CN106905320A - It is a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong - Google Patents
It is a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong Download PDFInfo
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- CN106905320A CN106905320A CN201510980745.3A CN201510980745A CN106905320A CN 106905320 A CN106905320 A CN 106905320A CN 201510980745 A CN201510980745 A CN 201510980745A CN 106905320 A CN106905320 A CN 106905320A
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- buddhist nun
- shandong
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 239000012046 mixed solvent Substances 0.000 claims description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000001291 vacuum drying Methods 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000000463 material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 8
- 238000005457 optimization Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 30
- 238000005755 formation reaction Methods 0.000 description 30
- 238000003756 stirring Methods 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- JINGTHAMOZKCNR-UHFFFAOYSA-N C(=O)OC(C)(C)C.OC1CNCCC1 Chemical class C(=O)OC(C)(C)C.OC1CNCCC1 JINGTHAMOZKCNR-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- SXWZKIXXIJHINC-UHFFFAOYSA-N [N].C1(=CC=CC=C1)CCCC(=O)O Chemical compound [N].C1(=CC=CC=C1)CCCC(=O)O SXWZKIXXIJHINC-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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 provides and a kind of is adapted to medicinal replace Buddhist nun and its preparation according to Shandong.It is described low for Buddhist nun's impurity content according to Shandong, thus drug safety is higher.Of the invention to replace Buddhist nun's preparation process is simple according to Shandong, with low cost, optimization and exploitation to medicine have important value.
Description
Technical field
It is more particularly to a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong the present invention relates to chemical medicine.
Background technology
B cell malignant tumour includes chronic lymphocytic leukemia (CLL), ALL (ALL), small pouring
Bar cell lymphoma (SLL), lymphoma mantle cell (MCL), follicular lymphoma (FL), Diffuse Large B-Cell Lymphoma
(DLBCL), Huppert's disease (MM) andMacroglobulinemia (WM).Traditional treatment includes benzenebutanoic acid nitrogen
The cell toxicity medicaments such as mustard, endoxan, fludarabine and bendamustine.Though these conventional medicaments can relief of symptoms, not
The survival of patients time can effectively be extended.And some patients are poor to chemotherapy side effect, it is bad that patients with recurrent there is also chemotherapeutics
Significant reaction increases and antitumor curative effect is reduced etc..
Molecular targeted therapy new drug is according to Shandong for Buddhist nun's (ibrutinib) (formula 1) for Bruton EGFR-TKs (BTK) suppress
Agent, its cancer cell that is accurately located at fast-growth different from cellulotoxic chemotherapeutics can avoid the injury to normal cell,
Reduce the toxic and side effects such as alopecia, gastrointestinal reaction and the bone marrow suppression of classic chemotherapy medicine.Controlled as MCL and CLL for Buddhist nun according to Shandong
Treat medicine and first obtain FDA (Food and Drug Adminstration) (FDA) approval after in November, 2013 and 2 months 2014.The FDA of in January, 2015
The application for expanding idicatio for Buddhist nun according to Shandong is have approved again, i.e., for treating WM.
There are various crystal formations for Buddhist nun's compound according to Shandong.Patent application CN104736178A discloses anhydrous for 3 kinds of Buddhist nun according to Shandong
Compound crystal formation (respectively crystal formation A, crystal formation B, crystal formation C) and 3 kinds of solvate crystal formations (respectively MIBK solvates crystal formation D, first
Solvate crystal formation E, Methanol solvate crystal formation F), wherein, use recrystallisation solvent methyl tertiary butyl ether(MTBE) (MTBE), diisopropyl
Ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl iso-butyl ketone (MIBK) (MIBK), methyl ethyl ketone (MEK), acetone,
Methyl alcohol, nitromethane, 10% water propanone or 10% aqueous isopropanol replace Buddhist nun A to amorphous can acquisition for Buddhist nun's crystallization according to Shandong according to Shandong
Crystal formation.According to Shandong for Buddhist nun's A crystal formations X-ray powder diffraction (XRPD) figure 2- θ values be 5.7 ± 0.1 °, 13.6 ± 0.1 °, 16.1 ±
There is characteristic peak at 0.1 °, 18.9 ± 0.1 °, 21.3 ± 0.1 ° and 21.6 ± 0.1 °.
