CN105085517B - A kind of crystal type Pa Boxini free alkali hydrate and preparation method thereof - Google Patents
A kind of crystal type Pa Boxini free alkali hydrate and preparation method thereof Download PDFInfo
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- CN105085517B CN105085517B CN201510477254.7A CN201510477254A CN105085517B CN 105085517 B CN105085517 B CN 105085517B CN 201510477254 A CN201510477254 A CN 201510477254A CN 105085517 B CN105085517 B CN 105085517B
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- boxini
- free alkali
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- hydrate
- alkali hydrate
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- 239000003513 alkali Substances 0.000 title claims abstract description 65
- 239000013078 crystal Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 33
- 239000007864 aqueous solution Substances 0.000 claims description 28
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 11
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 7
- 239000011736 potassium bicarbonate Substances 0.000 claims description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- -1 salt compounds Chemical class 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000005586 carbonic acid group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 28
- 239000002798 polar solvent Substances 0.000 abstract description 3
- 239000002585 base Substances 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 238000000634 powder X-ray diffraction Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 210000003746 feather Anatomy 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
-
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a kind of crystal type Pa Boxini free alkali hydrate, the X-ray diffraction spectrogram of described crystal type Pa Boxini free alkali hydrate includes the characteristic peaks shown in following 2 θ angles: 5.7 °, 7.8 °, 8.3 °, 8.9 °, 11.4 °, 13.1 ° and 16.7 °, 2 θ value degree of accuracy are ± 0.2 °.The Pa Boxini free alkali hydrate Form I that the present invention provides has good shelf-stability relative to crystal formation A and crystal formation B, and the dissolubility in water and in polar solvent is significantly improved than crystal formation A and crystal formation B simultaneously.
Description
Technical field
The present invention relates to the preparation method of a kind of Pa Boxini free alkali, particularly relate to a kind of crystal type handkerchief and win
The preparation method of western Buddhist nun's free alkali hydrate.
Background technology
At present, Pa Boxini (Palbociclib) is a selectivity, every developed by Pfizer
Day takes cell cycle protein dependent kinase (CDK) 4/6 inhibitor once, postmenopausal women
ER is positive, demonstrate powerful curative effect in the advanced breast cancer of HER2 negative form, has obtained FDA breakthrough
Medicine certification.On February 3rd, 2015, Pa Boxini obtains approval listing in the U.S..Pa Boxini
The chemical name of free alkali is: 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine
-2-base] amino]-8H-pyrido [2,3-D] pyrimidin-7-ones, shown in formula I
Patent WO2014128588 A1 discloses the free alkali crystal formation A and crystal formation B of Pa Boxini.Crystal formation
The X powder diffraction figure of A about 8.0 °, 10.1 °, 10.3 ° and 11.5 ° ± 0.2 °ο2 θ of deviation
Place has characteristic peak；The X powder diffraction figure of crystal formation B about 6.0 °, 10.9 °, 12.8 °, 16.4 ° and
19.8 ° ± 0.2οAt 2 θ of deviation, there is characteristic peak.
The Pa Boxini free alkali Form I that the present invention provides has well relative to crystal formation A and crystal formation B
Storage stability, has than crystal formation A and crystal formation B with the dissolubility in polar solvent in water simultaneously and substantially carries
High.The preparation technology of this free alkali has been amplified to feather weight, process stabilizing at present, is suitable for extensive work
Industry metaplasia is produced.
Summary of the invention
Present invention aim to address subproblem present in existing Pa Boxini free alkali technology of preparing,
A kind of crystal type Pa Boxini free alkali hydrate and preparation method thereof is provided.
The crystal type Pa Boxini free alkali hydrate that the present invention provides is named as Form I, molecular formula
Shown in formula I, this crystallization is pharmaceutically acceptable form.
