CN106986871B - A kind of crystal form and its preparation method and application of deuterated Palbociclib - Google Patents
A kind of crystal form and its preparation method and application of deuterated Palbociclib Download PDFInfo
- Publication number
- CN106986871B CN106986871B CN201710198725.XA CN201710198725A CN106986871B CN 106986871 B CN106986871 B CN 106986871B CN 201710198725 A CN201710198725 A CN 201710198725A CN 106986871 B CN106986871 B CN 106986871B
- Authority
- CN
- China
- Prior art keywords
- crystal form
- preparation
- deuterated palbociclib
- deuterated
- palbociclib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to compound crystal forms and its preparation method and application, and in particular to a kind of crystal form and its preparation method and application of deuterated Palbociclib.2 angles θ of deuterated Palbociclib crystal form X-ray powder diffraction of the invention characterize, including 9.98 ± 0.2 °, 10.19 ± 0.2 °, 11.45 ± 0.2 °, 13.97 ± 0.2 °, 17.03 ± 0.2 °, 19.62 ± 0.2 °, 20.09 ± 0.2 °, 22.43 ± 0.2 °, 22.93 ± 0.2 ° have characteristic diffraction peak.The advantages such as the crystal form has stability good, and curative effect is stablized, can be used for preparing the application in terms of CDK4/6 inhibitor medicaments.The invention also discloses the preparation method of deuterated Palbociclib crystal form object, the structural homogeneity with higher of crystal form obtained by the preparation method and crystal form purity, high income.
Description
Technical field
The present invention relates to crystal forms of compound and its preparation method and application, and in particular to a kind of deuterated Palbociclib
Crystal form and its preparation method and application.
Background technique
Palbociclib is a kind of New Target tropism CDK4/6 inhibitor, can selective depression cyclin according to
Rely property kinases 4 and 6 (CDK4/6), restores cell cycle control, block tumor cell proliferation (Chinese Journal of New Drugs and Clinical Remedies
2016,326-329；Chinese drug evaluation 2016,426-430).FDA has authorized Palbociclib treatment advanced stage or metastatic
The breakthrough sex therapy identification of ER+/HER2- breast cancer.Palbociclib has been found that patient vitals can be extended and slows down breast cancer
Tumour growth provides new selection for patient with breast cancer and clinician, other indications of the drug are carrying out clinic
It tests (non-small cell lung cancer, lymthoma, Huppert's disease etc.).
Currently, it is domestic had it is numerous reported about Palbociclib, such as Chinese patent CN1051531149A,
CN104496983A, CN105418603A, CN104910149A etc. report respectively non-deuterated Palbociclib synthesis or
Preparation method.
Chinese patent (application notification number: CN104447739A) discloses a kind of deuterated Palbociclib derivative, preparation
Method and application, it is deuterated by the selectivity to Palbociclib, the medicine of drug is improved for property, and then improves drug
Curative effect, safety and tolerance, and the structural formula of specifically disclosed derivative is as follows: formula (I) is that single deuterium replaces
Palbociclib, formula (II) are that single deuterium replaces Palbociclib organic acid or inorganic acid complex；Formula (III) is the substitution of six deuteriums
Palbociclib, formula (IV) be six deuteriums replace Palbociclib organic acid or inorganic acid complex.
Currently, both at home and abroad it is not yet reported that the synthetic method of the Palbociclib replaced with three deuteriums, also takes without three deuteriums
The Palbociclib crystal form in generation and its preparation method of crystal form.Crystal form is solid matter state existing for drug, and drug crystal forms are ground
Studying carefully is exactly research to drug base state, only there is the understanding compared adequately and comprehensively to chemicals crystal form state,
It is possible that finding the more properly drug crystal forms solid matter with treatment disease.Drug crystal forms can influence the physicochemical property of drug,
Directly affect the basis that clinical drug plays treatment disease effect.Therefore study deuterated Palbociclib stable crystal form and its
Preparation method is of great significance.
Summary of the invention
The purpose of the present invention is to provide the crystal forms and its preparation method and application of deuterated Palbociclib shown in Formula V.
A kind of crystal form of deuterated Palbociclib shown in formula V,
Using CuK α spectral line, the X-ray powder diffraction indicated with 2 θ angles is in following position: 9.98 ± 0.2 °, 10.19 ±
0.2 °, 11.45 ± 0.2 °, 13.97 ± 0.2 °, 17.03 ± 0.2 °, 19.62 ± 0.2 °, 20.09 ± 0.2 °, 22.43 ± 0.2 °,
22.93 ± 0.2 ° have characteristic diffraction peak.