Found by the research to various recrystallisation solvents, methyl alcohol, water mixed solvent have more excellent Impurity removal effect, energy
Obtain high-purity replaces Buddhist nun's A crystal formations according to Shandong, and crystallized product HPLC purity is more than 99%.And methanol prices are cheap, it is suitable for work
Industry metaplasia is produced.But, obtain not good for Buddhist nun's sample appearance according to Shandong is crystallized with methyl alcohol, water mixed solvent, easily form larger hard
Block, moisture is difficult removal, and the undue drying temperature or extension time of improving can influence to replace the stability of Buddhist nun according to Shandong；And these are larger
Solubility property is poor after lump drying.
CN104327085A discloses a kind of height of the mixed crystallization solvent preparation of use isopropanol or acetone and normal heptane
Solubility replaces Buddhist nun's crystal formation according to Shandong, and compared with the crystal formation A of patent WO2013184572A1, the crystal formation solubility of CN104327085 exists
0.15mg/L is brought up to from 0.1mg/L in the simulated intestinal fluid of pH5.0, is brought up to from 0.36mg/L in the simulated gastric fluid of pH1.8
0.5mg/L.The new crystal form X ray powder diffraction pattern of CN104327085A 2- θ values be 5.2 ° ± 0.2 °, 17.6 ° ± 0.2 °,
22.1 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.4 ° ± 0.2 °, there is at 20.8 ° ± 0.2 ° characteristic peak, and CN104736178A A
Crystal formation characteristic peak is entirely different, and actually two kinds different to replace Buddhist nun's crystal formation according to Shandong.
The content of the invention
Found by numerous studies, crystallized with methyl alcohol, water mixed solvent for Buddhist nun according to Shandong and only produce a kind of crystal formation, and use third
Ketone, normal heptane mixed solvent crystallization can produce two kinds of different crystal forms.Inventor surprisingly, it is found that, optimization acetone, normal heptane
The crystallization processes parameter of mixed solvent, particularly described acetone, normal heptane mixed solvent and Yi Lu for Buddhist nun ratio for 5ml/g~
50ml/g, can obtain with CN104736178A have same characteristic features peak according to Shandong replace Buddhist nun's A crystal formations.Although A crystal formations of the present invention and
The crystal formation of CN104327085A is two kinds of different crystal formations, but A crystal formations outward appearance of the invention is good, and particle is uniform, soluble, molten
Solution property is significantly higher than the crystallized product of methyl alcohol, water mixed solvent.Also, acetone, normal heptane mixed solvent be not aqueous, crystallization is easily dried
It is dry.
The present invention provide it is a kind of be adapted to it is medicinal according to Shandong for Buddhist nun preparation method, its preparation method comprises the following steps：
(1) first crystallized with methyl alcohol, water mixed solvent；
(2) acetone, normal heptane mixed solvent crystallization, the acetone, normal heptane mixed solvent and Yi Lu is used to replace the ratio of Buddhist nun again
Example is 5ml/g~50ml/g；
(3) removal recrystallisation solvent is dried, is obtained and is adapted to medicinal replace Buddhist nun according to Shandong.
Methyl alcohol, water volume ratio are preferably 1 described in the step (1):1~10:1, more preferably 1:1~4:1；
Methyl alcohol, water mixed solvent and Yi Lu described in the step (1) are preferably 1ml/g~100ml/g for the ratio of Buddhist nun,
More preferably 5ml/g~50ml/g；
Acetone, normal heptane volume ratio are preferably 1 described in the step (2):1~1:10, more preferably 1:1~1:4；
The drying mode is preferably constant pressure and dry or drying under reduced pressure, is more preferably vacuum dried.
The vacuum drying temperature is preferably 10 DEG C~70 DEG C, more preferably 20 DEG C~60 DEG C, more preferably 25 DEG C~50 DEG C.
