CN116675672A - New preparation method of antifungal medicine - Google Patents
New preparation method of antifungal medicine Download PDFInfo
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- CN116675672A CN116675672A CN202310656895.3A CN202310656895A CN116675672A CN 116675672 A CN116675672 A CN 116675672A CN 202310656895 A CN202310656895 A CN 202310656895A CN 116675672 A CN116675672 A CN 116675672A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title description 4
- 230000000843 anti-fungal effect Effects 0.000 title description 3
- 229940121375 antifungal agent Drugs 0.000 title description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 16
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- KKLCYBZPQDOFQK-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC=C1 KKLCYBZPQDOFQK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011914 asymmetric synthesis Methods 0.000 claims abstract description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 6
- 239000003429 antifungal agent Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 55
- 239000003054 catalyst Substances 0.000 claims description 14
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical group [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 5
- 125000001979 organolithium group Chemical group 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- UWLFCNHEPBTLHT-UHFFFAOYSA-N neopentyllithium Chemical compound [Li]CC(C)(C)C UWLFCNHEPBTLHT-UHFFFAOYSA-N 0.000 claims description 2
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 claims description 2
- CUBIJGNGGJBNOC-UHFFFAOYSA-N palladium;tris(2-methylphenyl)phosphane Chemical compound [Pd].CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C CUBIJGNGGJBNOC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 10
- -1 difluoro ethyl acetate compound Chemical class 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 13
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010017533 Fungal infection Diseases 0.000 description 4
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- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- CCNNVRZLXOPTID-UHFFFAOYSA-N ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)C1=CC=C(Br)C=N1 CCNNVRZLXOPTID-UHFFFAOYSA-N 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
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- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 2
- LAEVVSWHUPCDKL-UHFFFAOYSA-N 1-(2-bromoethyl)tetrazole Chemical compound BrCCN1C=NN=N1 LAEVVSWHUPCDKL-UHFFFAOYSA-N 0.000 description 2
- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 2
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 108010016076 Octreotide Proteins 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
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- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960002700 octreotide Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
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- 238000010791 quenching Methods 0.000 description 2
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- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- XHUIIORNGYDUIT-UHFFFAOYSA-N 1-(2-chloroethyl)tetrazole Chemical compound ClCCN1C=NN=N1 XHUIIORNGYDUIT-UHFFFAOYSA-N 0.000 description 1
- CPNRQWYCMUXLOE-UHFFFAOYSA-N 1-(2-iodoethyl)tetrazole Chemical compound ICCN1C=NN=N1 CPNRQWYCMUXLOE-UHFFFAOYSA-N 0.000 description 1
- AJCSNHQKXUSMMY-UHFFFAOYSA-N 1-chloro-2,4-difluorobenzene Chemical compound FC1=CC=C(Cl)C(F)=C1 AJCSNHQKXUSMMY-UHFFFAOYSA-N 0.000 description 1
- YKLDMAPEGQYZRT-UHFFFAOYSA-N 2,4-difluoro-1-iodobenzene Chemical compound FC1=CC=C(I)C(F)=C1 YKLDMAPEGQYZRT-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- UXFIHQYEBHLHSQ-UHFFFAOYSA-N CCOC(=O)C(F)(F)c1ccc(I)cn1 Chemical compound CCOC(=O)C(F)(F)c1ccc(I)cn1 UXFIHQYEBHLHSQ-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 208000004483 Dyspareunia Diseases 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 108010013803 Sterol 14-Demethylase Proteins 0.000 description 1
- 206010056530 Vulvovaginal pruritus Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- OWBJAYNOEOGWTJ-UHFFFAOYSA-N ethyl 2-(5-chloropyridin-2-yl)-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)C1=CC=C(Cl)C=N1 OWBJAYNOEOGWTJ-UHFFFAOYSA-N 0.000 description 1
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- 230000002349 favourable effect Effects 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
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- 150000007517 lewis acids Chemical group 0.000 description 1
- BITPAXWTJXOWKL-UHFFFAOYSA-N lithium;oxolane Chemical compound [Li].C1CCOC1 BITPAXWTJXOWKL-UHFFFAOYSA-N 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 229940125956 metalloenzyme inhibitor Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
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- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
The invention discloses a novel preparation method of an antifungal drug, which comprises the following steps: step 1, (2, 2-trifluoro ethoxy) phenylboronic acid pinacol ester and a difluoro ethyl acetate compound are subjected to Suzuki coupling reaction to obtain 2, 2-difluoro-2- (5- (4- (2, 2-trifluoro ethoxy) phenyl) pyridin-2-yl) ethyl acetate; step 2, coupling the product obtained in the step 1 with a difluorobromobenzene compound to obtain 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone; and step 3, carrying out asymmetric synthesis reaction on the product obtained in the step 2 and a tetrazole compound to obtain the octreonazole. Compared with the prior art, the novel method for synthesizing the octreonazole has the advantages of obvious advantages, short route, high yield and environmental friendliness.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and in particular relates to a novel preparation method of an antifungal drug.