It is an object of the invention to be achieved through the following technical solutions:
A kind of crystal type Pa Boxini free alkali hydrate, its chemical name is 6-acetyl group-8-cyclopenta
-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] amino]-8H-pyrido [2,3-D] pyrimidine-7-
Ketone, includes the characteristic peaks shown in following 2 θ angles at its X-ray diffraction spectrogram: 5.7 °, 7.8 °,
8.3 °, 8.9 °, 11.4 °, 13.1 ° and 16.7 °, 2 θ value degree of accuracy are ± 0.2 °.
Preferably, the infrared waves spectrogram of described crystal type Pa Boxini free alkali hydrate includes following master
Want crest: 2947cm-1, 1650cm-1, 1260cm-1, 1142cm-1And 825cm-1。
Preferably, described crystal type Pa Boxini free alkali hydrate has 4.0-4.4% at 100 DEG C-150 DEG C
Thermo-gravimetric loss.
Preferably, the water content of described crystal type Pa Boxini free alkali hydrate is 3.69-4.07%.
Preferably, in differential scanning calorimetry spectrogram, described crystal type Pa Boxini free alkali hydrate
At 152 DEG C and 277 DEG C, endothermic event occurs；At 198 DEG C, exothermal event occurs.
The method preparing above-mentioned crystal type Pa Boxini free alkali hydrate, by the salt chemical combination of Pa Boxini
Stir sucking filtration after thing is free in the aqueous solution of inorganic base to prepare.
Preferably, described inorganic base is the one of sodium bicarbonate, sodium carbonate, Lithium hydrate, potassium bicarbonate
Or it is multiple.
Preferably, the salt compounds of described Pa Boxini is Pa Boxini isethionate, Pa Boxi
Buddhist nun's hydroxyethylsulfonic acid. disalt, Pa Boxini mono-hydrochlorate, Pa Boxini dihydrochloride, the mono-first of Pa Boxini
Sulfonate, Pa Boxini dimethanesulfonate one or more.
Preferably, described preparation temperature is 10 DEG C-60 DEG C.
Beneficial effects of the present invention: the Pa Boxini free alkali Form I that the present invention provides is relative to crystal formation
A and crystal formation B has good shelf-stability, and the dissolubility in water and in polar solvent compares crystal formation simultaneously
A and crystal formation B is significantly improved.The preparation technology of this free alkali has been amplified to feather weight, technique at present
Stable, it is suitable for large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram of Form I of the present invention；
Fig. 2 is the infrared ray spectrogram of Form I of the present invention；
Fig. 3 is the thermogravimetry spectrogram of Form I of the present invention；
Fig. 4 is differential scanning calorimetry (DSC) spectrogram of Form I of the present invention.
Detailed description of the invention
Present inventors have found that the compound crystallizing out Formulas I from aqueous solvent, and this change
The crystal of hydrate type Form I of compound has the good character of operation and characteristic.In order to be better described
The present invention, below in conjunction with the accompanying drawing in the embodiment of the present invention, enters the technical scheme in the embodiment of the present invention
Row clearly and completely describes.
The preparation method of a kind of crystal type Pa Boxini free alkali hydrate Form I, by Pa Boxini's
After salt compounds is free in the aqueous solution of inorganic base, constant temperature stirring sucking filtration prepares.Described inorganic base is carbon
Acid hydrogen sodium, sodium carbonate, Lithium hydrate, potassium bicarbonate one or more.The salt of described Pa Boxini
Compound is Pa Boxini isethionate, Pa Boxini hydroxyethylsulfonic acid. disalt, Pa Boxini mono-salt
Hydrochlorate, Pa Boxini dihydrochloride, the mono-mesylate of Pa Boxini, the one of Pa Boxini dimethanesulfonate
Plant or multiple.Described preparation temperature is 10 DEG C-60 DEG C.The crystal type Pa Boxi prepared by said method
The X-ray diffraction spectrogram of Buddhist nun free alkali hydrate Form I includes the characteristic peak shown in following 2 θ angles
Value: 5.7 °, 7.8 °, 8.3 °, 8.9 °, 11.4 °, 13.1 ° and 16.7 °, 2 θ value degree of accuracy are ± 0.2 °,
As shown in Figure 1.The infrared waves spectrogram of described crystal type Pa Boxini free alkali hydrate Form I wraps
Include following main crest: 2947cm-1, 1650cm-1, 1260cm-1, 1142cm-1And 825cm-1, such as figure
Shown in 2.The water content of described crystal type Pa Boxini free alkali hydrate Form I is 3.69-4.07%,
The thermo-gravimetric loss of 4.0-4.4% is had, as shown in Figure 3 at 100 DEG C-150 DEG C.Described crystal type Pa Boxi
There is heat absorption at 152 DEG C and 277 DEG C in Buddhist nun's free alkali hydrate Form I differential scanning calorimetry spectrogram
Event；At 198 DEG C, exothermal event occurs, as shown in Figure 4.