The preparation method of deuterated Palbociclib crystal form shown in a kind of formula (V), comprising the following steps: will be deuterated
Palbociclib is distributed in solvent, is warming up to 40~130 DEG C, stirs 1~3h, is cooled to 20~45 DEG C, stand crystallization 10~
Filter cake is collected in 30h, filtering, it is dry to get.
In the preparation method of the deuterated Palbociclib crystal form, the solvent is water, acetone, ethyl acetate, benzene first
Ether, propyl alcohol, butyl acetate, ethyl alcohol, dimethyl sulfoxide one or more mixed liquor.Further, the solvent is benzene
The mixed liquor of methyl ether and butyl acetate.Further, the volume ratio of the in the mixed solvent methyl phenyl ethers anisole and butyl acetate is
3:1.
In the preparation method of the deuterated Palbociclib crystal form, the heating is preferably warming up to 80~100 DEG C.
In the preparation method of the deuterated Palbociclib crystal form, the time of the stirring is preferably 2h.
In the preparation method of the deuterated Palbociclib crystal form, the speed of the cooling is 10 DEG C per hour, preferably
To be cooled to 20 DEG C.
In the preparation method of the deuterated Palbociclib crystal form, the time for standing crystallization is preferably 15h.
Research for deuterated Palbociclib crystal form shown in formula (V), the present invention is using X-ray generally acknowledged in the world
The crystal form of deuterated Palbociclib is studied and characterized to powder diffraction method (XRPD).
Instrument and equipment: X ' the Pert PRO type of Dutch Panaco company production, incident light are CuK α spectral line, operating voltage
40KV, tube current 40mA, 10 °/min of surface sweeping speed.
Testing conditions: operating voltage 35KV, tube current 30mA, angular range: 2-40 °, step-length: 0.01 °/step, wavelength
1.5406。
Deuterated Palbociclib crystal form shown in formula (V) in the present invention, X-ray powder diffraction figure are basic such as Fig. 1 institute
Show.Its more detailed data is as shown in table 1.
The X-ray powder diffraction peak value of the crystal form of the deuterated Palbociclib of the present invention of table 1
In table 1,2 θ at X-ray powder diffraction peak are indicated, error range is ± 0.5 °.It should be understood that X-ray powder
2 θ values of last diffraction pattern can vary slightly between sample between machine, and numberical range may differ by 0.5 unit, or
0.2 unit, or 0.1 unit of difference are differed, therefore cited numerical value cannot be construed to absolute value.
Likewise, it should be understood that peak area, peak height may also differ 10 units, 5 units, 2 units, 1 list
Position；Peak intensity etc. may also differ 5%, 3%, and 1% unit is not intended to absolutely relatively, and indicates that instrument and equipment
The offset that error may cause.
In view of to have height to have low for the intensity at the peak of the expression of 2 θ angles, the intensity at especially some peaks is lower than highest peak
20%, the data precision of characterization is affected by instrument condition, in fact it could happen that biggish error, therefore it is high to choose peak intensity
In 20% peak value as characteristic peak of the invention.
Deuterated Palbociclib crystal form provided by the invention has as follows with the X-ray powder diffraction that 2 θ angles indicate
Shown in characteristic diffraction peak: 9.98 ± 0.5 °, 10.19 ± 0.5 °, 11.45 ± 0.5 °, 13.97 ± 0.5 °, 17.03 ± 0.5 °,
19.62 ± 0.5 °, 20.09 ± 0.5 °, 22.43 ± 0.5 °, 22.93 ± 0.5 °.
Preferably, deuterated Palbociclib crystal form provided by the invention, the X-ray powder diffraction indicated with 2 θ angles
With characteristic diffraction peak as follows: 9.98 ± 0.2 °, 10.19 ± 0.2 °, 11.45 ± 0.2 °, 13.97 ± 0.2 °, 17.03
± 0.2 °, 19.62 ± 0.2 °, 20.09 ± 0.2 °, 22.43 ± 0.2 °, 22.93 ± 0.2 °.
