CN115772166B - An addition salt of an S1P1 receptor agonist, its crystal form and pharmaceutical composition - Google Patents
An addition salt of an S1P1 receptor agonist, its crystal form and pharmaceutical composition Download PDFInfo
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- CN115772166B CN115772166B CN202211395981.5A CN202211395981A CN115772166B CN 115772166 B CN115772166 B CN 115772166B CN 202211395981 A CN202211395981 A CN 202211395981A CN 115772166 B CN115772166 B CN 115772166B
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- PCUZOERZYRZAEE-UHFFFAOYSA-M sodium 1-[[2-fluoro-4-[5-[4-(2-methylpropyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]azetidine-3-carboxylate Chemical compound CC(C)CC1=CC=C(C=C1)C1=NC(=NO1)C1=CC=C(CN2CC(C2)C(=O)O[Na])C(F)=C1 PCUZOERZYRZAEE-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/06—Antipsoriatics
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明公开了S1P1受体介导疾病或病症的药物1‑{2‑氟‑4‑[5‑(4‑异丁基苯基)‑1,2,4‑噁二唑‑3‑基]‑苄基}‑3‑吖丁啶羧酸的盐型及其晶型。本发明还公开了所述盐型或其晶型的制备方法、其药物组合物及其用于制备治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。The present invention discloses a salt form and a crystal form of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidine carboxylic acid, a drug for S1P1 receptor-mediated diseases or conditions. The present invention also discloses a preparation method of the salt form or its crystal form, a pharmaceutical composition thereof, and use thereof in preparing a drug for treating and/or preventing diseases or conditions mediated by S1P1 receptors.
Description
Technical Field
The application belongs to the technical field of pharmaceutical chemistry preparation and crystallization. In particular to a salt form of a drug of a disease or a condition mediated by an S1P1 receptor and a crystal form thereof, and also relates to a preparation method of the salt form or the crystal form, a pharmaceutical composition and application thereof.
Background
1- { 2-Fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid having the formula C 23H24FN3O3 and the molecular weight 409.45, and the chemical structure is shown in the formula A below.
The term "1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid" is used interchangeably herein with "the compound of formula a".
The compound shown in the formula A has S1P1 receptor agonist activity and selectivity specificity and has obviously shortened in vivo half-life, so that the compound is a high-quality second-generation S1P1 receptor agonist. Numerous studies have shown that there are a variety of S1P1 receptor agonists that are able to bind to cognate receptors expressed on lymphocytes and result in the internalization of S1P1 receptors, which in turn prevents lymphocyte export. Therefore, S1P1 receptor agonists can reduce the ability of the human body to initiate an immune response by preventing lymphocyte trafficking, and thus can be used as immunosuppressants for the treatment of various autoimmune diseases.
In theory, the compounds of formula A may form salts with one or more acid compounds of formula X mHn, wherein H is a dissociable hydrogen ion, X is a pharmaceutically acceptable anion, and m and n are natural numbers, or with one or more pharmaceutically acceptable cations, such as alkali metal ions or other pharmaceutically acceptable organic cations.
The identification, preparation, composition and use of the compounds of formula a are disclosed in patent document CN103450171a, which is incorporated by reference herein. Specifically, a preparation method of such a compound is disclosed in example 2. Patent document CN105315266a (which is incorporated by reference into the present application) discloses 12 crystalline forms of the compound represented by formula a. The inventors have found that these free bases all have very low water solubility, 1.1 μg/mL in water at 25 ℃, and exhibit different stable forms in different solvent environments, e.g. form I is the most stable form in water and form IV is the most stable form in organic solvents. The limitation of this compound is that they are insoluble in water in the free base form and that polymorphism is evident. Therefore, the research on the salt form of the compound shown in the formula A has very important practical significance, and certain undesirable physicochemical or biopharmaceutical properties of the medicine can be improved through salification, such as changing the solubility or dissolution rate, polymorphism and the like of the medicine.
Disclosure of Invention
In view of the shortcomings of the prior art, it is an object of the present invention to provide a salt form of a compound of formula a and crystalline forms thereof, which have one or more improved properties, particularly in terms of polymorphism, solubility, stability of the crystalline form, chemical stability and the like. For example, the salt forms of the compounds of formula a according to the present invention have one or more improved properties in hygroscopicity, solubility, thermal stability (melting point and decomposition temperature) compared to other conventional salt forms, such as potassium, calcium, hydrochloride, citrate, phosphate.
The second object of the present invention is to provide a method for preparing a salt form of a compound represented by formula a, wherein the compound represented by formula a has low solubility in most solvents and the solubility is not significantly improved at a temperature, so that it is difficult to form a salt by using a conventional solution-solution mixing reaction. The preparation method of the salt form adopts various modes of suspension-solution, solid-solvent, mixed reaction of suspension-suspension and solid-suspension to form salt, adopts a crystal form detection method to monitor the salt forming completeness, and adopts ion chromatography to confirm the salt forming ratio. Compared with the conventional salification method, the salt type preparation method of the compound shown in the formula A has good operability in salification of low-solubility compounds.
The invention also provides a salt form of the compound shown in the formula A and a pharmaceutical composition and application of the salt form and the crystal form of the compound.
According to the object of the present invention, there is provided 1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid sodium salt, which is a compound of the formula A wherein the compound and sodium ions are formed in a 1:1 molar ratio, and which has the structure shown in the following formula:
the term "1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid sodium salt" is used interchangeably herein with "the sodium salt of the compound of formula a".
The sodium salt of the compound of formula a of the present invention is substantially crystalline, preferably anhydrous, hydrated or unsolvated. More preferably, according to the object of the present invention, there is provided a crystalline form of the sodium salt of the compound represented by formula a, which has characteristic peaks at 4.4±0.2°, 6.6±0.2°, 14.7±0.2° and 17.2±0.2° in the X-ray powder diffraction pattern expressed in terms of 2θ angle.
Further preferably, the present invention provides a crystalline form of the sodium salt of the compound of formula a, said crystalline form having an X-ray powder diffraction pattern expressed in terms of 2Θ having characteristic peaks and their relative intensities at the following positions:
Without limitation, one typical example of a crystalline form of the sodium salt of the compound of formula a has an X-ray powder diffraction (XRPD) pattern as shown in figure 2. More preferably, the fourier infrared spectrum of the crystalline form of the sodium salt of the compound of formula a has characteristic peaks at wavenumbers 1560cm-1、1505cm-1、1476cm-1、1417cm-1、1365cm-1、1276cm-1、885cm-1、849cm-1 and 756cm -1.
According to the purpose of the invention, the invention provides a preparation method of a sodium salt of a compound shown in a formula A or a crystal form thereof, which comprises the following steps of mixing and reacting the compound shown in the formula A with sodium hydroxide in a molar ratio of 1:1-1:5 in a solvent selected from alcohol, ketone, ether, water, nitrile or a mixture thereof, removing the solvent after the reaction is finished, and drying.
According to an embodiment of the present invention, in the preparation of the salt form, in the operation of removing the solvent after completion of the reaction, a part of the solvent may be removed first, cooled and centrifuged to dry the obtained solid, or the whole solvent may be removed after completion of the reaction, and the obtained solid may be dried by adding the solvent again to the solid, beating and centrifuging.
According to an embodiment of the present invention, for the preparation of the crystalline form, in the operation of removing the solvent after completion of the reaction, a part of the solvent may be removed first, and after cooling (for example, to room temperature), a solid may be precipitated, and the obtained solid may be dried.
Preferably, the solvent is selected from methanol, ethanol, acetone, diethyl ether, water, acetonitrile or mixtures thereof.
Preferably, the molar ratio of the compound shown in the formula A to the sodium hydroxide is 1:1.0-1:1.3.
Preferably, the reaction is carried out at 10-60 ℃, more preferably at room temperature, preferably with stirring for a period of 1-48 hours, more preferably 3-24 hours.
Preferably, the drying is performed under vacuum, and the temperature of the drying is 10 to 60 ℃, more preferably 10 to 40 ℃.
Preferably, the drying time is 1 to 48 hours, more preferably 1 to 24 hours.
