CN114437079A - Crystal form of pyrrole pyrimidine five-membered nitrogen heterocyclic compound - Google Patents
Crystal form of pyrrole pyrimidine five-membered nitrogen heterocyclic compound Download PDFInfo
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- CN114437079A CN114437079A CN202111268081.XA CN202111268081A CN114437079A CN 114437079 A CN114437079 A CN 114437079A CN 202111268081 A CN202111268081 A CN 202111268081A CN 114437079 A CN114437079 A CN 114437079A
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Images
Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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 invention discloses a free alkali crystal form A, a phosphate crystal form B and a phosphate crystal form C of a compound shown as a formula (I), and discloses a preparation method and application thereof. The free alkali crystal form A and the phosphate crystal form B have good stability and solubility, and are more suitable to be used as preparation raw materials.
Description
The present application claims priority from a prior application entitled "crystalline form of pyrrole pyrimidine pentanitrogen heterocycles" filed at 30.10.2020 to the national intellectual property office under application number 202011199567.8, which is incorporated herein by reference in its entirety.
Technical Field
The invention belongs to the technical field of pharmaceutical crystal forms, and particularly relates to a novel crystal form of a pyrrole pyrimidine five-membered nitrogen heterocyclic compound, and a preparation method and application thereof.
Background
The JAK (janus kinase) kinase is a family of intracellular non-receptor tyrosine kinases that mediate signals produced by cytokines and are passed down through the JAK-STAT signaling pathway. There are currently four known JAK family members: JAK Kinase 1(JAK1), JAK Kinase 2(JAK2), JAK Kinase 3(JAK3), and Tyrosine Kinase 2(Tyrosine Kinase, TYK 2). JAK-dependent cytokines are involved in the pathogenesis of a variety of inflammatory and autoimmune diseases, and JAK inhibitors are widely used in the treatment of a variety of inflammatory diseases.
Patent CN201710055590.1 discloses a compound represented by formula (I) which is a novel JAK kinase inhibitor, has high selectivity for JAK2, and can reduce side effects and improve safety when used as a therapeutic agent for diseases related to JAK kinase such as rheumatoid arthritis, polycythemia vera, psoriasis, essential thrombocythemia, and myelofibrosis.
The solid compound prepared according to the patent CN201710055590.1 has high hygroscopicity, low stability, solubility and bioavailability, and can not meet the clinical medicinal requirements.
Different crystal forms of solid chemical drugs can cause different solubility and stability, thereby affecting the absorption and bioavailability of the drugs and causing the difference of clinical efficacy. However, there is no report on the crystal form of the compound of formula (I) at present, and therefore, it is necessary to perform a comprehensive systematic polymorphic screening of the compound of formula (I) to select the crystal form most suitable for development.
Disclosure of Invention
The invention aims to provide a novel crystal form of a compound shown in a formula (I), a preparation method and application of the novel crystal form;
the purpose of the invention can be realized by the following technical scheme:
the invention firstly provides a crystal form A of a compound shown as a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A expressed by a 2 theta angle has the following characteristic peaks: 5.6 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.6 +/-0.2 degrees and 28.3 +/-0.2 degrees.
Preferably, the crystal form a provided by the invention also has characteristic peaks at 2 θ of 11.2 ± 0.2 °, 12.0 ± 0.2 °, 12.9 ± 0.2 °, 13.4 ± 0.2 °, 14.8 ± 0.2 °, 17.6 ± 0.2 °, 19.3 ± 0.2 °, 20.5 ± 0.2 °, 21.3 ± 0.2 °, 22.5 ± 0.2 °, 23.0 ± 0.2 °, 24.8 ± 0.2 °, 25.4 ± 0.2 °, 27.9 ± 0.2 °, 30.0 ± 0.2 °, 30.7 ± 0.2 °, 33.4 ± 0.2 ° and 34.9 ± 0.2 °.
More preferably, the present invention provides crystalline form a having an X-ray powder diffraction pattern substantially in accordance with figure 1.
