CN108779122B - Crystal form of bisulfate of JAK kinase inhibitor and preparation method thereof - Google Patents
Crystal form of bisulfate of JAK kinase inhibitor and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a crystal form of a bisulfate of a JAK kinase inhibitor and a preparation method thereof. In particular, the invention relates to (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) hexahydrocyclopenta [ c)]A III crystal form of pyrrole-2 (1H) -formamide bisulfate and a preparation method thereof. The III crystal form of the compound shown in the formula (I) has good crystal form stability, and the used crystallization solvent has low toxicity and low residue, and can be better used for clinical treatment.
Description
Technical Field
The invention relates to a crystal form III of (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide hydrogen sulfate, a preparation method thereof, application thereof in a pharmaceutical composition and application of the crystal form III and the composition in preparation of medicines for treating and/or preventing arthritis diseases.
Background
Arthritis is the most common chronic disease worldwide, causes of arthritis are many, and causes of joint injury are different. At present, Tofacitinib (CP-690550) is a novel oral JAK pathway inhibitor developed by Perey company, and Tofacitinib is a first-in-class drug (first-in-drug) for treating rheumatoid arthritis (rhematoid arthritis). Based on the structure of Tofacitinib, WO2013091539 discloses a series of JAK kinase inhibitor compounds with in vivo and in vitro activity and high absorption.
Patent application WO2014194741 discloses (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide hydrogen sulfate salt represented by formula (I).
Patent applications WO2016054959 and WO2016070697 disclose crystal forms I and II, respectively, of a compound of formula (I). However, the above crystal forms all have the defect of poor solubility, and a crystal form with better solubility needs to be found out deeply.
Disclosure of Invention
The invention aims to provide a crystal form III of (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide hydrosulfate (shown aS a formula (I)), and the crystal form has good stability and solubility.
The technical scheme of the invention is as follows:
the invention provides a III crystal form of a compound shown as a formula (I), which is characterized in that: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta angles, which has characteristic peaks at 7.43, 9.60, 11.19, 18.18, 19.31, 19.64, 21.25, 22.80 and 25.63, wherein the error range of 2 theta of each characteristic peak is +/-0.2,
in a preferred embodiment of the present invention, there is provided a crystalline form III of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta angles, wherein the III crystal form has characteristic peaks at 7.43, 9.09, 9.60, 11.19, 13.13, 14.90, 16.35, 18.18, 19.31, 19.64, 21.25, 22.80, 25.63 and 28.10, and the error range of 2 theta of each characteristic peak is +/-0.2.
In a preferred embodiment of the present invention, there is provided a crystalline form III of the compound of formula (I), characterized in that an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ angles is obtained using Cu-ka radiation, said crystalline form III having characteristic peaks at 7.43, 9.09, 9.60, 11.19, 12.27, 13.13, 13.95, 14.90, 16.35, 17.76, 18.18, 19.31, 19.64, 21.25, 21.82, 22.45, 22.80, 23.43, 24.42, 25.63, 26.37, 27.49, 28.10, 29.07, 30.07, 31.32, 32.13, 32.90, 33.50, 34.64, 35.73, 36.69, 37.70 and 38.48, wherein the error range of each characteristic peak 2 θ is ± 0.2.
In a preferred embodiment of the present invention, the present invention further provides a process for preparing a crystalline form of compound III of formula (I), said process comprising:
(1) dissolving a compound shown in a formula (I) in dimethyl sulfoxide, adding an anti-solvent, and stirring for crystallization;
(2) filtering, and drying the solid to obtain the target III crystal form.
The addition mode of the anti-solvent is as follows:
adding for multiple times or adding for one time;
the multiple additions are preferably added in ten portions (each at intervals of 10min) or in three portions (each at intervals of 20 min).
The anti-solvent is selected from ester solvents, ketone solvents, ether solvents, nitrile solvents or alcohol solvents, the ester solvents are preferably ethyl acetate, the ketone solvents are preferably acetone or methyl isobutyl ketone, the ether solvents are preferably tetrahydrofuran or 1, 4-dioxane, the nitrile solvents are preferably acetonitrile, and the alcohol solvents are preferably methanol.