Preferably, deuterated Palbociclib crystal form provided by the invention, the X-ray powder diffraction indicated with 2 θ angles
With characteristic diffraction peak as follows: 9.98 ± 0.1 °, 10.19 ± 0.1 °, 11.45 ± 0.1 °, 13.97 ± 0.1 °, 17.03
± 0.1 °, 19.62 ± 0.1 °, 20.09 ± 0.1 °, 22.43 ± 0.1 °, 22.93 ± 0.1 °.
Further preferably, the crystal form of the deuterated Palbociclib of the present invention is penetrated using CuK α spectral line with the X that 2 θ angles indicate
Line powder diffraction is in following position: 9.981 °, 10.1929 °, 11.4512,13.9701 °, 17.0322 °, 19.6222 °,
20.0905 °, 22.4269 °, 22.9327 ° have characteristic diffraction peak.
Further preferably, deuterated Palbociclib crystal form provided by the invention is indicated using CuK α spectral line with 2 θ angles
X-ray powder diffraction in following position: 7.9115 °, 9.981 °, 10.1929 °, 11.4512 °, 13.9701 °,
15.0235°、15.9022°、17.0322°、17.6313°、18.3803°、18.6392°、19.6222°、20.0905°、
20.4888°、21.0786°、21.791°、22.4269°、22.9327°、23.6454°、24.0257°、26.0195°、
27.3311°、28.1959°、28.8058°、30.0161°、31.0287°、31.5215°、34.461°、35.5924°、
37.3177 °, 39.139 ° have characteristic diffraction peak.
A kind of application of deuterated Palbociclib crystal form in terms of preparing CDK4/6 inhibitor medicaments.
Deuterated Palbociclib crystal form of the invention is the deuterated Palbociclib crystal form reported for the first time both at home and abroad, the crystalline substance
Type is mainly used for medicinal usage, and compare no crystal form drug, which has stability good, and curative effect stabilization etc. is excellent
Gesture, specific effect are as shown in table 2.
Physicochemical property contrast table of the table 2 without compound shown in crystal form and fixed crystal form formula (V)
| Project | Without compound shown in crystal form formula (V) | Compound shown in fixed crystal form formula (V) |
| Fusing point | 186℃ | 206℃ |
| Stability (deuterated rate is lower) | ≦6months | ≧2years |
The preparation method of deuterated Palbociclib crystal form of the invention, be deuterated Palbociclib solid is dissolved in it is organic
In solvent, solubility is increased by heating, stirring is completely dissolved deuterated Palbociclib, is reducing solubility by cooling
Standing precipitates crystal, the structural homogeneity with higher of crystal form obtained by the preparation method and crystal form purity, high income；The preparation side
Method simple process, it is easy to operate, it is at low cost, it is easy to automation control, adapts to promote and apply
Detailed description of the invention
Fig. 1 is the XRD spectra of the powder diffraction of the deuterated Palbociclib crystal form of embodiment 1.
Specific embodiment
This hair embodiment will be described in further detail, be should not be construed as limiting the invention below.
Deuterated Palbociclib synthetic route of the invention is as follows::
The preparation method of deuterated Palbociclib derivative of the invention, including the following steps:
1) it synthesizes compound DP-1: taking the compound A of 36g to be added in the tetrahydrofuran of 250mL, system is cooled to 0 DEG C；
Under nitrogen protection, the tetrahydrofuran solution of 240mL isopropylmagnesium chloride (1M) is slowly added dropwise, after being added dropwise, system heating
To room temperature and the reaction was continued 1h；Then the compound B of 35g is added, the reaction was continued overnight, and the saturation NH of saturation is added4Cl solution
Quenching reaction is extracted with ethyl acetate three times, merges organic phase, dry, and concentration obtains 44g compound DP-1；It is closed in this step
The process of compound shown in accepted way of doing sth DP-1 is referring to the preparation method in patent document (104447739 A of CN).
