WO2023241507A1 - Forme cristalline d'un composé alkynylpyridine et son procédé de préparation - Google Patents
Forme cristalline d'un composé alkynylpyridine et son procédé de préparation Download PDFInfo
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- WO2023241507A1 WO2023241507A1 PCT/CN2023/099660 CN2023099660W WO2023241507A1 WO 2023241507 A1 WO2023241507 A1 WO 2023241507A1 CN 2023099660 W CN2023099660 W CN 2023099660W WO 2023241507 A1 WO2023241507 A1 WO 2023241507A1
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- reagent
- solvent
- crystal form
- compound
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Links
- 239000013078 crystal Substances 0.000 title claims abstract description 79
- 150000001875 compounds Chemical class 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000003153 chemical reaction reagent Substances 0.000 claims description 147
- 239000002904 solvent Substances 0.000 claims description 79
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 38
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 18
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 16
- 229940011051 isopropyl acetate Drugs 0.000 claims description 16
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012046 mixed solvent Substances 0.000 claims description 13
- 238000001228 spectrum Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 9
- 239000011698 potassium fluoride Substances 0.000 claims description 9
- 235000003270 potassium fluoride Nutrition 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 230000004580 weight loss Effects 0.000 claims description 5
- 208000031888 Mycoses Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003759 ester based solvent Substances 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003462 sulfoxides Chemical group 0.000 claims description 4
- 206010017533 Fungal infection Diseases 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 31
- 238000000034 method Methods 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 230000005855 radiation Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000002421 cell wall Anatomy 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 238000010183 spectrum analysis Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 206010046914 Vaginal infection Diseases 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 229920001503 Glucan Polymers 0.000 description 2
- 101001074628 Homo sapiens Phosphatidylinositol-glycan biosynthesis class W protein Proteins 0.000 description 2
- 102100036253 Phosphatidylinositol-glycan biosynthesis class W protein Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- JCXKHYLLVKZPKE-UHFFFAOYSA-N benzotriazol-1-amine Chemical compound C1=CC=C2N(N)N=NC2=C1 JCXKHYLLVKZPKE-UHFFFAOYSA-N 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- IVILGUFRMDBUEQ-UHFFFAOYSA-N 5-iodopyridin-2-amine Chemical compound NC1=CC=C(I)C=N1 IVILGUFRMDBUEQ-UHFFFAOYSA-N 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 102100024023 Histone PARylation factor 1 Human genes 0.000 description 1
- 101001047783 Homo sapiens Histone PARylation factor 1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 206010042938 Systemic candida Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 208000017773 candidemia Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 230000006740 morphological transformation Effects 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000010512 thermal transition Effects 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/20—Quaternary compounds thereof
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
Definitions
- the present invention relates to a crystal form of an alkynylpyridine compound and a preparation method thereof, in particular to a crystal form of a compound represented by formula (I) and a preparation method thereof.
- Invasive fungal diseases are the most lethal type of fungal infections, and the morbidity and mortality are rising sharply.
- the fungal cell wall is mainly composed of glucan, chitin and mannose protein.
- Glycosylphosphatidylinositol egg-anchored protein (GPI-AP) is anchored on the cell membrane and cell wall, mediating the interaction between mannose protein and glucan.
- Cross-linking has an important impact on fungal cell wall synthesis, adhesion and morphological transformation.
- Gwt1 is a key acetylase in the GPI synthesis process and plays an important role in the formation of GPI precursors. Inhibiting Gwt1 activity blocks GPI-AP synthesis, and the fungal surface mannoprotein cannot be cross-linked to the cell wall, thereby destroying its ability to adhere to the host surface and cell wall integrity, thereby exerting an antifungal effect.