The results of the crystal form A, TGA and DSC provided by the invention are shown in figure 2, the weight loss of a sample heated to 150 ℃ is 1.9%, and an endothermic peak begins to appear near 234.1 ℃. Thus, form a is an anhydrous form.
The invention also relates to a preparation method of the crystal form A, which comprises the following steps: the phosphate salt of the compound of formula (I) is crystallized from methanol, water, dimethyl sulfoxide/isopropyl acetate, dimethyl sulfoxide/toluene or ethanol/water.
When the inventors of the present application carried out studies on the crystal form of the compound of formula (I), they found that the solubility of the compound of formula (I) is extremely low, and most solvents cannot dissolve it, so that they could not be subjected to crystal form studies. When the phosphate crystal form is researched, the inventor of the application unexpectedly finds that the phosphate crystal form is converted into the free base crystal form of the compound shown in the formula (I) under certain conditions. Disproportionation of the phosphate form to the free base form a is observed in various systems such as methanol, ethanol, isopropanol, N-dimethylformamide, water, and the like. Through further research, the compound of formula (I) can be prepared into a crystal form of a free base, namely a crystal form A, by crystallizing phosphate of the compound of formula (I) in a partial solvent, such as methanol, water, dimethyl sulfoxide/isopropyl acetate, dimethyl sulfoxide/toluene or ethanol/water.
When ethanol/water crystallization is used, the compound of formula (I) is obtained as free base form a when the ratio of ethanol to water is less than 6: 1.
Preferably, the compound of formula (I) is prepared as free base form a by crystallization using methanol, water, dimethyl sulfoxide/isopropyl acetate or dimethyl sulfoxide/toluene as solvent.
It is another object of the present invention to provide a crystalline form B of the phosphate salt of the compound of formula (I), said crystalline form B having the following characteristic peaks in the X-ray powder diffraction pattern expressed in terms of 2 Θ angles: 15.19 +/-0.2 degrees, 18.56 +/-0.2 degrees and 22.89 +/-0.2 degrees.
Preferably, the crystal form B provided by the invention also has characteristic peaks at the positions of 7.63 +/-0.2 degrees, 10.57 +/-0.2 degrees, 13.59 +/-0.2 degrees, 14.41 +/-0.2 degrees, 16.22 +/-0.2 degrees, 16.73 +/-0.2 degrees, 18.21 +/-0.2 degrees, 19.05 +/-0.2 degrees, 19.47 +/-0.2 degrees, 20.51 +/-0.2 degrees, 21.16 +/-0.2 degrees and 21.94 +/-0.2 degrees of 2 theta.
More preferably, the present invention provides form B having an X-ray powder diffraction pattern substantially in accordance with figure 3.
The results of the crystal form B, TGA and DSC provided by the invention are shown in figure 4, the sample loses 2.0 percent before 150 ℃, and an endothermic peak begins to appear near 216.3 ℃. Thus, form B is an anhydrous form.
The invention provides a preparation method of a crystal form B, which comprises the following steps: prepared by reacting a compound of formula (I) with phosphoric acid in an ethanol/acetonitrile solvent.
Wherein, when the volume ratio of the ethanol to the acetonitrile is 1:3, the crystal form B of the phosphate of the compound shown in the formula (I) can be satisfactorily prepared. Through IC detection, PO in the crystal form B of the prepared compound shown as the formula (I)4 3-The ion content was 19.3% (theoretical 19.1%), so that 1 molecule of free base in form B bound 1 molecule of phosphoric acid.
When the inventor uses other organic solvents, such as ethanol, acetone, ethyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran and the like as reaction solvents, the content of phosphate ions in the obtained solid is different from a theoretical value. When a mixed solvent of ethanol and acetonitrile in a volume ratio of 3:1 was used, a phosphate compound could not be obtained.
Preferably, form B is prepared with a molar ratio of phosphoric acid to the compound of formula (I) above 1.5.