The nuclear-magnetism information of compound DP-1 are as follows:1H NMR(400MHz,CDCl3): δ 8.82 (s, 1H), 8.37 (s, 1H),
8.19-8.16 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.76), 7.35-7.32 (dd, 1H, J1=2.92, J2=
9.12), 5.96-5.79 (m, 1H), 3.62-3.60 (t, 4H, J=4.84), 3.13-3.11 (t, 4H, J=4.72), 2.61 (s,
3H),2.34-2.27(m,2H),2.12-2.07(m,2H),1.91-1.88(m,2H),1.69-1.64(m,2H),1.49(s,
9H)；
2) it synthesizes compound DP-2: the compound DP-1 of 5g being taken to be dissolved in Isosorbide-5-Nitrae-dioxane of 600mL, 1.0eq is added
Sodium hydride and 30.0eq deuterium-oxide (D2O), back flow reaction 30 hours under nitrogen protection, are spin-dried for, ethyl acetate are added to dissolve, and satisfy
And brine It, it is dry, it is concentrated to give 5g compound DP-2；
The nuclear magnetic resonance information of compound DP-2 are as follows:1H NMR(400MHz,CDCl3): δ 8.82 (s, 1H), 8.37 (s,
1H), 8.19-8.16 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.76), 7.35-7.32 (dd, 1H, J1=2.92,
), J2=9.12 5.96-5.79 (m, 1H), 3.62-3.60 (t, 4H, J=4.84), 3.13-3.11 (t, 4H, J=4.72),
2.34-2.27(m,2H),2.12-2.07(m,2H),1.91-1.88(m,2H),1.69-1.64(m,2H),1.49(s,9H)；
3) synthesize compound DP-3: under nitrogen protection, take 450mg compound DP-2,240mg vinyl n-butyl ether,
The Pd (OAc) of 10mg2, 50mg dppf, 160mg DIEPA, be added in the n-BuOH of 20mL, system is warming up to 95 DEG C of reactions
20h；After reaction, concentrate system, column Chromatographic purification obtain 290mg compound DP-3；
The nuclear magnetic resonance information of compound DP-3 are as follows:1H NMR(400MHz,CDCl3): δ 8.77 (s, 1H), 8.25 (s,
1H), 8.22-8.20 (d, 1H, J=9.04), 8.05-8.04 (d, 1H, J=2.6), 7.35-7.32 (dd, 1H, J1=2.92,
J2=9.08), 5.95-5.86 (m, 1H), 4.53 (d, 1H, J=2.24), 4.18 (d, 1H, J=2.24), 3.88-3.84 (t,
2H, J=6.6), 3.63-3.60 (t, 4H, J=4.84), 3.13-3.10 (t, 4H, J=4.76), 2.38-2.30 (m, 2H),
2.14-2.03(m,2H),1.87-1.81(m,2H),1.76-1.70(m,2H),1.69-1.64(m,2H),1.49(s,9H),
1.47-1.39 (m, 2H), 0.96-0.92 (t, 3H, J=7.36)；
4) it synthesizes deuterated Palbociclib compound shown in formula (V): taking 300mg compound DP-3 that 20mL dichloro is added
In methane, at room temperature, about 1mL concentrated hydrochloric acid is added dropwise, is stirred overnight at room temperature, thick yellow solid is precipitated in system, and saturation is added
NaHCO3Solution is adjusted to system in alkalescent, and system is extracted with dichloromethane, and organic phase is dry, and concentration obtains 210mg formula (V) institute
The deuterated Palbociclib compound shown；
The nuclear magnetic resonance information of deuterated Palbociclib compound shown in formula (V) are as follows:1H NMR(400MHz,CDCl3):
δ 8.82 (s, 1H), 8.21 (s, 1H), 8.17-8.15 (d, 1H, J=9.04), 8.06-8.05 (d, 1H, 2.84), 7.35-7.31
(dd, 1H, J12=2.96, J13=9.08), 5.92-5.83 (m, 1H), 3.17-3.15 (t, 4H, J=4.24), 3.06-3.09
(t, 4H, J=4.24), 2.37 (s, 3H), 2.34-2.31 (m, 2H), 2.08-2.01 (m, 2H), 1.90-1.85 (m, 2H),
1.71-1.67(m,2H)。
Deuterated Palbociclib used in following embodiment is prepared by with the above method.
Embodiment 1
The present embodiment is used to prepare the crystal form of deuterated Palbociclib shown in formula (V), and including the following steps: will be deuterated
Palbociclib solid 1.5g is distributed in methyl phenyl ethers anisole 72mL and butyl acetate 24mL mixed liquor, be heated to 125 DEG C completely it is molten
Solution, is cooled to 100 DEG C, and solution becomes cloudy, and stirs 2 hours, is cooled to 20 DEG C with 10 DEG C per hour, stands 15 hours, slowly analyses
Crystalline substance, filtering, obtains 1.2g solid, vacuum drying to get.