Enter on the one hand, the present invention provide it is a kind of be adapted to it is medicinal according to Shandong for Buddhist nun preparation method, its preparation method include it is as follows
Step：
(1) take according to Shandong for Buddhist nun's crude product, it is 1 to add volume ratio:1~4:1 methyl alcohol, water mixed solvent, filter after being sufficiently stirred for
Obtain solid, vacuum drying；
(2) to learn from else's experience and add volume ratio 1 for Buddhist nun according to Shandong after drying:1~1:4 acetone, normal heptane mixed solvent, are sufficiently stirred for
After be filtrated to get solid, the acetone, normal heptane mixed solvent and Yi Lu are 5ml/g~50ml/g for the ratio of Buddhist nun；
(3) vacuum drying removal recrystallisation solvent, obtains and is adapted to medicinal replace Buddhist nun according to Shandong.
Enter on the one hand, preparation method of the present invention according to Shandong for Buddhist nun comprises the following steps：
(1) take according to Shandong for Buddhist nun's crude product, it is 1 to add volume ratio:1~4:1 methyl alcohol, water mixed solvent, filter after being sufficiently stirred for
Obtain solid, 25 DEG C~50 DEG C vacuum dryings；
(2) to learn from else's experience and add volume ratio 1 for Buddhist nun according to Shandong after drying:1~1:4 acetone, normal heptane mixed solvent, are sufficiently stirred for
After be filtrated to get solid, the acetone, normal heptane mixed solvent and Yi Lu are 5ml/g~50ml/g for the ratio of Buddhist nun；
(3) 25 DEG C~50 DEG C vacuum drying removal recrystallisation solvents, obtain and are adapted to medicinal replace Buddhist nun according to Shandong.
Activated carbon decolorizing can be added in crystallization process, but it is inessential；Can also add crystal seed in crystallization process, but it is non-must
Will.
The present invention provide it is a kind of be adapted to it is medicinal according to Shandong for Buddhist nun preparation method, by increasing acetone and normal heptane mixed solvent
Crystallisation step, improves the deficiency of methyl alcohol, water mixed solvent crystallized product in terms of moisture and solubility, obtains with high-purity
With high-dissolvability Buddhist nun is replaced according to Shandong.The order of the two-step crystallization step is extremely important, and the present invention can not be obtained after putting the cart before the horse
It is adapted to medicinal replace Buddhist nun according to Shandong.
The present invention can be also removed effectively according to Shandong for the impurity in Buddhist nun.In single step acetone of the invention, normal heptane mixed solvent
Under 4 Crystallization, the A crystal formation HPLC purity for obtaining only has 95%.Using methyl alcohol, water mixed solvent can effectively remove according to
Moisture removal is effectively removed in Shandong then for water soluble salt and organic impurities in Buddhist nun's crude product using acetone and normal heptane mixed solvent,
Finally vacuum drying removal residual recrystallisation solvent.What the present invention was obtained can reach more than 99.5% according to Shandong for Buddhist nun's purity, and single miscellaneous
Less than 0.1%.
It is adapted to medicinal replace Buddhist nun according to Shandong the invention provides a kind of.With A crystal formations disclosed in prior art according to Shandong for Buddhist nun compared with,
It is of the invention low for Buddhist nun's impurity content according to Shandong, thus medicine stability is good, it is safe；And high-purity of the invention replaces Buddhist nun according to Shandong
Solubility is high, is conducive to improving drug effect, reduces drugloading rate.High-purity of the invention replaces Buddhist nun's preparation process is simple, low cost according to Shandong
Honest and clean, optimization and exploitation to medicine have important value.The preparation method is simple, effective, is adapted to large-scale industrial production,
With larger commercial application value.
On the other hand, Buddhist nun's preparation is replaced according to Shandong the invention provides one kind, the preparation is by the described high-purity of therapeutically effective amount
Du Yilu is mixed for Buddhist nun with one or more pharmaceutic adjuvant.
Brief description of the drawings
Fig. 1 schemes for the XRPD of inventive samples
Specific embodiment
The specific embodiment of form, makees further specifically to the above of the invention by the following examples
It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following examples.