Preferably, the mass volume ratio of the compound shown in the formula A to the solvent in the preparation method is 1 mg/1 mL-50 mg/1 mL, more preferably 2.5 mg/1 mL-41 mg/1 mL.
The solvent removal can be performed by conventional techniques in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying, preferably, the solvent is removed by nitrogen blowing, volatilization or filtration, and preferably, the experimental temperature of the solvent removal is 10-60 ℃.
The sodium salt of the compound shown in the formula A and the crystal form thereof have the following beneficial effects:
1) The polymorphism of the sodium salt of the compound represented by formula A of the present invention is not obvious.
2) The solubility of the sodium salt of the compound shown in the formula A in water at 25 ℃ is 10mg/mL, and compared with the free state of the known compound shown in the formula A, the solubility in water is obviously improved, and the bioavailability is better.
3) The solubility of the sodium salt of the compound shown in the formula A in water at 25 ℃ is 10mg/mL, and compared with the conventional salt forms such as the calcium salt of the compound shown in the formula A, the hydrochloride of the compound shown in the formula A, the citrate of the compound shown in the formula A, the phosphate of the compound shown in the formula A and the like, the solubility in water is obviously improved, and the bioavailability is better.
4) Compared with the free state of the compound shown in the formula A, the crystal form of the sodium salt of the compound shown in the formula A is stable in an aqueous system, so that the sodium salt has better application value in wet granulation or suspension dosage forms.
5) The crystal form of the sodium salt of the compound shown in the formula A is placed for 4 months at room temperature under the condition of relative humidity of 10% -90%, and the appearance, XRPD and melting point of the crystal form are unchanged. The sodium salt of the compound shown in the formula A and the crystal form thereof have good storage stability, and can better avoid the quality, safety and stability problems, such as impurity crystal forms, solubility differences and the like, of the pharmaceutical active ingredient and the preparation dosage form containing the sodium salt of the compound shown in the formula A or the crystal form thereof in the processes of pharmaceutical manufacturing and/or storage and the like.
The invention also provides a pharmaceutical composition comprising the sodium salt of the compound of formula A and/or a crystalline form thereof and optionally at least one pharmaceutically acceptable carrier or excipient.
The invention also provides application of the sodium salt of the compound shown in the formula A and/or a crystal form thereof in preparing medicines for treating and/or preventing diseases or symptoms mediated by the S1P1 receptor.
According to the object of the present invention, there is provided 1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid sulfate which is a compound of the formula A wherein the compound is formed with sulfuric acid in a molar ratio of 2:1, and which has the structure shown in the following formula:
The term "1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid sulfate" is used interchangeably herein with "sulfate of the compound of formula a".
The sulfate salt of the compound of formula a of the present invention is substantially crystalline, preferably anhydrous, hydrated or unsolvated. More preferably, according to the object of the present invention, there is provided a crystalline form of a sulfate salt of a compound represented by formula A, using Cu-K alpha radiation, which has characteristic peaks at positions of 5.4.+ -. 0.2 °, 8.1.+ -. 0.2 °, 14.8.+ -. 0.2 °, 16.7.+ -. 0.2 ° and 18.3.+ -. 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2. Theta. Angle.
More preferably, the X-ray powder diffraction pattern of the crystalline form of the sulfate salt of the compound of formula A, expressed in terms of 2θ, has characteristic peaks at 5.4.+ -. 0.2 °, 8.1.+ -. 0.2 °, 14.8.+ -. 0.2 °, 15.6.+ -. 0.2 °, 16.7.+ -. 0.2 °, 18.3.+ -. 0.2 °, 21.0.+ -. 0.2 °, 22.0.+ -. 0.2 °, 22.9.+ -. 0.2 °, 25.2.+ -. 0.2 ° and 26.3.+ -. 0.2 °.
Further preferably, the present invention provides a crystalline form of a sulfate salt of a compound represented by formula a, the crystalline form having an X-ray powder diffraction pattern expressed in terms of 2Θ having characteristic peaks and relative intensities at:
without limitation, one typical example of a crystalline form of the sulfate salt of the compound of formula a has an X-ray powder diffraction (XRPD) pattern as shown in figure 6.
The Fourier infrared spectrum of the crystalline form of the sulfate salt of the compound shown in formula A has characteristic peaks at wave numbers of 1733cm-1、1438cm-1、1346cm-1、1230cm-1、1184cm-1、1109cm-1、1063cm-1、1009cm-1、885cm-1、854cm-1 and 758cm -1.
According to the purpose of the invention, the preparation method of the sulfate of the compound shown in the formula A or the crystal form thereof comprises the following steps of respectively forming suspension or solution of the compound shown in the formula A and sulfuric acid in a molar ratio of 1:0.4-1:10 in a solvent selected from alcohol, ketone, cyclic ether, acetonitrile, water or a mixture thereof, mixing and reacting, removing the solvent after the reaction is finished, and drying.
According to an embodiment of the present invention, for the preparation of the salt form, in the operation of removing the solvent after completion of the reaction, a part of the solvent may be removed first, filtered or centrifuged to dry the obtained solid, or the whole solvent may be removed after completion of the reaction, and optionally the solvent may be added again to the solid, slurried and centrifuged again to dry the obtained solid.
According to a specific embodiment of the present invention, for the preparation of the crystalline form, in the operation of removing the solvent after completion of the reaction, all the solvent may be removed first, and the obtained solid may be dried after adding water and ultrasonic waves and then centrifuging.
Preferably, the solvent is selected from methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile or mixtures thereof.
Preferably, the molar ratio of the compound shown in the formula A to sulfuric acid is 1:0.4-1:7.9.
Preferably, the reaction is carried out at-10 to 60 ℃, more preferably at 10 to 40 ℃, preferably, the reaction is carried out with stirring for a period of 1 to 72 hours, more preferably 1 to 24 hours.
Preferably, the drying temperature is 10-60 ℃, more preferably 10-40 ℃.
Preferably, the drying time is 1 to 48 hours, more preferably 1 to 24 hours.
Preferably, the mass volume ratio of the compound shown in the formula A to the solvent in the preparation method is 1 mg/1 mL-50 mg/1 mL, more preferably 4 mg/1 mL-35 mg/1 mL.
The solvent removal can be performed by conventional techniques in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying, preferably, nitrogen blowing, centrifugation or filtration, and preferably, the experimental temperature of the solvent removal is 10-60 ℃.
The term "sulfuric acid" refers to concentrated sulfuric acid having a concentration of 98% by weight and is commercially available.
The sulfate of the compound shown in the formula A and the crystal forms thereof have the following beneficial effects:
1) The sulfate polymorphism of the compound represented by formula A of the present invention is not obvious.
2) The solubility of the sulfate of the compound shown in the formula A in water at 25 ℃ is 19 mug/mL, and compared with the free state of the known compound shown in the formula A, the solubility in water is obviously improved, and the bioavailability is better.
3) The solubility of the sulfate of the compound shown in the formula A in water at 25 ℃ is 19 mug/mL, and compared with the conventional salt forms such as the calcium salt of the compound shown in the formula A, the hydrochloride of the compound shown in the formula A, the citrate of the compound shown in the formula A, the phosphate of the compound shown in the formula A and the like, the sulfate of the compound shown in the formula A has obviously improved solubility in water and better bioavailability.
4) The sulfate of the compound represented by the formula A has a weight gain of 0.7% in a relative humidity range of 20% -80%, and has lower moisture absorption and weight gain compared with conventional salt forms such as potassium salt of the compound represented by the formula A, calcium salt of the compound represented by the formula A, hydrochloride of the compound represented by the formula A, citrate of the compound represented by the formula A, phosphate of the compound represented by the formula A and the like, so that the compound has better storage stability.
5) The crystal form of the sulfate of the compound shown in the formula A is stable in an aqueous system, so that the sulfate has good application value in wet granulation or suspension dosage forms.