Embodiment 2
The present embodiment is used to prepare the crystal form of deuterated Palbociclib shown in formula (V), and including the following steps: will be deuterated
Palbociclib solid 1.5g is distributed in methyl phenyl ethers anisole 100mL and acetone 15mL mixed liquor, is heated to 40 DEG C and is completely dissolved, stirs
It mixes 3 hours, is cooled to 20 DEG C with 10 DEG C per hour, stands 30 hours, slow crystallization, filtering obtains 0.65g solid, and vacuum is dry
It is dry to get.
Embodiment 3
The present embodiment is used to prepare the crystal form of deuterated Palbociclib shown in formula (V), and including the following steps: will be deuterated
Palbociclib solid 1.5g is distributed in methyl phenyl ethers anisole 200mL and acetone 20mL mixed liquor, is heated to 80 DEG C and is completely dissolved, stirs
It mixes 1 hour, is cooled to 30 DEG C with 10 DEG C per hour, stands 20 hours, slow crystallization, filtering obtains 2.1g solid, and vacuum is dry
It is dry to get.
Embodiment 4
The present embodiment is used to prepare the crystal form of deuterated Palbociclib shown in formula (V), and including the following steps: will be deuterated
Palbociclib solid 1.5g is distributed in methyl phenyl ethers anisole 100mL and acetone 60mL mixed liquor, is heated to 90 DEG C and is completely dissolved, stirs
It mixes 2 hours, is cooled to 25 DEG C with 10 DEG C per hour, stands 10 hours, slow crystallization, filtering obtains 0.95g solid, and vacuum is dry
It is dry to get.
Embodiment 5
X-ray powder diffraction instrument used in the present invention is X ' the Pert PRO type of Dutch Panaco company production, incident
Light is the α spectral line of CuK, operating voltage 40KV, tube current 40mA, 10 °/min of surface sweeping speed.
The deuterated Palbociclib crystal prepared to embodiment 1 is analyzed with X-ray powder diffraction, testing conditions are as follows:
Operating voltage 35KV, tube current 30mA, angular range: 2-40 encloses, step-length: 0.01 encloses: step, wavelength 1.5406.Its X-ray powder
Last diffraction pattern is as shown in Figure 1.The X-ray powder diffraction indicated with 2 θ angles is with diffraction maximum as follows: 7.9115 °,
9.981°、10.1929°、11.4512°、13.9701°、15.0235°、15.9022°、17.0322°、17.6313°、
18.3803°、18.6392°、19.6222°、20.0905°、20.4888°、21.0786°、21.791°、22.4269°、
22.9327°、23.6454°、24.0257°、26.0195°、27.3311°、28.1959°、28.8058°、30.0161°、
31.0287°、31.5215°、34.461°、35.5924°、37.3177°、39.139°。
Wherein peak intensity be higher than 20% characteristic peak are as follows: 9.981 °, 10.1929 °, 11.4512 °, 13.9701 °,
17.0322°、19.6222°、20.0905°、22.4269°、22.9327°。
Embodiment 6
X-ray powder diffraction instrument used in the present invention is X ' the Pert PRO type of Dutch Panaco company production, incident
Light is the α spectral line of CuK, operating voltage 40KV, tube current 40mA, 10 face velocity voltage of surface sweeping speed.
The deuterated Palbociclib crystal prepared to embodiment 2 is analyzed with X-ray powder diffraction, testing conditions are as follows:
Operating voltage 35KV, tube current 30mA, angular range: 2-40 encloses, step-length: 0.01 encloses: step, wavelength 1.5406.The present embodiment
X-ray powder diffraction figure is basic as shown in Figure 1, consistent with the qualification result of embodiment 5.
Embodiment 7
X-ray powder diffraction instrument used in the present invention is X ' the Pert PRO type of Dutch Panaco company production, incident
Light is the α spectral line of CuK, operating voltage 40KV, tube current 40mA, 10 face velocity voltage of surface sweeping speed.
The deuterated Palbociclib crystal prepared to embodiment 3 is analyzed with X-ray powder diffraction, testing conditions are as follows:
Operating voltage 35KV, tube current 30mA, angular range: 2-40 encloses, step-length: 0.01 encloses: step, wavelength 1.5406.The present embodiment
X-ray powder diffraction figure is basic as shown in Figure 1, consistent with the qualification result of embodiment 5.
Embodiment 8
X-ray powder diffraction instrument used in the present invention is X ' the Pert PRO type of Dutch Panaco company production, incident
Light is the α spectral line of CuK, operating voltage 40KV, tube current 40mA, 10 face velocity voltage of surface sweeping speed.
