CN115246817A - Crystal form beta of compound A benzoate, preparation method thereof and pharmaceutical composition containing crystal form - Google Patents
Crystal form beta of compound A benzoate, preparation method thereof and pharmaceutical composition containing crystal form Download PDFInfo
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- CN115246817A CN115246817A CN202210458284.3A CN202210458284A CN115246817A CN 115246817 A CN115246817 A CN 115246817A CN 202210458284 A CN202210458284 A CN 202210458284A CN 115246817 A CN115246817 A CN 115246817A
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- compound
- benzoate
- crystal form
- beta
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 239000013078 crystal Substances 0.000 title claims abstract description 68
- 229940126062 Compound A Drugs 0.000 title claims abstract description 63
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000002441 X-ray diffraction Methods 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004455 differential thermal analysis Methods 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 8
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract description 3
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 description 21
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 13
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 230000004584 weight gain Effects 0.000 description 9
- 235000019786 weight gain Nutrition 0.000 description 9
- 238000012360 testing method Methods 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- JVGVCOKSHMRMAP-UHFFFAOYSA-N 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene Chemical compound FC1=CC=C(Br)C(CN=C=S)=C1 JVGVCOKSHMRMAP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 3
- 102000012479 Serine Proteases Human genes 0.000 description 3
- 108010022999 Serine Proteases Proteins 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- -1 1 H-NMR(400MHz Natural products 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- 206010056997 Impaired fasting glucose Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 2
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 2
- 229960001667 alogliptin Drugs 0.000 description 2
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- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 239000012044 organic layer Substances 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- IYGSUIRVOLFPLD-UHFFFAOYSA-N 1-amino-3-[(2-bromo-5-fluorophenyl)methyl]thiourea Chemical compound NNC(=S)NCC1=CC(F)=CC=C1Br IYGSUIRVOLFPLD-UHFFFAOYSA-N 0.000 description 1
- CZLWYKAZAVYQIK-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(Br)C(CBr)=C1 CZLWYKAZAVYQIK-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CEIKPTLXEHWGMB-XFULWGLBSA-N 2-[[3-[(3R)-3-aminopiperidin-1-yl]-6-methyl-5-oxo-1,2,4-triazin-4-yl]methyl]-4-fluorobenzonitrile benzoic acid Chemical compound OC(=O)c1ccccc1.Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2C#N)c1=O CEIKPTLXEHWGMB-XFULWGLBSA-N 0.000 description 1
- IXSWMXRAIPXMRH-OAHLLOKOSA-N 2-[[3-[(3r)-3-aminopiperidin-1-yl]-6-methyl-5-oxo-1,2,4-triazin-4-yl]methyl]-4-fluorobenzonitrile Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)C(C)=NN=C1N1CCC[C@@H](N)C1 IXSWMXRAIPXMRH-OAHLLOKOSA-N 0.000 description 1
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- SFZKGGOGCNQPJY-CIUDSAMLSA-N Ser-Asp-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N SFZKGGOGCNQPJY-CIUDSAMLSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- 210000004899 c-terminal region Anatomy 0.000 description 1
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- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
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- 229940107700 pyruvic acid Drugs 0.000 description 1
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- 235000009518 sodium iodide Nutrition 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
- C07C63/06—Benzoic acid
- C07C63/08—Salts thereof
-
- 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 & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of chemical medicine preparation, and particularly relates to a crystal form beta of a dipeptidyl peptidase-IV inhibitor compound A benzoate, a preparation method thereof, and a pharmaceutical composition containing the crystal form.
Description
Technical Field
The invention belongs to the field of chemical medicine preparation, and particularly relates to a crystal form beta of a dipeptidyl peptidase-IV inhibitor compound A benzoate, a preparation method thereof, and a pharmaceutical composition containing the crystal form.
Background
Dipeptidyl peptidase IV (DPP-IV) is a serine protease that specifically hydrolyzes Xaa-Pro or Xaa-Ala dipeptides at the N-terminus of a polypeptide or protein. DPP-IV is a non-canonical serine protease, and the Ser-Asp-His catalytic triad in the C-terminal region is in reverse order unlike a canonical serine protease.
DPP-IV has a variety of physiologically relevant substrates, such as inflammatory chemokines, normal T-cell expressed and secreted factors (RANTES), eotaxin and macrophage derived chemokines, neuropeptides such as neuropeptide Y (NPY) and substance P5, vasoactive peptides, incretins such as glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP).
