CN108341818A - Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof - Google Patents
Ba Ruike replaces Buddhist nun and its phosphatic novel crystal forms and preparation method thereof Download PDFInfo
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- CN108341818A CN108341818A CN201710043849.0A CN201710043849A CN108341818A CN 108341818 A CN108341818 A CN 108341818A CN 201710043849 A CN201710043849 A CN 201710043849A CN 108341818 A CN108341818 A CN 108341818A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides Ba Ruike of the present invention for Buddhist nun III crystal forms and Ba Ruike for Buddhist nun's phosphate crystal form D and preparation method thereof.Ba Ruike has for Buddhist nun's III crystal form X x ray diffration pattern xs is included in 2 θ of the angle of diffraction：Diffraction maximum at 4.238 ± 0.2 degree, 12.558 ± 0.2 degree, 16.747 ± 0.2 degree, 25.194 ± 0.2 degree, 29.466 ± 0.2 degree.Ba Ruike has for the X x ray diffration pattern xs of Buddhist nun's phosphate crystal form D is included in 2 θ of the angle of diffraction：Diffraction maximum at 3.217 ± 0.2 degree, 12.609 ± 0.2 degree, 17.825 ± 0.2 degree, 19.665 ± 0.2 degree, 20.671 ± 0.2 degree, 22.055 ± 0.2 degree.Gained crystal form of the invention has preferable comprehensive performance advantage, the effect of so as to improve the types of drugs and exploitability, is extremely important for the clinical application of Buddhist nun's drug for Ba Ruike.
Description
Technical field
The present invention relates to the polymorphics that a kind of Ba Ruike as JAK inhibitor replaces Buddhist nun, and in particular, to a kind of Ba Ruike
For Buddhist nun III crystal forms and Ba Ruike for Buddhist nun's phosphate form D and preparation method thereof.
Background technology
Ba Ruike replaces Buddhist nun (Baricitinib), chemical name { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d]
Pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3- bases } acetonitrile, shown in structural formula following (I).
Patent of invention CN 102026999B disclose the preparation method and use of the compound；Patent of invention WO
Ba Ruike is disclosed in 2015145286 for the amorphous and preparation method thereof of Buddhist nun；
Patent of invention WO20150166434 discloses Ba Ruike and (for ease of identification, is defined herein as crystal form for Buddhist nun's novel crystal forms
Ia), the x-ray diffraction pattern of the crystal form, which has, is included in 2 θ of the angle of diffraction：5.31 degree, 4.65 degree, 3.52 degree, 3.48 degree,
Diffraction maximum at 7.06 degree, 5.91 degree, 5.75 degree, 5.43 degree and 2.98 degree.The crystal form is in about 180.63 DEG C and about 207.98 DEG C
Differential scanning calorimetry (DSC) thermogram with heat absorption.It is about 3% by the water content that thermogravimetric analysis (TGA) measures.
Chinese patent application CN105924444A discloses Ba Ruike and replaces Buddhist nun novel crystal forms I and II, also discloses Ba Ruike
For Buddhist nun's phosphate crystal form A, B and C and preparation method thereof.
105601635 A of Chinese patent application CN disclose Ba Ruike and replace the phosphatic A crystal forms of Buddhist nun, H crystal form and I crystal
And preparation method thereof, with preferable solubility, bioavilability can be improved.
In general, solid drugs molecule has a variety of crystal habits such as polycrystalline, eutectic；The not isomorphous of same drug molecule
Type in crystal structure, stability, productibility, draw moist, bioavilability etc. and might have significant difference, to directly
The effect of influencing drug and exploitability.Therefore, Ba Ruike has for the research of Buddhist nun's polymorph in pharmaceuticals in drug research and development industry
Extremely important meaning.
Invention content
The object of the present invention is to provide a kind of Ba Ruike to replace Buddhist nun's III crystal forms.
The purpose of the present invention can be realized by the following method：
A kind of Ba Ruike replaces Buddhist nun's III crystal forms, and the x-ray diffraction pattern of the crystal form, which has, is included in 2 θ of the angle of diffraction：
Diffraction at 4.238 ± 0.2 degree, 12.558 ± 0.2 degree, 16.747 ± 0.2 degree, 25.194 ± 0.2 degree, 29.466 ± 0.2 degree
Peak.
