CN108779122A - A kind of crystal form of disulfate and preparation method thereof of jak kinase inhibitor - Google Patents
A kind of crystal form of disulfate and preparation method thereof of jak kinase inhibitor Download PDFInfo
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- CN108779122A CN108779122A CN201880001322.4A CN201880001322A CN108779122A CN 108779122 A CN108779122 A CN 108779122A CN 201880001322 A CN201880001322 A CN 201880001322A CN 108779122 A CN108779122 A CN 108779122A
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- 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
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- 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
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- 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]
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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
Abstract
The present invention relates to a kind of crystal forms of disulfate and preparation method thereof of jak kinase inhibitor.Specifically, the present invention relates to (3aR, 5s, 6aS)-N- (3- methoxyl groups -1,2,4- thiadiazoles -5- bases) -5- (methyl (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) amino) hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide disulfate III crystal forms and preparation method thereof.The III crystal forms of formula (I) compound of the present invention have good stability of crystal form, and recrystallisation solvent low toxicity and low residue used, can be preferably applied to clinical treatment.
Description
The present invention relates to (3aR, 5s, 6aS)-N- (3- methoxyl group -1,2,4- thiadiazoles -5- base) -5- (methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) and hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide disulfate III crystal form and preparation method thereof, in pharmaceutical composition application and the III crystal form, composition preparation treatment and/or prevention arthritis disease drug in purposes.
The reason of arthritis is the most common chronic disease in the whole world, causes arthritic reason very much, causes joint injury is also had nothing in common with each other.At present, Tofacitinib (CP-690550) is a kind of new oral JAK pathway inhibitor of Pfizer's research and development, and Tofacitinib is the pioneering drug (first-in-class drug) for rheumatoid arthritis (rheumatoid arthritis) treatment.Structure based on Tofacitinib, WO2013091539 disclose a series of with the inside and outside activity of body, the jak kinase inhibitor compound of high-selenium corn.
(3aR shown in formula (I) is disclosed in patent application WO2014194741,5s, 6aS)-N- (3- methoxyl group -1,2,4- thiadiazoles -5- base) -5- (methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide disulfate.
Patent application WO2016054959, WO2016070697 individually disclose the I crystal of compound shown in formula (I), II crystal form.But above-mentioned crystal form haves the defects that solubility is poor, needs deeply to grope to find the better crystal form of solubility.
Summary of the invention
The technical problem to be solved in the present invention is to provide one kind (3aR, 5s, 6aS)-N- (3- methoxyl group -1,2,4- thiadiazoles -5- base) -5- (methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) and hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide disulfate (as shown in formula (I)) III crystal form, which has good stability and dissolubility.
Technical scheme is as follows:
The present invention provides a kind of III crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, obtains the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 7.43,9.60,11.19,18.18,19.31,19.64,21.25, there is characteristic peak at 22.80 and 25.63, wherein, the error range of each 2 θ of characteristic peak is ± 0.2
In a preferred embodiment of the present invention scheme, the present invention provides a kind of III crystal form of compound shown in formula (I), it is characterised in that: is radiated using Cu-K α, obtains the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, the III crystal form is 7.43,9.09,9.60,11.19,13.13,14.90,16.35,18.18,19.31,19.64,21.25,22.80, there is characteristic peak at 25.63 and 28.10, wherein the error range of each 2 θ of characteristic peak is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention provides a kind of III crystal form of compound shown in formula (I), it is characterized in that, it is radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, the III crystal form is 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, 33.5 There is characteristic peak at 0,34.64,35.73,36.69,37.70 and 38.48, wherein the error range of each 2 θ of characteristic peak is ± 0.2.
In a preferred embodiment of the present invention scheme, the present invention further provides a kind of methods for preparing the crystal form of compound III shown in formula (I), which comprises
(1) compound shown in formula (I) is dissolved in dimethyl sulfoxide, anti-solvent, stirring and crystallizing is added；
(2) it filters, up to target III crystal form after solid is dry.