The inventors of the present application studied the disproportionation phenomenon of form B. In ethanol solution, form B was directly stirred for 4 days with partial disproportionation to free base form a. While the free base solid of formula (I) and 1.5 equivalents or more of phosphoric acid were stirred in ethanol for 3 days, only phosphate form B was formed. Therefore, more than 1.5 equivalents of phosphoric acid is required to be added when preparing the phosphate crystal form B.
The invention also provides a crystalline form C of the compound of formula (I). The X-ray powder diffraction pattern substantially corresponds to that of figure 5. Form C can be prepared by crystallization of form B in a mixed solvent of DMF and DCM, but converts to a mixed form of free base form a and phosphate form B after standing overnight at room temperature.
It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of form a or form B and a pharmaceutically acceptable carrier, diluent or excipient.
The invention provides a new free base crystal form A and a new phosphate crystal form B of a compound shown in a formula (I) or a mixture of the two, which can be used for preparing a medicament for treating autoimmune diseases, in particular to the application of a medicinal preparation for treating rheumatoid arthritis.
In summary, no patent or literature reports the crystal form of the compound shown in the formula (I), the solubility of the compound shown in the formula (I) is very low, and the crystal form research is difficult.
The crystal form provided by the invention has good stability and obvious process purification effect. Can well avoid crystal transformation in the process of medicine storage and development, thereby avoiding the change of bioavailability and drug effect.
The crystal forms A and B provided by the invention have no hygroscopicity or low hygroscopicity, meet the requirements of bioavailability and drug effect, do not need special drying conditions in the preparation process, simplify the preparation process and post-treatment process of the medicine, are not easily influenced by humidity, have no harsh requirements on storage conditions, are convenient for long-term storage, greatly reduce the cost in the aspects of material storage and quality control, and have very strong economic value.
In conclusion, the crystal forms a and B provided by the invention have significant progress compared with the prior art, and especially compared with the solid compound prepared in example 1 of patent CN201710055590.1, the crystal forms a and B have lower hygroscopicity, higher stability, solubility and bioavailability, and provide support for the research of the preparation in the future, thereby meeting different clinical medication requirements.
Drawings
Figure 1 is an X-ray powder diffraction (XRD) pattern of form a of the present invention;
figure 2 is a thermogravimetric analysis (TGA) and differential scanning analysis (DSC) plot of form a of the present invention;
FIG. 3 is an X-ray powder diffraction (XRD) pattern of phosphate form B of the present invention;
FIG. 4 is a thermogravimetric analysis (TGA) and differential scanning analysis (DSC) plot of phosphate form B of the present invention;
figure 5 is an X-ray powder diffraction (XRD) pattern of form C of the present invention;
figure 6 is a graph of dynamic moisture sorption (DVS) of the free base form a of the present invention;
figure 7 is an XRPD overlay of the free base form a of the present invention before and after dynamic moisture sorption (DVS) testing;
figure 8 is a graph of dynamic moisture sorption (DVS) of phosphate form B of the present invention;
figure 9 is an XRPD overlay of the phosphate form B of the present invention before and after dynamic moisture sorption (DVS) testing.
Detailed Description
For better understanding of the present invention, the following embodiments are further described, but the present invention is not limited to the specific embodiments.
The detection instrument and the method comprise the following steps:
the instrument used for X-ray powder diffraction (XRD) was a Bruker D8 Advance differential, equipped with a theta-2 theta goniometer, Mo monochromator, Lynxeye detector. The acquisition software was Diffrac Plus XRDCommander and the analysis software was MDI Jade 5.0. The instrument is calibrated prior to use with a standard (typically corundum) carried by the instrument itself. The detection conditions are as follows: the 2 theta scanning angle range is 3-40 degrees, the step size is 0.013 degrees, and the scanning is continuously carried out for 7 minutes. And (3) detection process: the samples were tested at room temperature using Ka X-ray with a copper target wavelength of 1.54nm under 45kV and 40mA operating conditions, and the samples to be tested were placed on an organic glass slide. Unless otherwise specified, the samples were not ground prior to testing.