Further, a kind of Ba Ruike replaces Buddhist nun's III crystal forms, and the x-ray diffraction pattern of the crystal form, which has, is included in diffraction
2 θ of angle：4.238 ± 0.2 degree, 12.558 ± 0.2 degree, 16.747 ± 0.2 degree, 19.121 ± 0.2 degree, 25.194 ± 0.2 degree,
Diffraction maximum at 25.403 ± 0.2 degree, 29.466 ± 0.2 degree, 38.147 ± 0.2 degree.
In a kind of scheme, a kind of Ba Ruike has peak form characteristics shown in Figure of description 1, diffraction for Buddhist nun's III crystal forms
Angle (2 θ), interplanar distance (d) and relative intensity (%) such as following table：
Table 1
| Peak serial number | 2θ,° | D values | Relative intensity |
| 1 | 4.238 | 20.834 | 10.4 |
| 2 | 11.338 | 7.798 | 1.4 |
| 3 | 12.558 | 7.043 | 100.0 |
| 4 | 16.335 | 5.422 | 2.2 |
| 5 | 16.747 | 5.290 | 21.0 |
| 6 | 19.121 | 4.638 | 7.3 |
| 7 | 19.289 | 4.598 | 2.4 |
| 8 | 20.962 | 4.235 | 2.3 |
| 9 | 22.094 | 4.020 | 1.2 |
| 10 | 22.452 | 3.957 | 1.4 |
| 11 | 25.194 | 3.532 | 18.9 |
| 12 | 25.403 | 3.503 | 5.4 |
| 13 | 25.596 | 3.477 | 1.1 |
| 14 | 26.229 | 3.395 | 2.2 |
| 15 | 29.466 | 3.029 | 24.1 |
| 16 | 29.849 | 2.991 | 1.5 |
| 17 | 30.116 | 2.965 | 1.8 |
| 18 | 33.232 | 2.694 | 1.5 |
| 19 | 33.672 | 2.660 | 1.0 |
| 20 | 36.697 | 2.447 | 1.6 |
| 21 | 37.176 | 2.417 | 2.9 |
| 22 | 38.147 | 2.357 | 6.6 |
Ba Ruike starts to melt in the DSC thermograms of Buddhist nun's III crystal forms at 213.76 DEG C, and 215.71 DEG C nearby have
One sharp endothermic peak, fusing point are 213.76 DEG C or so, the 10 DEG C/min of DSC heating rates, and error is 3 DEG C.
The present invention also provides the preparation methods that a kind of Ba Ruike replaces Buddhist nun's III crystal forms, comprise the following steps：
1) isopropanol/water in the mixed solvent is added for Buddhist nun's crude product in Ba Ruike, dissolved by heating；
2) mixture slow cooling obtained by step 1) is stood into crystallization to 5~10 DEG C；
3) filtration drying obtains solid.
Further, the volume ratio of in the mixed solvent water and isopropanol is 1：7~30, Ba Ruike replace Buddhist nun's crude product and isopropyl
The ratio of alcohol/water mixed solvent is 1：25~40g/ml.
The preparation method of the application is repeated several times, obtained Ba Ruike is flat crystal for Buddhist nun's III crystal forms, by Ma Er
Literary laser particle analyzer carries out droplet measurement, and volume average particle size is 20 microns, repeatedly tests its numerical value 18.7~23.3
Between micron.
The applicant replaces Buddhist nun's preparation method according to Ba Ruike disclosed in WO2015166434, obtains powder crystal Ia, passes through
Malvern laser particle analyzer carries out droplet measurement, and volume average particle size is 8.3 microns, and it is average to test obtained volume every time
Grain size is respectively less than 9 microns.
The Ba Ruike that the present invention obtains is larger for Buddhist nun's III crystal form grain sizes, more regular, compared with conventionally known method,
It is easy filtering, has clear superiority in industrially prepared.
It is a further object to provide a kind of Ba Ruike to replace Buddhist nun's phosphate crystal form D.