Method of testing is as follows:
X-ray powder diffraction data uses XPert Pro MPD (Multi-Purpose
Diffractometer) measure, light pipe type: Empyrean XRD tube Cu LFF HR；Voltage
Electric current: 45kV, 40mA；Detector: the super detector of X ' Celerator；Scan pattern: even
Continuous scanning；Sweep limits: 3 ° of-40 ° of 2 θ；
Infrared test INSTRUMENT MODEL: intelligent Fourier infrared spectrograph, Nicolet I5s.
Differential scanning calorimeter model DSC NETZSCH 200F3.Test condition is 80ml/min N2, rise
Temperature 10 DEG C/min of speed.
Specific embodiment:
Pa Boxini free alkali hydrate Form I is prepared by Pa Boxini isethionate
Example one: 8.6g sodium bicarbonate is dissolved in stirring and dissolving in 400ml water, is warming up to 60 DEG C.Will
7.0g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] hydroxyethylsulfonic acid. disalt (the Pa Boxini hydroxyethylsulfonic acid. of-8H-pyrido [2,3-D] pyrimidin-7-ones
Disalt) it is dissolved in 80ml water, it is made into aqueous solution, then this aqueous solution is added dropwise to 60 DEG C of above-mentioned preparation
Sodium bicarbonate aqueous solution in, drip while stir, separate out yellow solid.Drip and finish, be incubated 60 DEG C of stirrings 2
Hour, sucking filtration obtains Pa Boxini free alkali hydrate 3.5g, records XRPD spectrogram consistent with Fig. 1.
Example two: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.Will
7.0g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] hydroxyethylsulfonic acid. disalt (the Pa Boxini hydroxyethylsulfonic acid. of-8H-pyrido [2,3-D] pyrimidin-7-ones
Disalt) it is dissolved in 80ml water, it is made into aqueous solution, then this aqueous solution is added dropwise to 10 DEG C of above-mentioned preparation
Sodium bicarbonate aqueous solution in, drip while stir, separate out yellow solid.Drip and finish, be incubated 10 DEG C of stirrings 2
Hour, sucking filtration obtains Pa Boxini free alkali hydrate 3.5g, records XRPD spectrogram consistent with Fig. 1.
Example three: 10.3g potassium bicarbonate is dissolved in 400ml water in 10 DEG C of stirring and dissolving.By 7.0g 6-
Acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] amino]-8H-pyrido
The isethionate (Pa Boxini hydroxyethylsulfonic acid. disalt) of [2,3-D] pyrimidin-7-ones is dissolved in 80ml
In water, it is made into aqueous solution, then the potassium bicarbonate of 10 DEG C that this aqueous solution is added dropwise to above-mentioned preparation is water-soluble
In liquid, drip while stir, separate out yellow solid.Dripping and finish, be incubated 10 DEG C and stir 2 hours, sucking filtration obtains
To Pa Boxini free alkali hydrate 3.0g, record XRPD spectrogram consistent with Fig. 1.