The DSC endothermic peak value of the crystal form III of the invention is 209.5-228 ℃, preferably 209.8-218 ℃, and more preferably 217.04 ℃.
The invention further relates to a pharmaceutical composition of the crystal form III of the compound shown in the formula (I), which consists of the crystal form III and a pharmaceutically acceptable carrier, diluent or excipient.
The invention also relates to a method for preparing the pharmaceutical composition, which is characterized by comprising the step of mixing the III crystal form with a pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to a III crystal form of the compound shown in the formula (I) or an application of a III crystal form pharmaceutical composition in preparation of medicines for treating JAK kinase-related diseases, wherein the diseases are selected from rheumatism and rheumatoid arthritis.
And performing structure determination and crystal form research on the III crystal form of the compound shown in the formula (I) through an X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The method of recrystallization is not particularly limited, and the recrystallization can be carried out by a usual recrystallization operation method. For example, the compound represented by the formula (I) as a raw material is dissolved in an organic solvent, and then an anti-solvent is added to the solution to crystallize the compound, and after completion of crystallization, the crystals are filtered and dried to obtain desired crystals.
The crystallization method comprises room temperature crystallization, cooling crystallization and the like.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.
Detailed Description
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "ketone solvent" according to the present invention refers to a compound in which a carbonyl group (-C (O)) is bonded to two hydrocarbon groups, and the ketone can be classified into aliphatic ketone, alicyclic ketone, aromatic ketone, saturated ketone and unsaturated ketone according to the difference of the hydrocarbon groups in the molecule, and specific examples include, but are not limited to: acetone, methyl butanone or methyl isobutyl ketone.
The "ester solvent" according to the present invention refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
The "ether solvent" according to the present invention refers to a chain compound or a cyclic compound containing an ether bond-O-and having 1 to 10 carbon atoms, and specific examples include, but are not limited to: propylene glycol methyl ether, tetrahydrofuran or 1, 4-dioxane.
The term "alcoholic solvent" as used herein means a compound in which one or more "hydroxyl groups" are substituted for "C1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "hydroxy" and "C1-6Alkyl "is as defined above, specific examples include, but are not limited to: methanol, ethanol, propanol or 2-propanol.
The "nitrile solvent" in the invention means that one or more "cyano groups" are substituted for "C1-6Groups derived from one or more hydrogen atoms of alkyl groups, said "cyano" and "C1-6Alkyl "is as defined above, specific examples include, but are not limited to: acetonitrile or propionitrile.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, and the first-order diffraction peak is takenAnd n is 1), when the X-ray is incident on an atomic plane with d lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The term "2 theta or 2 theta angle" as used herein means a diffraction angle, theta is a Bragg angle in degrees or less, and the error range of 2 theta is + -0.1 to + -0.5, preferably + -0.1 to + -0.3, more preferably + -0.2.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
The invention also relates to a pharmaceutical composition comprising the III crystal form of the compound shown in the formula (I) and optionally one or more medicinal carriers and/or diluents. The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the form III or pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
Furthermore, the pharmaceutical compositions of the present invention may also be administered to a patient or subject in need of such treatment by any suitable mode of administration, for example, oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, oral solid preparations such as tablets, capsules, pills, granules and the like; or oral liquid preparations such as oral solution, oral suspension, syrup, etc. When formulated into oral preparations, the pharmaceutical preparations may further contain suitable fillers, binders, disintegrants, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be manufactured by a conventional method in the existing pharmaceutical field. When preparing injection, the pharmaceutical preparation can be added with no additive, or added with proper additive according to the nature of the medicine. When used for rectal administration, the pharmaceutical preparation may be formulated into suppositories and the like. For pulmonary administration, the pharmaceutical formulation may be formulated as an inhalant or a spray. In certain preferred embodiments, the crystalline form III of the present invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline form III of the present invention is present in a pharmaceutical composition or medicament in the form of a unit dose.