Inhibition of DPP-IV in vivo can increase endogenous GLP-1 (7-36) levels and reduce the production of its antagonist GLP-1 (9-36). Therefore, DPP-IV inhibitors may be useful in diseases associated with DPP-IV activity, such as type 2 diabetes, diabetic dyslipidemia, impaired Glucose Tolerance (IGT), impaired Fasting Glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
The DPP-IV inhibitor Alogliptin (Alogliptin) shows good treatment effect on type 2 diabetes clinically, and is approved to be marketed in the United states. Therefore, DPP-IV inhibitors are currently considered as new therapeutic approaches for the treatment of type 2 diabetes.
PCT/CN2010/080370 describes a series of DPP-IV inhibitors of novel parent nuclear structures. The compound A is a compound A, and the chemical name of the compound A is as follows: (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 (5H) -yl) methyl) -4-fluorobenzonitrile (the product obtained using this prior art process was a yellow oil), formula: c 17 H 19 FN 6 O, molecular weight: 342, the chemical structural formula is shown as the following formula (I):
international patent application WO2015110078A1 discloses a benzoate of compound a, and patent CN201510033908.7 discloses a crystalline form α compound of compound a benzoate prepared by a methanol aqueous solvent system, and its characteristic peaks are shown in 2 θ at 9.13 ± 0.2, 16.02 ± 0.2, 18.13 ± 0.2, and 23.91 ± 0.2. The applicant of the present invention repeats the method of the patent to obtain the crystal form alpha, but finds that the crystallization process in the patent is difficult to dry and is not easy to industrialize, and the crystallization compound is improved in moisture-attracting property to a certain extent, but the moisture-attracting problem still exists. Therefore, there is a need in the art to obtain a benzoate salt of compound a that is easily prepared, has high purity, low hygroscopicity, and better stability to meet market demand.
Patent CN201610533117.5 discloses an amorphous form of compound a benzoate and a method for its preparation. Further research by the applicant of the invention finds that the amorphous solid has stronger hygroscopicity, the weight is increased by 8.25% when the amorphous solid is placed at a relative humidity of 80%, and the stability is poor. The requirement of the bulk drugs with high hygroscopicity on packaging and storage conditions is strict, so that the production cost of the drugs is increased, and the production and the application are not facilitated.
In order to solve the above problems, the present invention mainly aims to provide a new solid form with excellent properties suitable for drug development, and through a great deal of experimental studies, the present invention finds a new crystal form of compound a benzoate, which has advantages in hygroscopicity, stability, flowability, and the like.
Disclosure of Invention
One of the objects of the present invention is to provide a stable crystalline form of the compound a benzoate, a stable dipeptidyl peptidase-IV (DPP-IV) reversible competitive inhibitor.
The chemical name of compound a benzoate is: (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 (5H) -yl) methyl) -4-fluorobenzonitrile benzoate, formula: c 17 H 19 FN 6 O·C 7 H 6 O 2 Molecular weight: 464.49, chemical structural formula is formula (II),
the crystal form beta of the benzoate of the compound A serving as the dipeptidyl peptidase-IV inhibitor has a characteristic peak at 18.87 degrees expressed by a 2theta angle in an X-ray diffraction pattern, and the error is +/-0.2 degrees. Further, there are characteristic peaks at 9.74 °, 14.54 °, 18.87 °, 22.13 °, 25.36 ° and 26.74 ° with an error of ± 0.2 °.
Specifically, the crystal form β of the benzoate of the compound a has characteristic peaks expressed in an X-ray diffraction pattern at 2 θ angles of 8.87 °, 9.74 °, 12.58 °, 14.54 °, 18.87 °, 19.51 °, 20.13 °, 22.13 °, 25.36 ° and 26.74 °, with an error of ± 0.2 °. Further specifically, the crystal form has characteristic peaks at 8.87 °, 9.74 °, 12.58 °, 14.54 °, 18.87 °, 19.51 °, 20.13 °, 20.77 °, 22.13 °, 23.35 °, 24.08 °, 25.36 °, 26.74 °, 27.83 °, 29.53 °, 30.38 °, 31.75 ° and 33.25 °, with an error of ± 0.2 °. It should be noted that: different samples of a particular crystalline form have the same major XRPD peaks, but the minor peaks in the powder pattern may vary. In addition, when the isomorphous sample obtained by the corresponding method is detected by the same instrument and detection method by the ordinary skilled person in the art, each 2 θ angle error is usually within ± 0.2 ° (the meaning that each 2 θ angle error is usually within ± 0.2 ° refers to most of characteristic peaks, for example, more than 80% of characteristic peak error is within the range, and the error of a few characteristic peaks which are occasionally out of the range is considered to belong to the XRPD spectrogram of the same crystal form); moreover, the characteristic peak of each displacement is a medium-intensity absorption peak, and other weak absorption peaks may be obviously changed due to experimental operation errors. Therefore, the X-ray diffraction absorption peak is not limited to the above specific value, and a possible error range should be considered.