Example four: 10.6g sodium carbonate is dissolved in 400ml water in 10 DEG C of stirring and dissolving.By 7.0g 6-
Acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] amino]-8H-pyrido
The isethionate (Pa Boxini hydroxyethylsulfonic acid. disalt) of [2,3-D] pyrimidin-7-ones is dissolved in 80ml
In water, it is made into aqueous solution, then this aqueous solution is added dropwise to the aqueous sodium carbonate of 10 DEG C of above-mentioned preparation
In, drip while stir, separate out yellow solid.Dripping and finish, be incubated 10 DEG C and stir 2 hours, sucking filtration obtains
Pa Boxini free alkali hydrate 3.1g, records XRPD spectrogram consistent with Fig. 1.
Example five: 2.4g Lithium hydrate is dissolved in 400ml water in 10 DEG C of stirring and dissolving.By 7.0g 6-
Acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] amino]-8H-pyrido
The isethionate (Pa Boxini hydroxyethylsulfonic acid. disalt) of [2,3-D] pyrimidin-7-ones is dissolved in 80ml
In water, it is made into aqueous solution, then the Lithium hydrate of 10 DEG C that this aqueous solution is added dropwise to above-mentioned preparation is water-soluble
In liquid, drip while stir, separate out yellow solid.Dripping and finish, be incubated 10 DEG C and stir 2 hours, sucking filtration obtains
To Pa Boxini free alkali hydrate 3.2g, record XRPD spectrogram consistent with Fig. 1.
Example six: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.Will
5.7g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] hydroxyethylsulfonic acid. one salt (the Pa Boxini hydroxyethylsulfonic acid. of-8H-pyrido [2,3-D] pyrimidin-7-ones
One salt) it is dissolved in 80ml water, it is made into aqueous solution, then this aqueous solution is added dropwise to 10 DEG C of above-mentioned preparation
Sodium bicarbonate aqueous solution in, drip while stir, separate out yellow solid.Drip and finish, be incubated 10 DEG C of stirrings 2
Hour, sucking filtration obtains Pa Boxini free alkali hydrate 3.5g, records XRPD spectrogram consistent with Fig. 1.
Pa Boxini free alkali hydrate Form I is prepared by Pa Boxini hydrochlorate
Example seven: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.Will
5.2g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] dihydrochloride (Pa Boxini dihydrochloride) of-8H-pyrido [2,3-D] pyrimidin-7-ones is dissolved in 80ml
In water, it is made into aqueous solution, then the sodium bicarbonate of 10 DEG C that this aqueous solution is added dropwise to above-mentioned preparation is water-soluble
In liquid, drip while stir, separate out yellow solid.Dripping and finish, be incubated 10 DEG C and stir 2 hours, sucking filtration obtains
To Pa Boxini free alkali hydrate 3.7g, record XRPD spectrogram consistent with Fig. 1.
Example eight: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.Will
4.8g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] hydrochlorate (Pa Boxini mono-hydrochlorate) of-8H-pyrido [2,3-D] pyrimidin-7-ones is dissolved in 80ml
In water, it is made into aqueous solution, then the sodium bicarbonate of 10 DEG C that this aqueous solution is added dropwise to above-mentioned preparation is water-soluble
In liquid, drip while stir, separate out yellow solid.Dripping and finish, be incubated 10 DEG C and stir 2 hours, sucking filtration obtains
To Pa Boxini free alkali hydrate 3.0g, record XRPD spectrogram consistent with Fig. 1.
Example nine: use 5.2g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyrrole
Pyridine-2-base] amino] dihydrochloride (Pa Boxini bis-hydrochloric acid of-8H-pyrido [2,3-D] pyrimidin-7-ones
Salt) it is raw material, use potassium bicarbonate, sodium carbonate, Lithium hydrate to do alkali respectively, concrete operations mode is such as
Described in example seven, below by acquired results display as shown in table 1.
