CN109897034A - A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition - Google Patents
A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition Download PDFInfo
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- CN109897034A CN109897034A CN201711325686.1A CN201711325686A CN109897034A CN 109897034 A CN109897034 A CN 109897034A CN 201711325686 A CN201711325686 A CN 201711325686A CN 109897034 A CN109897034 A CN 109897034A
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- former times
- crystal form
- pabuk former
- times benefit
- benefit cloth
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Abstract
The invention discloses a kind of high-purity crystal form A Pabuk former times benefit cloth, the impure A of the high-purity crystal form A Pabuk former times benefit cloth bag and/or impurity B are all respectively smaller than 0.1 weight %, and Pabuk former times benefit cloth purity is not less than 99.5%.In addition, additionally providing preparation method, pharmaceutical composition and the purposes of the high-purity crystal form A Pabuk former times benefit cloth.
Description
Technical field
The invention belongs to pharmaceutical technology fields, more specifically to a kind of high-purity crystal form A Pabuk former times benefit cloth and its system
Preparation Method and pharmaceutical composition.
Background technique
Pabuk former times benefit cloth (Palbociclib), chemical name are as follows: 6- acetyl group -8- cyclopenta -5- methyl -2- (5- piperazine -
1- base-pyridine -2- base amino) -8H- pyrido [2,3-d] pyrimidin-7-ones, be Pfizer exploitation cyclin according to
Rely type kinase (CDK-4 and 6) inhibitor；It goes through to list in the U.S. within Pabuk former times benefit cloth capsule on 2 3rd, 2015, with Letrozole
Combination is to have estrogen receptor (the ER)-positive, human epidermal growth factor receptor 2 (HER2)-feminine gender late-stage breast cancer postmenopausal women
Treatment disease is shifted to it as being initially based on endocrine therapy.
Using traditional approach prepare Pabuk former times benefit cloth (WO2005005426A1) there are particles it is small, be easy to assemble and agglomerate
Problem；The substance of greater particle size is obtained using the preparation method of CN201480009556.5, but purity and impurity presence are asked
Topic, special impurity A and impurity B content are higher.
Summary of the invention
The present inventor has surprisingly been discovered a kind of high-purity crystal form A Pabuk former times benefit cloth, either impurity content still
Granularity is adapted to pharmaceutically use.
The object of the present invention is to provide a kind of high-purity crystal form A Pabuk former times benefit cloth.
It is a further object to provide the preparation methods of above-mentioned high-purity crystal form A Pabuk former times benefit cloth.
Third object of the present invention is to provide the pharmaceutical compositions comprising above-mentioned high-purity crystal form A Pabuk former times benefit cloth.
Fourth object of the present invention is to provide the pharmaceutical composition comprising above-mentioned high-purity crystal form A Pabuk former times benefit cloth.
In embodiments of the invention, the present invention provides a kind of high-purity crystal form A Pabuk former times benefit cloth, the high-purities
The impure A of crystal form A Pabuk former times benefit cloth bag and/or impurity B are all respectively smaller than 0.1 weight %
In a preferred embodiment of the invention, a kind of high-purity crystal form A Pabuk former times benefit cloth provided by the invention, wherein
The impure A of the high-purity crystal form A Pabuk former times benefit cloth bag and/or impurity B are all respectively smaller than 0.09 weight %；Pabuk former times benefit cloth is pure
Degree is not less than 99.5%.
In a preferred embodiment of the invention, a kind of high-purity crystal form A Pabuk former times benefit cloth provided by the invention, wherein
X-ray powder of the XRPD map of the high-purity crystal form A Pabuk former times benefit cloth included in the peak of the angle of diffraction (2 θ) 10.1 ± 0.2 spreads out
Penetrate peak, it is preferable that it includes the diffraction maximums at the peak of the angle of diffraction (2 θ) 8.0 ± 0.2 and 10.1 ± 0.2；It is highly preferred that it includes
In the diffraction maximum of the angle of diffraction (2 θ) 8.0 ± 0.2,10.1 ± 0.2 and 11.5 ± 0.2；It is particularly preferred that it includes in the angle of diffraction (2
θ) 8.0 ± 0.2,10.1 ± 0.2 and 11.5 ± 0.2 diffraction maximum；Or substantially as shown in.
In a preferred embodiment of the invention, a kind of high-purity crystal form A Pabuk former times benefit cloth provided by the invention, wherein
The high-purity crystal form A Pabuk former times benefit cloth has following particle diameter distribution: (i) D10 value is 3-4 μm；(ii) D25 value is 6-7 μm；
Or (iii) D50 value is 9-10 μm；Or (iv) D75 value is 14-15 μm；Or (v) D90 value is 19-20 μm；Or (i), (ii),
(iii), the combination of (iv) and (v)；It is particularly preferred that the particle diameter distribution includes (i), (ii), (iii), (iv) and (v).
In particularly preferred embodiment of the invention, a kind of high-purity crystal form A Pabuk former times benefit cloth provided by the invention,
In, the high-purity crystal form A Pabuk former times benefit cloth has following particle diameter distribution: (i) D10 value is 3.934 μm；(ii) D25 value is
6.107μm；(iii) D50 value is 9.541 μm；(iv) D75 value is 14.300 μm；(v) D90 value is 19.639 μm.
Second aspect, the present invention provides the preparation methods of above-mentioned high-purity crystal form A Pabuk former times benefit cloth, including walk as follows
It is rapid:
(1) the in the mixed solvent stirring of Pabuk former times benefit cloth addition halide and C1-C4 alkanol is warming up to and is completely dissolved,
Temperature is 40-65 DEG C；
(2) it is down to room temperature, is filtered, the mixed solvent of halide and C1-C4 alkanol elutes；
(3) removal halide can be distilled by being warming up under mother liquor stirring, add C1-C4 alkanol；Stirring filters, decompression
It is drying to obtain.
In embodiments of the invention, the preparation method of above-mentioned high-purity crystal form A Pabuk former times benefit cloth provided by the invention,
Wherein, the halide is all dichloromethane or chloroform.
In embodiments of the invention, the preparation method of above-mentioned high-purity crystal form A Pabuk former times benefit cloth provided by the invention,
Wherein, the C1-C4 alkanol is all methanol, ethyl alcohol or isopropanol.
In embodiments of the invention, the preparation method of above-mentioned high-purity crystal form A Pabuk former times benefit cloth provided by the invention,
Wherein, the volume ratio of the in the mixed solvent halide and C1-C4 alkanol of the halide and C1-C4 alkanol is 10/1~4/
1, it is preferable that be 5/1.
The third aspect, the present invention provides the pharmaceutical compositions of above-mentioned high-purity crystal form A Pabuk former times benefit cloth, include above-mentioned
High-purity crystal form A Pabuk former times benefit cloth and pharmaceutically acceptable carrier.
In a preferred embodiment of the invention, the drug of above-mentioned high-purity crystal form A Pabuk former times benefit cloth provided by the invention
Composition is capsule, which includes 1 to 200mg above-mentioned high-purity crystal form A Pabuk former times benefit cloth.
Fourth aspect, the present invention provides above-mentioned high-purity crystal form A Pabuk former times benefit cloth or its pharmaceutical composition as treatment
The purposes of cancer drug.
Detailed description of the invention
Fig. 1 shows be the embodiment of the present invention 1 crystal form A Pabuk former times benefit cloth XRPD.
What Fig. 2 was indicated is the particle diameter distribution of the crystal form A Pabuk former times benefit cloth of the embodiment of the present invention 1.
Specific embodiment
Comparative example 1:
Take Pabuk former times benefit cloth 50g that n-butanol (400m1) and methyl phenyl ethers anisole (600ml) is added, stirring is warming up to 95~100 DEG C,
80 DEG C are cooled to after all dissolutions.Add Pabuk former times benefit cloth (A type) crystal seed 0.25g (0.005 equivalent), insulated and stirred 3 hours.
10 DEG C are cooled to during 350 minutes with 0.2 DEG C // minute, filtering is first eluted with methyl phenyl ethers anisole, then eluted with normal heptane, filter cake
Vacuum drying obtains product (A crystal form) about 40.6g.Yield: 81.2%.The content of impurity A is about 0.26%, the content of impurity B
About 0.17%, purity 99.34%.(the little particle free alkali of 6. compound of CN201480009556.5 embodiment becomes big
The conversion of grain free alkali)
Embodiment 1:
Pabuk former times benefit cloth 50g addition 800ml methylene chloride/methanol (5/1) stirring is taken to be warming up to complete molten, about 50 DEG C.It is down to
Room temperature filters, methylene chloride/methanol (5/1) elution.It is warming up to 60 DEG C or so distillation removal methylene chloride under mother liquor stirring, mends
Add methanol to 500ml.Stirring filters after 1 hour, and 60 DEG C are dried under reduced pressure to obtain about 47.6g.Yield: 95.2%.The content of impurity A is about
It is 0.03%, impurity B is not detected, purity 99.79%.
Crystal form is consistent with patent crystal form A.
Embodiment 2:
Pabuk former times benefit cloth 50g addition 800ml methylene chloride/ethyl alcohol (8/1) stirring is taken to be warming up to complete molten, about 50 DEG C.It is down to
Room temperature filters, methylene chloride/ethyl alcohol (5/1) elution.It is warming up to 60 DEG C or so distillation removal methylene chloride under mother liquor stirring, mends
Add ethyl alcohol to 500ml.Stirring filters after 1 hour, and 60 DEG C are dried under reduced pressure to obtain about 48.4g.Yield: 96.8%.The content of impurity A is about
It is 0.06%, the content of impurity B is about 0.03%, purity 99.69%.
Embodiment 3:
Pabuk former times benefit cloth 50g addition 1000ml methylene chloride/isopropanol (8/1) stirring is taken to be warming up to complete molten, about 60 DEG C.Drop
It to room temperature, filters, methylene chloride/isopropanol (5/1) elution.60 DEG C or so distillation removal dichloromethanes are warming up under mother liquor stirring
Alkane adds isopropanol to 500ml.Stirring filters after 1 hour, and 60 DEG C are dried under reduced pressure to obtain about 46.4g.Yield.92.8%.Impurity A
Content be about 0.06%, the content of impurity B is about 0.02%, purity 99.62%.
Embodiment 4:
Pabuk former times benefit cloth 50g addition 500ml chloroform/methanol (5/1) stirring is taken to be warming up to complete molten, about 50 DEG C.Room temperature is down to,
It filters, chloroform/methanol (5/1) elution.Mother liquor stirs lower 60 DEG C or so distillations and removes chloroform, adds methanol to 500ml.Stirring 1
It is filtered after hour, 60 DEG C are dried under reduced pressure to obtain about 46.5g.Yield: 93%.The content of impurity A is to be not detected, and the content of impurity B is
It is not detected, purity 99.81%.
Embodiment 5:
Pabuk former times benefit cloth 50g addition 600ml chloroform/ethanol (5/1) stirring is taken to be warming up to complete molten, about 50 DEG C.Room temperature is down to,
It filters, chloroform/ethanol (5/1) elution.Mother liquor stirs lower 60 DEG C or so distillations and removes chloroform, adds ethyl alcohol to 500ml.Stirring 1
It is filtered after hour, 60 DEG C are dried under reduced pressure to obtain about 47.2g.Yield: 94.4%.The content of impurity A is about 0.07%, and impurity B contains
Amount about 0.01%, purity 99.72%.
Embodiment 6:
Pabuk former times benefit cloth 50g addition 800ml chloroform/isopropanol (8/1) stirring is taken to be warming up to complete molten, about 50 DEG C.It is down to room
Temperature filters, chloroform/isopropanol (5/1) elution.Mother liquor stirs lower 60 DEG C or so distillations and removes chloroform, adds isopropanol extremely
500ml.Stirring filters after 1 hour, and 60 DEG C are dried under reduced pressure to obtain about 48.3g.Yield: 96.6%.
The content of impurity A is about 0.08%, and the content of impurity B is about 0.04%, purity 99.62%.
Claims (10)
1. a kind of high-purity crystal form A Pabuk former times benefit cloth, the impure A of the high-purity crystal form A Pabuk former times benefit cloth bag and/or impurity B
It is all respectively smaller than 0.1 weight %, Pabuk former times benefit cloth purity is not less than 99.5%；
2. high-purity crystal form A Pabuk former times benefit cloth as described in claim 1, wherein the high-purity crystal form A Pabuk former times benefit cloth bag
Impure A and/or impurity B are all respectively smaller than 0.09 weight %.
3. high-purity crystal form A Pabuk former times benefit cloth as described in claim 1, wherein the high-purity crystal form A Pabuk former times benefit cloth
Powder x-ray diffraction peak of the XRPD map included in the peak of the angle of diffraction (2 θ) 10.1 ± 0.2, it is preferable that it includes in the angle of diffraction
The diffraction maximum at the peak of (2 θ) 8.0 ± 0.2 and 10.1 ± 0.2；It is highly preferred that it includes in the angle of diffraction (2 θ) 8.0 ± 0.2,10.1
± 0.2 and 11.5 ± 0.2 diffraction maximum；It is particularly preferred that it includes in the angle of diffraction (2 θ) 8.0 ± 0.2,10.1 ± 0.2 and
11.5 ± 0.2 diffraction maximum；Or substantially as shown in.
4. high-purity crystal form A Pabuk former times benefit cloth as described in claim 1, wherein the high-purity crystal form A Pabuk former times benefit cloth tool
Have following particle diameter distribution: (i) D10 value is 3-4 μm；(ii) D25 value is 6-7 μm；Or (iii) D50 value is 9-10 μm；Or (iv)
D75 value is 14-15 μm；Or (v) D90 value is 19-20 μm；Or (i), the combination of (ii), (iii), (iv) and (v)；It is especially excellent
Selection of land, the particle diameter distribution include (i), (ii), (iii), (iv) and (v).
5. the preparation method of high-purity crystal form A Pabuk former times benefit cloth as described in claim 1, includes the following steps:
(1) the in the mixed solvent stirring of Pabuk former times benefit cloth addition halide and C1-C4 alkanol is warming up to and is completely dissolved, temperature
It is 40-65 DEG C；
(2) it is down to room temperature, is filtered, the mixed solvent of halide and C1-C4 alkanol elutes；
(3) removal halide can be distilled by being warming up under mother liquor stirring, add C1-C4 alkanol；Stirring is filtered, is dried under reduced pressure
To obtain the final product.
6. preparation method as claimed in claim 5, wherein the halide is all dichloromethane or chloroform.
7. preparation method as claimed in claim 5, wherein the C1-C4 alkanol is all methanol, ethyl alcohol or isopropanol.
8. preparation method as claimed in claim 5, wherein the in the mixed solvent of the halide and C1-C4 alkanol is halogenated
The volume ratio of methane and C1-C4 alkanol is 10/1~4/1, it is preferable that is 5/1.
9. a kind of pharmaceutical composition, it includes the high-purity crystal form A Pabuk former times benefit cloth and pharmacy of any one of claim 1-4
Upper acceptable carrier.
10. the high-purity crystal form A Pabuk former times benefit cloth or claim 9 described pharmaceutical composition of any one of claim 1-4 are made
For the purposes for the treatment of cancer drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711325686.1A CN109897034A (en) | 2017-12-07 | 2017-12-07 | A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711325686.1A CN109897034A (en) | 2017-12-07 | 2017-12-07 | A kind of high-purity crystal form A Pabuk former times benefit cloth and preparation method thereof and pharmaceutical composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112759589A (en) * | 2019-11-01 | 2021-05-07 | 暨南大学 | Pyrimidopyridinones and their use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112759589A (en) * | 2019-11-01 | 2021-05-07 | 暨南大学 | Pyrimidopyridinones and their use |
| CN112759589B (en) * | 2019-11-01 | 2022-04-08 | 暨南大学 | Pyrimidopyridinones and their use |
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