More specifically, the X-ray diffraction pattern of the crystal form beta of the benzoate of the compound A is shown in the attached figure 1 or the attached figure 2.
X-ray diffraction detection conditions:
x-ray diffraction a sharp-shadow (Empyrean) X-ray diffractometer was used, and the X-ray diffraction was measured at a Cu target K α ray, voltage: 45.0kV, current: 40.0mA, divergence slit 1/4 degrees, step size 0.0262606 degrees, 2theta range measured under the condition of 30s residence time per step: 3 to 40 degrees.
The differential scanning calorimetry curve of the crystal form beta of the benzoate of the compound A has an initial value of an endothermic peak at 95.77 +/-5 ℃ and a peak value of the endothermic peak at 105.73 +/-5 ℃.
More specifically, the DSC spectrum of the crystal form beta of the benzoate of the compound A is shown as the attached figure 3.
The thermogravimetric analysis curve of the crystal form beta of the benzoate of the compound A is about 2.85% of weight loss at 110.00 +/-5 ℃.
More specifically, the crystal form beta of the benzoate of the compound A has a TG spectrum shown in figure 4.
The water content of the crystal form beta of the benzoate of the compound A is 1.5-5%, and the detection of the water content in the crystal form beta of the benzoate of the compound A can adopt a method commonly used in the field, such as a Karl Fischer method and/or a thermogravimetric analysis method. Specifically, the water content of the crystal form β of the benzoate salt of the compound a is 1.9% or 3.8% as measured by the karl fischer method.
The compound A benzoate has high stability of the crystal form beta, has lower hygroscopicity and better stability compared with the compound A benzoate crystal form alpha obtained by CN201510033908.7, is more beneficial to the clinical application of the compound A benzoate, and fully ensures the safety and the effectiveness of medication.
The invention also aims to provide a preparation method of the crystal form beta of the compound A benzoate, which has a simple process and can be realized under the normal temperature condition.
The compound A can be prepared according to a method disclosed in PCT/CN2010/080370, and the specific synthetic route and the main reaction conditions are as follows:
a process for preparing the crystalline form β of compound a benzoate comprising the steps of:
and (2) putting the refined product of the compound A into a reaction bottle, adding an organic solvent for dissolving, stirring, adding benzoic acid and a small amount of water, keeping the temperature of the system at 5-15 ℃, stirring until a large amount of solid is separated out, filtering, washing a filter cake with the organic solvent, and performing vacuum drying at room temperature to prepare the crystal form beta of the compound A benzoate. The organic solvent is one or a mixture of two of ethyl acetate, isopropyl acetate, methyl acetate, ethyl formate and isobutyl acetate.
Still another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned compound a, crystalline form β of benzoate, and one or more pharmaceutically acceptable carriers.
The carrier comprises various pharmaceutic adjuvants, packaging materials, delivery tools and the like, and is selected according to the requirements of the preparation, for example, the adjuvants comprise a filler, a disintegrant, a binder, a lubricant and the like, and can be suitable for oral administration, inhalation, parenteral administration or surface use; the dosage form includes but is not limited to injection, solution preparation, tablet, capsule, granule, etc.
The pharmaceutical composition can be used for preparing medicines for treating related diseases caused by DPP-IV, in particular type 2 diabetes.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. compared with the crystal form alpha, the crystal form beta of the compound A benzoate has lower hygroscopicity, is more beneficial to ensuring the clinical curative effect and safe medication of the compound A benzoate, and simultaneously provides more choices for the optimization of the compound A benzoate preparation prescription.
2. Compared with the crystal form alpha of the compound A, the crystal form beta of the benzoate of the invention and the amorphous form disclosed in the patent CN201610533117.5, the benzoate of the invention has better fluidity and is easier to prepare and use the pharmaceutical composition and the pharmaceutical preparation.
3. The method for preparing the crystal form beta of the compound A benzoate is simple and rapid, can be used for preparing the compound A benzoate at normal temperature, and is easy for industrial production.