Thermogravimetric analysis (TGA): the instrument model is as follows: TA/TGA Q500, purge gas: nitrogen gas 40ml/min, heating rate: 10 ℃/min, temperature range: 5 to 350 ℃.
Differential Scanning Calorimetry (DSC): the instrument model is as follows: TA/DSC Q200, purge gas: nitrogen gas 40ml/min, heating rate: 10 ℃/min, temperature range: 20-250 ℃.
Dynamic moisture sorption (DVS): and (3) purging gas: nitrogen gas 200ml/min, heating rate: 10 ℃/min, dm/dt: 0.002%/min, RH range: 0% RH-95% RH-0% RH, RH gradient: 5 percent.
The solid used in the examples was obtained according to patent CN201710055590.1, example 1.
Example 1
A solution of the free base solid (53g,0.1328mol) in acetonitrile (2.4L) and ethanol (800mL) was added to the reaction flask, phosphoric acid (20g,0.2mol) was added, and the mixture was stirred at 80 ℃ overnight. Cooling the reaction system to room temperature, separating out solids, and filtering to obtain phosphate crystal form B solid (50.3g, yield: 76%, PO)4 3-The contents are as follows: 19.3%).
MS(m/s):400[M+H]+；
1H-NMR(400MHz,DMSO-d6):δ1.17(t,J＝7.4Hz,3H),2.14(m,J＝8.0Hz,2H),2.83(d,J＝10Hz,2H),2.96(t,J＝10.6Hz,2H),3.05(m,J＝7.3Hz,2H),3.29(s,2H),3.56(m,J＝4.2Hz,2H),7.10(m,J＝1.7Hz,1H),7.63(t,J＝2.0Hz,1H),8.45(s,1H),8.71(s,1H),8.82(s,1H),12.15(s,1H)。
In a similar manner, using acetonitrile as solvent, PO is obtained as a solid4 3-The content of PO in the obtained solid is 23.1% when ethanol or isopropanol is used as solvent4 3-The content is about 22.1%.
Example 2
Weighing about 15mg of phosphate crystal form B in a 20 ml small bottle, adding dimethyl sulfoxide to dissolve until the solution is clear, dropwise adding isopropanol into the clear solution, and stirring while dropwise adding until a solid is separated out. The solid was collected and tested for XRPD to give form a as the free base. The XRPD pattern is shown in FIG. 1.
Phosphate form B was obtained using the same experimental procedure using dimethylsulfoxide/methyl isobutyl ketone, dimethylsulfoxide/ethyl acetate, N/N-dimethylformamide/toluene, N/N-dimethylformamide/isopropyl acetate, N/N-dimethylformamide/1, 4 dioxane, N/N-dimethylformamide/methyl tert-butyl ether, ethanol/dichloromethane (1: 2)/toluene, ethanol/dichloromethane (1: 2)/N-heptane, etc. as crystallization solvents. The XRPD pattern is shown in FIG. 3.
Example 3
Weighing about 10mg of phosphate crystal form B into a small bottle of 3 mL, adding about 2.0-2.4mL of methanol to prepare a clarified solution, or filtering with a nylon filter membrane (0.45 mu m) to obtain a clarified solution, sealing with a sealing membrane at room temperature, puncturing 2-4 small holes, standing for natural volatilization, collecting the obtained solid, and carrying out XRPD test to obtain a free alkali crystal form A.
Using the same experimental procedure, using ethanol/dichloromethane (v/v ═ 1:2), ethanol/chloroform (v/v ═ 1:3) as the crystallization solvent, phosphate form B was obtained.
Example 4
About 15mg of each portion of phosphate form B was weighed into an amount of solvent 1, the filtrate was filtered and taken in a 3 ml vial, another 20 ml vial was taken and about 3 ml of solvent 2 was added thereto, the 3 ml vial was opened into the 20 ml vial, sealed and left to stand at room temperature. When solid evolution was observed, the solid was removed for XRPD testing. The test results are shown in table 1.