- the invention provides the C crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 19.9390 ⁇ 0.200°,
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.3246 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.8423 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 24.0607 ⁇ 0.200°, 25.6600 ⁇ 0.200°, 27.1949 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 10.7005 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 20.8423 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 24.0607 ⁇ 0.200°, 25.6600 ⁇ 0.2 00°, 27.1949 ⁇ 0.200°, 28.9541 ⁇ 0.200°, 30.3507 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 20.3246 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, 12.7114 ⁇ 0.200°, 15.8368 ⁇ 0.200°, 18.7250 ⁇ 0.200°, 19.9390 ⁇ 0.200°, 21.7115 ⁇ 0.200°, 22.3334 ⁇ 0.200°, 23.0090 ⁇ 0.200°, 25.6600 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975 ⁇ 0.200°, 7.9169 ⁇ 0.200°, and/or 10.7005 ⁇ 0.200°, and/or 12.7114 ⁇ 0.200°, and/or 15.8368 ⁇ 0.200°, and/or 18.7250 ⁇ 0.200°, and/or 19.9390 ⁇ 0.200°, and/or 20.3246 ⁇ 0.200°, and/or 20.8423 ⁇ 0.200°, and/or 21.2448 ⁇ 0.200 °, and/or 21.7115 ⁇ 0.200°, and/or 22.3334 ⁇ 0.200°, and/or 23.0090 ⁇ 0.200°, and/or 23.8153 ⁇ 0.200°, and/or 24.0607 ⁇ 0.200°, and/or 25.0930 ⁇ 0.200°, and/or 25.6600 ⁇ 0.200°, and/or 27.1949 ⁇ 0.200°, and/or 28.9541 ⁇ 0.200
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.00°, 7.92°, 10.70°, 12.71°, 15.84°, 18.72°, 19.94°, 20.32 °, 20.84°, 21.24°, 21.71°, 22.33°, 23.01°, 23.82°, 24.06°, 25.09°, 25.66°, 27.19°, 28.95°, 30.35°, 31.17°.
- the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.9975°, 7.9169°, 10.7005°, 12.7114°, 15.8368°, 18.7250°, 19.9390°, 20.3246 °, 20.8423°, 21.2448°, 21.7115°, 22.3334°, 23.0090°, 23.8153°, 24.0607°, 25.0930°, 25.6600°, 27.1949°, 28.9541°, 30.3507°, 31.1749°.
- the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 1.
- the differential scanning calorimetry curve of the above-mentioned C crystal form has an endothermic peak at 199.2 ⁇ 3°C.
- the DSC pattern of the above-mentioned C crystal form is shown in Figure 2.
- thermogravimetric analysis curve of the above-mentioned C crystal form has a weight loss of 2.28% at 150 ⁇ 3°C.
- the TGA spectrum of the above crystal form C is shown in Figure 3.
- the invention provides the D crystal form of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern of Cu, K ⁇ radiation has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 21.4231 ⁇ 0.200°,
- the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 7.4609 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 18.6712 ⁇ 0.200°, 21.4231 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.0789 ⁇ 0.200°, 7.4609 ⁇ 0.200°, 8.1226 ⁇ 0.200°, 12.1939 ⁇ 0.200°, 14.9322 ⁇ 0.200°, 18.2233 ⁇ 0.200°, 18.6712 ⁇ 0.200°, 21.4231 ⁇ 0.200°, 22.4812 ⁇ 0.200°, 26.2452 ⁇ 0.200°.
- the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.75°, 4.08°, 7.46°, 8.12°, 12.19°, 14.93°, 18.22°, 18.67 °, 19.38°, 21.42°, 22.48°, 26.25°.
- the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.7520°, 4.0789°, 7.4609°, 8.1226°, 12.1939°, 14.9322°, 18.2233°, 18.6712 °, 19.3838°, 21.4231°, 22.4812°, 26.2452°.
- the XRPD pattern of the above-mentioned crystal form D is basically as shown in Figure 4.
- the XRPD spectrum analysis data of the above-mentioned D crystal form is as shown in Table 2:
- the invention also provides a preparation method of compound 1-6, which includes the following reaction steps:
- Reagent 4A is selected from inorganic bases
- Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
- Reagent 4C is selected from inorganic bases
- Reagent 4D is selected from palladium catalysts
- Reagent 4E is selected from organophosphine ligands
- Solvent 4F is selected from ester solvents.
- Reagent 4A is selected from potassium fluoride
- Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
- Reagent 4C is selected from cesium carbonate
- Reagent 4D is selected from palladium acetate
- Reagent 4E is selected from Xphos
- Solvent 4F is selected from isopropyl acetate.
- the preparation method of compound 1-6 wherein the volume ratio of DMF and water in the mixed solvent of solvent 4B is 5 to 8:1.