The III crystal form of the compound shown in the formula (I) can be used for preparing medicines for treating JAK kinase related diseases. The present application therefore also relates to the use of the crystalline form III of the compound of formula (I) according to the invention for the preparation of a medicament for use in a medicament for the treatment of a disease associated with JAK kinases. Furthermore, the present application relates to a method of inhibiting a disease associated with a JAK kinase, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the crystalline form III of the compound of formula (I) of the present invention, or the pharmaceutical composition of the present invention.
In certain preferred embodiments, the disease is a disease associated with JAK kinases selected from the group consisting of rheumatoid and rheumatoid arthritis.
Advantageous effects of the invention
Compared with the prior art, the technical scheme of the invention has the following advantages:
researches show that the III crystal form of the compound shown in the formula (I) prepared by the invention has excellent solubility and higher purity, and the crystal form is not changed and has good stability under the conditions of illumination, high temperature and high humidity through XRPD detection; the HPLC purity change is small, and the chemical stability is high; the III crystal form of the compound shown in the formula (I) obtained by the technical scheme of the invention can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
Figure 1 is an XRPD pattern of a crystalline form of compound III shown in formula (I).
FIG. 2 is a DSC chart of a crystal form III of the compound shown in the formula (I).
FIG. 3 is an XRPD pattern of an amorphous form of a compound of formula (I).
FIG. 4 is a DSC of amorphous form of the compound of formula (I).
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the experiment:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 1 STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 40-300 deg.C
2. X-ray Powder Diffraction Spectroscopy (XRPD)
The instrument model is as follows: bruker D8 Focus X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40kV, current: 40mA
Example 1: (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazol-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxamide hydrogensulfate (prepared aS described in patent application W02014194741)
Adding (3aR,5s,6aS) -N- (3-methoxy-1, 2, 4-thiadiazole-5-yl) -5- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide (140g, 0.34mol) into a reaction bottle, adding anhydrous methanol (350g) and dichloromethane (2.0kg), suspending and stirring, slowly adding sulfuric acid (34.8g, 0.36mol) dropwise at room temperature, clarifying a reaction solution, and stirring for reacting for 30 min. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to obtain the objective product (168g, yield 90%). The X-ray diffraction spectrum of the sample is shown in figure 3, the characteristic absorption peak of amorphous form is shown, the DSC spectrum is shown in figure 4, the characteristic absorption peak of melting is not seen below 300 ℃, and the product is determined to be amorphous solid according to the result.
Example 2
Adding a sample (50mg) of the compound of formula (I) (prepared as in example 1) to a reaction flask, adding DMSO (150. mu.L), stirring and dissolving at 25 ℃, gradually adding ethyl acetate (1mL) at 100. mu.L each time, with an interval of about 10min, after addition, turning off the heating after 1.5h, stirring for about 40h, filtering, and drying the precipitate under vacuum to obtain a solid sample, which has a diffraction angle 2 θ of 7.44(11.87), 9.10(9.72), 9.61(9.20), 11.20(7.89), 12.28(7.20), 13.14(6.73), 13.96(6.34), 14.91(5.94), 16.35(5.42), 17.76(4.99), 18.19(4.87), 19.31(4.59), 19.66(4.51), 21.27(4.17), 21.82(4.07), 24.95 (24.95), 22.90 (3.35), 22.35.35 (3.65), 3.35.35 (19 (19.59), 19.35), 3.35.44, 3.35, 3.65), 3.35, 3.44 (19, 3.44, 3.19 (19), 3.19, characteristic peaks are found at 32.15(2.78), 32.91(2.72), 33.50(2.07), 34.63(2.59), 35.73(2.51), 36.73(2.45), 37.64(2.39) and 38.47(2.34), and the crystal form is defined as form III.