TABLE 1
Form C was transformed to a mixture of free base form a and phosphate form B after standing overnight at room temperature and the XRPD comparison spectrum is shown in figure 5.
Example 5
About 20mg of phosphate form B was weighed into a 3 mL vial, 1.0mL of a mixed solvent of dimethyl sulfoxide/toluene (v/v ═ 1:5) was added, and after stirring at 50 ℃ for 1 hour, the clear solution was filtered (teflon filter, 0.45 μm), and the obtained filtrate was cooled from 50 ℃ to 5 ℃ at a rate of 0.1 ℃/min and thermostatted at 5 ℃. If the sample is clear, the sample is turned to room temperature to volatilize. The precipitated solid was collected and subjected to XRPD testing to give free base form a.
Using the same experimental procedure, when ethanol/chloroform (v/v ═ 1:3) was used as the crystallization solvent, phosphate form B was obtained. When N, N-dimethylformamide/methyl isobutyl ketone (v/v ═ 1:5) or methanol/water (v/v ═ 3:1) was used as a crystallization solvent, the system was clear and no solid precipitated.
Example 6
About 15mg each of the phosphate form B was weighed into a 1.5 ml glass vial, 0.5ml of the solvents listed in table 2 were added, respectively, and the resulting suspension was stirred at room temperature for about 4 days, after which the solid was collected by centrifugation and subjected to XRPD testing. The test results are shown in Table 2.
TABLE 2
Example 7
About 20mg of each phosphate form B sample was weighed into an HPLC glass vial, 0.5mL methanol was added, and after the resulting suspension was stirred at 50 ℃ for about 4 days, the solid was collected by centrifugation and subjected to XRPD testing to give the free base form a.
The phosphate crystal form B is obtained by using acetone, ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile as a crystallization solvent by the same experimental method. When ethanol is used as a solvent, a mixed crystal of a free base crystal form A and a phosphate crystal form B is obtained.
Example 8
To assess the risk of disproportionation of phosphate form B in EtOH, the stability of phosphate form B was examined at different acid-base molar ratios under room temperature conditions. The results are given in Table 3 below.
TABLE 3
Example 9
To evaluate the stability of free base form a and phosphate form B under different humidity conditions, samples were dried beforehand under 0% RH conditions to remove possible adsorption solvents or water and subjected to DVS tests at a constant temperature of 25 ℃.
When the humidity reached 80%, the water adsorption of free base form a was 0.015%, indicating that free base form a had almost no hygroscopicity and the form did not change before and after DVS testing, as shown in fig. 6 and 7. The moisture adsorption of phosphate form B was 1.17%, indicating that phosphate form B is slightly hygroscopic and XRPD results show that the sample forms did not change before and after DVS testing, as shown in figures 8 and 9.
Example 10
The solid state stability of the free base form a and the phosphate form B under different conditions was examined, and the conditions and results are shown in table 4 below.
The results show that the crystal forms and the purities of the free alkali crystal form A and the phosphate crystal form B do not change obviously, so that the free alkali crystal form A and the phosphate crystal form B have better physical and chemical stability.
Example 11
Bioavailability testing of free base form a
Experimental animals: male CD-1 mice 6.
The administration scheme is as follows: the intravenous injection dose is 1.0mg/kg, and the administration volume is 1 mL/kg; the oral dosage is 5 mg/kg.
Preparing an intravenous injection medicament: the appropriate amount of OB756 was weighed out and dissolved in 5% DMAC, 5% solutol and 90% saline at a concentration of 0.2 mg/mL.
Preparing oral medicines: an appropriate amount of OB756 was weighed out and made into a homogeneous suspension with 0.5% MC and 0.4% Tween80 at a concentration of 0.5 mg/mL.
The blood samples of the mice were assayed by LC-MS and showed an average bioavailability (F) of the free base form A of 28.8% in CD-1 mice.