Table 1 Pa Boxini dihydrochloride uses dissimilar inorganic base to prepare Pa Boxini free alkali Form I
Pa Boxini free alkali hydrate Form I is prepared by Pa Boxini mesylate
Example ten: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.Will
6.4g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] two methanesulfonic acids (Pa Boxini dimethanesulfonate) of-8H-pyrido [2,3-D] pyrimidin-7-ones are dissolved in
In 80ml water, it is made into aqueous solution, then this aqueous solution is added dropwise to the sodium bicarbonate of 10 DEG C of above-mentioned preparation
In aqueous solution, drip while stir, separate out yellow solid.Drip and finish, be incubated 10 DEG C and stir 2 hours, take out
Filter obtains Pa Boxini free alkali hydrate 3.6g, records XRPD spectrogram consistent with Fig. 1.
Example 11: 8.6g sodium bicarbonate is dissolved in 400ml water in 10 DEG C of-20 DEG C of stirring and dissolving.
By 5.4g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] ammonia
Base] methanesulfonic acid (Pa Boxini mono-mesylate) of-8H-pyrido [2,3-D] pyrimidin-7-ones is dissolved in
In 80ml water, it is made into aqueous solution, then this aqueous solution is added dropwise to the sodium bicarbonate of 10 DEG C of above-mentioned preparation
In aqueous solution, drip while stir, separate out yellow solid.Drip and finish, be incubated 10 DEG C and stir 2 hours, take out
Filter obtains Pa Boxini free alkali hydrate 3.5g, records XRPD spectrogram consistent with Fig. 1.
Example 12: use 6.4g 6-acetyl group-8-cyclopenta-5-methyl-2-[[5-(piperazine-1-base)
Pyridine-2-base] amino] dimethanesulfonate (Pa Boxini bis-of-8H-pyrido [2,3-D] pyrimidin-7-ones
Mesylate) it is raw material, use potassium bicarbonate, sodium carbonate, Lithium hydrate to do alkali, concrete operations respectively
Mode is as described in example seven, below by acquired results display as shown in table 2.
Table 2 Pa Boxini dihydrochloride uses dissimilar inorganic base to prepare Pa Boxini free alkali Form I
The above-mentioned crystal type Pa Boxini free alkali hydrate Form I contrast of present invention offer is former grinds crystal formation
Form A and Form B has good dissolubility and storage stability.Concrete correction data is as follows:
1. Pa Boxini free alkali hydrate Form I and free alkali crystal formation A and crystal formation B is molten in water
Solution degree correction data (mg/ml), as shown in table 3:
Table 3 Pa Boxini free alkali hydrate Form I, crystal formation A, crystal formation B dissolubility correction data in water
Data above is it can be seen that Pa Boxini free alkali hydrate Form I crystal difference in water
At a temperature of dissolubility, be superior to former grind free alkali crystal formation A and crystal formation B.
2. Pa Boxini free alkali hydrate Form I and free alkali crystal formation A and crystal formation B is in room temperature
The stability correction data that (25 DEG C) store is as shown in table 4:
Table 4 Pa Boxini free alkali hydrate Form I, crystal formation A, crystal formation B are in the stability pair of room temperature storage
Compare data
Above correction data is it can be seen that Pa Boxini free alkali hydrate Form I depositing at room temperature
Storage stability is essentially identical with Yuan Yan producer free alkali Form A crystal formation and Form B crystal form.
The above, the only present invention preferably detailed description of the invention, but protection scope of the present invention is not
Being confined to this, any those familiar with the art, can in the technical scope of present disclosure
The change readily occurred in or replacement, all should contain within protection scope of the present invention.Therefore, this
Bright protection domain should be as the criterion with the protection domain of claims.
Claims (8)
1. a crystal type Pa Boxini free alkali hydrate, it is characterised in that described crystal type handkerchief is won
The X-ray diffraction spectrogram of western Buddhist nun's free alkali hydrate includes the characteristic peaks shown in following 2 θ angles:
5.7 °, 7.8 °, 8.3 °, 8.9 °, 11.4 °, 13.1 ° and 16.7 °, 2 θ value degree of accuracy are ± 0.2 °, point
Minor structure is as shown in Equation 1
The water content of described crystal type Pa Boxini free alkali hydrate is 3.69-4.07%.