6) The crystalline form of the sulfate salt of the compound of formula A of the present invention is maintained for 1 month under normal, high temperature (60 ℃) and accelerated (40 ℃ to 75% relative humidity) conditions without changing its appearance, XRPD and melting point. The sulfate of the compound shown in the formula A and the crystal form thereof have good storage stability, and can better ensure the quality, safety and stability problems, such as impurity crystal forms, solubility differences and the like, of the pharmaceutical active ingredient and the preparation dosage form containing the sulfate of the compound shown in the formula A or the crystal form thereof in the processes of pharmaceutical manufacturing and/or storage and the like.
The invention also provides a pharmaceutical composition comprising the sulphate salt of the compound of formula a and/or a crystalline form thereof and optionally at least one pharmaceutically acceptable carrier or excipient.
The invention also provides application of the sulfate of the compound shown in the formula A and/or a crystal form thereof in preparing medicines for treating and/or preventing diseases or symptoms mediated by the S1P1 receptor.
According to the object of the present invention, there is provided 1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid maleate salt which is a compound represented by the formula A wherein the compound is formed with maleic acid in a 1:1 molar ratio, and which has the structure represented by the formula:
the term "1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid maleate salt" is used interchangeably herein with "maleate salt of the compound of formula a.
The maleate salt of the compound of formula a of the present invention is substantially crystalline, preferably anhydrous, hydrated or unsolvated. More preferably, according to the object of the present invention, there is provided a crystalline form of maleate salt of a compound represented by formula A, having characteristic peaks at positions of 10.6.+ -. 0.2 °, 16.3.+ -. 0.2 °, 19.5.+ -. 0.2 °, 21.5.+ -. 0.2 ° and 26.9.+ -. 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2-theta using Cu-K alpha radiation.
More preferably, the X-ray powder diffraction pattern of the crystalline form of the maleate salt of the compound of formula A, expressed as a 2 theta angle, has characteristic peaks at 7.0.+ -. 0.2 °, 10.6.+ -. 0.2 °, 13.6.+ -. 0.2 °, 16.3.+ -. 0.2 °, 19.5.+ -. 0.2 °, 20.1.+ -. 0.2 °, 21.5.+ -. 0.2 °, 24.5.+ -. 0.2 ° and 26.9.+ -. 0.2 °.
Further preferably, the present invention provides a crystalline form of the maleate salt of the compound of formula a, the crystalline form having an X-ray powder diffraction pattern expressed in terms of 2Θ angles with characteristic peaks and relative intensities at:
without limitation, one typical example of a crystalline form of the maleate salt of the compound of formula a has an X-ray powder diffraction (XRPD) pattern as shown in figure 10.
The Fourier infrared spectrum of the crystalline form of the maleate salt of the compound of formula A has characteristic peaks at wavenumbers of 1734cm-1、1574cm-1、1485cm-1、1439cm-1、1364cm-1、1346cm-1、1080cm-1、1003cm-1、893cm-1、871cm-1、757cm-1 and 729cm -1.
According to the purpose of the invention, the invention provides a preparation method of the maleate salt of the compound shown in the formula A or a crystal form thereof, which comprises the steps of respectively forming a suspension or a solution of the compound shown in the formula A and maleic acid in a molar ratio of 1:1-1:5 in a solvent selected from alcohol, ketone, ether (including cyclic ether), ester, water or a mixture thereof, mixing and reacting, removing the solvent after the reaction is finished, and drying.
Preferably, the solvent is selected from ethanol, acetone, diethyl ether, water, ethyl acetate, 1, 4-dioxane or mixtures thereof.
Preferably, the molar ratio of the compound shown in the formula A to the maleic acid is 1:1.0-1:2.6.
Preferably, the reaction is carried out at-10 to 60 ℃, more preferably at 10 to 40 ℃, preferably, the reaction is carried out under stirring for 10 to 72 hours, more preferably, 10 to 24 hours.
Preferably, the drying temperature is 10-60 ℃, more preferably 10-40 ℃.
Preferably, the drying time is 1 to 48 hours, more preferably 1 to 24 hours.
Preferably, the mass volume ratio of the compound shown in the formula A to the solvent in the preparation method is 1 mg/1 mL-50 mg/1 mL, more preferably 4 mg/1 mL-26 mg/1 mL.
The maleate salt and the crystal form of the compound shown in the formula A have the following beneficial effects:
1) The maleate salt polymorphism of the compound represented by formula A of the present invention is not obvious.
2) The maleate of the compound shown in the formula A has the solubility of 16 mug/mL in water at 25 ℃, and compared with the free state of the known compound shown in the formula A, the maleate has the solubility obviously improved, and has better bioavailability.
3) The solubility of the maleate of the compound shown in the formula A in water is 16 mug/mL at 25 ℃, and compared with the conventional salt forms such as the calcium salt of the compound shown in the formula A, the hydrochloride of the compound shown in the formula A, the citrate of the compound shown in the formula A, the phosphate of the compound shown in the formula A and the like, the maleate of the compound shown in the formula A has obviously improved solubility in water and better bioavailability.
4) The maleate salt of the compound shown in the formula A has a weight gain of 0.4% in a relative humidity range of 20% -80%, and has lower moisture absorption and weight gain compared with conventional salt forms such as potassium salt of the compound shown in the formula A, calcium salt of the compound shown in the formula A, hydrochloride of the compound shown in the formula A, citrate of the compound shown in the formula A, phosphate of the compound shown in the formula A and the like, so that the maleate salt has better storage stability.
5) The maleate crystal form of the compound shown in the formula A is stable in an aqueous system, so that the maleate crystal form has good application value in wet granulation or suspension dosage forms.
6) The crystalline form of the maleate salt of the compound of formula a of the present invention is maintained for 1 month under conventional, high temperature (60 ℃) and accelerated (40 ℃ to 75% relative humidity) conditions without changing its appearance, XRPD and melting point. The crystal form of the maleate of the compound shown in the formula A has good storage stability, and can better ensure the quality, safety and stability problems, such as impurity crystal forms, solubility differences and the like, of the pharmaceutical active ingredient and the preparation dosage form containing the maleate of the compound shown in the formula A or the crystal form thereof in the processes of pharmaceutical manufacturing and/or storage and the like.
The invention also provides a pharmaceutical composition comprising the maleate salt of the compound of formula A and/or a crystalline form thereof and optionally at least one pharmaceutically acceptable carrier or excipient.
The invention also provides application of the maleate salt of the compound shown in the formula A and/or the crystal form thereof in preparing medicines for treating and/or preventing diseases or symptoms mediated by the S1P1 receptor.
In any preparation method of the sodium salt of the compound represented by formula a, the crystal form of the sodium salt of the compound represented by formula a, the sulfate of the compound represented by formula a, the crystal form of the sulfate of the compound represented by formula a, the maleate of the compound represented by formula a and the crystal form of the maleate of the compound represented by formula a of the present invention:
unless specifically noted, "room temperature" refers to a temperature of about 10-30 ℃.
The "cyclic ether" may be tetrahydrofuran, 1, 4-dioxane, etc.
The stirring may be performed by conventional methods in the art, for example, stirring methods including magnetic stirring and mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
The "solvent removal" may be carried out by methods conventional in the art, such as filtration, evaporation, centrifugation, nitrogen blowing or spin drying. The "filtration" is typically performed at room temperature at a pressure less than atmospheric pressure, preferably at a pressure less than 0.09MPa. The spinning method is generally to spin at a pressure less than atmospheric pressure, preferably at a pressure less than 0.09MPa, the nitrogen blowing method is to blow nitrogen gas through a nitrogen blowing instrument and volatilize liquid by utilizing the rapid flow of the nitrogen gas, the specific operation of the spinning method is to place a sample to be separated into a centrifuge tube, for example, the centrifugation is carried out at a speed of 6000 rpm until the solid is totally deposited at the bottom of the centrifuge tube, and the specific operation of the volatilizing method is to volatilize a sample solution to a solvent at different temperatures in an open mode. The experimental temperature of the solvent removal is preferably 10-60 ℃.
The "drying" may be accomplished using techniques conventional in the art, such as ambient drying, forced air drying, or reduced pressure drying. The pressure may be reduced or normal, preferably less than 0.09MPa. The drying apparatus and method are not limited, and may be a fume hood, a forced air oven, a spray dryer, fluidized bed drying or a vacuum oven, and may be performed under reduced pressure or without reduced pressure, preferably with a pressure of less than 0.09Mpa.