- the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 4.0-6.0:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5 ⁇ 1.5:1, the molar ratio of reagent 4C to compound 1-5 is 3 ⁇ 5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01 ⁇ 0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02 ⁇ 0.04:1.
- the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 4.0 to 6.0:1.
- the preparation method of compound 1-6 wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1.5:1.
- the molar ratio of reagent 4C to compound 1-5 is 3 to 5:1.
- the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
- the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.04:1.
- the preparation method of compound 1-6 wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1, and the molar ratio of compound 1-3 to compound 1-5 is 0.5 ⁇ 1:1, the molar ratio of reagent 4C to compound 1-5 is 3.5 ⁇ 4.5:1, the molar ratio of reagent 4D to compound 1-5 is 0.01 ⁇ 0.02:1, the molar ratio of reagent 4E to compound 1-5 It is 0.02 ⁇ 0.03:1.
- the preparation method of compound 1-6, wherein the molar ratio of reagent 4A to compound 1-5 is 5.0 to 5.5:1.
- the preparation method of compound 1-6 wherein the molar ratio of compound 1-3 to compound 1-5 is 0.5 to 1:1.
- the molar ratio of reagent 4C to compound 1-5 is 3.5 to 4.5:1.
- the molar ratio of reagent 4D to compound 1-5 is 0.01 to 0.02:1.
- the preparation method of compound 1-6 wherein the molar ratio of reagent 4E to compound 1-5 is 0.02 to 0.03:1.
- the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10-40°C, and the temperature range of the reaction system with compound 1-3, reagent 4B is controlled to be 10-40°C.
- the reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 60 to 100°C.
- the preparation method of compound 1-6 wherein the temperature range of the reaction system of compound 1-5, reagent 4A, and solvent 4B is controlled to be 10 to 40°C.
- the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 60 to 100°C.
- the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C, and the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C.
- the reaction system temperature range of 4C, reagent 4D, reagent 4E, and solvent 4F is 75 to 85°C.
- the preparation method of compound 1-6 wherein the reaction system temperature range of compound 1-5, reagent 4A, and solvent 4B is controlled to be 15-25°C.
- the temperature range of the reaction system with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 75 to 85°C.
- the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 3 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 8 to 24 hours.
- the preparation method of compound 1-6 wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 8 to 24 hours.
- the preparation method of compound 1-6 includes controlling the reaction time of compound 1-5 with reagent 4A and solvent 4B to be 0.5 to 1.5 hours, and controlling the reaction time with compound 1-3, reagent 4C, The reaction time of reagent 4D, reagent 4E, and solvent 4F is 10 to 20 hours.
- the preparation method of compound 1-6 wherein the reaction time with compound 1-3, reagent 4C, reagent 4D, reagent 4E, and solvent 4F is controlled to be 10 to 20 hours.
- the preparation method of compound 1-6 includes the following reaction steps:
- Reagent 3A is selected from metal catalysts
- Solvent 3B is selected from nitrile solvents
- Reagent 3C is selected from trimethylsilylacetylene
- Reagent 3D is selected from palladium catalyst
- Reagent 3E is selected from organic bases
- Reagent 4A is selected from inorganic bases
- Solvent 4B is selected from acyl solvents or mixed solvents of acyl solvents and water;
- Reagent 4C is selected from inorganic bases
- Reagent 4D is selected from palladium catalysts
- Reagent 4E is selected from organophosphine ligands
- Solvent 4F is selected from ester solvents.
- Reagent 3A is selected from copper iodide
- Solvent 3B is selected from acetonitrile
- Reagent 3C is selected from trimethylsilylacetylene
- Reagent 3D is selected from ditriphenylphosphine palladium chloride
- Reagent 3E is selected from triethylamine
- Reagent 4A is selected from potassium fluoride
- Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
- Reagent 4C is selected from cesium carbonate
- Reagent 4D is selected from palladium acetate
- Reagent 4E is selected from Xphos
- Solvent 4F is selected from isopropyl acetate.