Embodiment 1
According to Shandong for Buddhist nun as prepared by the method described in Chinese patent application CN101610676B.By 101g 4- amino -3-
(4- Phenoxyphenyls) -1H- pyrazolos [3,4-d] pyrimidine and 330g polymer connect triphenyl phasphine (TPP) (polymerlab) with
5L tetrahydrofurans (THF) are mixed.To sequentially adding 3- hydroxy piperidine -1- t-butyl formates (200g in gained mixture；
2.0 equivalents), diisopropyl azodiformate (99mL).The reactant mixture is stirred at room temperature overnight.The reaction is filtered to mix
Compound, then with purified by flash chromatography (pentane/ethyl acetate=1/1), is obtained with removing resin, and concentrated reaction mixture
Intermediate (55g).Above-mentioned intermediate (48.3g) is processed 1 hour with the 4N HCl/ dioxane solutions of 1L, is then concentrated to dryness.
Residue is dissolved in dichloromethane, adds triethylamine (42mL), is subsequently added into acryloyl chloride (10mL).Terminate this after 2 hours anti-
Should.The reactant mixture is washed with 5% (weight) aqueous citric acid solution, then uses salt water washing.Organic layer is dried simultaneously through MgSO4
Concentration, obtains according to Shandong for Buddhist nun's crude product, and HPLC purity is 90%.
Embodiment 2
Take and replace Buddhist nun crude product 20g according to Shandong according to prepared by embodiment 1,200ml methyl alcohol is dissolved under stirring, under being stirred after dissolving
100ml water is added dropwise over, 3h is kept stirring for after adding, be filtrated to get solid, 45 DEG C of vacuum dryings.What is dried replaces Buddhist nun's solid according to Shandong
Containing larger agglomerate thing, dissolubility is bad.
Embodiment 3
Take and add 100ml acetone and 100ml normal heptanes for Buddhist nun's crude product 10g according to Shandong according to prepared by embodiment 1, stir at room temperature
4h is mixed, solid is filtrated to get, 50 DEG C of vacuum drying 4h, obtain A crystal formations replaces Buddhist nun according to Shandong, described small and equal for Buddhist nun's particle according to Shandong
Even, dissolubility is good.
Embodiment 4
Take and replace Buddhist nun crude product 20g according to Shandong according to prepared by embodiment 1,200ml methyl alcohol is dissolved under stirring, under being stirred after dissolving
100ml water is added dropwise over, 3h is kept stirring for after adding, be filtrated to get solid, 45 DEG C of vacuum dryings.
Learn from else's experience and add 50ml acetone and 100ml normal heptanes for Buddhist nun 10g according to Shandong after drying, 4h is stirred at room temperature, filter
To solid, 30 DEG C of vacuum drying 4h, the high-purity for obtaining A crystal formations replaces Buddhist nun according to Shandong, and HPLC purity is 99.6%, and all impurity are equal
Less than 0.1%.
Embodiment 5
Take and replace Buddhist nun crude product 15g according to Shandong according to prepared by embodiment 1,400ml methyl alcohol is dissolved under stirring, under being stirred after dissolving
100ml water is added dropwise over, 4h is kept stirring for after adding, be filtrated to get solid, 30 DEG C of vacuum dryings.
Learn from else's experience and add 25ml acetone and 25ml normal heptanes for Buddhist nun 10g according to Shandong after drying, 3h is stirred at room temperature, be filtrated to get
Solid, room temperature in vacuo dries 6h, and obtain A crystal formations replaces Buddhist nun according to Shandong, and sample HPLC purity is 99.7%, and all impurity are below
0.1%.
Embodiment 6
Take and replace Buddhist nun crude product 30g according to Shandong according to prepared by embodiment 1,100ml methyl alcohol is dissolved under stirring, under being stirred after dissolving
100ml water is added dropwise over, 3h is kept stirring for after adding, be filtrated to get solid, 50 DEG C of vacuum dryings.