The Ba Ruike of the present invention can be realized by the following method for Buddhist nun's phosphate crystal form D：
A kind of Ba Ruike replaces Buddhist nun phosphate crystal form D, and the x-ray diffraction pattern of the crystal form, which has, is included in 2 θ of the angle of diffraction：
3.217 ± 0.2 degree, 12.609 ± 0.2 degree, 17.825 ± 0.2 degree, 19.665 ± 0.2 degree, 20.671 ± 0.2 degree, 22.055 ±
Diffraction maximum at 0.2 degree.
Further, a kind of Ba Ruike replaces Buddhist nun phosphate crystal form D, and the x-ray diffraction pattern of the crystal form, which has, to be included in
2 θ of the angle of diffraction：3.217 ± 0.2 degree, 12.609 ± 0.2 degree, 13.707 ± 0.2 degree, 16.647 ± 0.2 degree, 17.825 ± 0.2
Degree, 19.665 ± 0.2 degree, 20.671 ± 0.2 degree, 22.055 ± 0.2 degree, 22.981 ± 0.2 degree, 23.620 ± 0.2 degree,
Diffraction maximum at 25.287 ± 0.2 degree, 26.355 ± 0.2 degree.
In a kind of scheme, a kind of Ba Ruike has peak form characteristics shown in Figure of description 3 for Buddhist nun's phosphate crystal form D,
The angle of diffraction (2 θ), interplanar distance (d) and relative intensity (%) such as following table：
Table 2
Ba Ruike starts to melt, 176.49 DEG C attached in the DSC thermograms of Buddhist nun's phosphate crystal form D at 173.57 DEG C
Close there are one sharp endothermic peak, fusing point is 173.57 DEG C or so, the 10 DEG C/min of DSC heating rates, and error is 3 DEG C.
The present invention also provides the preparation methods that a kind of Ba Ruike replaces Buddhist nun's phosphate crystal form D, comprise the following steps：
A, acetonitrile/water in the mixed solvent is added for Buddhist nun's phosphate crude product in Ba Ruike, dissolved by heating；
B, mixture slow cooling obtained by step A is stood into crystallization to 5~10 DEG C；
C, filtration drying obtains solid powder.
Further, the volume ratio of in the mixed solvent water and acetonitrile is 1：7~30, Ba Ruike replace Buddhist nun's phosphate crude product and second
The ratio of nitrile/water mixed solvent is 1：25~40g/ml.
By the crystal form obtained by the present invention with reference to 2010 editions annex XIX J drug draws moist test guidelines of Chinese Pharmacopoeia,
25 DEG C ± 1 DEG C of experiment condition, 80% relative humidity carry out drawing moist weightening experiment, as a result, it has been found that, the Ba Ruike of present invention gained
It is moist almost without drawing for Buddhist nun phosphate crystal form D for Buddhist nun III crystal forms and Ba Ruike：Draw wet weightening and be respectively less than 0.2%, and in high humidity
Crystalline state variation does not occur under environment.
The Ba Ruike of gained of the invention replaces Buddhist nun phosphate crystal form D for Buddhist nun III crystal forms and Ba Ruike, under hot and humid environment
Carried out after placement crystal form XRD variation test and and heat stability testing is carried out in thermostatic drying chamber, as a result, it has been found that, this product has
Good thermal stability and preferable storage and processing stability, it is not easy to occur to turn crystalline substance.
Powder x-ray diffraction figure of the present invention is the collection of illustrative plates obtained with CuK alpha rays.For the of the same race of same compound
Crystal form, X-ray diffractogram have similitude, characterize the d values error of peak position generally within ± 2%, big portion on the whole
Point error does not exceed ± 2%, and relative intensity error may be larger, but variation tendency is consistent.In addition, in the identification of mixture
In, since the factors such as content decline can cause part diffracted ray to lack, at this point, without relying on the whole observed in high-purity sample
Bands of a spectrum or even a bands of a spectrum may also be characteristic to given crystallization.Determine the specification and claims of the present invention
In powder x-ray diffraction collection of illustrative plates 2 θ of the angle of diffraction when, the value of gained is interpreted as in the range of ± 1.0 degree of the value, compared with
It is in the range of value ± 0.2 degree well, the powder x-ray diffraction figure is the collection of illustrative plates obtained with CuK alpha rays.DSC heat
The value of fusing point in analysis chart, gained is interpreted as in the range of ± 3.0 DEG C of degree of the value, preferably ± 1 DEG C in the value
In the range of.