The adding manner of anti-solvent of the present invention are as follows:
Repeatedly it is added or is added at one time；
The multiple addition is preferably added (every minor tick 10min) in ten times or (every minor tick 20min) is added in three times.
Anti-solvent of the present invention is selected from esters, ketone, ethers, nitrile or alcohols solvent, the esters solvent ethyl acetate, the preferred acetone of the ketones solvent or methylisobutylketone, the preferred tetrahydrofuran of the ether solvent or 1,4- dioxane, the preferred acetonitrile of nitrile solvents, the preferred methanol of alcohols solvent.
The DSC endothermic peak of III crystal form of the present invention is 209.5 DEG C~228 DEG C, preferably 209.8 DEG C~218 DEG C, more preferably 217.04 DEG C.
The invention further relates to the pharmaceutical composition of the III crystal form of compound shown in formula (I), described pharmaceutical composition is made of III crystal form and pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to a kind of methods for preparing aforementioned pharmaceutical compositions, which is characterized in that the method includes being mixed by III crystal form with pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the pharmaceutical composition of the III crystal form of compound shown in formula (I) or III crystal form in preparation treatment with jak kinase in relation to the purposes in disease medicament, the disease is selected from rheumatism and rheumatoid arthritis.
By the way that X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC) carry out structure determination to the III crystal form of compound shown in acquired formula (I), crystal form is studied.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, anti-solvent crystallization is added after being dissolved in organic solvent with compound shown in raw material formula (I), after the completion of crystallization, through filtration drying, required crystallization can be obtained.
The method of crystallization of the present invention has room temperature crystallization, cooling crystallization etc..
Starting material used in crystal form preparation method of the present invention can be compound shown in any form of formula (I), and concrete form includes but is not limited to: amorphous, any crystal form etc..
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, Science and Technology noun used herein has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, the definition and explanation of part relational language is provided below.In addition, with the definition of term provided herein and being construed to quasi- when the definition of term provided herein and explanation and the inconsistent normally understood meaning of those skilled in the art.
" ketones solvent " of the present invention refers to the compound that carbonyl (- C (O) -) is connected with two alkyl, according to the difference of alkyl in molecule, ketone can be divided into aliphatic ketone, alicyclic ketone, aromatic ketone, saturated ketone and beta-unsaturated ketone, and specific example includes but is not limited to: acetone, espeleton or methylisobutylketone.
" esters solvent " of the present invention refers to the conjugate for the lower alcohol that the rudimentary organic acid that carbon atom quantity is 1 to 4 and carbon atom quantity are 1 to 6, and specific example includes but is not limited to: ethyl acetate, isopropyl acetate or butyl acetate.
" ether solvent " of the present invention refers to the chain compound or cyclic compound that containing ehter bond-O- and carbon atom number is 1 to 10, and specific example includes but is not limited to: propylene glycol monomethyl ether, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane.
" alcohols solvent " of the present invention refers to one or more " hydroxyl " substitution " C
1-6Group derived from one or more hydrogen atoms on alkyl ", " hydroxyl " and " C
1-6As defined hereinabove, specific example includes but is not limited to alkyl ": methanol, ethyl alcohol, propyl alcohol or 2- propyl alcohol.
" nitrile solvents " of the present invention refer to one or more " cyano " substitution " C
1-6Group derived from one or more hydrogen atoms on alkyl ", " cyano " and " C
1-6As defined hereinabove, specific example includes but is not limited to alkyl ": acetonitrile or propionitrile.
" X-ray powder diffraction collection or XRPD " of the present invention refer to according to bragg's formula 2d sin θ=n λ (in formula, λ be X-ray wavelength,
The series n of diffraction is any positive integer, generally take first-order diffraction peak, n=1), when X-ray is with the sweep angle θ (complementary angle of incidence angle, also known as Bragg angle) when being incident on a certain atomic plane with d lattice plane spacing of crystal or partial crystals sample, it is just able to satisfy Bragg equation, to measure this group of X-ray powder diffraction figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers in sample heating or thermostatic process, temperature difference, differential heat flow between measurement sample and reference substance, to characterize all physical changes related with fuel factor and chemical change, the transformation information of sample is obtained.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree, the error range of 2 θ are ± 0.1~± 0.5, preferably ± 0.1~± 0.3, more preferably ± 0.2.