Claims (10)
1. A crystalline form a of a compound of formula (I) characterized by: the X-ray powder diffraction pattern of the crystal form A expressed by the angle of 2 theta has the following characteristic peaks: 5.6 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.6 +/-0.2 degrees and 28.3 +/-0.2 degrees;
2. form a according to claim 1, characterized in that: the X-ray powder diffraction pattern of the crystal form A also has characteristic peaks at the 2 theta of 11.2 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.8 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.4 +/-0.2 degrees, 27.9 +/-0.2 degrees, 30.0 +/-0.2 degrees, 30.7 +/-0.2 degrees, 33.4 +/-0.2 degrees and 34.9 +/-0.2 degrees.
3. Form a according to claim 1, characterized in that: the X-ray powder diffraction pattern substantially corresponds to that of figure 1.
4. A process for preparing form a according to any one of claims 1 to 3, characterized in that: the phosphate salt of the compound of formula (I) is crystallized from methanol, water, dimethyl sulfoxide/isopropyl acetate, dimethyl sulfoxide/toluene or ethanol/water, preferably methanol, water, dimethyl sulfoxide/isopropyl acetate or dimethyl sulfoxide/toluene.
5. A phosphate crystalline form B of a compound of formula (I) characterized by: the X-ray powder diffraction pattern of the crystal form B expressed by the angle of 2 theta has the following characteristic peaks: 15.19 +/-0.2 degrees, 18.56 +/-0.2 degrees, 22.89 +/-0.2 degrees;
6. the phosphate crystalline form B of claim 5, characterized in that: the X-ray powder diffraction pattern of the crystal form B also has characteristic peaks at 2 theta of 7.63 +/-0.2 degrees, 10.57 +/-0.2 degrees, 13.59 +/-0.2 degrees, 14.41 +/-0.2 degrees, 16.22 +/-0.2 degrees, 16.73 +/-0.2 degrees, 18.21 +/-0.2 degrees, 19.05 +/-0.2 degrees, 19.47 +/-0.2 degrees, 20.51 +/-0.2 degrees, 21.16 +/-0.2 degrees and 21.94 +/-0.2 degrees.
7. The crystalline form B of claim 5, characterized in that: the X-ray powder diffraction pattern substantially corresponds to that of figure 3.
8. A method of preparing form B according to any one of claims 6 to 7, characterized in that: preparing the compound of formula (I) and phosphoric acid in ethanol/acetonitrile; preferably, the volume ratio of ethanol to acetonitrile is 1: 3.
9. The method of claim 8, wherein: the molar ratio of phosphoric acid to the compound of formula (I) is above 1.5.
10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form a of any one of claims 1-2 or the crystalline form B of any one of claims 6-7 and a pharmaceutically acceptable carrier, diluent or excipient.
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| CN101448826A (en) * | 2005-12-13 | 2009-06-03 | 因塞特公司 | Heteroaryl-substituted pyrrolo [2,3-b] pyrroles and pyrrolo [2,3-b] pyrimidines as inhibitors of Bissaelectrical kinases |
| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
| CN104024256A (en) * | 2011-09-07 | 2014-09-03 | 因塞特公司 | Processes and intermediates for making a JAK inhibitor |
| CN106905322A (en) * | 2016-01-26 | 2017-06-30 | 杭州华东医药集团新药研究院有限公司 | Pyrrolopyrimidine penta azacyclo derivative and its application |
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| CN101448826A (en) * | 2005-12-13 | 2009-06-03 | 因塞特公司 | Heteroaryl-substituted pyrrolo [2,3-b] pyrroles and pyrrolo [2,3-b] pyrimidines as inhibitors of Bissaelectrical kinases |
| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
| CN104024256A (en) * | 2011-09-07 | 2014-09-03 | 因塞特公司 | Processes and intermediates for making a JAK inhibitor |
| CN106905322A (en) * | 2016-01-26 | 2017-06-30 | 杭州华东医药集团新药研究院有限公司 | Pyrrolopyrimidine penta azacyclo derivative and its application |
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