The "crystalline form" as used herein refers to a compound that has a unique molecular arrangement or configuration within the crystal lattice as evidenced by the X-ray powder diffraction pattern characterization shown. It is well known to those skilled in the art that experimental errors therein depend on instrument conditions, sample preparation, and sample purity. The 2 theta angle of the peaks in the XRD pattern will generally vary slightly from instrument to instrument and sample to sample. The difference of peak angles may differ by 1 °,0.8 °,0.5 °,03 °,0.1 °, etc., depending on the apparatus, and usually allows an error of ±0.2°, so that the difference of peak angles cannot be the only standard. The relative intensities of the peaks may vary with the sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the only or determining factor. The influence of experimental factors such as sample height will cause an overall shift in peak angle, usually allowing for a certain shift. Thus, it will be appreciated by those skilled in the art that any crystalline form having characteristic peaks that are the same or similar to the X-ray powder diffraction pattern of the present invention is within the scope of the present invention. "Single crystalline form" refers to a single crystalline form as detected by X-ray powder diffraction.
The novel salt forms of the compounds of formula a described herein are substantially pure, single, and substantially free of any other crystalline or amorphous forms. "substantially pure" in the context of the present invention, when used in reference to a new crystalline form, means that the new crystalline form represents at least 80% by weight, more preferably at least 90% by weight, especially at least 95% by weight, and especially at least 99% by weight of the compound present.
The compound represented by the formula A as a starting material of the present invention can be produced by a process for producing CN 103450171A.
Further, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the salt forms of the invention and/or crystalline forms and amorphous forms thereof or the salt forms and amorphous forms thereof prepared by the process of the invention, and optionally at least one pharmaceutically acceptable carrier or excipient. The salt forms and crystal forms of the compound shown in the formula A comprise sodium salt of the compound shown in the formula A, crystal forms of sodium salt of the compound shown in the formula A, sulfate of the compound shown in the formula A, crystal forms of sulfate of the compound shown in the formula A, maleate of the compound shown in the formula A and crystal forms of maleate of the compound shown in the formula A. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable salts of the compounds of formula A or crystalline forms of salts or amorphous forms of salts.
The pharmaceutical composition can be formulated into dosage forms, preferably oral, parenteral (including subcutaneous, intramuscular, and intravenous), rectal, transdermal, buccal, nasal, etc., including but not limited to solid, liquid, semi-liquid, aerosol, or suppository forms. For example, dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions, dosage forms suitable for parenteral administration include aqueous or non-aqueous solutions or emulsions, dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers, dosage forms suitable for transdermal administration include ointments, creams, and dosage forms suitable for nasal administration include aerosols, sprays. The dosage forms described above may be adapted for rapid release, delayed release or modified release of the active ingredient, as desired.
The pharmaceutically acceptable carriers of the present invention include solid carriers including, but not limited to, diluents such as starches, pregelatinized starches, lactose, powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, sorbitol, sugar, and the like, binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and the like, disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidone, croscarmellose sodium, colloidal silicon dioxide, and the like, lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, and the like, glidants such as colloidal silicon dioxide, and the like, complex forming agents such as various grades of cyclodextrin and resins, release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, methylcellulose, methyl methacrylate, waxes, and the like. The pharmaceutically acceptable carrier of the present invention also includes liquid carriers, and specifically includes, but is not limited to, solvents such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil, ethanol, propanol, glycerol, and the like, in aqueous, oily or alcoholic solutions. In addition, carriers such as polyethylene glycol and polypropylene glycol may be used. Other pharmaceutically acceptable carriers may also be optionally used depending on the dosage form, including, for example, but not limited to, film forming agents, plasticizers, colorants, flavorants, viscosity modifying agents, preservatives, antioxidants, osmotic agents, buffers, and the like. Each carrier must be acceptable, compatible with the other ingredients of the formulation, and not deleterious to the patient.
The pharmaceutical composition may be prepared using methods well known to those skilled in the art. In preparing the pharmaceutical compositions, the sodium salt of the compound of formula a, the crystalline form of the sodium salt of the compound of formula a, the sulfate salt of the compound of formula a, the crystalline form of the sulfate salt of the compound of formula a, the maleate salt of the compound of formula a, the crystalline form of the maleate salt of the compound of formula a, or a combination thereof of the present invention are admixed with one or more pharmaceutically acceptable carriers, optionally, with one or more additional pharmaceutically active ingredients. The solid formulations may be prepared by mixing, granulating, etc., and the liquid or semi-liquid dosage forms may be prepared by mixing, dissolving, dispersing, emulsifying, etc.
Further, the present invention provides the use of the salt forms of the invention and/or the crystalline forms and amorphous forms thereof or the salt forms and/or the crystalline forms and amorphous forms thereof obtained by the preparation process of the invention for the preparation of a medicament for the treatment and/or prevention of diseases or disorders mediated by the S1P1 receptor. Wherein the salt form and crystalline forms and amorphous forms thereof include a sodium salt of the compound of formula a, a crystalline form of a sodium salt of the compound of formula a, a sulfate salt of the compound of formula a, a crystalline form of a sulfate salt of the compound of formula a, a maleate salt of the compound of formula a, a crystalline form of a maleate salt of the compound of formula a, or a combination thereof. The disease or condition mediated by the S1P1 receptor is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune diseases, chronic inflammatory diseases, asthma, inflammatory neuropathy, arthritis, transplantation, crohn' S disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, diseases associated with angiogenesis, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel disease, insulin and non-insulin dependent diabetes and other related immune diseases, preferably the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.
Further, the present invention provides a method for the treatment and/or prophylaxis of a disease or condition mediated by the S1P1 receptor, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a salt of the invention and/or a crystalline form thereof or a combination thereof or a pharmaceutical composition thereof, wherein the salt and crystalline form and amorphous form thereof comprise the sodium salt of the compound of formula a, the crystalline form of the sodium salt of the compound of formula a, the sulfate salt of the compound of formula a, the crystalline form of the sulfate salt of the compound of formula a, the maleate salt of the compound of formula a, the crystalline form of the maleate salt of the compound of formula a, or a combination thereof. The disease or condition mediated by the S1P1 receptor is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune diseases, chronic inflammatory diseases, asthma, inflammatory neuropathy, arthritis, transplantation, crohn' S disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, diseases associated with angiogenesis, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel disease, insulin and non-insulin dependent diabetes and other related immune diseases, preferably the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. The subject includes, but is not limited to, a mammal. The crystalline forms and amorphous forms provided herein, or combinations thereof, or pharmaceutical compositions thereof, may be co-administered with other therapies or therapeutic agents. Moreover, the dosage of a compound or pharmaceutical composition required to effect a treatment, prevention, or alleviation, etc., will generally depend upon the particular compound being administered, the patient, the particular disease or disorder and its severity, the route and frequency of administration, etc., and will need to be determined by the attending physician on a case-by-case basis.
Drawings
FIG. 1 is an IR spectrum of a sodium salt of a compound represented by formula A of example 3 of the present invention.
FIG. 2 is an XRPD pattern for the sodium salt of the compound of formula A of example 3 of the invention.
FIG. 3 is a TGA spectrum of the sodium salt of the compound of formula A of example 3 of the present invention.
FIG. 4 is a DSC chart of the sodium salt of the compound of formula A of example 3 of the present invention.
FIG. 5 is an IR spectrum of a sulfate salt of the compound represented by formula A of example 13 of the present invention.
FIG. 6 is an XRPD pattern for the sulfate salt of the compound of formula A of example 13 of the invention.
FIG. 7 is a TGA spectrum of sulfate salt of the compound of formula A of example 13 of the present invention.
FIG. 8 is a DSC chart of the sulfate salt of the compound of formula A of example 13 of the present invention.
FIG. 9 is an IR spectrum of maleate salt of the compound shown in formula A of example 21 of the present invention.
FIG. 10 is an XRPD pattern for the maleate salt of the compound of formula A of example 21 of the present invention.
FIG. 11 is a TGA spectrum of the maleate salt of the compound of formula A of example 21 of the present invention.
FIG. 12 is a DSC chart of the maleate salt of the compound of formula A of example 21 of the present invention.
Detailed Description
The invention will be further understood by the following examples, which are not intended to limit the invention. The detection instrument and the method are as follows:
X-ray powder diffraction (XPRD) the instrument is Bruker D8 Advance diffractometer. Samples were tested at room temperature. The detection conditions are as follows, the angle range is 3-40 degrees 2 theta, the step length is 0.02 degrees 2 theta, and the speed is 0.2 seconds/step.
Differential thermal analysis (DSC) data were obtained from TA Instruments Q200 MDSC. The detection method comprises the steps of placing 1-10 mg of a sample in a closed small-hole aluminum crucible, and heating the sample from room temperature to 250 ℃ under the protection of 40mL/min dry N2 at a heating rate of 10 ℃.
Thermogravimetric analysis (TGA) data were taken from TA Instruments Q500 TGA. The detection method comprises the steps of placing 5-15 mg of a sample in a platinum crucible, and heating the sample from room temperature to 300 ℃ under the protection of 40mL/min dry N2 at a heating rate of 10 ℃/min by adopting a segmented high-resolution detection mode.
Hydrogen spectral data (1 HNMR) were obtained from Bruker Avance II DMX 400MHZ nuclear magnetic resonance spectrometer. 1-5 mg of the sample is weighed, and about 0.5mL of deuterated reagent is dissolved into a nuclear magnetic sample tube for detection.
Infrared spectroscopic analysis (IR) data were obtained from Bruker transducer 27, with both instrument control software and data analysis software being OPUS. Usually, an ATR device is adopted, and an infrared absorption spectrum is collected within the range of 600-4000 cm -1.
Dynamic moisture sorption analysis (DVS) data and isothermal sorption analysis data were taken from TA Instruments Q5000 TGA. The detection method comprises the steps of taking 1-10 mg of sample, placing the sample in a platinum crucible, and detecting weight change in the process of changing relative humidity from 20% to 80%.
HPLC solubility data was taken from Agilent 1260 high performance liquid chromatograph. The chromatographic column is Poroshell EC-C18 (2.7.50 mm,4.6 μm), the detection wavelength is 254nm, the temperature of the detection column is 40 ℃, the flow rate is 1.5mL/min, and the sample injection amount is 5 mu L. Samples were taken and dissolved in mobile phase B to prepare a sample solution having a concentration of about 0.45mg/mL, and the sample concentration was measured by HPLC according to the following gradient method.
Ion Chromatograph (IC) data were obtained from Dionex ICS-900, workstation and analytical software Chromeleon Console, and external standard methods were used for ion content detection.
The ultrasonic operation in the examples can promote sample dissolution, and the apparatus is an ultrasonic cleaner, which is operated at 40kHz for 15 minutes.
Preparation example 1 preparation of Compound of formula A
The compound represented by formula a can be produced by the production method of example 2 of patent document CN103450171 a.
Specifically, a solution of 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzaldehyde (9.0 g,27.8 mmol), 3-azetidinecarboxylic acid (2.8 g,27.8 mmol) and acetic acid (10 mL) in methanol-tetrahydrofuran (200 mL/200 mL) was stirred at room temperature for 2 hours, and after adding a solution of sodium cyanoborohydride (10.3 g,163.5 mmol) in methanol (600 mL), stirring was continued at room temperature for 16 hours, filtration was performed, the cake was washed with methanol (100 mL), and dried to obtain 2.0g of a white solid product.
1H-NMR(400MHz,CD3OD)δ：8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H), Shown to be a compound of formula A, namely 1- { 2-fluoro-4- [5- (4-isobutylphenyl) -1,2, 4-oxadiazol-3-yl ] -benzyl } -3-azetidinecarboxylic acid.
Preparation example 2 salt form screening and preparation of Compounds of formula A
2.1 Salt Screen
According to the structure of the compound shown in the formula A, 12 kinds of I acids and 3 kinds of I bases are selected for salt screening experiments. The experimental setup and results are shown in table 1 below.
TABLE 1 salt screen experimental setup and results
2.2 Preparation of partial salts
And (3) taking acetone and water as reaction solvents, and taking the compound shown in the formula A as a salt with a molar ratio of free state to ion of 1:1.2, and taking IC (integrated circuit) as a detection salt forming ratio to prepare citrate of the compound shown in the formula A, phosphate of the compound shown in the formula A, hydrochloride of the compound shown in the formula A, potassium salt of the compound shown in the formula A and calcium salt of the compound shown in the formula A.
EXAMPLE 1 preparation of sodium salt of Compound of formula A
14.50Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 0.5mL of methanol is added and stirred to form a suspension, sodium hydroxide solution (1.75 mg of sodium hydroxide is added into 0.45mL of methanol) is added dropwise to the methanol suspension of the compound represented by formula A, stirring is carried out at room temperature for about 10 minutes to form a clear solution, stirring is continued for 3 hours, then nitrogen is blown off at room temperature to remove the solvent to 0.2mL, colorless transparent clear solution is obtained, cooling is carried out to 5 ℃ to obtain a suspension, centrifugation is carried out, and solid is dried at room temperature in vacuum for 16 hours to obtain the sodium salt of the compound represented by formula A.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 2 preparation of sodium salt of Compound of formula A
40.71Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 0.4mL of methanol is added and stirred to form a suspension, sodium hydroxide solution (4.0 mg of sodium hydroxide is added to 2.8mL of methanol) is added dropwise to the methanol suspension of the compound represented by formula A, stirring is carried out at room temperature for about 1 hour to form a clear solution, stirring is continued for 2 hours, filtration is carried out, the filtrate is volatilized at room temperature to remove the solvent to 0.2mL, the suspension is obtained, centrifugation is carried out, and the solid is dried at room temperature in vacuum for 24 hours to obtain the sodium salt of the compound represented by formula A.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 3 preparation of sodium salt of Compound of formula A
4.9Mg of sodium hydroxide is weighed, 1.0mL of water is added into the ultrasonic solution, the clear solution is added into 40.7mg of the compound shown in the formula A prepared in preparation example 1 in a dropwise manner, the mixture is stirred at room temperature for 24 hours and then filtered, the filtrate is subjected to nitrogen blowing at 60 ℃ to remove the solvent until the volume of the solvent reaches 0.2mL, light yellow transparent clear solution is obtained, the mixture is cooled to room temperature to precipitate solid, and the solid is centrifuged and dried at 40 ℃ in vacuum for 1 hour to obtain the sodium salt of the compound shown in the formula A.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
The IR spectrum of the sodium salt is shown in fig. 1.
The XRD pattern of the sodium salt is shown in FIG. 2.
The TGA profile of the sodium salt is shown in figure 3.
The DSC of the sodium salt is shown in FIG. 4.
EXAMPLE 4 preparation of sodium salt of Compound of formula A
3.5Mg of sodium hydroxide is weighed, 1.0mL of acetone/water (4:1) is added for ultrasonic dissolution, the clear liquid is added dropwise to 29.2mg of the compound shown in the formula A prepared in preparation example 1, the mixture is stirred at room temperature for 16 hours and then filtered, and a filter cake is placed at 40 ℃ for vacuum drying for 1 hour, so that the sodium salt of the compound shown in the formula A is obtained.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 5 preparation of sodium salt of Compound of formula A
5.05Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.2mL of diethyl ether: ethanol (4:1) was added and stirred to form a suspension, sodium hydroxide solution (0.65 mg of sodium hydroxide was added to 0.3mL of diethyl ether: ethanol (volume ratio: 4:1)) was added dropwise to the diethyl ether: ethanol suspension of the compound represented by formula A, stirred at room temperature for 24 hours, then filtered, the filtrate was volatilized at 60℃to remove the solvent, and the solid was slurried with 0.2mL of diethyl ether for 1 hour and centrifuged, and the centrifuged solid was left to stand at room temperature and dried under vacuum for 19 hours to obtain the sodium salt of the compound represented by formula A of the present invention.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 6 preparation of sodium salt of Compound of formula A
8.02Mg of the compound represented by the formula A prepared in preparation example 1 was weighed, 8.0mL of n-butanol, methyl tert-butyl ether (1:1) and 2.5mg of sodium hydroxide solid were added, stirred at 60 ℃ for 1 hour, filtered, the filtrate was distilled off at 60 ℃ to remove the solvent, the solid was slurried with 0.2mL of n-butanol, methyl tert-butyl ether (1:1) for 1 hour, centrifuged, and the centrifuged solid was dried at 40 ℃ for 48 hours under vacuum to obtain the sodium salt of the compound represented by the formula A of the present invention.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 7 preparation of sodium salt of Compound of formula A
45.01Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.9mL of butanone: n-propanol (2:1) and 19.5mg of sodium hydroxide solid were added, stirred at 60 ℃ for 48 hours, filtered, the filtrate was distilled off at room temperature to remove the solvent, the solid was slurried with 0.2mL of butanone: n-propanol (2:1) for 1 hour, centrifuged, and the centrifuged solid was dried at 60 ℃ under vacuum for 40 hours to obtain the sodium salt of the compound represented by formula A of the present invention.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 8 preparation of sodium salt of Compound of formula A
Weighing 4.69mg of sodium hydroxide, adding 1.0mL of water, ultrasonically dissolving, adding the clear liquid into 38.77mg of the compound shown in the formula A prepared in the preparation example 1, adding 14.0mL of water, stirring for 16 hours, filtering, blowing out the solvent from the filtrate at 50 ℃ to 0.2mL, obtaining yellowish transparent clear liquid, cooling to 5 ℃ to precipitate solid, centrifuging, and vacuum drying the solid at 40 ℃ for 24 hours to obtain the sodium salt of the compound shown in the formula A.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 9 preparation of sodium salt of Compound of formula A
6.15Mg of the compound represented by the formula A prepared in preparation example 1 was weighed, 3.0mL of methanol/isopropyl ether (1:1) and 1.3mg of sodium hydroxide solid were added, stirred at 40 ℃ for 1 hour, the filtrate was filtered off by rotary evaporation at 50 ℃ to remove the solvent, the solid was slurried with 0.1mL of methanol/isopropyl ether (1:1) for 1 hour, centrifuged, and the centrifuged solid was dried at 25 ℃ under vacuum for 24 hours to obtain the sodium salt of the compound represented by the formula A of the present invention.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 10 preparation of sodium salt of Compound of formula A
35.62Mg of the compound of formula A prepared in preparation example 1 is weighed, 1.2mL of acetonitrile and 8.7mg of sodium hydroxide solid are added, stirring is carried out for 3 hours at 35 ℃, filtering is carried out, the solvent is removed to 0.2mL by rotary evaporation at room temperature, colorless transparent clear liquid is obtained, cooling is carried out until the solid is separated out at 5 ℃, centrifugation is carried out, and the solid is placed at 40 ℃ and dried in vacuum for 30 hours, thus obtaining the sodium salt of the compound of formula A.
IC characterization shows that the sodium salt of the compound shown in the formula A is formed by reacting the compound shown in the formula A and sodium ions in a molar ratio of 1:1.
EXAMPLE 11 preparation of sulfate salt of Compound of formula A
76.02Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 5.2mL of methanol is added and stirred to form a suspension, a sulfuric acid solution (7.3 mg of 98% sulfuric acid is added to 7.6mL of methanol) is added dropwise to the methanol suspension of the compound represented by formula A, stirring is carried out at room temperature for 5 hours to obtain a suspension, 5.0mL of methanol is added and stirring is continued for 1 hour, filtration is carried out, the filtrate is subjected to nitrogen stripping at room temperature until 1.0mL of solvent is removed, suspension is obtained, filtration is carried out, and the solid is dried at room temperature in vacuum for 20 hours, thus obtaining the sulfate of the compound represented by formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 12 preparation of sulfate salt of Compound of formula A
34.41Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 1.0mL of ethanol is added and stirred to form a suspension, 24.82mg of sulfuric acid with concentration of 98% is added to the ethanol suspension of the compound represented by formula A, the mixture is stirred at room temperature for 24 hours and then filtered, and a filter cake is dried at 40 ℃ in vacuum for 10 hours to obtain the sulfate of the compound represented by formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 13 preparation of sulfate salt of Compound of formula A
Weighing 4.63mg of the compound shown in the formula A prepared in preparation example 1, adding 0.2mL of n-propanol, stirring to form a suspension, dropwise adding a sulfuric acid solution (8.79 mg of 98% sulfuric acid into 0.3mL of n-propanol) into the n-propanol suspension of the compound shown in the formula A, stirring at room temperature for 16 hours, filtering, blowing off the solvent from the filtrate at room temperature by nitrogen to obtain an oily substance, adding water into the oily substance to ultrasonically form a suspension, centrifuging, and vacuum drying the solid at room temperature for 24 hours to obtain the sulfate of the compound shown in the formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
The IR spectrum of the sulfate is shown in FIG. 5.
The XRD pattern of the sulfate salt is shown in FIG. 6.
The TGA profile of the sulfate salt is shown in fig. 7.
The DSC chart of the sulfate is shown in FIG. 8.
EXAMPLE 14 preparation of sulfate salt of Compound of formula A
10.02Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 1.0mL of water is added and stirred to form a suspension, 7.88mg of 98% sulfuric acid is added to the aqueous suspension of the compound represented by formula A, stirring is carried out at 40 ℃ for 24 hours, then filtration is carried out, and the filter cake is dried at 60 ℃ in vacuum for 1 hour, thus obtaining the sulfate of the compound represented by formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 15 preparation of sulfate salt of Compound of formula A
34.4Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 1.0mL of water was added and stirred to form a suspension, a sulfuric acid solution (25.0 mg of 98% sulfuric acid was added to 0.5 mL) was added dropwise to the aqueous suspension of the compound represented by formula A, stirred at room temperature for 24 hours, then filtered, and the cake was dried under vacuum at 40℃for 1 hour to obtain the sulfate of the compound represented by formula A of the present invention.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 16 preparation of sulfate salt of Compound of formula A
10.25Mg of the compound represented by formula A prepared in preparation example 1 is weighed, 0.2mL of water is added and stirred to form a suspension, 8.25mg of 98% sulfuric acid and 1.0mL of acetone are sequentially added to the aqueous suspension of the compound represented by formula A, stirring is carried out at room temperature for 1 hour to obtain clear liquid, filtering is carried out, the solvent is removed by blowing nitrogen from the filtrate at room temperature, and the solid is dried at room temperature in vacuum for 24 hours to obtain the sulfate of the compound represented by formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 17 preparation of sulfate salt of Compound of formula A
10.40Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.2mL of water, 7.92mg of 98% sulfuric acid and 1.0mL of tetrahydrofuran were sequentially added to the compound represented by formula A, stirring was carried out at room temperature for 3 hours to obtain a clear solution, filtration was carried out, the filtrate was purged with nitrogen at 60℃to 0.3mL to obtain a suspension, centrifugation was carried out, and the solid was dried under vacuum at 40℃for 20 hours to obtain the sulfate of the compound represented by formula A of the present invention.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 18 preparation of sulfate salt of Compound of formula A
Weighing 4.15mg of the compound shown in the formula A prepared in preparation example 1, adding 0.2mL of water and acetonitrile (1:4), stirring to form a suspension, adding a sulfuric acid solution (3.2 mg of sulfuric acid with the concentration of 98% into 0.3mL of water and acetonitrile (1:4)) dropwise into the water and acetonitrile (1:4) suspension of the compound shown in the formula A, stirring at room temperature for 24 hours, filtering, blowing the solvent to 0.1mL at room temperature by nitrogen in the filtrate to obtain a suspension, centrifuging, and drying the solid at 50 ℃ in vacuum for 1 hour to obtain the sulfate of the compound shown in the formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 19 preparation of sulfate salt of Compound of formula A
5.0Mg of the compound represented by the formula A prepared in preparation example 1 is weighed, 5.0mL of sec-butyl alcohol, butanone (1:4) and 10.3mg of 98% sulfuric acid are added, stirring is carried out for 30 hours at-10 ℃, then filtration is carried out, the filtrate is subjected to nitrogen blowing at 40 ℃ to remove the solvent until 0.1mL, a suspension is obtained, centrifugation is carried out, and the solid is dried in vacuum at 60 ℃ for 10 hours, thus obtaining the sulfate of the compound represented by the formula A.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 20 preparation of sulfate salt of Compound of formula A
40.0Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.4ml of 1, 4-dioxane: water (1:1) was added and stirred to form a suspension, a sulfuric acid solution (96.7 mg of 98% sulfuric acid was added to 0.4ml of 1, 4-dioxane: water (1:1)) was added dropwise to the 1, 4-dioxane: water (1:1) suspension of the compound represented by formula A, stirred at 60℃for 72 hours, then filtered, the solvent was removed by blowing nitrogen at 60℃from the filtrate, the solid was slurried with 0.2ml of 1, 4-dioxane: water (1:1) for 1 hour, centrifuged, and the solid was dried at 40℃under vacuum for 48 hours after centrifugation to obtain the sulfate of the compound represented by formula A of the present invention.
IC characterization shows that the sulfate of the compound shown in the formula a is formed by reacting the compound shown in the formula a with sulfuric acid in a molar ratio of 2:1.
EXAMPLE 21 preparation of maleate salt of Compound of formula A
51.7Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 1.0mL of acetone was added, a maleic acid solution (17.7 mg of maleic acid was added to 1.0mL of acetone) was added dropwise to the acetone system of the compound represented by formula A under stirring, stirring was carried out at room temperature for 24 hours, filtration was carried out, and vacuum drying was carried out at 40℃for 16 hours, to obtain the maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
The maleate salt IR spectrum is shown in FIG. 9.
The maleate salt XRD pattern is shown in figure 10.
The maleate TGA profile is shown in figure 11.
The maleate DSC chart is shown in FIG. 12.
EXAMPLE 22 preparation of maleate salt of Compound of formula A
10.37Mg of the compound represented by formula A prepared in preparation example 1 was weighed, a maleic acid solution (3.91 mg of maleic acid was added to 1.0mL of ethanol) was added dropwise to the compound represented by formula A, stirred at room temperature for 10 hours, filtered, and the cake was dried under vacuum at 25℃for 20 hours to obtain a maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 23 preparation of maleate salt of Compound of formula A
7.63Mg of the compound represented by formula A prepared in preparation example 1 was weighed, a maleic acid solution (4.47 mg of maleic acid was added to 1.0mL of water) was added dropwise to the compound represented by formula A, stirred at 40℃for 24 hours, filtered, and the cake was dried at 40℃under vacuum for 1 hour to obtain a maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 24 preparation of maleate salt of Compound of formula A
10.70Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 3.52mg of maleic acid and 1.0mL of diethyl ether were added to the compound represented by formula A, stirred at room temperature for 24 hours, filtered, and the cake was dried under vacuum at 10℃for 24 hours to obtain the maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 25 preparation of maleate salt of Compound of formula A
13.33Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 1.5mL of ethyl acetate was added, a maleic acid solution (5.14 mg of maleic acid was added to 1.0mL of ethyl acetate solution) was added dropwise to the ethyl acetate system of the compound represented by formula A under stirring, stirring was carried out at room temperature for 18 hours, filtration was carried out, and the cake was dried under vacuum at 40℃for 1 hour to obtain the maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 26 preparation of maleate salt of Compound of formula A
6.04Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 1.0mL of 1, 4-dioxane was added, and a maleic acid solution (4.4 mg of maleic acid was added to 0.4mL of 1, 4-dioxane) was added dropwise to the 1, 4-dioxane system of the compound represented by formula A under stirring, stirred at room temperature for 20 hours, filtered, and the cake was dried under vacuum at 50℃for 24 hours to obtain 34.3mg of maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 27 preparation of maleate salt of Compound of formula A
5.0Mg of the compound represented by the formula A prepared in preparation example 1 was weighed, 4.7mg of maleic acid and 5.0mL of methyl ethyl ketone: methyl formate (2:1) were added, stirred at 60℃for 30 hours, filtered, and dried at 56℃under vacuum for 37 hours to obtain the maleate salt of the compound represented by the formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 28 preparation of maleate salt of Compound of formula A
40.5Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.6mL of methanol: methyl tert-butyl ether (1:1) was added, and a maleic acid solution (11.5 mg of maleic acid was added to 0.4mL of methanol: methyl tert-butyl ether (1:1) solution) was added dropwise to the methanol: methyl tert-butyl ether (1:1) system of the compound represented by formula A under stirring, stirred at 45℃for 48 hours, filtered, and dried at 40℃under vacuum for 48 hours to obtain the maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
EXAMPLE 29 preparation of maleate salt of Compound of formula A
50.0Mg of the compound represented by formula A prepared in preparation example 1 was weighed, 0.5mL of n-butanol/isopropyl acetate (3:1) was added, and a maleic acid solution (70.9 mg of maleic acid was added to 0.5mL of n-butanol/isopropyl acetate (3:1) solution) was added dropwise to the n-butanol/isopropyl acetate (3:1) system of the compound represented by formula A under stirring, stirred at-10℃for 72 hours, filtered, and dried at 60℃under vacuum for 30 hours to obtain the maleate salt of the compound represented by formula A of the present invention.
IC characterization shows that the maleate of the compound shown in the formula A is prepared by reacting the compound shown in the formula A and maleic acid in a molar ratio of 1:1 to form a salt.
Comparative example 1 solubility of sodium salt of Compound of formula A
The sodium salt of the compound shown in the formula A is taken for carrying out the solubility experiment in water, and the specific operation is that 5mg of the sodium salt of the compound shown in the formula A is taken in a 20ml glass bottle, deionized water is gradually added dropwise at 25 ℃ for ultrasonic treatment until the solution is clear. The solubility of the sample in water was calculated.
TABLE 2 solubility in Water of sodium salt of the Compound of formula A of the invention
| Sample name | Solubility (mg/mL) |
| Sodium salt of Compound of formula A | 10 |
As can be seen from Table 2, the sodium salt of the compound of formula A of the present invention has higher solubility and thus better bioavailability.
Comparative example 2 comparison of thermal stability of Compound salt of formula A
DSC and TGA analysis are carried out on sodium salt of the compound shown in the formula A, conventional salt (citrate of the compound shown in the formula A, phosphate of the compound shown in the formula A and hydrochloride of the compound shown in the formula A) to obtain melting point and decomposition temperature data of each salt type.
TABLE 3 melting point data for sodium salts and other conventional salts of the compounds of formula A of the invention
| Salt type | Melting point (° C) | Decomposition temperature (°c) |
| Sodium salt of Compound of formula A | 234 | 275 |
| Citrate salt of the Compound represented by formula A | 152 | 154 |
| Phosphates of compounds of formula A | 160 | 190 |
| Hydrochloride of the compound represented by formula A | 163 | 145 |
As is clear from Table 3, the sodium salt of the compound represented by formula A of the present invention has a very high melting point and decomposition temperature and thus has better thermal stability than the conventional salts (citrate salt of the compound represented by formula A, phosphate salt of the compound represented by formula A, hydrochloride salt of the compound represented by formula A).
Comparative example 3 solubility comparison of salt form of Compound represented by formula A
The method comprises the steps of taking 5mg of the free compound shown in the formula A, the conventional salt (the calcium salt of the compound shown in the formula A, the citrate of the compound shown in the formula A, the phosphate of the compound shown in the formula A, the hydrochloride of the compound shown in the formula A), the sulfate of the compound shown in the formula A and the maleate of the compound shown in the formula A, and placing 15mL of deionized water into a 20mL glass bottle, stirring for 2 hours. Samples were filtered and the concentration was measured by HPLC. The solubility of the active ingredient in water in the sample was calculated.