Drawings
FIG. 1 is an X-ray diffraction pattern of the crystal form beta of benzoate of Compound A obtained in example 2 of the present invention
FIG. 2 is an X-ray diffraction pattern of the crystal form beta of the benzoate salt of the compound A obtained in example 3 of the present invention
FIG. 3 is a DSC chart of the crystal form beta of benzoate of the compound A obtained in example 2 of the present invention
FIG. 4 is a TG spectrum of the crystal form beta of benzoate of Compound A obtained in example 2 of the present invention
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
All the detection data/spectra of the present invention can be obtained by using analytical detection instruments of conventional types in the art and conventional detection methods under detection conditions known in the art, and the present invention will be further described in detail with reference to the following examples and drawings, but the embodiments of the present invention are not limited thereto.
The X-ray powder diffraction (PXRD) spectrogram disclosed by the invention is obtained by detecting with a Pasnake sharp shadow (Empyrean) X-ray powder diffractometer under the detection conditions: cu-Ka radiation, wavelength
1/4 degree of divergent slit, 45kV of X-ray light tube voltage, 40mA of X-ray light tube current, 3-40 degrees (2 theta) of scanning range, 0.0262606 degrees of step size, and 30s of dwell time of each step.
The DSC spectrogram of the invention is obtained by adopting a scanning calorimeter Q2000 (American TA instrument) for detection, and the detection conditions are as follows: the temperature rise rate is 10 ℃/min, and the temperature is raised from room temperature to a specific temperature.
The TG spectrogram is obtained by adopting a thermogravimetric analyzer Q500 (American TA instrument) for detection, and the detection conditions are as follows: the temperature is increased at a rate of 10 ℃/min and heated from room temperature to a specific temperature.
EXAMPLE 1 preparation of Compound A
Compound a was prepared according to the methods of PCT/CN2010/080370 instructions, examples 2 and 3, using the following technical synthetic route:
the compound A is obtained by the reaction of the compound A, 1 H-NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H).MS:m/z,343(100％,M+1)。
the preparation method comprises the following specific steps:
step A.1-bromo-4-fluoro-2- (isothiocyanatomethyl) benzene (2)
To a solution of 1-bromo-2- (bromomethyl) -4-fluorobenzene (1,5.36g, 20.0 mmol) in DMF (20 mL) were added sodium iodide (1.20g, 8.00mmol) and potassium thiocyanate (3.88g, 40.0 mmol). The mixture was heated to 80 ℃ under nitrogen atmosphere for reaction for 12 hours, cooled to room temperature, added with 100mL of water and extracted with ethyl acetate (50 mL. Times.2), the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 1-bromo-4-fluoro-2- (isothiocyanatomethyl) benzene (2).
Step B.N- (2-bromo-5-fluorophenylmethyl) hydrazinothiocarboxamide (3)
A solution of hydrazine hydrate (80%, 2.22g,35.5 mmol) in 1,4-dioxane (20 mL) was cooled to 0 deg.C and a solution of 1-bromo-4-fluoro-2- (methyl isothiocyanate) benzene (2, 3.16g,12.8 mmol) in 1,4-dioxane (5 mL) was added. The mixture was stirred at room temperature for 2h, 100mL of ice water was added thereto, a solid precipitated, filtered, washed with water, and dried over night with phosphorus pentoxide to give N- (2-bromo-5-fluorobenzyl) hydrazinothiocarbamide (3). MS: M/z,278 (100%, M + 1), 280 (100%), 300 (10%, M + 23), 302 (10%).
Step C, methyl 2- (2- (2-bromo-5-fluorobenzothiocarboxamide) hydrazino) propionate (4)
To a solution of pyruvic acid (352mg, 4.00mmol) in methanol (15 mL) was added N- (2-bromo-5-fluorobenzyl) hydrazinocarbothioamide (3, 1.112g, 4.00mmol) followed by 5 drops of concentrated sulfuric acid, the mixture was heated to reflux for 7h, most of the solvent was evaporated, the residue was extracted with ethyl acetate (150 mL), the organic layer was washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous magnesium sulfate, and concentrated by suction filtration to give methyl 2- (2- ((2-bromo-5-fluorobenzamidothiocarbamide) hydrazino) propionate (4), MS: M/z,362 (100%, M + 1), 364 (100%), 384 (60%, M + 23), 386 (60%).
Step D.4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5 (2H) -one
(5)
Freshly prepared sodium methoxide (0.4M) from sodium (273mg, 11.88mmol) and dry methanol (30 mL) is dissolved in 30mL of methanol to which methyl 2- (2- (2-bromo-5-fluorobenzothiocarboxamide) hydrazino) propionate (4, 1.434g, 3.96mmol) is added, the mixture is heated under reflux for 22H, most of the solvent is evaporated off, the residue is diluted with 100mL of water, the pH is adjusted to 1-2 with 2N concentrated hydrochloric acid, ethyl acetate is extracted (50 mL × 2), the combined extract layers are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by suction filtration to give a crude product, which is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether =20% -30%) to give 4- (2-bromo-5-fluorobenzyl) -6-methyl-3-thio-3,4-dihydro-1,2,4-triazin-5 (2H) -one (5), MS: M/z,330 (65%, M + 1), M +1, 32332 (60%, M + 23%, 23).
Step E.4- (2-bromo-5-fluorobenzyl) -6-methylYl-3- (methylthio) -1,2,4-triazin-5 (4H) -one (6)
4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5 (2H) -one (5,914mg, 2.77mmol) was suspended in 15mL of ethanol, and sodium hydroxide (111mg, 2.77mmol) and iodomethane (787 mg, 5.54mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes to give a clear yellow solution, the reaction was diluted with 100mL of water, extracted with ethyl acetate (30 mL. Times.2), the combined extract layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether =20 to 25%) to give 4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3- (methylthio) -1,2,4-triazin-5 (4H) -one (6). 1 H NMR(400MHz,DMSO,ppm):δ7.73(m,1H),7.16(br,1H),7.05(d,1H),5.09(s,2H),2.56(s,3H),2.32(s,3H).MS:m/z,344(100％,M+1),346(100％)。
Step F. (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-
Triazin-3-yl) piperidin-3-yl) carbamates (8)
4- (2-bromo-5-fluorophenylmethyl) -6-methyl-3- (methylthio) -1,2,4-triazin-5 (4H) -one (6, 180mg, 0.523mmol) and (R) -tert-butylpiperidin-3-ylcarbamate (7, 208mg, 1.04mmol) were ground for 5 minutes, heated to 135 ℃ under nitrogen for 13 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 10-50%) to give (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidin-3-yl) carbamate (8). MS: M/z,496 (100%, M + 1), 498 (100%).
Step G. (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-
Triazin-3-yl) piperidin-3-yl) carbamates (9)
To a mixture of sodium carbonate (53mg, 0.50mmol), palladium acetate (3mg, 0.013mmol) and 0.5mL of N-methylpyrrolidone were added 3 drops of isopropanol and 2 drops of water, the mixture was stirred at room temperature for 5 minutes, and (R) -tert-butyl (1- (4- (2-bromo-5-fluorophenylmethyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidin-3-yl) aminomethyl was addedA solution of the acid ester (8,246mg, 0.496mmol) in NMP (1.0 mL) was heated to 140 ℃ and K was added 4 [Fe(CN) 6 ].3H 2 O (190mg, 0.496mmol), heating at 140 deg.C for 12h, cooling to room temperature, adding 10mL of water, extracting with ethyl acetate (20 mL. Times.2), combining the organic layers, washing with saturated brine, drying over anhydrous magnesium sulfate, vacuum-filtering and concentrating to obtain a crude product, and purifying by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 20-35%) to obtain (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidin-3-yl) carbamate (9), MS: M/z,418 (20%), 443 (100%, M + 1), 465 (95%, M + 23).
Step H. (R) -2- ((3- (3-aminopiperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 (5H) -yl)
Methyl) -4-fluorobenzonitrile (10, compound A)
To 1mL of a dichloromethane solution of (R) -tert-butyl (1- (4- (2-cyano-5-fluorobenzyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidin-3-yl) carbamate (9, 37mg) was added trifluoroacetic acid 0.5mL, stirred at room temperature for 1H, neutralized with a saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, concentrated by suction filtration to give a crude product, and purified by silica gel column chromatography (eluent: dichloromethane/methanol/ammonia = 92).
1 H NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H).MS:m/z,343(100％,M+1)。
EXAMPLE 2 preparation of Compound A benzoate form beta
Taking 10.0g to 250ml of the refined product of the compound A, adding ethyl acetate (68 ml) into a reaction bottle for dissolving, stirring for 1 to 2 hours, and cooling to 5 to 15 ℃. Adding 3.56g of benzoic acid and 0.53g of water, and reacting for 8-10 h under the condition of heat preservation; in the reaction process, a large amount of solid is separated out, filtered, the filter cake is washed by a proper amount of ethyl acetate, and the filter cake is vacuum-dried at room temperature to obtain about 11.4g of the crystal form beta of the compound A benzoate. Purity 99.5% and water content 3.8%.