The deuterated Palbociclib crystal prepared to embodiment 4 is analyzed with X-ray powder diffraction, testing conditions are as follows:
Operating voltage 35KV, tube current 30mA, angular range: 2-40 encloses, step-length: 0.01 encloses: step, wavelength 1.5406.The present embodiment
X-ray powder diffraction figure is basic as shown in Figure 1, consistent with the qualification result of embodiment 5.
Embodiment 9
Deuterated Palbociclib crystal form prepared by embodiment 1 can inhibit the activity of CDK4/6 kinases, can be used for preparing
In terms of CDK4/6 inhibitor medicaments.
Experimental example
This experimental example detects the bioactivity of gained Palbociclib derivative.
Sample message: the crystal form of deuterated Palbociclib shown in the formula (V) in embodiment 1.
Test content: test respectively deuterated Palbociclib shown in formula (V) of the present invention crystal form object and
The suppression of Palbociclib cell cycle protein dependent kinase 4 (CDK4) and cell cycle protein dependent kinase 6 (CDK6)
Production is used, and the results are shown in Table 3.As 3 content of table it is found that deuterated Palbociclib shown in formula V its to CDK6 and
The inhibiting effect of CDK4 is more efficient.
3 biological activity test of table
Claims (10)
1. the crystal form of deuterated Palbociclib shown in a kind of Formula V,
It is characterized in that, the X-ray powder diffraction indicated with 2 θ angles is in following position using CuK α spectral line: 9.98 ± 0.2 °,
10.19 ± 0.2 °, 11.45 ± 0.2 °, 13.97 ± 0.2 °, 17.03 ± 0.2 °, 19.62 ± 0.2 °, 20.09 ± 0.2 °, 22.43
± 0.2 °, 22.93 ± 0.2 ° have characteristic diffraction peak.
2. the crystal form of deuterated Palbociclib according to claim 1, which is characterized in that CuK α spectral line is used, with 2 angles θ
Spend indicate X-ray powder diffraction in following position: 7.9115 °, 9.981 °, 10.1929 °, 11.4512 °, 13.9701 °,
15.0235°、15.9022°、17.0322°、17.6313°、18.3803°、18.6392°、19.6222°、20.0905°、
20.4888°、21.0786°、21.791°、22.4269°、22.9327°、23.6454°、24.0257°、26.0195°、
27.3311°、28.1959°、28.8058°、30.0161°、31.0287°、31.5215°、34.461°、35.5924°、
37.3177 °, 39.139 ° have characteristic diffraction peak.
3. a kind of preparation method of the crystal form of deuterated Palbociclib described in claim 1, which is characterized in that including following
Step: the deuterated Palbociclib is distributed in solvent, is warming up to 40~130 DEG C, stirs 1~3h, it is cooled to 20~
45 DEG C, 10~30h of crystallization is stood, filter cake is collected in filtering, is drying to obtain.
4. the preparation method of the crystal form of deuterated Palbociclib according to claim 3, which is characterized in that described is molten
Agent is the mixing of water, acetone, ethyl acetate, methyl phenyl ethers anisole, propyl alcohol, butyl acetate, ethyl alcohol, dimethyl sulfoxide one or more
Liquid.
5. the preparation method of the crystal form of deuterated Palbociclib according to claim 4, which is characterized in that described is molten
Agent is the mixed liquor of methyl phenyl ethers anisole and butyl acetate, and wherein the volume ratio of methyl phenyl ethers anisole and butyl acetate is 3:1.
6. the preparation method of the crystal form of deuterated Palbociclib according to claim 3, which is characterized in that the heating
To be warming up to 80~100 DEG C.
7. the preparation method of the crystal form of deuterated Palbociclib according to claim 3, which is characterized in that the stirring
Time be 2h.
8. the preparation method of the crystal form of deuterated Palbociclib according to claim 3, which is characterized in that the cooling
To be cooled to 20 DEG C.
9. the preparation method of the crystal form of deuterated Palbociclib according to claim 3, which is characterized in that the standing
The time of crystallization is 15h.