TABLE 4 solubility in water of the free form and the salt form of the compound of formula A
| Sample name | Solubility (μg/mL) |
| The free state of the compound shown in the formula A | 1.1 |
| Sulfate of the compound represented by formula A | 19.2 |
| Maleate salt of compound represented by formula A | 16.1 |
| Calcium salt of Compound of formula A | 2.5 |
| Citrate salt of the Compound represented by formula A | 5.3 |
| Phosphates of compounds of formula A | 6.7 |
| Hydrochloride of the compound represented by formula A | 3.8 |
As shown in Table 4, the sulfate salt of the compound represented by formula A and the maleate salt of the compound represented by formula A of the present invention have about 10 to 20 times higher solubility in water at 25℃than the known free state of the compound represented by formula A, and have about 3 to 8 times higher solubility in water at 25℃than other conventional salts (calcium salt of the compound represented by formula A, citrate salt of the compound represented by formula A, phosphate salt of the compound represented by formula A, hydrochloride salt of the compound represented by formula A), and thus have better bioavailability.
Comparative example 4 comparison of hygroscopicity of salt type of Compound represented by formula A
The sulfate salt of the compound represented by formula a and the maleate salt of the compound represented by formula a of the present invention were taken and subjected to DVS analysis with respect to conventional salts (potassium salt of the compound represented by formula a, calcium salt of the compound represented by formula a, citrate salt of the compound represented by formula a, phosphate salt of the compound represented by formula a, hydrochloride salt of the compound represented by formula a), to obtain hygroscopicity data of each salt form.
TABLE 5 hygroscopicity data of the sulfate salt of the Compound of formula A and the maleate salt of the Compound of formula A of the invention with other conventional salts
| Salt type | Moisture uptake (%) | Appearance of |
| Sulfate of the compound represented by formula A | 0.7 | Powder |
| Maleate salt of compound represented by formula A | 0.4 | Powder |
| Potassium salt of Compound of formula A | 17.5 | Deliquescence into a solution |
| Calcium salt of Compound of formula A | 1.2 | Powder |
| Citrate salt of the Compound represented by formula A | 0.7 | Powder |
| Phosphates of compounds of formula A | 1.2 | Powder |
| Hydrochloride of the compound represented by formula A | 1.2 | Powder |
As can be seen from table 5, the sulfate salt of the compound represented by formula a and the maleate salt of the compound represented by formula a of the present invention have lower moisture absorption and weight gain than conventional salts (potassium salt of the compound represented by formula a, calcium salt of the compound represented by formula a, citrate salt of the compound represented by formula a, phosphate salt of the compound represented by formula a, hydrochloride salt of the compound represented by formula a), and thus have better storage stability, and can better avoid quality, safety and stability problems during pharmaceutical manufacturing and/or storage and the like.
Comparative example 5 comparison of stability of crystalline forms of salts of the Compound of formula A
Taking the crystal forms of the sulfate and the maleate of the compound shown in the formula A for stability experiments, wherein the crystal forms are prepared by respectively taking 60mg of the crystal forms of the sulfate and the maleate of the compound shown in the formula A, placing the 60mg of the crystal forms under the conditions of conventional (25 ℃ sealed and light-shielding), high temperature (60 ℃ sealed and light-shielding) and acceleration (40 ℃ to 75% relative humidity open and light-shielding) for 30 days, and examining the stability of the crystal forms.
TABLE 6 statistics of results of test of the crystal form of sulfate salt of the compound of formula A and the crystal form stability of maleate salt of the compound of formula A according to the present invention
As can be seen from Table 6, the crystal forms of the sulfate and maleate of the compound of formula A of the present invention have good stability, and are suitable for various environmental conditions of manufacture, storage and transportation.
Comparative example 6 comparison of stability of Crystal forms of salts of Compounds of formula A
Taking the crystal forms of the sodium salt of the compound shown in the formula A, the sulfate salt of the compound shown in the formula A and the maleate salt of the compound shown in the formula A, forming suspension in the solvent shown in the table 7, stirring for 3 days at room temperature, and comparing the results of comparative example 1 in the patent CN105315266A with the results of the crystal form stability examination.
TABLE 7 statistics of the results of the test of the stability of the salt form and the free form of the compound of formula A in a solvent
From Table 7, it is clear that the compound of formula A has inconsistent final crystal forms in different solvents, which indicates that the compound of formula A has mixed crystals easily during the preparation process, and the crystal forms are difficult to control. The salt forms of the compound shown in the formula A are single, so that the compound has more flexibility in solvent selection in the production process and is more stable.
All patent documents and non-patent publications cited in this specification are incorporated herein by reference in their entirety.
The foregoing is merely illustrative of the embodiments of the present invention, and the scope of the present invention is not limited thereto, and any changes or substitutions that may be made by those skilled in the art without departing from the inventive concept are intended to be included within the scope of the present invention.
Claims (18)
1. A crystalline form of a sodium salt of a compound of formula a, the sodium salt of a compound of formula a having the structure:
Characterized in that, using Cu-ka radiation, the X-ray powder diffraction pattern of the crystalline form expressed in terms of 2θ has characteristic peaks and their relative intensities at the following positions:
2. the crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern as shown in figure 2.
3. The crystalline form of claim 1 or 2, characterized by fourier infrared spectra of the crystalline form having characteristic peaks at wavenumbers 1560cm "1, 1505 cm" 1, 1476cm "1, 1417 cm" 1, 1365cm "1, 1276 cm" 1, 885cm "1, 849 cm" 1, and 756cm "1.
4. A process for the preparation of a crystalline form of the sodium salt of any one of claims 1 to 3, comprising the steps of:
In a solvent selected from C 1～C4 alcohol, C 3～C4 ketone, C 4～C6 ether, water, nitrile or a mixture thereof, mixing and reacting a compound shown in a formula A with sodium hydroxide in a molar ratio of 1:1-1:5, removing the solvent after the reaction is finished, and drying.
5. The method of claim 4, wherein the solvent is selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile, and mixtures thereof.
6. The preparation method according to claim 4 or 5, wherein the molar ratio of the compound represented by formula a to sodium hydroxide is 1:1.0 to 1:1.3.
7. The method according to claim 4 or 5, wherein the reaction is carried out at 10 to 60 ℃.
8. The method of claim 4 or 5, wherein the reaction is carried out at room temperature.
9. The method according to claim 4 or 5, wherein the reaction is carried out under stirring for a period of 1 to 48 hours.
10. The method according to claim 4 or 5, wherein the reaction is carried out under stirring for 3 to 24 hours.
11. The method according to claim 4 or 5, wherein the drying is performed under vacuum, and the drying temperature is 10-60 ℃.
12. The method according to claim 4 or 5, wherein the drying is performed under vacuum, and the drying temperature is 10-40 ℃.
13. The method according to claim 4 or 5, wherein the drying time is 1 to 48 hours.
14. The method according to claim 4 or 5, wherein the drying time is 1 to 24 hours.
15. The method according to claim 4 or 5, wherein the mass to volume ratio of the compound represented by formula A to the solvent in the method is1 mg/1 mL-50 mg/1 mL.
16. The method according to claim 4 or 5, wherein the mass to volume ratio of the compound of formula A to the solvent is 2.5 mg/1 mL-41 mg/1 mL.
17. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a crystalline form of the sodium salt of any one of claims 1 to 3, and optionally at least one pharmaceutically acceptable carrier or excipient.
18. Use of a crystalline form of the sodium salt of any one of claims 1 to 3 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by the S1P1 receptor, wherein the disease or condition is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, crohn' S disease or ulcerative colitis.
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| CN105315266A (en) * | 2014-08-01 | 2016-02-10 | 苏州康乃德生物医药有限公司 | Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid |
| CN108299412A (en) * | 2017-01-11 | 2018-07-20 | 苏州康乃德生物医药有限公司 | A kind of addition salt of S1P1 receptor agonist and its crystal form and pharmaceutical composition |
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| CN108299412A (en) * | 2017-01-11 | 2018-07-20 | 苏州康乃德生物医药有限公司 | A kind of addition salt of S1P1 receptor agonist and its crystal form and pharmaceutical composition |
| CN112778290A (en) * | 2017-01-11 | 2021-05-11 | 苏州康乃德生物医药有限公司 | Addition salt of S1P1 receptor agonist, crystal form and pharmaceutical composition thereof |
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| CN108299412A (en) | 2018-07-20 |
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