" interplanar distance or interplanar distance (d value) " of the present invention refers to that space lattice selects the unit vector a of the two neighboring lattice point of connection of 3 irrelevancy rows, b, c, dot matrix is divided into juxtaposed parallelepiped unit, referred to as interplanar distance by them.Space lattice is divided according to determining parallelepiped unit line, obtains a set of rectilinear grid, referred to as space lattice or lattice.Dot matrix and lattice are respectively the different crystal faces with the periodicity of the Points And lines of geometry reflection crystal structure, and interplanar distance (the distance between parallel crystal face of i.e. adjacent two) is different；Unit is
Or angstrom.
The invention further relates to, the III crystal form including formula (I) compound represented, and the pharmaceutical composition of optional one or more pharmaceutical carriers and/or diluent.Pharmaceutically acceptable any dosage form can be made in described pharmaceutical composition.For example, III crystal form of the invention or pharmaceutical preparation can be formulated as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection, injection sterile powder and concentrated solution for injection), suppository, inhalant or spray.
In addition, described pharmaceutical composition of the invention can also be with any suitable administration mode, such as the modes such as oral, parenteral, rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for when being administered orally, described pharmaceutical composition to can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation also may include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the pharmaceutical preparation can be made into injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, the conventional method in existing pharmaceutical field is can be used to be produced in described pharmaceutical composition.When preparing injection, additives can be added without in the pharmaceutical preparation, suitable additives can also be added according to the property of drug.When being used for rectally, the pharmaceutical preparation can be made into suppository etc..When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred aspects, III crystal form of the invention is to treat and/or prevention effective dose is present in pharmaceutical composition or drug.In certain preferred aspects, III crystal form of the invention is present in pharmaceutical composition or drug in the form of unit dose.
The III crystal form of formula (I) compound of the present invention can be used for preparing treatment with jak kinase in relation to the purposes in disease medicament.Therefore, the application further relates to, and the III crystal form of formula (I) compound of the present invention is used to prepare the purposes of drug, and the drug is used to treat the purposes in the drug of disease related with jak kinase.In addition, the application further relates to, a method of inhibiting disease related with jak kinase comprising to the III crystal form or pharmaceutical composition of the invention of subject with this need application treatment and/or the formula (I) compound of the present invention of prevention effective dose.
In certain preferred aspects, the disease is disease related with jak kinase, is selected from rheumatism and rheumatoid arthritis.
Advantageous effect of the invention
Compared with prior art, technical solution of the present invention has the advantage that
Research has shown that the III crystal form dissolubility of compound shown in formula (I) prepared by the present invention is excellent, purity is higher, under conditions of illumination, high temperature, high humidity crystal form do not change through XRPD detection, stability of crystal form it is good；The variation of HPLC purity is small, chemical stability is high；The III crystal form of compound shown in the formula (I) that technical solution of the present invention obtains can satisfy the medicinal requirements of production and transport storage, and stable processing technique repeats controllably, can adapt in industrialized production.
Fig. 1 is the XRPD map of compound III crystal form shown in formula (I).
Fig. 2 is the DSC map of compound III crystal form shown in formula (I).
Fig. 3 is the unbodied XRPD map of compound shown in formula (I).
Fig. 4 is the unbodied DSC map of compound shown in formula (I).
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is only used to illustrate the technical scheme of the present invention, and non-limiting the spirit and scope of the invention.
Test the test condition of instrument:
1, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model: Mettler Toledo DSC 1STAR
e System
Purge gass: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 40-300 DEG C
2, X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
Instrument model: Bruker D8Focus X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 2-40
o
Voltage: 40kV, electric current: 40mA
Embodiment 1:(3aR, 5s, 6aS)-N- (3- methoxyl group -1,2,4- thiadiazoles -5- base) -5- (methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide disulfate (can be prepared by the method in patent application WO2014194741)
By (3aR, 5s, 6aS)-N- (3- methoxyl group -1,2,4- thiadiazoles -5- base) -5- (methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) hexahydro cyclopentano [c] pyrroles -2 (1H)-formamide (140g, 0.34mol) it is added in reaction flask, anhydrous methanol (350g), methylene chloride (2.0kg) is added, suspend stirring, and sulfuric acid (34.8g, 0.36mol) is slowly added dropwise at room temperature, reaction solution clarification, is stirred to react 30min.It is filtered to remove insoluble matter, filtrate decompression concentration is dry, obtains target product (168g, yield 90%).The X-ray diffraction spectrogram of the sample is shown in Fig. 3, shows that DSC spectrogram is shown in Fig. 4, has no melting characteristic absorption peak at 300 DEG C or less without crystal form characteristic absorption peak, determines therefrom that product is amorphous solid.
Embodiment 2
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be added in reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added ethyl acetate (1mL), 100 μ L are added every time, midfeather about 10min, it finishes, heating is closed after 1.5h, stir about 40h, filtering, solid sample is obtained after sediment vacuum drying, through 2 θ of XRPD detection of diffracted angle in 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), 22.47 (3.95), 22.80 (3.90), 23.44 (3.79), 24.44 (3.64), 25.65 (3.47), 26.38 (3.38), 27.49 (3.24), 28.13 (3.17), 29.10 (3.07), 30.08 (2.97), 31.34 (2.85), 32.15 (2.78), 32.91 (2.72), 33.50 (2.07), 34.63 (2.59), 35.73 (2.51) , there are characteristic peak in 36.73 (2.45) at 37.64 (2.39) and 38.47 (2.34), this crystal form are defined as III crystal form.
Embodiment 3
Formula (I) compound (is prepared) sample (500mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (1.5mL), stirring and dissolving at 60 DEG C, it is added methanol (10mL), close heating, stirring and crystallizing, filtering, it is dried in vacuo to obtain solid sample 393mg, yield 78.6%.This crystal form is defined as III crystal form, the XRPD map of the crystallized sample is shown in that Fig. 1, DSC spectrogram are shown in Fig. 2, and fusing point is near 217.04, and initial fusion temperature is 209.82 DEG C, and characteristic peak positions are as shown in the table:
Table 1, III crystal form characteristic peak
Embodiment 4
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added acetone (1mL), 100 μ L, midfeather about 10min are added every time；It finishes, heating is closed after 1.5h, stir about 40h is filtered, and sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 5
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added acetone (1mL), it is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 6
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C is added at one time acetone (1mL), finishes, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 7
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added tetrahydrofuran (1mL), 100 μ L are added every time, midfeather about 10min, it finishes, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 8
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added tetrahydrofuran (1mL), it is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 9
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added 1,4- dioxane (1mL), 100 μ L are added every time, midfeather about 10min, it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 10
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added 1,4- dioxane (1mL), is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, finish, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 11
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C is added at one time 1,4- dioxane (1mL), it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 12
Formula (I) compound (is prepared) sample (50mg) to be placed in a reaction flask as described in Example 1, is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added acetonitrile (1mL), 100 μ L are added every time, midfeather about 10min is finished, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 13
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added acetonitrile (1mL), it is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 14
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added methylisobutylketone (1mL), 100 μ L are added every time, midfeather about 10min, it finishes, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 15
Formula (I) compound (is prepared) sample (50mg) to be placed in a reaction flask as described in Example 1, is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added methanol (1mL), 100 μ L are added every time, midfeather about 10min is finished, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 16
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C, it is gradually added methanol (1mL), it is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, it finishes, heating, stir about 40h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 17
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 25 DEG C is added at one time methanol (1mL), finishes, heating is closed after 1.5h, stir about 40h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 18
Formula (I) compound (is prepared) sample (50mg) to be placed in a reaction flask as described in Example 1, is added DMSO (150 μ L), stirring and dissolving at 50 DEG C, it is gradually added acetone (1mL), 100 μ L are added every time, midfeather about 10min is finished, heating is closed after 1.5h, stir about 20h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 19
Formula (I) compound (is prepared) sample (50mg) to be placed in a reaction flask as described in Example 1, is added DMSO (150 μ L), stirring and dissolving at 50 DEG C, it is gradually added methanol (1mL), 100 μ L are added every time, midfeather about 10min is finished, heating is closed after 1.5h, stir about 20h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 20
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 50 DEG C, it is gradually added methanol (1mL), it is added in three times, respectively 300 μ L, 300 μ L, 400 μ L, midfeather about 20min, it finishes, heating, stir about 20h is closed after 1.5h, filtering, sediment is dried in vacuo to obtain solid, and the XRPD map and DSC map of the crystallized sample are compared through research, determines that product is III crystal form.