Term " multi-crystalline compounds " refers to the different crystal forms of the same compound and includes but not limited to comprising identical chemical combination
Object hydrate (such as：There are the combination water in crystalline texture) and solvate (such as：Other combinations than water are molten
Agent) other solid state molecular forms.The phenomenon that same drug molecule forms a variety of crystal forms referred to as polymorph in pharmaceuticals, drug polycrystalline
The phenomenon that type is generally existing in solid drugs.
Term " powder x-ray diffraction collection of illustrative plates " (abbreviation XRD) refers to the diffraction pattern that experimental observation arrives or the ginseng from it
Number.Powder x-ray diffraction collection of illustrative plates is characterized by peak position and peak intensity.
" intensity, CPS " are " intensity integration counts per second's " in XRD spectrum
It writes a Chinese character in simplified form, represents diffraction peak intensity, the powder x-ray diffraction figure is the collection of illustrative plates obtained with CuK alpha rays.
Description of the drawings
Fig. 1 show the powder x-ray diffraction figure that Ba Ruike of the present invention replaces Buddhist nun's III crystal forms.The longitudinal axis indicates peak intensity, horizontal
Axis indicates the angle of diffraction (2 θ).
Fig. 2 show the DSC thermograms that Ba Ruike of the present invention replaces Buddhist nun's III crystal forms.The longitudinal axis indicates that mW/mg, horizontal axis are indicated
Temperature DEG C.
Fig. 3 show Ba Ruike of the present invention to scheme for the TG of Buddhist nun's III crystal forms.
Fig. 4 show the powder x-ray diffraction figure that Ba Ruike of the present invention replaces Buddhist nun's phosphate crystal form D.The longitudinal axis indicates peak intensity
Degree, horizontal axis indicate the angle of diffraction (2 θ).
Fig. 5 show the DSC thermograms that Ba Ruike of the present invention replaces Buddhist nun's phosphate crystal form D.The longitudinal axis indicates mW/mg, horizontal axis
Indicate temperature DEG C.
Fig. 6 show Ba Ruike of the present invention to scheme for the TG of Buddhist nun's phosphate crystal form D.
The present invention provides Ba Ruike of the present invention to replace Buddhist nun phosphate crystal form D and its preparation side for Buddhist nun III crystal forms and Ba Ruike
Method.The Ba Ruike of gained of the invention replaces Buddhist nun phosphate crystal form D for Buddhist nun III and Ba Ruike, and crystal form grain size is larger, can from XRD spectrum
To find out, compared with existing disclosed crystal form, crystal form purity is higher, more regular, does not contain hemihedral crystal or stray crystal, metamict crystals
Deng；On the other hand, the Ba Ruike obtained by the application is preferable for Buddhist nun's phosphate crystal form D stability for Buddhist nun III and Ba Ruike, almost without
Draw moist, the solubility of product is preferable, can improve bioavilability.Overall merit, present invention gained crystal form have preferable
The effect of so as to improve the types of drugs and exploitability, Ba Ruike is answered for the clinic of Buddhist nun's drug for performance advantage
With being extremely important.
Specific implementation mode
Following embodiment further describes the present invention, and still, these embodiments are only for illustrating the present invention, rather than right
The limitation of the scope of the invention.
Embodiment 1：Ba Ruike replaces the preparation of Buddhist nun's crude product
(4- (1- (3- (cyano methyl) -1- (ethylsulfonyl) azetidins are sequentially added in 250mL round bottom reaction bulbs
Base -3- bases) -1H- pyrazoles -4- bases) -7H- pyrrolo-es [2,3-D] pyrimidin-7-yl) methyl pivalate (4.00g), THF
The lower sodium hydrate aqueous solution 9.2mL that 1M is added dropwise is mixed in (80mL), methanol (20mL).Drop finish, stirred at 20~30 DEG C to
TLC detects raw material and disappears, and water 60mL, 1M hydrochloric acid solution condition pH to 7~8 is added.45 DEG C are concentrated under reduced pressure except major part has
Solvent is stirred overnight at 20~30 DEG C.Filtering, drain, 45 DEG C be dried in vacuo Ba Ruike replace Buddhist nun crude product 2.79g, yield
91%.
