CN106220626A - A kind of polymorphic of Pabuk former times profit cloth and preparation method thereof - Google Patents
A kind of polymorphic of Pabuk former times profit cloth and preparation method thereof Download PDFInfo
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- CN106220626A CN106220626A CN201610624450.7A CN201610624450A CN106220626A CN 106220626 A CN106220626 A CN 106220626A CN 201610624450 A CN201610624450 A CN 201610624450A CN 106220626 A CN106220626 A CN 106220626A
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- former times
- solvent
- pabuk former
- profit cloth
- times profit
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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 present invention relates to polymorphic of a kind of Pabuk former times profit cloth and preparation method thereof.In X-ray powder diffraction figure, angle represents with 2 θ, at 7.17 °, 7.62 °, 7.82 °, 8.49 °, 11.62 °, 11.81 °, 12.62 °, 22.96 °, 25.10 °, having characteristic peak near 25.63 °, 2 θ can have ± 0.2 ° of deviation, and differential scanning calorimetric thermogram shows one exothermic peak of appearance near 207 DEG C.The preparation method of crystal formation C disclosed by the invention is simple to operate, and solvent load is few and nontoxic, and production cost is low, has clear superiority in terms of industrialization, and whole novel crystalline form preparation technology achieves substantial progress, and technique has marked improvement.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to polymorphic and the preparation side thereof of a kind of Pabuk former times profit cloth
Method.
Background technology
Pabuk former times profit cloth, chemical entitled 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-
Base] amino]-8H-pyrido [2,3-D] pyrimidin-7-ones, structure formula (I) is as follows:
This medicine is developed by Pfizer, is in the February, the 2015 CDK4/6 inhibitor by the first approval of U.S. FDA,
Late period or transitivity ER for menopausal women+/HER2-Breast carcinoma, Pabuk former times profit cloth (Palbociclib) is a kind of breakthrough
Property, oral, targeting CDK4/6 specific inhibitor, for Selective depression cell cycle protein dependent kinase 4 and 6
(CDK4/6), recovering cell cycle and control, block the first-line treatment of tumor cell proliferation, the research of this new drug is successfully transitivity
Patient with breast cancer provide one important the newly selected, therefore there is wide market prospect.
World patent WO2014128588A1 discloses the free alkali crystal formation A and crystal formation B of Pabuk former times profit cloth.The X powder of crystal formation A
End diffraction pattern about 8.0 °, 10.1 °, 10.3 ° and 11.5 ° ± 2 θ of 0.2 ° of deviation at there is characteristic peak；The X powder of crystal formation B
Diffraction pattern about 6.0 °, 10.9 °, 12.8 °, 16.4 ° and 19.8 ° ± 2 θ of 0.2 ° of deviation at there is characteristic peak.The product of preparation
Through influence factor's experiment investigation such as high temperature, high humidity, illumination after product, the change of its impurity has the trend of rising.
The X-ray diffraction spectrogram of Chinese patent CN 105085517A free alkali hydrate includes shown in following 2 θ angles
Characteristic peaks: 5.7 °, 7.8 °, 8.3 °, 8.9 °, 11.4 °, 13.1 ° and 16.7 °, 2 θ value degree of accuracy are ± 0.2 °, its preparation technology
Separating out from the aqueous solution rich in inorganic salt, can bring the risk that residue on ignition exceeds standard, the product of preparation does not carries out preparation dissolution
Prescription contrast is ground, it is impossible to guarantee to reach the requirement of medicinal crystal-form with former.
In sum, the Pabuk former times profit cloth crystal formation kind of current document report is few, but this curative effect of medication is notable, before market
Scape is vast, therefore develops new Pabuk former times profit cloth medicinal crystal-form and is very important.
Summary of the invention
The invention discloses the polymorphic of a kind of Pabuk former times profit cloth, abbreviation crystal formation C:
Pabuk former times profit cloth crystal formation C is in X-ray powder diffraction figure, and angle represents with 2 θ, at 7.17 °, and 7.62 °, 7.82 °,
8.49 °, 11.62 °, 11.81 °, 12.62 °, 22.96 °, 25.10 °, there is near 25.63 ° characteristic peak, general 2 θ can have ±
0.2 ° of deviation, the differential scanning calorimetric thermogram of Pabuk former times profit cloth crystal formation C shows one exothermic peak of appearance near 207 DEG C.
The invention discloses the polymorphic preparation method of a kind of Pabuk former times profit cloth, including: by Pabuk former times profit cloth one definite proportion
The good solvent of example and the mixed solvent of atent solvent are warming up to 40～60 DEG C, after being completely dissolved, are naturally cooling to room temperature, add
After crystal seed, it is cooled to-20 DEG C～10 DEG C of crystallizes, filters, be vacuum dried and get final product.
Preferably, described good solvent is a kind of in DMF or dichloromethane, and atent solvent is acetone
Or it is a kind of in ethanol.