Crystal type Pa Boxini free alkali hydrate the most according to claim 1, it is characterised in that
The infrared waves spectrogram of described crystal type Pa Boxini free alkali hydrate includes following main crest:
2947cm-1, 1650cm-1, 1260cm-1, 1142cm-1And 825cm-1。
Crystal type Pa Boxini free alkali hydrate the most according to claim 1, it is characterised in that
Described crystal type Pa Boxini free alkali hydrate damages 100 DEG C-150 DEG C thermogravimetric amounts having 4.0-4.4%
Lose.
Crystal type Pa Boxini free alkali hydrate the most according to claim 1, it is characterised in that
In differential scanning calorimetry spectrogram, described crystal type Pa Boxini free alkali hydrate at 152 DEG C and
277 DEG C there is endothermic event；At 198 DEG C, exothermal event occurs.
5. the method for the arbitrary described crystal type Pa Boxini free alkali hydrate of preparation claim 1-4,
It is characterized in that, after being dissociated in the aqueous solution of inorganic base by the salt compounds of Pa Boxini, stir sucking filtration
Prepare.
Preparation method the most according to claim 5, it is characterised in that described inorganic base is carbonic acid
Hydrogen sodium, sodium carbonate, Lithium hydrate, potassium bicarbonate one or more.
Preparation method the most according to claim 5, it is characterised in that the salt of described Pa Boxini
Compounds is Pa Boxini isethionate, Pa Boxini hydroxyethylsulfonic acid. disalt, Pa Boxini mono-
Hydrochlorate, Pa Boxini dihydrochloride, Pa Boxini mono-mesylate, Pa Boxini dimethanesulfonate
One or more.
Preparation method the most according to claim 5, it is characterised in that described free process temperature
It it is 10 DEG C-60 DEG C.
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| CN106632311B (en) * | 2015-11-02 | 2021-05-18 | 上海科胜药物研发有限公司 | Preparation method of Palbociclib crystal form A and crystal form B |
| CN106800553A (en) * | 2015-11-26 | 2017-06-06 | 上海科胜药物研发有限公司 | A kind of crystal formation of Pa Boxini dihydroxy ethyls sulfonate |
| CN106800554A (en) * | 2015-11-26 | 2017-06-06 | 上海科胜药物研发有限公司 | A kind of crystal formation of Pa Boxini dihydrochlorides and preparation method thereof |
| WO2017130219A1 (en) * | 2016-01-25 | 2017-08-03 | Mylan Laboratories Limited | Amorphous solid dispersion of palbociclib |
| US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| CN106336411B (en) * | 2016-04-27 | 2018-03-06 | 上海医药集团股份有限公司 | The preparation technology and purposes of CDK4/6 inhibitor Pa Boxini high-purity raw medicines |
| CN109661393A (en) * | 2016-05-08 | 2019-04-19 | 上海诚妙医药科技有限公司 | Novel crystal forms of Pabuk former times benefit cloth and preparation method thereof and application thereof |
| WO2018009735A1 (en) * | 2016-07-07 | 2018-01-11 | Plantex Ltd. | Solid state forms of palbociclib dimesylate |
| CN108017629A (en) * | 2016-11-04 | 2018-05-11 | 上海奥博生物医药技术有限公司 | A kind of Pa Boxini amorphous states |
| 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 |
| CN114306245A (en) * | 2020-09-29 | 2022-04-12 | 深圳市药欣生物科技有限公司 | Pharmaceutical composition of amorphous solid dispersion and preparation method thereof |
| CN114149426B (en) * | 2021-12-13 | 2023-06-02 | 江苏海洋大学 | Parbosini pharmaceutical co-crystal and preparation method thereof |
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| CN104496983B (en) * | 2014-11-26 | 2016-06-08 | 苏州明锐医药科技有限公司 | A kind of preparation method of Pa Boxini |
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