Example 3
A sample (500mg) of the compound of formula (I) (prepared as in example 1) was placed in a reaction flask, DMSO (1.5mL) was added, dissolved with stirring at 60 deg.C, methanol (10mL) was added, heating was turned off, crystallization was performed with stirring, filtration was performed, and vacuum drying was performed to obtain a solid sample 393mg with a yield of 78.6%. This form is defined as form III and the XRPD pattern of the crystalline sample is shown in fig. 1, the DSC pattern is shown in fig. 2, the melting point is near 217.04, the onset melting temperature is 209.82 ℃, and the characteristic peak positions are shown in the following table:
table 1, III crystal form characteristic peaks
Example 4
A sample (50mg) of the compound of formula (I) (prepared as described in example 1) was placed in a reaction flask, DMSO (150. mu.L) was added, dissolved with stirring at 25 ℃, and acetone (1mL) was added stepwise, 100. mu.L each, with an interval of about 10 min; after the addition is finished, the heating is closed after 1.5h, the stirring is carried out for about 40h, the filtering is carried out, the precipitate is dried in vacuum to obtain a solid, and the XRPD pattern and the DSC pattern of the crystallization sample are compared through research to determine that the product is the III crystal form.
Example 5
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding acetone (1mL), adding the acetone in three times, wherein the volume of the acetone is 300 mu L, 300 mu L and 400 mu L respectively, the interval between the two times is about 20min, stopping heating after 1.5h, stirring for about 40h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 6
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, adding acetone (1mL) at one time, stopping heating after 1.5h, stirring for about 40h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is the III crystal form by researching and comparing an XRPD pattern and a DSC pattern of a crystal sample.
Example 7
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding tetrahydrofuran (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after the addition is finished, stirring for about 40h, filtering, drying a precipitate in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 8
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding tetrahydrofuran (1mL) and adding the mixture in three times, wherein the volume of the mixture is 300 mu L, 300 mu L and 400 mu L respectively, the interval between the two times is about 20min, after the addition is finished, closing and heating after 1.5h, stirring for about 40h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystallization sample are compared to determine that a product is a III crystal form.
Example 9
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding 1, 4-dioxane (1mL), adding 100 mu L each time, and separating for about 10min, after the addition is finished, closing heating after 1.5h, stirring for about 40h, filtering, drying the precipitate in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 10
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding 1, 4-dioxane (1mL) in three times, wherein the volume of the mixture is 300 mu L, 300 mu L and 400 mu L respectively, the interval is about 20min, after the addition is finished, turning off heating after 1.5h, stirring for about 40h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 11
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring at 25 ℃ to dissolve, adding 1, 4-dioxane (1mL) at one time, closing heating after 1.5h, stirring for about 40h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystal sample are researched and compared to determine that the product is the III crystal form.
Example 12
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding acetonitrile (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after 1.5h, stirring for 40h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystal sample are researched and compared to determine that the product is the III crystal form.
Example 13
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding acetonitrile (1mL), adding the acetonitrile in three times, wherein the volume of the acetonitrile is 300 mu L, 300 mu L and 400 mu L respectively, the interval between the two times is about 20min, stopping heating after 1.5h, stirring for about 40h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 14
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding methyl isobutyl ketone (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after the addition is finished, stirring for about 40h, filtering, drying a precipitate in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 15
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding methanol (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after 1.5h, stirring for 40h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystal sample are researched and compared to determine that the product is the III crystal form.
Example 16
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, gradually adding methanol (1mL), adding the mixture in three times, wherein the adding time is 300 mu L, 300 mu L and 400 mu L respectively, the middle time interval is about 20min, after the adding is finished, closing and heating after 1.5h, stirring for about 40h, filtering, and drying precipitates in vacuum to obtain a solid, and the XRPD pattern and the DSC pattern of the crystal sample are compared through research to determine that the product is the III crystal form.
Example 17
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 25 ℃, adding methanol (1mL) at one time, stopping heating after 1.5h, stirring for about 40h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is the III crystal form by researching and comparing an XRPD pattern and a DSC pattern of a crystal sample.