Learn from else's experience and add 50ml acetone and 200ml normal heptanes for Buddhist nun 5g according to Shandong after drying, 4h is stirred at room temperature, be filtrated to get
Solid, 50 DEG C of vacuum drying 8h, obtain A crystal formations replaces Buddhist nun according to Shandong, and sample HPLC purity is 99.7%, and all impurity are below
0.1%.
Embodiment 7
Carry out X-ray powder diffraction for Buddhist nun's sample according to Shandong by what embodiment 2~6 was obtained, collection of illustrative plates 2- θ values be 5.7 ±
There is characteristic peak at 0.1 °, 13.6 ± 0.1 °, 16.1 ± 0.1 °, 18.9 ± 0.1 °, 21.3 ± 0.1 ° and 21.6 ± 0.1 °, and specially
The crystal formation A of profit application CN104736178A is consistent.The sample collection of illustrative plates of embodiment 3 refers to accompanying drawing 1.
Claims (10)
1. it is a kind of be adapted to it is medicinal according to Shandong for Buddhist nun preparation method, it is characterised in that：
(1) first crystallized with methyl alcohol, water mixed solvent；
(2) use acetone, normal heptane mixed solvent crystallization, the acetone, normal heptane mixed solvent and Yi Lu again is for the ratio of Buddhist nun
5ml/g~50ml/g；
(3) removal recrystallisation solvent is dried, is obtained and is adapted to medicinal replace Buddhist nun according to Shandong.
2. method according to claim 1, it is characterised in that：Methyl alcohol, water volume ratio described in the step (1) are 1:1
~10:1.
3. method according to claim 1, it is characterised in that：Methyl alcohol described in the step (1), water mixed solvent and according to
Shandong is 1ml/g~100ml/g for the ratio of Buddhist nun.
4. method according to claim 1, it is characterised in that：Acetone, normal heptane volume ratio are 1 in the step (2):1
~1:10.
5. method according to claim 1, it is characterised in that：The drying mode is vacuum drying.
6. method according to claim 1, it is characterised in that：The vacuum drying temperature is 10 DEG C~70 DEG C.
7. method according to claim 1, it is characterised in that：
(1) take according to Shandong for Buddhist nun's crude product, it is 1 to add volume ratio:1~4:1 methyl alcohol, water mixed solvent, are filtrated to get after being sufficiently stirred for
Solid, vacuum drying；
(2) to learn from else's experience and add volume ratio 1 for Buddhist nun according to Shandong after drying:1~1:4 acetone, normal heptane mixed solvent, mistake after being sufficiently stirred for
Filter obtains solid, and the acetone, normal heptane mixed solvent and Yi Lu are 5ml/g~50ml/g for the ratio of Buddhist nun；
(3) vacuum drying removal recrystallisation solvent, obtains and is adapted to medicinal replace Buddhist nun according to Shandong.
8. method according to claim 1, it is characterised in that：
(1) take according to Shandong for Buddhist nun's crude product, it is 1 to add volume ratio:1~4:1 methyl alcohol, water mixed solvent, are filtrated to get after being sufficiently stirred for
Solid, 25 DEG C~50 DEG C vacuum dryings；
(2) to learn from else's experience and add volume ratio 1 for Buddhist nun according to Shandong after drying:1~1:4 acetone, normal heptane mixed solvent, mistake after being sufficiently stirred for
Filter obtains solid, and the acetone, normal heptane mixed solvent and Yi Lu are 5ml/g~50ml/g for the ratio of Buddhist nun；
(3) 25 DEG C~50 DEG C vacuum drying removal recrystallisation solvents, obtain and are adapted to medicinal replace Buddhist nun according to Shandong.
9. it is a kind of be adapted to it is medicinal replace Buddhist nun according to Shandong, it is prepared by any one of the claim 1~8 method.
10. one kind replaces Buddhist nun's preparation according to Shandong, medicinal with one or more for Buddhist nun according to Shandong described in the claim 9 by therapeutically effective amount
Auxiliary material is mixed.
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| CN201510980745.3A CN106905320A (en) | 2015-12-23 | 2015-12-23 | It is a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong |
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