Embodiment 2：Ba Ruike replaces the preparation of Buddhist nun's III crystal forms
By Ba Ruike for Buddhist nun's crude product 1.0g and water 3mL, isopropanol 30mL mixing is heated to molten in 80 DEG C of stirred in water bath
Chilly keeps the temperature half an hour.Slow cooling is stood overnight to 5~10 DEG C, crystallization, and filtering is drained.50 DEG C of forced air dryings obtain Ba Ruike
For Buddhist nun 0.81g.It is detected through XRD, Buddhist nun's III crystal forms is replaced for Ba Ruike.HPLC detects purity：99.89%.
Embodiment 3：Ba Ruike replaces the preparation of Buddhist nun's phosphate crude product
By Ba Ruike for Buddhist nun's crude product 1.0g and acetonitrile 33mL, mixing, phosphoric acid 0.36g.It is heated in 80 DEG C of stirred in water bath
Molten Chilly keeps the temperature 1 hour.Slow cooling is to 5~10 DEG C, and stirring and crystallizing, filtering is drained, and 50 DEG C of forced air dryings obtain Ba Ruike and replace Buddhist nun
Phosphate crude product 0.79g.
Embodiment 4：Ba Ruike replaces the preparation of Buddhist nun's phosphate crystal form D
By Ba Ruike obtained by embodiment 3-2 for Buddhist nun phosphate crude product 1.0g and water 3mL, acetonitrile 33mL mixing, in 80 DEG C of water
It is heated with stirring to molten Chilly in bath, keeps the temperature half an hour.Stop stirring, slow cooling stands overnight crystallization to 5~10 DEG C, filters, and takes out
It is dry.50 DEG C of forced air dryings obtain Ba Ruike and replace Buddhist nun phosphoric acid salt solid powder 0.80g, are detected through XRD, brilliant for Buddhist nun's phosphate for Ba Ruike
Type D.HPLC detects purity：99.95%.
Embodiment 5：Ba Ruike replaces the preparation of Buddhist nun's phosphate crystal form D
By Ba Ruike obtained by embodiment 3-2 for Buddhist nun phosphate crude product 1.0g and water 3mL, acetonitrile 33mL mixing, in 80 DEG C of water
It is heated with stirring to molten Chilly in bath, keeps the temperature half an hour.Stopping stirring, the crystal seed 10mg of crystal form D is added to 5~10 DEG C in slow cooling,
It stands overnight, crystallization, filters, drain, 50 DEG C of forced air dryings obtain Ba Ruike and replace Buddhist nun phosphoric acid salt solid powder 0.84g, are examined through XRD
It surveys, Buddhist nun's phosphate crystal form D is replaced for Ba Ruike.HPLC detects purity：99.97%.
Embodiment 6：Ba Ruike replaces Buddhist nun's phosphate crystal form D stability studies for Buddhist nun III crystal forms and Ba Ruike
Ba Ruike obtained by the application is every for the sampling of Buddhist nun's phosphate crystal form D solid powders for Buddhist nun III crystal forms and Ba Ruike
Part 0.200g is positioned in closed glass jar, is preserved under different temperatures in thermostatic drying chamber respectively, thermostabilization data are as follows：
Table 3
The Ba Ruike of the experimental result display present invention for Buddhist nun III crystal forms and Ba Ruike for Buddhist nun phosphate crystal form D 40 DEG C, 60
DEG C and 80 DEG C at preserve two weeks and have good thermal stability.