Preferably, described good solvent is DMF, and atent solvent is acetone.
Preferably, described good solvent is 1:10～1: 4 with the ratio of atent solvent.
Preferably, described good solvent is 1: 6 with the ratio of atent solvent.
Preferably, described cooling recrystallization temperature is-20 DEG C～10 DEG C.
Preferably, described cooling recrystallization temperature is-10 DEG C～0 DEG C.
Compared with prior art, the present invention has a following beneficial effect to the preparation method of the present invention:
Further illustrate beneficial effects of the present invention by tests below: Pabuk former times profit cloth crystal formation C prepared by the present invention with
Pabuk former times profit cloth prepared by world patent WO2014128588A1, has situation that related substance compares such as under each influence factor
Shown in table 1 below:
Table 1: Performance comparision
Table 1 result of the test shows, the Pabuk former times profit cloth crystal formation C prepared by the present invention is equal under high temperature, high humidity, illumination condition
Showing good stability, it is under each influence factor, and its HPLC purity is higher than patent (WO2014128588A1) method system
Standby Pabuk former times profit cloth.
Pabuk former times profit cloth crystal formation C prepared by the present invention and the Pabuk former times profit prepared by world patent WO2014128588A1
Cloth, the situation having related substance and dissolution to compare of prepared preparation is as shown in table 2 below:
Table 2: dissolution compares
Table 2 test shows, the Pabuk former times profit cloth crystal formation C purity of the present invention is higher, single the most miscellaneous is less than 0.10%, epigranular,
Higher with former reference preparation dissolution similarity of grinding, beneficially absorption of human body, reach the effect cured the sickness to save the patient, the above all and
Crystal formation has close association.
The preparation method of crystal formation C disclosed by the invention is simple to operate, and solvent load is few and nontoxic, and production cost is low, in work
Industry aspect has clear superiority, and whole novel crystalline form preparation technology achieves substantial progress, and technique has marked improvement
Property.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of Pabuk former times profit cloth crystal formation C；
Fig. 2 is the TG/DSC analysis chart of Pabuk former times profit cloth crystal formation C.
Detailed description of the invention:
Embodiment 1
The preparation of Pabuk former times profit cloth crystal formation C:
Pabuk former times profit cloth 5g is added in 50ml there-necked flask, is equipped with thermometer, condensing unit, oil bath and magnetic agitation,
Add 5ml DMF and 30ml acetone, magnetic agitation, be heated to 60 DEG C of whole dissolvings, stop heating, about 30
Minute being cooled to room temperature, add 0.01g crystal seed, ice maker is cooled to-10 DEG C～0 DEG C, crystallize 2～4h, and sucking filtration, filter cake is with a small amount of third
Ketone washs, and 35 DEG C are vacuum dried 12 hours, obtain white crystal 4.5g, yield: 90%, purity: 99.8%.White crystal X penetrates
Line powder diagram is shown in that Fig. 1, TG/DSC analysis chart is shown in Fig. 2.
Embodiment 2
Pabuk former times profit cloth 5g is added in 50ml there-necked flask, is equipped with thermometer, condensing unit, oil bath and magnetic agitation,
Add 5ml dichloromethane and 20ml ethanol, magnetic agitation, be heated to 55 DEG C of whole dissolvings, stop heating, within about 30 minutes, be cooled to
Room temperature, adds 0.01g crystal seed, and ice maker is cooled to-20 DEG C～-10 DEG C, crystallize 2～4h, sucking filtration, a small amount of washing with acetone of filter cake,
35 DEG C are vacuum dried 12 hours, obtain white crystal 4.3g, yield: 86%, purity: 99.7%.
Embodiment 3
Pabuk former times profit cloth 5g is added in 100ml there-necked flask, is equipped with thermometer, condensing unit, oil bath and magnetic agitation,
Add 5ml DMF and 50ml ethanol, magnetic agitation, be heated to 40 DEG C of whole dissolvings, stop heating, about 30
Minute being cooled to room temperature, add 0.01g crystal seed, ice maker is cooled to 0 DEG C～10 DEG C, crystallize 2～4h, and sucking filtration, filter cake is with a small amount of third
Ketone washs, and 40 DEG C are vacuum dried 12 hours, obtain white crystal 4.1g, yield: 82%, purity: 99.8%.
Embodiment 4
Pabuk former times profit cloth 5g is added in 100ml there-necked flask, is equipped with thermometer, condensing unit, oil bath and magnetic agitation,
Add 5ml dichloromethane and 50ml acetone, magnetic agitation, be heated to 44 DEG C of whole dissolvings, stop heating, within about 30 minutes, be cooled to
Room temperature, adds 0.01g crystal seed, and ice maker is cooled to-10 DEG C～0 DEG C, crystallize 2～4h, sucking filtration, a small amount of washing with acetone of filter cake, and 38
DEG C vacuum drying 12 hours, obtain white crystal 4.2g, yield: 84%, purity: 99.8%.
Embodiment 5
Pabuk former times profit cloth 5g is added in 50ml there-necked flask, is equipped with thermometer, condensing unit, oil bath and magnetic agitation,
Add 5ml DMF and 20ml acetone, magnetic agitation, be heated to 52 DEG C of whole dissolvings, stop heating, about 30
Minute being cooled to room temperature, add 0.01g crystal seed, ice maker is cooled to 0 DEG C～10 DEG C, crystallize 2～4h, and sucking filtration, filter cake is with a small amount of third
Ketone washs, and 40 DEG C are vacuum dried 12 hours, obtain white crystal 4.0g, yield: 80%, purity: 99.8%.
Claims (8)
1. the polymorphic of a Pabuk former times profit cloth, it is characterised in that crystal formation is in X-ray powder diffraction figure, and angle represents with 2 θ,
At 7.17 °, 7.62 °, 7.82 °, 8.49 °, 11.62 °, 11.81 °, 12.62 °, 22.96 °, 25.10 °, near 25.63 °, there is spy
Levying peak, 2 θ can have ± 0.2 ° of deviation, and differential scanning calorimetric thermogram shows one exothermic peak of appearance near 207 DEG C.
Concrete operations following steps:
With compound A and B as raw material, obtaining compound C by condensation reaction, compound C is through Heck coupling reaction
The alkene ether substituent group of compound D, compound D obtains Pabuk former times through resetting and sloughing tertbutyloxycarbonyl protection group under acid condition
Li Bu.
2. the polymorphic preparation method of a Pabuk former times profit cloth, it is characterised in that include following operation:
The Pabuk former times profit cloth mixed solvent of a certain proportion of good solvent and atent solvent is warming up to 40～60 DEG C, the most molten
Xie Hou, is naturally cooling to room temperature, after adding crystal seed, is cooled to-20 DEG C～10 DEG C of crystallizes, filters, is vacuum dried and get final product.
Method the most according to claim 2, it is characterised in that described good solvent is DMF or dichloro
One in methane, atent solvent is a kind of in acetone or alcohol.
Method the most according to claim 2, it is characterised in that the ratio of described good solvent and atent solvent be 1:10～
1:4.
Method the most according to claim 2, it is characterised in that described cooling recrystallization temperature is-20 DEG C～10 DEG C.
Method the most according to claim 3, it is characterised in that described good solvent is DMF, inertia
Solvent is acetone.
Method the most according to claim 4, it is characterised in that described good solvent is 1:6 with the ratio of atent solvent.
Method the most according to claim 5, it is characterised in that described cooling recrystallization temperature is-10 DEG C～0 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610624450.7A CN106220626A (en) | 2016-07-31 | 2016-07-31 | A kind of polymorphic of Pabuk former times profit cloth and preparation method thereof |
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| CN201610624450.7A CN106220626A (en) | 2016-07-31 | 2016-07-31 | A kind of polymorphic of Pabuk former times profit cloth and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866666A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Pa Boxini crystal-form compounds and preparation method thereof |
| CN108864078A (en) * | 2017-05-10 | 2018-11-23 | 江苏豪森药业集团有限公司 | The preparation method of Pa Boxini crystal form B |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| WO2016024249A1 (en) * | 2014-08-14 | 2016-02-18 | Sun Pharmaceutical Industries Limited | Crystalline forms of palbociclib |
| WO2016090257A1 (en) * | 2014-12-05 | 2016-06-09 | Crystal Pharmatech Inc. | Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib) |
-
2016
- 2016-07-31 CN CN201610624450.7A patent/CN106220626A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| WO2016024249A1 (en) * | 2014-08-14 | 2016-02-18 | Sun Pharmaceutical Industries Limited | Crystalline forms of palbociclib |
| WO2016090257A1 (en) * | 2014-12-05 | 2016-06-09 | Crystal Pharmatech Inc. | Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866666A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Pa Boxini crystal-form compounds and preparation method thereof |
| CN106866666B (en) * | 2017-04-06 | 2020-03-20 | 山东裕欣药业有限公司 | Palbociclib crystal form compound and preparation method thereof |
| CN108864078A (en) * | 2017-05-10 | 2018-11-23 | 江苏豪森药业集团有限公司 | The preparation method of Pa Boxini crystal form B |
| CN108864078B (en) * | 2017-05-10 | 2021-10-15 | 江苏豪森药业集团有限公司 | Preparation method of palbociclib crystal form B |
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Effective date of registration: 20170801 Address after: 210038 Nanjing economic and Technological Development Zone, Jiangsu, No. 20 Xingang Avenue Applicant after: Nanjing Cuccess Pharmaceutical Co., Ltd. Address before: High tech Zone camphor road in Hefei city Anhui province 230001 No. 168 Technology Industrial Park building D17/22 Applicant before: HEFEI YUANZHI PHARMACEUTICAL R & D CO., LTD. |
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Application publication date: 20161214 |
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