- the preparation method of compound 1-6 includes the following reaction steps:
- Reagent 1A is selected from terephthalol
- Solvent 1B is selected from DMF;
- Reagent 1C is selected from potassium tert-butoxide
- Solvent 2A is selected from anhydrous methylene chloride
- Reagent 2B is selected from sulfoxide dichloride
- Reagent 3A is selected from copper iodide
- Solvent 3B is selected from acetonitrile
- Reagent 3C is selected from trimethylsilylacetylene
- Reagent 3D is selected from ditriphenylphosphine palladium chloride
- Reagent 3E is selected from triethylamine
- Reagent 4A is selected from potassium fluoride
- Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
- Reagent 4C is selected from cesium carbonate
- Reagent 4D is selected from palladium acetate
- Reagent 4E is selected from Xphos
- Solvent 4F is selected from isopropyl acetate.
- the present invention also provides a preparation method of the compound of formula (I), which includes the following reaction steps:
- Reagent 1A is selected from terephthalol
- Solvent 1B is selected from DMF;
- Reagent 1C is selected from potassium tert-butoxide
- Solvent 2A is selected from anhydrous methylene chloride
- Reagent 2B is selected from sulfoxide dichloride
- Reagent 3A is selected from copper iodide
- Solvent 3B is selected from acetonitrile
- Reagent 3C is selected from trimethylsilylacetylene
- Reagent 3D is selected from ditriphenylphosphine palladium chloride
- Reagent 3E is selected from triethylamine
- Reagent 4A is selected from potassium fluoride
- Solvent 4B is selected from DMF or a mixed solvent of DMF and water;
- Reagent 4C is selected from cesium carbonate
- Reagent 4D is selected from palladium acetate
- Reagent 4E is selected from Xphos
- Solvent 4F is selected from isopropyl acetate
- Solvent 5A is selected from anhydrous tetrahydrofuran
- Reagent 5B is selected from sodium iodide.
- the present invention also provides the use of the C crystal form and the D crystal form of the compound of formula (I) in the preparation of drugs related to the treatment of deep fungal infections.
- the crystal form of the invention is stable, has good hygroscopicity, and has good prospects as a medicine, and the crystal form of the invention can effectively treat vaginal infections.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the relative intensities of diffraction peaks can change due to preferred orientation due to factors such as crystal morphology. Where there is an influence of preferred orientation, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. Furthermore, there may be slight errors in the position of the peaks for any given crystalline form, as is also known in the art of crystallography. For example, due to changes in temperature, movement of the sample, or calibration of the instrument when analyzing the sample, the position of the peak may move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2 degrees. Therefore, it is well known to those skilled in the art that when determining each crystal This error should be taken into account when constructing.
- DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal.
- the thermal transition temperature and melting point errors are typically within about 5°C or 3°C.
- DSC peak or melting point This refers to the DSC peak or melting point ⁇ 5°C or ⁇ 3°C.
- DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary within a wider range. In addition, since the melting process of a substance is accompanied by decomposition, the melting temperature is related to the heating rate.
- the TGA weight loss temperature may differ due to factors such as measuring instruments, measuring methods/conditions, etc. There may be an error in the weight loss temperature for any particular crystal form, which may be about ⁇ 5°C, and may be about ⁇ 3°C.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
- single crystal X-ray diffraction uses a Bruker D8venture diffractometer to collect diffraction intensity data on the cultured single crystal.
- the light source is CuK ⁇ radiation.
- the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
- Xphos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl
- DMF represents N,N-dimethylformamide
- Test method About 10 ⁇ 20mg sample is used for XRPD detection.
- Light tube voltage 45kV
- light tube current 40mA
- DSC Differential Scanning Calorimeter
- Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
- TGA Thermal Gravimetric Analyzer
- Test method Take a sample (2 ⁇ 5 mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C or a weight loss of 20% at a heating rate of 10°C/min.
- Test conditions Take a sample (10 ⁇ 20mg) and place it in the DVS sample tray for testing.
- RH (%) range: 0-95%
- Figure 1 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form C of the compound of formula (I);
- Figure 2 is the DSC spectrum of the crystal form C of the compound of formula (I);
- Figure 3 is the TGA spectrum of the crystal form C of the compound of formula (I);
- Figure 4 is the XRPD spectrum of Cu-K ⁇ radiation of the crystal form D of the compound of formula (I);
- Figure 5 is the DVS spectrum of the crystal form C of the compound of formula (I).
- step 1
- 2-Amino-5-iodopyridine (2.0Kg, 90.9mol) was dissolved in acetonitrile (20L), and copper iodide (86.6g, 0.45mol) and trimethylsilyl acetylene (1.16Kg, 11.8 mol), triethylamine (2.76Kg, 27.3mol) and diphenylphosphine palladium chloride (63.8g, 0.091mol).
- the reaction mixture was stirred at 20°C for 1 hour. HPLC detected that the reaction was complete.
- the reaction solution was directly concentrated under reduced pressure.
- the filter cake is the hydrochloride of the compound of formula (I).
- the filter cake was then slurried with a mixture of isopropyl alcohol (10L) and pure water (2.5L), filtered, and dried to obtain the C crystal form of the compound of formula (I) (700g, 47.1% yield).
- the hygroscopic weight gain of the crystal form C of the compound of formula (I) at 25° C. and 80% RH is 0.42%, and it is slightly hygroscopic.
- Test Example 1 In vivo efficacy study of compound C crystal form of formula (I) in candidemia model (VVC)
- Microbial pathogen Candida albicans ATCC MYA-4788;
- Inoculation level and route of inoculation 1.44E+05CFU/mouse, vaginal instillation infection;
- vehicle vehicle
- compound C crystal form 2, 6, 20mpk group of formula (I): oral administration of 1-aminobenzotriazole (ABT) 22 hours after infection, and intraperitoneal injection of the compound to be tested at 24 hours to start treatment .
- ABT 1-aminobenzotriazole
- mice in each group were infected, the vaginal tissue homogenates of the mice were taken for CFU counting.
- a stable vaginal infection model can be established after mice are instilled with a certain dose of Candida albicans ATCC MYA-4788 through the vagina.
- the bacterial load of vaginal tissue in the Vehicle group was 5.03 ⁇ 0.29 lg.
- the bacterial load in vaginal tissue at doses of 20mpk, 6mpk, and 2mpk of compound C of formula (I) was reduced by 2.79 lg, 1.58 lg, and 0.68 lg respectively (P ⁇ 0.001, P ⁇ 0.05, P >0.05), and shows a certain dose-effect relationship.
- the bactericidal effect of the crystal form C of the compound of formula (I) is very significant at a dose of 20mpk.
- the crystal form of the present invention can effectively treat vaginal infection, and the crystal form C of compound of formula (I) has excellent medicinal efficacy.
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Abstract
La présente invention concerne une forme cristalline d'un composé alcynylpyridine et son procédé de préparation. Plus précisément, l'invention concerne une forme cristalline d'un composé représenté par la formule (I) et son procédé de préparation.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005033079A1 (fr) * | 2003-09-30 | 2005-04-14 | Eisai Co., Ltd. | Agent antifongique a compose heterocyclique |
CN101300250A (zh) * | 2005-10-31 | 2008-11-05 | 卫材R&D管理有限公司 | 杂环取代吡啶衍生物及含有该衍生物的抗真菌剂 |
CN101918417A (zh) * | 2007-12-27 | 2010-12-15 | 卫材R&D管理有限公司 | 杂环和膦酰基氧基甲基取代的吡啶衍生物以及含有它的抗真菌剂 |
CN112638371A (zh) * | 2018-06-25 | 2021-04-09 | 安普利克斯制药公司 | 被杂环和氨基取代的吡啶衍生物 |
WO2022127782A1 (fr) * | 2020-12-15 | 2022-06-23 | 南京明德新药研发有限公司 | Composé aminopyridine et son application |
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2023
- 2023-06-12 WO PCT/CN2023/099660 patent/WO2023241507A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005033079A1 (fr) * | 2003-09-30 | 2005-04-14 | Eisai Co., Ltd. | Agent antifongique a compose heterocyclique |
CN101300250A (zh) * | 2005-10-31 | 2008-11-05 | 卫材R&D管理有限公司 | 杂环取代吡啶衍生物及含有该衍生物的抗真菌剂 |
CN101918417A (zh) * | 2007-12-27 | 2010-12-15 | 卫材R&D管理有限公司 | 杂环和膦酰基氧基甲基取代的吡啶衍生物以及含有它的抗真菌剂 |
CN112638371A (zh) * | 2018-06-25 | 2021-04-09 | 安普利克斯制药公司 | 被杂环和氨基取代的吡啶衍生物 |
WO2022127782A1 (fr) * | 2020-12-15 | 2022-06-23 | 南京明德新药研发有限公司 | Composé aminopyridine et son application |
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