Example 18
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 50 ℃, gradually adding acetone (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after 1.5h, stirring for about 20h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystal sample are researched and compared to determine that the product is the III crystal form.
Example 19
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 50 ℃, gradually adding methanol (1mL), adding 100 mu L each time, keeping the interval of 10min, stopping heating after 1.5h, stirring for about 20h, filtering, and drying precipitates in vacuum to obtain a solid, wherein the XRPD pattern and the DSC pattern of the crystal sample are researched and compared to determine that the product is the III crystal form.
Example 20
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 50 ℃, gradually adding methanol (1mL), adding the methanol in three times, wherein the volume of the methanol is 300 mu L, 300 mu L and 400 mu L respectively, the interval between the two is about 20min, stopping heating after 1.5h, stirring for about 20h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is a III crystal form by researching and comparing an XRPD pattern and a DSC pattern of the crystal sample.
Example 21
Placing a sample (50mg) of a compound (prepared according to the method of example 1) shown in the formula (I) into a reaction bottle, adding DMSO (150 mu L), stirring and dissolving at 50 ℃, adding methanol (1mL) at one time, stopping heating after 1.5h, stirring for about 20h, filtering, drying precipitates in vacuum to obtain a solid, and determining that the product is the III crystal form by researching and comparing an XRPD pattern and a DSC pattern of a crystal sample.
Example 22
The amorphous product sample obtained in example 1 and the crystal form III product sample obtained in example 3 were placed open and laid flat, the stability of the samples under the conditions of illumination (4500Lux), heating (40 ℃, 60 ℃), high humidity (RH 75%, RH 90%) was examined, the sampling time was examined for 5 days and 10 days, and the purity results of HPLC were shown in Table 1.
And (3) test results:
TABLE 2 comparison of the stability of the crystalline form of the compound III of the formula (I) according to the invention with respect to the amorphous form
Conclusion of the experiment
The stability examination results in table 2 show that:
under the conditions of illumination, high humidity and high temperature open placement, the influence of high humidity on the crystal form III is small, but under the conditions of illumination and high temperature, the stability of the crystal form III is obviously superior to that of an amorphous sample, and the crystal form is not changed through XRPD detection, which shows that the stability of the crystal form III is obviously superior to that of the amorphous sample.
Example 23 comparison of solubility of form III of the present invention with forms I and II of the prior art
And (3) testing the sample: form III (prepared according to the method of example 3), form I (which can be prepared according to the method of WO 2016054959), form II (which can be prepared according to the method of WO 2016070697).
Solvent: water, 0.1N HCl.
And (3) test results:
table 3 comparison of the saturation solubilities of form III, form I and form II of the compounds of formula (I)
Conclusion of the experiment
The results of the experiments shown in table 3 show that: the saturated solubility of the crystal form III in water or 0.1N HCl is higher than that of the crystal form I or the crystal form II, and the solubility of the crystal form III is better.
Claims (9)
1. A crystalline form III of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed in diffraction angle 2 theta angles, which has characteristic peaks at 7.43, 9.60, 11.19, 18.18, 19.31, 19.64, 21.25, 22.80 and 25.63, wherein the error range of 2 theta of each characteristic peak is +/-0.2,
2. the crystalline form III of the compound of formula (I) according to claim 1, characterized in that it has characteristic peaks at 7.43, 9.09, 9.60, 11.19, 13.13, 14.90, 16.35, 18.18, 19.31, 19.64, 21.25, 22.80, 25.63 and 28.10, wherein each characteristic peak has a 2 Θ error within ± 0.2.
3. The crystalline form III of the compound of formula (I) of claim 2, characterized in that it has characteristic peaks at 7.43, 9.09, 9.60, 11.19, 12.27, 13.13, 13.95, 14.90, 16.35, 17.76, 18.18, 19.31, 19.64, 21.25, 21.82, 22.45, 22.80, 23.43, 24.42, 25.63, 26.37, 27.49, 28.10, 29.07, 30.07, 31.32, 32.13, 32.90, 33.50, 34.64, 35.73, 36.69, 37.70, and 38.48, wherein each characteristic peak has a 2 Θ error range of ± 0.2.