Embodiment 7：Ba Ruike replaces Buddhist nun's phosphate crystal form D stability studies for Buddhist nun III crystal forms and Ba Ruike
The crystal form III and Ba Ruike that the present invention is prepared are relatively wet 25 DEG C/60% respectively for Buddhist nun's phosphate crystal form D
It is placed under conditions of degree, 40 DEG C/75% relative humidity, measures its XRD diagram, detect crystal form situation of change and variation of melting point situation,
The experimental results are shown inthe following table:
Table 4
The results show, Ba Ruike of the invention is for Buddhist nun III crystal forms and Ba Ruike for Buddhist nun phosphate crystal form D in high wet bar
Part decentralization postpones the angles main 2 θ of XRD spectrum and significant changes do not occur for diffraction peak intensity, and crystal form remains unchanged, variation of melting point
In error range, crystalline state does not change, and is not susceptible to turn crystalline substance, it is shown that good stability of crystal form.
Embodiment 8：Ba Ruike draws moist research for Buddhist nun III crystal forms and Ba Ruike for Buddhist nun's phosphate crystal form D
The Ba Ruike of the 10mg present invention is taken to replace Buddhist nun phosphate crystal form D for Buddhist nun III crystal forms and Ba Ruike respectively, the traditional Chinese medicines with reference in
2010 editions annex XIX J drug draws moist test guidelines of allusion quotation, 25 DEG C ± 1 DEG C of experiment condition, 80% relative humidity is drawn
Moist weightening experiment, using dynamic water absorption (DVS) instrument test it is respective draw it is moist.It is tested, is averaged three times respectively
Value, the experimental results are shown inthe following table：
Table 5
| Crystal form type | Average weight gain |
| Ba Ruike replaces Buddhist nun's III crystal forms | 0.15% |
| Ba Ruike replaces Buddhist nun's phosphate crystal form D | 0.10% |
The result shows that Ba Ruike of the invention replaces Buddhist nun phosphate crystal form D under 80% humidity for Buddhist nun III crystal forms and Ba Ruike
After balance, weightening respectively less than 0.2% is moist almost without drawing.
Embodiment 9：Ba Ruike studies for Buddhist nun and Ba Ruike for Buddhist nun's phosphate grain size
Malvern laser is respectively adopted in the crystal form that crystal, embodiment 2 and embodiment 4 obtained by WO2015016634 obtains
Particle size analyzer carries out grain size test, compares its volume average particle size, the results are shown in table below：
Table 6
As a result, it has been found that the present invention gained Ba Ruike for Buddhist nun III and Ba Ruike replace Buddhist nun phosphate crystal form D, crystal form grain size compared with
Greatly, hence it is evident that be higher than known crystal form Ia, crystal form is more regular, is easy filtering.
Embodiment 10：Ba Ruike replaces Buddhist nun's phosphate crystal form D solubility studies
1. the configuration of reference substance solution
Two parts of 3 sample of Example about 45mg with methanol dilution and is settled to scale and does mother liquor in 100mL volumetric flasks.
Precision measures in 1mL to 100mL volumetric flasks, is diluted with water and is settled to scale, as a contrast product 1 and reference substance 2.
2. the configuration of test solution
The sample aqueous solution waved in slot is shaken in 35 DEG C of thermostatic water bath water-baths 24 hours is taken, 10 points are centrifuged through 10000RPM
Clock takes clear liquid, and absorbance is measured at 1nm wavelength.It is as follows to obtain experimental data：
Table 7
As a result, it has been found that Ba Ruike obtained by the application is 4.8mg/mL or so for the solubility of Buddhist nun's phosphate form D in water,
And stable level is maintained in minute.The Ba Ruike that the application obtains is apparent for Buddhist nun's phosphate form D solubility
Better than the known crystal form of the prior art.
Claims (6)
1. a kind of Ba Ruike replaces Buddhist nun's III crystal forms, the x-ray diffraction pattern of the crystal form, which has, is included in 2 θ of the angle of diffraction：4.238
Diffraction maximum at ± 0.2 degree, 12.558 ± 0.2 degree, 16.747 ± 0.2 degree, 25.194 ± 0.2 degree, 29.466 ± 0.2 degree, institute
It is the collection of illustrative plates obtained with CuK alpha rays to state powder x-ray diffraction figure.