The H nuclear magnetic data for the resulting compound a benzoate was as follows: 1 HNMR(DMSO-d 6 ,400MHz,ppm):δ7.96-7.88(m,3H),7.45-7.26(m,5H),6.80(brs,3H),5.21(dd,2H),3.41(d,1H),3.11-3.08(m,2H),2.91-2.79(m,2H),2.23(s,3H),1.95-1.91(m,1H),1.78-1.74(m,1H),1.57-1.42(m,2H).MS:m/z,341(100％,M-1),343(100％,M+1)。
the X-ray diffraction pattern of the crystal form beta of the obtained benzoate of the compound A is shown in figure 1, and the specific characteristic absorption peaks are as follows: characteristic peaks are found at 8.87 °, 9.74 °, 12.58 °, 14.54 °, 18.87 °, 19.51 °, 20.13 °, 20.77 °, 22.13 °, 23.35 °, 24.08 °, 25.36 °, 26.74 °, 27.83 °, 29.53 °, 30.38 °, 31.75 ° and 33.25 °. The DSC spectrum is shown in figure 3, and the TG spectrum is shown in figure 4.
EXAMPLE 3 preparation of Compound A benzoate form beta
Taking 12.0g to 250ml of the refined product of the compound A, adding methyl acetate (76 ml) into a reaction bottle for dissolving, stirring for 1 to 2 hours, and cooling to 5 to 15 ℃. Adding benzoic acid (4.27 g) and water (0.65 g), and reacting for 8-10 h under heat preservation; in the reaction process, a large amount of solid is separated out, filtered, the filter cake is washed by a proper amount of ethyl acetate, and the filter cake is vacuum-dried at room temperature to obtain about 12.1g of the crystal form beta of the compound A benzoate. Purity 99.3%, water 1.9%.
The X-ray diffraction pattern of the crystal form beta of the obtained benzoate of the compound A is shown in figure 2, and the specific characteristic absorption peaks are as follows: characteristic peaks exist at 8.84 °, 9.72 °, 12.60 °, 14.56 °, 18.87 °, 19.50 °, 20.08 °, 21.00 °, 22.10 °, 23.37 °, 24.07 °, 25.32 °, 26.76 °, 27.79 °, 29.51 °, 30.36 °, 31.73 ° and 33.20 °.
In the comparison between the absorption peaks in FIGS. 1 and 2, the error was. + -. 0.2 ℃ as shown in Table 1 below.
TABLE 1X-ray diffraction data for Compound A benzoate form β
Wherein, no. = serial number, rel. Int. = Relative Intensity, pos. [ ° 2Th. ] = Position [ ° 2Theta ], and the error is ± 0.2 °. Int. = Relative Intensity is merely an approximate Intensity representing the Intensity of a characteristic peak, and should not be limited to a specific crystal form.
X-ray diffraction detection conditions:
x-ray diffraction a sharp-shadow (Empyrean) X-ray diffractometer was used, and the X-ray diffraction was measured at a Cu target K α ray, voltage: 45.0kV, current: 40.0mA, divergence slit 1/4 degrees, step size 0.0262606 degrees, 2theta range measured under the condition of 30s residence time per step: 3 to 40 degrees.
To summarize: according to the XRD spectra and characteristic peak data of fig. 1 and 2, the most intense characteristic absorption peak at 18.87 ° is shown by 2 θ angle with an error of ± 0.2 ° and a relative absorption intensity of 100%.
Further, the crystal form has characteristic peaks at 9.74 degrees, 14.54 degrees, 18.87 degrees, 22.13 degrees, 25.36 degrees and 26.74 degrees, the error is +/-0.2 degrees, and the relative absorption intensity is more than 50 percent.
Specifically, the crystal form has characteristic peaks at 8.87 degrees, 9.74 degrees, 12.58 degrees, 14.54 degrees, 18.87 degrees, 19.51 degrees, 20.13 degrees, 22.13 degrees, 25.36 degrees and 26.74 degrees, the error is +/-0.2 degrees, the relative absorption intensity is greater than 30 percent, and other substances can be distinguished in detail to represent the crystal form. Further specifically, the crystal form has characteristic peaks at 8.87 °, 9.74 °, 12.58 °, 14.54 °, 18.87 °, 19.51 °, 20.13 °, 20.77 °, 22.13 °, 23.35 °, 24.08 °, 25.36 °, 26.74 °, 27.83 °, 29.53 °, 30.38 °, 31.75 ° and 33.25 °, the error is ± 0.2 °, the relative absorption intensity is greater than 10%, and other substances can be distinguished in more detail to represent the crystal form. Other weak absorption peaks may be obviously changed due to experimental operation errors, and other absorption peaks are considered unnecessary absorption peaks when the crystal form is characterized by the other weak absorption peaks for a person skilled in the art.
Example 4 preparation of the crystalline form alpha disclosed in patent CN201510033908.7 and amorphous form disclosed in patent CN201610533117.5
According to the preparation method disclosed by the patent CN201510033908.7, the compound A benzoate crystal form alpha disclosed by the patent CN201510033908.7 is prepared.
According to the preparation method disclosed by the patent CN201610533117.5, the compound A disclosed by the patent CN201610533117.5 is prepared and obtained in an amorphous form.
Example 5 hygroscopicity comparison experiment
According to the guidance of the general technical requirement of drug hygroscopicity test guiding principle in the fourth part of the Chinese pharmacopoeia 2020 edition, the hygroscopicity experiments are carried out under the same conditions by using the crystal form beta of the benzoate of the compound A obtained in the example 2 and the example 3, and the crystal form alpha (the crystal form alpha is short for the example 4) obtained by the preparation method disclosed in the CN201510033908.7 and the amorphous (the amorphous is short for the example 4) obtained by the preparation method disclosed in the patent CN201610533117.5, and the experimental method and the results are as follows:
1. placing a dry glass weighing bottle with a plug (the outer diameter is 50mm, the height is 15 mm) in a constant-temperature constant-humidity incubator (the set temperature is 25 ℃ plus or minus 1 ℃, and the relative humidity is 80 percent plus or minus 2 percent) in the previous day, and precisely weighing (m 1);
2. taking a proper amount of the test sample, flatly paving the test sample in a weighing bottle, wherein the thickness of the test sample is about 1mm, and precisely weighing (m 2);
3. opening the weighing bottle, and placing the weighing bottle and the bottle cap under the constant temperature and humidity condition for 24 hours;
4. the weighing bottle cap was closed and precision weighed (m 3).
Percent weight gain = (m 3-m 2)/(m 2-m 1) × 100%
TABLE 2 hygroscopicity test results
Deliquescence: absorb sufficient water to form liquid
Has the characteristics of moisture absorption: the moisture-drawing weight gain is not less than 15%. (moisture absorption weight gain is more than or equal to 15%)
Moisture absorption: the moisture-inducing weight gain is less than 15% but not less than 2%. (moisture absorption weight gain is less than 15% and is more than or equal to 2%)
Slightly hygroscopic: the moisture-inducing weight gain is less than 2% but not less than 0.2%. (moisture absorption weight gain is less than 2% and more than or equal to 0.2%)
No or almost no hygroscopicity: the moisture-drawing weight gain is less than 0.2 percent. (moisture absorption weight gain < 0.2%)
Example 6 comparative flowability test
A certain amount of the crystal form β of the benzoate of compound a obtained in example 2 and example 3, and the crystal form α obtained by the publicly disclosed preparation method of CN201510033908.7 (referred to as the crystal form α in example 4 for short) and the amorphous form obtained by the publicly disclosed preparation method of patent CN201610533117.5 (referred to as the amorphous form in example 4 for short) were weighed, respectively and stably placed in a 50ml measuring cylinder to a scale position of 20ml, and the bulk density thereof was detected and calculated. Adjusting parameters of the BT-1001 intelligent powder characteristic tester, and detecting the angle of repose. The results are shown in table 3 below:
TABLE 3 flowability test results
From the above data it can be seen that: compared with the crystal form alpha obtained by CN201510033908.7 and the amorphous obtained by CN201610533117.5, the crystal form beta of the compound A benzoate prepared by the invention has smaller angle of repose and larger bulk density, and the fact that the crystal form beta of the compound A benzoate provided by the invention has better fluidity is reflected in that the angle of repose of a crystal form beta sample is smaller than that of the crystal disclosed by the patent document, and the bulk density is larger than that of the crystal disclosed by the patent document.
