the crystal form I of Chinese mugwort Saperconazole as described in claim 1, which is characterized in that the X-ray powder diffraction of the crystal form I
Map has X-ray powder diffraction collection substantially as shown in Fig. 1.
4. the crystal form I of Chinese mugwort Saperconazole as described in claim 1, which is characterized in that the fusing point of the crystal form I is about
121.97±1℃。
5. a kind of method for preparing the crystal form I such as the described in any item Chinese mugwort Saperconazoles of Claims 1 to 4, which is characterized in that described
Method includes:
(d) Chinese mugwort Saperconazole crude product is added in intensive polar solvent and is dissolved by heating, obtain solution；
(e) into solution made from step (d), poor solvent is added, the temperature for being naturally cooling to precipitate crystal precipitates crystal, mistake
Filter, the crystal form I of dry Chinese mugwort Saperconazole.
6. the method for the crystal form I of preparation Chinese mugwort Saperconazole as claimed in claim 5, which is characterized in that
In step (d),
The intensive polar solvent is selected from one or more of methanol, ethyl alcohol, isopropanol, tetrahydrofuran, the dissolution
Temperature be 40~80 DEG C；
The w/v of the Chinese mugwort Saperconazole crude product and intensive polar solvent is 1Kg:(2~3) L；
In step (e),
The poor solvent is selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), water；
The temperature precipitated crystal is 0~25 DEG C；
The w/v of the Chinese mugwort Saperconazole crude product and poor solvent is 1Kg:(1~3) L.
7. the method for the crystal form I of preparation Chinese mugwort Saperconazole as claimed in claim 5, which is characterized in that
In step (d),
The intensive polar solvent is ethyl alcohol；The temperature of the dissolution is 60~65 DEG C；
In step (e),
The poor solvent is water；
The temperature precipitated crystal is 10~25 DEG C.
8. the method for the crystal form I of preparation Chinese mugwort Saperconazole as claimed in claim 5, which is characterized in that also wrapped before step (d)
Include following steps:
(a) in a solvent, thioamides II and the bromo- 4'- cyano-acetophenone of 2- are added, condensation reaction occurs for heating, must react
Liquid；
(b) reaction solution of concentration step (a), crystallizes in organic solvent, and filtering, must end Saperconazole hydrobromate；
(c) by step (b) the Saperconazole hydrobromate alkali process obtained that ends, extraction obtains Chinese mugwort Saperconazole crude product.
9. the method for the crystal form I of preparation Chinese mugwort Saperconazole as claimed in claim 8, which is characterized in that
In step (a),
The reaction temperature of the condensation reaction is 30~65 DEG C, and the reaction time is 20~24 hours；
The solvent is selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), ethyl alcohol；
The molar ratio of the thioamides II and the bromo- 4'- cyano-acetophenone of 2- is 1:0.95~1:1.3；
In step (b),
The organic solvent is selected from one or more of petroleum ether, n-hexane, methyl tertiary butyl ether(MTBE), ethyl acetate；
The crystallization is two sections of crystallizations, first precipitates crystal at 40~55 DEG C, is then cooled to 15~25 DEG C again and continues to precipitate crystal；
The time of the crystallization is 3~24 hours；
In step (c),
The alkali is selected from one or more of sodium bicarbonate, sodium carbonate, sodium hydroxide.
10. the method for the crystal form I of preparation Chinese mugwort Saperconazole as claimed in claim 8, which is characterized in that
In step (a),
The reaction temperature of the condensation reaction is 40~45 DEG C,
The solvent is ethyl alcohol；
The molar ratio of the thioamides II and the bromo- 4'- cyano-acetophenone of 2- is 1:1.05~1:1.1；
In step (b),
The organic solvent is ethyl acetate；
The crystallization is at 40~55 DEG C, and stirring precipitates crystal 1~4h, is down to 15~25 DEG C naturally, continue to precipitate crystal 2~
6h；
In step (c),
The alkali is selected from one or both of sodium bicarbonate and sodium carbonate.
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| CN106317044A (en) * | 2015-06-30 | 2017-01-11 | 刘玫君 | Method for manufacturing isavuconazole or ravuconazole |
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| CN106749221A (en) * | 2016-12-15 | 2017-05-31 | 扬子江药业集团有限公司 | Chinese mugwort Saperconazole monohydrate crystal form and preparation method thereof |
| CN106749222A (en) * | 2016-12-15 | 2017-05-31 | 重庆东得医药科技有限公司 | Crystal formation A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117330660A (en) * | 2023-09-14 | 2024-01-02 | 广州医科大学附属第一医院（广州呼吸中心） | Method for detecting isaconazole by UPLC-MS/MS combination and application |
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