2. Ba Ruike as described in claim 1 replaces Buddhist nun's III crystal forms, it is characterised in that the x-ray diffraction pattern of the crystal form has
Have and is included in 2 θ of the angle of diffraction：4.238 ± 0.2 degree, 12.558 ± 0.2 degree, 16.747 ± 0.2 degree, 19.121 ± 0.2 degree,
Diffraction maximum at 25.194 ± 0.2 degree, 25.403 ± 0.2 degree, 29.466 ± 0.2 degree, 38.147 ± 0.2 degree, the powder X-ray-
X ray diffration pattern x is the collection of illustrative plates obtained with CuK alpha rays.
3. described in claim 1 bar of Rake replaces the preparation method of Buddhist nun's III crystal forms, comprise the following steps：
1) isopropanol/water in the mixed solvent is added for Buddhist nun's crude product in Ba Ruike, dissolved by heating；
2) mixture slow cooling obtained by step 1) is stood into crystallization to 5~10 DEG C；
3) filtration drying obtains solid.
4. a kind of Ba Ruike replaces Buddhist nun phosphate crystal form D, the x-ray diffraction pattern of the crystal form, which has, is included in 2 θ of the angle of diffraction：
3.217 ± 0.2 degree, 12.609 ± 0.2 degree, 17.825 ± 0.2 degree, 19.665 ± 0.2 degree, 20.671 ± 0.2 degree, 22.055 ±
Diffraction maximum at 0.2 degree, the powder x-ray diffraction figure are the collection of illustrative plates obtained with CuK alpha rays.
5. Ba Ruike as claimed in claim 4 replaces Buddhist nun's phosphate crystal form D, it is characterised in that the X-ray diffraction of the crystal form
Figure, which has, is included in 2 θ of the angle of diffraction：3.217 ± 0.2 degree, 12.609 ± 0.2 degree, 13.707 ± 0.2 degree, 16.647 ± 0.2 degree,
17.825 ± 0.2 degree, 19.665 ± 0.2 degree, 20.671 ± 0.2 degree, 22.055 ± 0.2 degree, 22.981 ± 0.2 degree, 23.620
Diffraction maximum at ± 0.2 degree, 25.287 ± 0.2 degree, 26.355 ± 0.2 degree, the powder x-ray diffraction figure are penetrated with CuK α
The collection of illustrative plates that line obtains.
6. the Ba Ruike described in claim 4 replaces the preparation method of Buddhist nun's phosphate crystal form D, comprise the following steps：
A, acetonitrile/water in the mixed solvent is added for Buddhist nun's phosphate crude product in Ba Ruike, dissolved by heating；
B, mixture slow cooling obtained by step A is stood into crystallization to 5~10 DEG C；
C, filtration drying obtains solid powder.
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| CN115160221A (en) * | 2022-07-26 | 2022-10-11 | 上海歆贻医药科技有限公司 | Delitinib crystal form compound and application |
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| CN104230894A (en) * | 2013-06-06 | 2014-12-24 | 南京华威医药科技开发有限公司 | Triazole compound |
| CN104230917A (en) * | 2013-06-24 | 2014-12-24 | 南京华威医药科技开发有限公司 | Hydrates of proline derivative salt and production method thereof |
| WO2015166434A1 (en) * | 2014-05-01 | 2015-11-05 | Sun Pharmaceutical Industries Limited | Crystalline form of baricitinib |
| CN105924444A (en) * | 2015-03-11 | 2016-09-07 | 苏州晶云药物科技有限公司 | Crystal form of JAK inhibitor and preparation method thereof |
| WO2016205487A1 (en) * | 2015-06-19 | 2016-12-22 | Eli Lilly And Company | PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF {1-(ETHYLSULFONYL)-3-[4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL]AZETIDIN-3-YL}ACETONITRILE |
| CN105693731A (en) * | 2016-01-26 | 2016-06-22 | 上海宣创生物科技有限公司 | Baricitinib polymorph A and preparation method thereof |
| CN105601635A (en) * | 2016-02-01 | 2016-05-25 | 上海宣创生物科技有限公司 | Crystal forms A, H and I of barrack gefitinib phosphate and preparation methods thereof |
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| CN115160221A (en) * | 2022-07-26 | 2022-10-11 | 上海歆贻医药科技有限公司 | Delitinib crystal form compound and application |
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