EXAMPLE 7 preparation of pharmaceutical composition
Compound A benzoate (form beta) 6.78g
Dextrin 84.00g
The materials are evenly mixed according to a conventional method, and are respectively filled into common gelatin capsules in 1000 equal parts to obtain 1000 capsules.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (11)
1. A crystalline form β of compound a benzoate, characterized by: the crystal form beta of the benzoate of the compound A has characteristic peaks expressed by 2theta angles at 9.74 degrees, 14.54 degrees, 18.87 degrees, 22.13 degrees, 25.36 degrees and 26.74 degrees in an X-ray diffraction pattern, and the error is +/-0.2 degrees; the chemical structural formula of the compound A benzoate is shown as the following formula (II),
2. compound a benzoate salt of crystalline form β according to claim 1, characterized in that: the crystal form beta of the benzoate of the compound A has characteristic peaks at 8.87 degrees, 9.74 degrees, 12.58 degrees, 14.54 degrees, 18.87 degrees, 19.51 degrees, 20.13 degrees, 22.13 degrees, 25.36 degrees and 26.74 degrees which are expressed by 2theta angles in an X-ray diffraction pattern, and the error is +/-0.2 degrees.
3. Compound a benzoate salt of crystalline form β according to claim 1, characterized in that: the crystal form beta of the benzoate of the compound A has characteristic peaks expressed by 2theta angles in an X-ray diffraction pattern at 8.87 degrees, 9.74 degrees, 12.58 degrees, 14.54 degrees, 18.87 degrees, 19.51 degrees, 20.13 degrees, 20.77 degrees, 22.13 degrees, 23.35 degrees, 24.08 degrees, 25.36 degrees, 26.74 degrees, 27.83 degrees, 29.53 degrees, 30.38 degrees, 31.75 degrees and 33.25 degrees, and the error is +/-0.2 degrees.
4. Compound a benzoate salt of crystalline form β according to claim 1, characterized in that: the endothermic peak in the differential thermal analysis spectrum of the crystal form beta of the benzoate of the compound A is located at 105.73 +/-5 ℃.
5. Compound A in crystalline form β according to claim 1, characterized in that: the X-ray diffraction pattern of the crystal form beta of the benzoate of the compound A is shown in the attached figure 1 or the attached figure 2.
6. Compound A in crystalline form β as claimed in claim 4, characterized in that: the differential thermal analysis spectrum of the crystal form beta of the benzoate of the compound A is shown in the attached figure 3.
7. The crystalline form β of compound a benzoate according to any one of claims 1-6, characterized in that: the TG pattern of the crystal form beta of the benzoate of the compound A is shown in the attached figure 4.
8. The crystalline form β of compound a benzoate according to any one of claims 1-6, characterized in that: the water content of the crystal form beta of the compound A benzoate is 1.5-5%.
9. A process for the preparation of compound a benzoate salt form β according to any one of claims 1 to 8, comprising the steps of: and (2) putting the refined product of the compound A into a reaction bottle, adding an organic solvent for dissolving, stirring, adding benzoic acid and a small amount of water, keeping the temperature of the system at 5-15 ℃, stirring until a large amount of solid is separated out, filtering, washing a filter cake with the organic solvent, and performing vacuum drying at room temperature to prepare the crystal form beta of the compound A benzoate.
10. The method of claim 9, wherein: the organic solvent is one or a mixture of two of ethyl acetate, isopropyl acetate, methyl acetate, ethyl formate and isobutyl acetate.
11. A pharmaceutical composition characterized by: the pharmaceutical composition comprises the compound a of any one of claims 1 to 8, the crystalline form β of benzoate salt, and one or more pharmaceutically acceptable carriers.
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| CN102791701A (en) * | 2009-12-30 | 2012-11-21 | 上海复尚慧创医药研究有限公司 | 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase IV(DPP-IV) inhibitors |
| CN104803971A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Crystal form alpha of compound A-benzoate (1:1), preparation method thereof, and pharmaceutical composition containing crystal form alpha |
| CN104803972A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof |
| CN106349216A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Crystal form alpha of compound A, preparation method thereof, and medical composition comprising crystal form |
| CN106349215A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Amorphism of compound A benzoate, preparation method thereof, and amorphism-containing medicinal composition |
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| CN102791701A (en) * | 2009-12-30 | 2012-11-21 | 上海复尚慧创医药研究有限公司 | 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase IV(DPP-IV) inhibitors |
| CN104803971A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Crystal form alpha of compound A-benzoate (1:1), preparation method thereof, and pharmaceutical composition containing crystal form alpha |
| CN104803972A (en) * | 2014-01-24 | 2015-07-29 | 深圳信立泰药业股份有限公司 | Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof |
| CN106349216A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Crystal form alpha of compound A, preparation method thereof, and medical composition comprising crystal form |
| CN106349215A (en) * | 2015-07-15 | 2017-01-25 | 深圳信立泰药业股份有限公司 | Amorphism of compound A benzoate, preparation method thereof, and amorphism-containing medicinal composition |
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