Embodiment 21
Formula (I) compound (is prepared) sample (50mg) as described in Example 1 to be placed in a reaction flask, it is added DMSO (150 μ L), stirring and dissolving at 50 DEG C is added at one time methanol (1mL), finishes, heating is closed after 1.5h, stir about 20h, filtering, sediment are dried in vacuo to obtain solid, the XRPD map and DSC map of the crystallized sample are compared through research, determine that product is III crystal form.
Embodiment 22
The resulting amorphous products sample of embodiment 1 and the resulting III crystal form Product samples opening of embodiment 3 are divided into placement, investigate the stability of sample under the conditions of illumination (4500Lux), heating (40 DEG C, 60 DEG C), high humidity (RH75%, RH90%), investigating sample time is 5 days and 10 days, and HPLC detection purity the results are shown in Table 1.
Test result:
Compound III crystal form is compared with amorphous stability shown in table 2, formula (I) of the present invention
Conclusion (of pressure testing)
By table 2 study on the stability as the result is shown:
Under the conditions of illumination, high humidity, high temperature opening are placed, influence of the high humidity to the two is little, but under conditions of illumination, high temperature, the stability of III crystal form is significantly better than amorphous samples, it does not change through XRPD detection crystal form, it is amorphous to illustrate that III stability of crystal form of the invention is significantly better than.
Compared with crystal form I, crystal form II dissolubility disclosed in embodiment 23, crystal form III of the present invention and the prior art
Test sample: crystal form III (being prepared according to 3 method of embodiment), crystal form I (can be prepared according to WO2016054959 method), crystal form II (can be prepared according to WO2016070697 method).
Solvent: water, 0.1N HCl.
Test result:
The III crystal form of compound shown in table 3, formula (I) and I crystal, II crystal form saturation solubility compared with
Conclusion (of pressure testing)
Shown by 3 experimental result of table: saturation solubility of the crystal form III of the present invention in water or 0.1N HCl is all larger than crystal form I or crystal form II, the dissolubility of crystal form III of the present invention are more excellent.
Claims (9)
- The III crystal form of compound shown in formula (I), it is characterised in that: radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it is 7.43,9.60,11.19,18.18,19.31,19.64,21.25, there is characteristic peak at 22.80 and 25.63, wherein, the error range of each 2 θ of characteristic peak is ± 0.2
- III crystal form according to claim 1, which is characterized in that the III crystal form is 7.43,9.09,9.60,11.19,13.13,14.90,16.35,18.18,19.31,19.64, there is characteristic peak at 21.25,22.80,25.63 and 28.10, wherein the error range of each 2 θ of characteristic peak is ± 0.2.
- III crystal form according to claim 2, which is characterized in that the III crystal form is 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, there is characteristic peak at 34.64,35.73,36.69,37.70 and 38.48, wherein the error range of each 2 θ of characteristic peak is ± 0.2.
- A method of preparing the III crystal form as described in any one of claim 1-3, which is characterized in that the described method includes:1) compound shown in formula (I) is dissolved in dimethyl sulfoxide, anti-solvent, stirring and crystallizing is added；2) it filters, up to target III crystal form after solid is dry.
- Method as claimed in claim 4, which is characterized in that the adding manner of the anti-solvent are as follows: be repeatedly added or be added at one time.
- Method as claimed in claim 4, it is characterized in that, the anti-solvent is selected from esters, ketone, ethers, nitrile or alcohols solvent, the esters solvent ethyl acetate, the preferred acetone of the ketones solvent or methylisobutylketone, the preferred tetrahydrofuran of the ether solvent or Isosorbide-5-Nitrae-dioxane, the preferred acetonitrile of nitrile solvents, the preferred methanol of alcohols solvent.
- A kind of pharmaceutical composition, described pharmaceutical composition are made of III crystal form of any of claims 1-3 with pharmaceutically acceptable carrier, diluent or excipient.
- A method of preparing pharmaceutical composition, which is characterized in that the method includes being mixed by III crystal form of any of claims 1-3 with pharmaceutically acceptable carrier, diluent or excipient.
- For the pharmaceutical composition of III crystal form described in III crystal form, claim 7 containing any one of the claim 1-3 formula (I) compound in preparation treatment with jak kinase in relation to the purposes in disease medicament, the disease is selected from rheumatism and rheumatoid arthritis.
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| CN2017100517632 | 2017-01-20 | ||
| CN201710051763 | 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110028509A (en) * | 2019-05-27 | 2019-07-19 | 上海勋和医药科技有限公司 | The alternatively azolopyrimidines of property JAK2 inhibitor, its synthetic method and purposes |
| CN113698404A (en) * | 2020-05-21 | 2021-11-26 | 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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| 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 |
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| WO2013091539A1 (en) * | 2011-12-21 | 2013-06-27 | 江苏恒瑞医药股份有限公司 | Pyrrole six-membered heteroaryl ring derivative, preparation method therefor, and medicinal uses thereof |
| WO2014194741A1 (en) * | 2013-06-07 | 2014-12-11 | 江苏恒瑞医药股份有限公司 | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor |
| WO2016054959A1 (en) * | 2014-10-09 | 2016-04-14 | 江苏恒瑞医药股份有限公司 | Crystal form of bisulfate of jak inhibitor and preparation method therefor |
| WO2016070697A1 (en) * | 2014-11-05 | 2016-05-12 | 江苏恒瑞医药股份有限公司 | Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof |
| WO2017140254A1 (en) * | 2016-02-19 | 2017-08-24 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing jak kinase inhibitor or pharmaceutically acceptable salt thereof |
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2018
- 2018-01-19 TW TW107102047A patent/TW201827436A/en unknown
- 2018-01-19 WO PCT/CN2018/073310 patent/WO2018133823A1/en active Application Filing
- 2018-01-19 CN CN201880001322.4A patent/CN108779122B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013091539A1 (en) * | 2011-12-21 | 2013-06-27 | 江苏恒瑞医药股份有限公司 | Pyrrole six-membered heteroaryl ring derivative, preparation method therefor, and medicinal uses thereof |
| WO2014194741A1 (en) * | 2013-06-07 | 2014-12-11 | 江苏恒瑞医药股份有限公司 | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor |
| WO2016054959A1 (en) * | 2014-10-09 | 2016-04-14 | 江苏恒瑞医药股份有限公司 | Crystal form of bisulfate of jak inhibitor and preparation method therefor |
| WO2016070697A1 (en) * | 2014-11-05 | 2016-05-12 | 江苏恒瑞医药股份有限公司 | Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof |
| WO2017140254A1 (en) * | 2016-02-19 | 2017-08-24 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing jak kinase inhibitor or pharmaceutically acceptable salt thereof |
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| CN110028509A (en) * | 2019-05-27 | 2019-07-19 | 上海勋和医药科技有限公司 | The alternatively azolopyrimidines of property JAK2 inhibitor, its synthetic method and purposes |
| 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 |
| CN113698404A (en) * | 2020-05-21 | 2021-11-26 | 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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| TW201827436A (en) | 2018-08-01 |
| CN108779122B (en) | 2021-01-15 |
| WO2018133823A1 (en) | 2018-07-26 |
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