4. A process for preparing a crystalline form III of a compound of formula (I) as claimed in any one of claims 1 to 3, which process comprises:
1) dissolving a compound shown in a formula (I) in dimethyl sulfoxide, adding an anti-solvent, wherein the anti-solvent is selected from ester solvents, ketone solvents, ether solvents, nitrile solvents or alcohol solvents, and stirring for crystallization;
2) filtering, and drying the solid to obtain the III crystal form of the compound shown in the formula (I).
5. The method of claim 4, wherein the anti-solvent is added by: adding the mixture for multiple times or adding the mixture for one time.
6. The method according to claim 4, wherein the ester solvent is selected from ethyl acetate, the ketone solvent is selected from acetone or methyl isobutyl ketone, the ether solvent is selected from tetrahydrofuran or 1, 4-dioxane, the nitrile solvent is selected from acetonitrile, and the alcohol solvent is selected from methanol.
7. A pharmaceutical composition consisting of the crystalline form III of the compound of formula (I) as described in any one of claims 1-3 and a pharmaceutically acceptable carrier, diluent or excipient.
8. A process for the preparation of a pharmaceutical composition comprising the step of admixing a crystalline form III of a compound of formula (I) according to any one of claims 1 to 3 with a pharmaceutically acceptable carrier, diluent or excipient.
9. Use of a pharmaceutical composition comprising a crystalline form III of a compound of formula (I) as defined in any one of claims 1 to 3, or a crystalline form III of a compound of formula (I) as defined in claim 7, for the manufacture of a medicament for the treatment of a disease associated with JAK kinase, said disease being selected from rheumatoid and rheumatoid arthritis.
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| CN201710051763 | 2017-01-20 | ||
| CN2017100517632 | 2017-01-20 | ||
| PCT/CN2018/073310 WO2018133823A1 (en) | 2017-01-20 | 2018-01-19 | Crystal form of bisulfate of jak kinase inhibitor, and preparation method therefor |
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| CN111205290B (en) * | 2018-11-22 | 2021-10-08 | 江苏恒瑞医药股份有限公司 | Crystal form of JAK kinase inhibitor and preparation method thereof |
| CN110028509B (en) * | 2019-05-27 | 2020-10-09 | 上海勋和医药科技有限公司 | Pyrrolopyrimidines as selective JAK2 inhibitors, and synthesis method and application thereof |
| CN113698404B (en) * | 2020-05-21 | 2023-06-16 | 江苏恒瑞医药股份有限公司 | Hexahydrocyclopenta [ c ] pyrrole-2 (1H) -formamide compound with low solvent residue and preparation method thereof |
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| US9527851B2 (en) * | 2011-12-21 | 2016-12-27 | Jiangsu Hengrui Medicine Co., Ltd. | Pyrrole six-membered heteroaryl ring derivative, preparation method thereof, and medicinal uses thereof |
| AU2014277506B2 (en) * | 2013-06-07 | 2017-08-31 | Jiangsu Hengrui Medicine Co., Ltd. | Bisulfate of Janus kinase (JAK) inhibitor and preparation method therefor |
| CN105566327A (en) * | 2014-10-09 | 2016-05-11 | 江苏恒瑞医药股份有限公司 | JAK kinase inhibitor bisulfate crystal type I and preparation method thereof |
| DK3216790T3 (en) * | 2014-11-05 | 2019-11-25 | Jiangsu Hengrui Medicine Co | CRYSTALLIC FORM OF JAK CHINESE INHIBITOR-BISULPHATE AND A PROCEDURE FOR PREPARING THEREOF |
| EP3417861B1 (en) * | 2016-02-19 | 2020-09-23 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing jak kinase inhibitor or pharmaceutically acceptable salt thereof |
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