10. a kind of crystal form answering in terms of preparing CDK4/6 inhibitor medicaments of deuterated Palbociclib described in claim 1
With.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710198725.XA CN106986871B (en) | 2017-03-29 | 2017-03-29 | A kind of crystal form and its preparation method and application of deuterated Palbociclib |
| PCT/CN2017/080668 WO2018176513A1 (en) | 2017-03-29 | 2017-04-14 | Crystal form of deuterated palbociclib and preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710198725.XA CN106986871B (en) | 2017-03-29 | 2017-03-29 | A kind of crystal form and its preparation method and application of deuterated Palbociclib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106986871A CN106986871A (en) | 2017-07-28 |
| CN106986871B true CN106986871B (en) | 2019-02-26 |
Family
ID=59412307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710198725.XA Active CN106986871B (en) | 2017-03-29 | 2017-03-29 | A kind of crystal form and its preparation method and application of deuterated Palbociclib |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106986871B (en) |
| WO (1) | WO2018176513A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336886A (en) * | 2018-12-07 | 2019-02-15 | 重庆三圣实业股份有限公司 | A kind of preparation method of Pa Boxini and products thereof |
| CN111718340A (en) * | 2019-03-20 | 2020-09-29 | 浙江同源康医药股份有限公司 | Crystal form, preparation method and application of deuterated Palbociclib compound |
| CN111285852A (en) * | 2020-04-02 | 2020-06-16 | 广州博济医药生物技术股份有限公司 | Crystal form of deuterated oxitinib medicinal salt and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014150925A2 (en) * | 2013-03-15 | 2014-09-25 | Concert Pharmaceuticals, Inc. | Deuterated palbociclib |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
-
2017
- 2017-03-29 CN CN201710198725.XA patent/CN106986871B/en active Active
- 2017-04-14 WO PCT/CN2017/080668 patent/WO2018176513A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014150925A2 (en) * | 2013-03-15 | 2014-09-25 | Concert Pharmaceuticals, Inc. | Deuterated palbociclib |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106986871A (en) | 2017-07-28 |
| WO2018176513A1 (en) | 2018-10-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106986871B (en) | A kind of crystal form and its preparation method and application of deuterated Palbociclib | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN103755648B (en) | New impurity of a kind of Gefitinib and preparation method thereof | |
| CN106967064B (en) | Deuterated Palbociclib derivative, preparation method and applications | |
| CN105017176B (en) | A kind of hydrobromic acid Vortioxetine crystal and preparation method thereof | |
| CN102267983B (en) | Sym-triazine derivative compounds containing sym-tetrazine rings and preparation method thereof | |
| CN108727329B (en) | N-hydroxyethyl formamido substituted dibenzoxanthene and application thereof | |
| CN108358884B (en) | Preparation method of temspiramycin (17-AAG) intermediate | |
| CN111018772A (en) | 5-sulfonamide substituted isatin derivatives with anti-tumor activity | |
| CN110407841A (en) | A kind of synthetic method of anti-tumor drug Rui Boxini | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN106478636B (en) | Ticagrelor crystal form and preparation method | |
| CN104945364A (en) | Icaritin compound and application of compound | |
| CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
| CN108358923B (en) | Sophoridine pyrrole and indole derivatives, and preparation method and application thereof | |
| CN106336443B (en) | The synthetic method of a kind of nucleoside compound | |
| CN111892488A (en) | Method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone | |
| CN111718326B (en) | Quinoline structure-containing NNN-type pyrimidine hydrazone cobalt (II) complex and preparation method and application thereof | |
| CN116102530B (en) | Cyano-substituted dibenzoxanthene compound and application thereof | |
| CN108864100B (en) | Salt of mercaptopurine and metformin, preparation method and crystal structure thereof | |
| CN115073547B (en) | Steroid carboline derivative, preparation method and application thereof, and anti-tumor pharmaceutical composition | |
| CN106632416B (en) | Using 1- (2- pyridines) -9- isopentyl-B-carboline as the chlorination copper complex and its synthetic method of ligand and application | |
| CN108084201B (en) | Oxoindolspirotetrahydrofuran skeleton material, crystal thereof and preparation method thereof | |
| CN109369425B (en) | Preparation method of fenofibric acid choline salt | |
| CN106478676B (en) | The copper-nitrate complex of 1 (2 pyridine) 9 (2 Phenoxyethyl) β carbolines and synthetic method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20180321 Address after: 313100 Zhejiang Huzhou city Changxin Economic Development Zone Mingzhu road 1278 Changxin World Trade Building A 14 floor 1403-2 room Applicant after: Zhejiang homologous health medicine Limited by Share Ltd Address before: No. 7, Holly Street, Zhengzhou high tech Zone, Henan Province Applicant before: TETRANOV PHARMACY STOCK INC. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |