CN106986871A - A kind of deuterated Palbociclib crystal formation and its preparation method and application - Google Patents
A kind of deuterated Palbociclib crystal formation and its preparation method and application Download PDFInfo
- Publication number
- CN106986871A CN106986871A CN201710198725.XA CN201710198725A CN106986871A CN 106986871 A CN106986871 A CN 106986871A CN 201710198725 A CN201710198725 A CN 201710198725A CN 106986871 A CN106986871 A CN 106986871A
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- 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.)
- Granted
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 form and its preparation method and application, and in particular to a kind of deuterated Palbociclib crystal formation and its preparation method and application.The deuterated Palbociclib crystal formations of the present invention are characterized with 2 θ angles of X ray powder diffractions, 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 crystal formation has stability good, the advantage such as curative effect is stable, available for the application prepared in terms of CDK4/6 inhibitor medicaments.The invention also discloses the preparation method of deuterated Palbociclib crystal formations thing, crystal formation has higher structural homogeneity and crystal form purity, high income obtained by the preparation method.
Description
Technical field
The present invention relates to crystal formation of compound and its preparation method and application, and in particular to a kind of deuterated Palbociclib
Crystal formation and its preparation method and application.
Background technology
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), recover 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 late periods or metastatic
The breakthrough sex therapy of ER+/HER2- breast cancer is assert.Palbociclib has been found to that patient vitals can be extended and slows down breast cancer
Tumour growth, is that patient with breast cancer and clinician provide new selection, other indications of the medicine carry out clinic
Test (non-small cell lung cancer, lymthoma, Huppert's disease etc.).
At present, it is domestic to have had numerous on Palbociclib reports, such as Chinese patent CN1051531149A,
CN104496983A, CN105418603A, CN104910149A etc. report respectively non-deuterated Palbociclib synthesis or
Preparation method.
Chinese patent (application notification number:CN104447739A a kind of deuterated Palbociclib derivatives, preparation) are disclosed
Method and application, it is deuterated by the selectivity to Palbociclib, the medicine of medicine is improved for property, and then improves medicine
Curative effect, security and tolerance, and the structural formula of specifically disclosed derivative is as follows：Formula (I) is single deuterium substitution
Palbociclib, formula (II) is single deuterium substitution Palbociclib organic acids or inorganic acid complex；Formula (III) replaces for six deuteriums
Palbociclib, formula (IV) be six deuteriums replace Palbociclib organic acids or inorganic acid complex.
At present, both at home and abroad it is not yet reported that the Palbociclib replaced with three deuteriums synthetic method, also takes without three deuteriums
The Palbociclib crystal formations and its preparation method of crystal formation in generation.Crystal formation is the solid matter state that medicine is present, and drug crystal forms are ground
It is exactly the research to medicine base state to study carefully, and only has the understanding compared adequately and comprehensively to chemicals crystal form state,
It is possible to find the drug crystal forms solid matter more properly with treating disease.Drug crystal forms can influence the physicochemical property of medicine,
Directly affect the basis that clinical drug plays treatment disease effect.Therefore study deuterated Palbociclib stable crystal form and its
Preparation method is significant.
The content of the invention
It is an object of the invention to provide deuterated Palbociclib crystal formation shown in Formula V and its preparation method and application.
A kind of crystal formation of deuterated Palbociclib shown in formula V,
Using CuK α spectral lines, the X-ray powder diffraction represented 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.
A kind of preparation method of deuterated Palbociclib crystal formations shown in formula (V), comprises 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~
30h, filtering, collection filter cake, dries, produces.
In the preparation method of described deuterated Palbociclib crystal formations, the solvent is water, acetone, ethyl acetate, benzene first
The one or more kinds of mixed liquor of ether, propyl alcohol, butyl acetate, ethanol, dimethyl sulfoxide (DMSO).Further, described solvent is benzene
The mixed liquor of methyl ether and butyl acetate.Further, the volume ratio of described in the mixed solvent methyl phenyl ethers anisole and butyl acetate is
3：1.
In the preparation method of described deuterated Palbociclib crystal formations, the heating is preferably to be warming up to 80~100 DEG C.
In the preparation method of described deuterated Palbociclib crystal formations, the time of the stirring is preferably 2h.
In the preparation method of described deuterated Palbociclib crystal formations, the speed of the cooling is 10 DEG C per hour, preferably
To be cooled to 20 DEG C.
In the preparation method of described deuterated Palbociclib crystal formations, the time for standing crystallization is preferably 15h.
For the research of the deuterated Palbociclib crystal formations shown in formula (V), the present invention is using X-ray generally acknowledged in the world
Deuterated Palbociclib crystal formation is studied and characterized to powder diffraction method (XRPD).
Instrument and equipment：X ' the Pert PRO types of Dutch PANalytical company production, incident light is CuK α spectral lines, 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 formations in the present invention shown in formula (V), its X-ray powder diffraction figure is basic such as Fig. 1 institutes
Show.Its more detailed data is as shown in table 1.
The X-ray powder diffraction peak value of the deuterated Palbociclib of the present invention of table 1 crystal formation
In table 1,2 θ at X-ray powder diffraction peak are represented, its error range is ± 0.5 °.It should be understood that X-ray powder
2 θ values of last diffraction pattern can be varied slightly between machine between sample, and its number range may differ by 0.5 unit, or
0.2 unit, or 0.1 unit of difference are differed, therefore cited numerical value can not 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 definitely compare, and indicates that instrument and equipment
Error caused may be offset.
In view of the intensity at the peak of the expression of 2 θ angles, to have height to have low, and especially the intensity at some peaks is less than highest peak
20%, its data precision characterized is influenceed larger by instrument condition, in fact it could happen that larger error, therefore it is high to choose peak intensity
Peak value in 20% is used as characteristic peak of the invention.
The deuterated Palbociclib crystal formations that the present invention is provided, the X-ray powder diffraction represented with 2 θ angles has as follows
Shown 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, the deuterated Palbociclib crystal formations that the present invention is provided, the X-ray powder diffraction represented 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, the deuterated Palbociclib crystal formations that the present invention is provided, the X-ray powder diffraction represented 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, deuterated Palbociclib of the invention crystal formation, using CuK α spectral lines, is penetrated with the X that 2 θ angles are represented
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, the deuterated Palbociclib crystal formations that the present invention is provided, using CuK α spectral lines, are represented 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 formations in terms of CDK4/6 inhibitor medicaments are prepared.
The deuterated Palbociclib crystal formations of the present invention are the deuterated Palbociclib crystal formations reported first both at home and abroad, the crystalline substance
Type is mainly used in medicinal usage, and compare no crystal formation medicine, and the fixation crystal formation medicine has stability good, and curative effect stabilization etc. is excellent
Gesture, specific effect is as shown in table 2.
Physicochemical property contrast table of the table 2 without compound shown in crystal formation and fixed crystal formation formula (V)
| Project | Without compound shown in crystal formation formula (V) | Compound shown in fixed crystal formation formula (V) |
| Fusing point | 186℃ | 206℃ |
| Stability (deuterated rate step-down) | ≦6months | ≧2years |
The present invention deuterated Palbociclib crystal formations preparation method, be deuterated Palbociclib solids are dissolved in it is organic
In solvent, by the increase solubility that heats up, stirring is completely dissolved deuterated Palbociclib, is passing through the reduction solubility that cools
Stand and separate out crystal, crystal formation has higher structural homogeneity and crystal form purity, high income obtained by the preparation method；The preparation side
Method technique is simple, and easy to operate, cost is low, it is easy to Automated condtrol, adapts to popularization and application
Brief description of the drawings
Fig. 1 is the XRD spectra of the powder diffraction of the deuterated Palbociclib crystal formations of embodiment 1.
Embodiment
This hair embodiment will be described in further detail, should not be construed as limiting the invention below.
The deuterated Palbociclib synthetic routes of the present invention are as follows：：
The preparation method of the deuterated Palbociclib derivatives of the present invention, comprises the following steps：
1) synthesis compound DP-1：Take 36g compound A to add in 250mL tetrahydrofuran, system is cooled to 0 DEG C；
Under nitrogen protection, it is slowly added dropwise after 240mL isopropylmagnesium chlorides (1M) tetrahydrofuran solution, completion of dropping, system heating
To room temperature and continue react 1h；Then 35g compound B is added, continues reaction and stays overnight, add the saturation NH of saturation4Cl solution
Reaction is quenched, is extracted with ethyl acetate three times, merges organic phase, dries, concentration obtains 44g compounds DP-1；Closed in this step
The process of compound shown in accepted way of doing sth DP-1 is with reference to the preparation method in patent document (A of CN 104447739).
Compound DP-1 nuclear-magnetism information is：1H NMR(400MHz,CDCl3)：δ8.82(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) synthesis compound DP-2：Take 5g compound DP-1 to be dissolved in 600mL Isosorbide-5-Nitrae-dioxane, add 1.0eq
Sodium hydride and 30.0eq deuterium-oxide (D2O), back flow reaction 30 hours under nitrogen protection, are spin-dried for, plus ethyl acetate dissolving, satisfy
And brine It, dry, be concentrated to give 5g compounds DP-2；
Compound DP-2 nuclear magnetic resonance information is：1H NMR(400MHz,CDCl3)：δ8.82(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) synthesis compound DP-3：Nitrogen protection under, take 450mg compounds DP-2,240mg vinyl n-butyl ether,
10mg Pd (OAc)2, 50mg dppf, 160mg DIEPA, add 20mL n-BuOH in, system is warming up to 95 DEG C of reactions
20h；After reaction terminates, concentrate system, column chromatography purifies to obtain 290mg compounds DP-3；
Compound DP-3 nuclear magnetic resonance information is：1H NMR(400MHz,CDCl3)：δ8.77(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) the deuterated Palbociclib compounds shown in synthesis formula (V)：300mg compounds DP-3 is taken to add 20mL dichloros
In methane, at room temperature, about 1mL concentrated hydrochloric acids are added dropwise, are stirred overnight at room temperature, system separates out thick yellow solid, add saturation
NaHCO3Solution, is adjusted to system in alkalescent, system is extracted with dichloromethane, organic phase is dried, and concentration obtains 210mg formulas (V) institute
The deuterated Palbociclib compounds shown；
The nuclear magnetic resonance information of deuterated Palbociclib compounds shown in formula (V) is：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 is prepared by with the above method in following embodiment.
Embodiment 1
The present embodiment is used for the crystal formation for preparing the deuterated Palbociclib shown in formula (V), comprises the following steps：Will be deuterated
Palbociclib solids 1.5g is distributed in methyl phenyl ethers anisole 72mL and butyl acetate 24mL mixed liquors, be heated to 125 DEG C completely it is molten
Solution, is cooled to 100 DEG C, solution turned cloudy is stirred 2 hours, and 20 DEG C are cooled to 10 DEG C per hour, stands 15 hours, slow analysis
Crystalline substance, filtering, obtains 1.2g solids, is dried in vacuo, produces.
Embodiment 2
The present embodiment is used for the crystal formation for preparing the deuterated Palbociclib shown in formula (V), comprises the following steps：Will be deuterated
Palbociclib solids 1.5g is distributed in methyl phenyl ethers anisole 100mL and acetone 15mL mixed liquors, is heated to 40 DEG C and is completely dissolved, stirs
Mix 3 hours, 20 DEG C are cooled to 10 DEG C per hour, stand 30 hours, slow crystallization, filtering obtains 0.65g solids, and vacuum is done
It is dry, produce.
Embodiment 3
The present embodiment is used for the crystal formation for preparing the deuterated Palbociclib shown in formula (V), comprises the following steps：Will be deuterated
Palbociclib solids 1.5g is distributed in methyl phenyl ethers anisole 200mL and acetone 20mL mixed liquors, is heated to 80 DEG C and is completely dissolved, stirs
Mix 1 hour, 30 DEG C are cooled to 10 DEG C per hour, stand 20 hours, slow crystallization, filtering obtains 2.1g solids, and vacuum is done
It is dry, produce.
Embodiment 4
The present embodiment is used for the crystal formation for preparing the deuterated Palbociclib shown in formula (V), comprises the following steps：Will be deuterated
Palbociclib solids 1.5g is distributed in methyl phenyl ethers anisole 100mL and acetone 60mL mixed liquors, is heated to 90 DEG C and is completely dissolved, stirs
Mix 2 hours, 25 DEG C are cooled to 10 DEG C per hour, stand 10 hours, slow crystallization, filtering obtains 0.95g solids, and vacuum is done
It is dry, produce.
Embodiment 5
X-ray powder diffraction instrument used in the present invention is X ' the Pert PRO types of Dutch PANalytical company production, incident
Light is CuK α spectral lines, operating voltage 40KV, tube current 40mA, 10 °/min of surface sweeping speed.
Deuterated Palbociclib crystal prepared by embodiment 1 is analyzed with X-ray powder diffraction, testing conditions are：
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.There is diffraction maximum as follows with the X-ray powder diffraction that 2 θ angles are represented：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 is higher than 20% characteristic peak：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 types of Dutch PANalytical company production, incident
Light is CuK α spectral lines, operating voltage 40KV, tube current 40mA, the face velocity voltage of surface sweeping speed 10.
Deuterated Palbociclib crystal prepared by embodiment 2 is analyzed with X-ray powder diffraction, testing conditions are：
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 types of Dutch PANalytical company production, incident
Light is CuK α spectral lines, operating voltage 40KV, tube current 40mA, the face velocity voltage of surface sweeping speed 10.
Deuterated Palbociclib crystal prepared by embodiment 3 is analyzed with X-ray powder diffraction, testing conditions are：
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 types of Dutch PANalytical company production, incident
Light is CuK α spectral lines, operating voltage 40KV, tube current 40mA, the face velocity voltage of surface sweeping speed 10.
Deuterated Palbociclib crystal prepared by embodiment 4 is analyzed with X-ray powder diffraction, testing conditions are：
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 formations prepared by embodiment 1 can suppress the activity of CDK4/6 kinases, available for preparing
In terms of CDK4/6 inhibitor medicaments.
Experimental example
This experimental example is detected to the bioactivity of gained Palbociclib derivatives.
Sample message：The crystal formation of the deuterated Palbociclib shown in formula (V) in embodiment 1.
Test content：Test respectively deuterated Palbociclib shown in formula (V) of the present invention crystal formation thing and
The suppression of Palbociclib cell cycles protein dependent kinase 4 (CDK4) and cell cycle protein dependent kinase 6 (CDK6)
Make and use, as a result as shown in table 3.From the content of table 3, deuterated Palbociclib shown in formula V its to CDK6 and
CDK4 inhibitory action is more efficient.
The biological activity test of table 3
Claims (10)
1. the crystal formation of the deuterated Palbociclib shown in Formula V a kind of,
Characterized in that, using CuK α spectral lines, the X-ray powder diffraction represented 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.
2. deuterated Palbociclib according to claim 1 crystal formation, it is characterised in that CuK α spectral lines are used, with 2 θ angles
The X-ray powder diffraction represented is spent 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. the preparation method of the crystal formation of the deuterated Palbociclib described in a kind of claim 1, it is characterised in that including following
Step：Described deuterated Palbociclib is distributed in solvent, 40~130 DEG C are warming up to, 1~3h is stirred, it is cooled to 20~
45 DEG C, 10~30h of crystallization is stood, filtering, collection filter cake are drying to obtain.
4. the preparation method of deuterated Palbociclib according to claim 3 crystal formation, it is characterised in that described is molten
Agent is water, acetone, ethyl acetate, methyl phenyl ethers anisole, propyl alcohol, butyl acetate, ethanol, the mixing of dimethyl sulfoxide (DMSO) one or more
Liquid.
5. the preparation method of deuterated Palbociclib according to claim 4 crystal formation, it is characterised 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 deuterated Palbociclib according to claim 3 crystal formation, it is characterised in that the heating
To be warming up to 80~100 DEG C.
7. the preparation method of deuterated Palbociclib according to claim 3 crystal formation, it is characterised in that the stirring
Time be 2h.
8. the preparation method of deuterated Palbociclib according to claim 3 crystal formation, it is characterised in that the cooling
To be cooled to 20 DEG C.
9. the preparation method of deuterated Palbociclib according to claim 3 crystal formation, it is characterised in that the standing
The time of crystallization is 15h.
10. a kind of crystal formation of the deuterated Palbociclib described in claim 1 answering in terms of CDK4/6 inhibitor medicaments are prepared
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 true CN106986871A (en) | 2017-07-28 |
| CN106986871B 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) |
Cited By (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 |
| 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 |
| 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 |
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 |
Cited By (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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106986871B (en) | 2019-02-26 |
| 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 | |
| CN108774270B (en) | Sorafenib antitumor platinum (II) complex targeting drug-resistant cells of human lung cancer and preparation method and application thereof | |
| CN105237452A (en) | Novel crystalline form of doxercalciferol and preparation method for novel crystalline form | |
| CN106045892A (en) | Novel methods for preparing silodosin and intermediates thereof | |
| CN103755648B (en) | New impurity of a kind of Gefitinib and preparation method thereof | |
| CN101792438A (en) | Method for synthesizing 1-substituted-1,2,3-tolyltriazole | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN114149470B (en) | Ruthenium nitrosyl (II) complex and preparation method and application thereof | |
| CN106967064B (en) | Deuterated Palbociclib derivative, preparation method and applications | |
| CN105693605B (en) | A kind of method of asymmetric synthesis of optical voidness (R)/(S) chloroquine | |
| 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 | |
| CN110092789B (en) | Indolo [2,3-b ] carbazole derivative and application thereof | |
| CN103254139A (en) | Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof | |
| CN105732495B (en) | Tetrahydroquinolinesas with optical activation and preparation method thereof | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN110407841A (en) | A kind of synthetic method of anti-tumor drug Rui Boxini | |
| CN109369772B (en) | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives | |
| WO2021244555A1 (en) | Chiral intermediate and preparation method therefor | |
| CN104945364A (en) | Icaritin compound and application of compound | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN106478636A (en) | Ticagrelor crystal formation and preparation method | |
| CN104098523B (en) | 1-isobutyryl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and preparation and application | |
| CN109516991A (en) | A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof | |
| CN114149426B (en) | Parbosini pharmaceutical co-crystal and preparation method thereof |
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 |