Background
Octreozole (otesecond) is an oral antifungal developed by mycovia pharmaceuticals, the first FDA approved drug for the treatment of recurrent vulvovaginal candidiasis (RVVC), and is used to reduce the chance of recurrence of recurrent vulvovaginal candidiasis (RVVC) in women without reproductive potential, effectively bind to and inhibit the CYP51 (K) of candida albicans d ，<39 nM); octreozole is an azole metalloenzyme inhibitor that catalyzes the early steps of the ergosterol biosynthetic pathway, a sterol required for fungal cell membrane formation and integrity, against the fungal sterol 14 alpha demethylase (CYP 51). Inhibition of CYP51 results in the accumulation of 14-methylated sterols, some of which are toxic to fungi. By containing tetrazole metal binding groups, the octreonazole has lower affinity to human CYP enzymes and no obvious effect。
Recurrent vulvovaginal candidiasis (RVVC), also known as chronic yeast infection, is a disease other than vulvovaginal candidiasis (VVC), defined as an acute episode of symptomatic yeast infection three or more times a year, with major symptoms including vaginal itching, burning, irritation, and inflammation. Some women may experience abnormal vaginal secretions, dyspareunia or urination pain, causing various but often severe discomfort and pain. Approximately 75% of adult females will be infected at least once during their lifetime with yeast infections, approximately half of which recur. Among these women, up to 9% of people suffer from RVVC. RVVC is a chronic infectious disease affecting approximately 1.38 million women worldwide each year, 600 thousands of women in the United states alone and 2900 ten thousand RVVC patients in China.
The approval of octreonazole was based on positive results of three phase 3 trials, including 875 patients in 232 sites in 11 countries. Of the RVVC females treated with octreotide, 93.3% in one clinical study, 96.1% had no recurrence during the 48 week maintenance period, while females receiving placebo were 57.2% and 60.6%, respectively (p < 0.001). In another clinical study, 89.7% of women receiving octreotide treated RVVC cleared their initial yeast infection and had no recurrence for a 50 week maintenance period, while the fluconazole and placebo treated RVVC was 57.1% (p < 0.001).
The chinese academic name of octreozole: (R) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -2-propanol of formula: c (C) 23 H 16 F 7 N 5 O 2 Molecular weight: 527.39, CAS registry number 1340593-59-0, having the chemical formula:
prior art document patent CN201680061980 reports the following synthetic route 1 for octreonazole:
the prior art document CN201180030668 reports the synthesis route 2 of octreonazole as follows:
the above-mentioned method 1 for synthesizing the octreonazole is longer in route and is difficult to implement, wherein the step 2 involves ultralow temperature reaction, the step 3 involves the use of the highly toxic nitromethane, the step 4 involves the pressurized hydrogenation reaction, the step 5 involves the use of the azido trimethylsilane which is an explosive dangerous material, and the step 6 involves the noble catalyst pd (dppf) cl 2 The use of the method is low in overall yield and has little industrialization significance.
In the above-mentioned method for synthesizing the octreonazole, step 1 uses the carcinogenic and explosive dangerous article diazomethane, step 5 obtains the octreonazole through splitting, not only the route is long, the yield is low, the industrialization significance is not great as well.
In order to alleviate the accessibility problem of the octreonazole, the invention provides a novel method for obtaining the single-configuration octreonazole through asymmetric synthesis with high efficiency, and the novel method has no report in the prior art, but also has the advantages of environmental friendliness, short route, high yield, low cost and the like although the novel method also relates to low-temperature reaction.
Disclosure of Invention
The invention provides a preparation method of an antifungal drug, which comprises the following steps:
step 1, (2, 2-trifluoro ethoxy) phenylboronic acid pinacol ester (compound of formula a) and a compound of formula b are subjected to Suzuki coupling reaction to obtain 2, 2-difluoro-2- (5- (4- (2, 2-trifluoro ethoxy) phenyl) pyridin-2-yl) ethyl acetate (compound of formula c);
step 2, coupling reaction of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (compound of formula c) with a compound of formula d to give 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (compound of formula e);
step 3, carrying out asymmetric synthesis reaction on 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (a compound of formula e) and a compound of formula f to obtain the octreonazole;
wherein the method comprises the steps of
In the compound of formula b, X1 is selected from I, br and Cl, preferably Br;
in the compound of formula d, X2 is selected from I, br and Cl, preferably Br;
in the compounds of formula f, X3 is selected from I, br and Cl, preferably Br.
The invention is characterized in that a route is designed, which is different from the new synthesis route of the octreonazole reported in the prior art patent CN201680061980 and CN201180030668, the octreonazole is prepared by 3 steps of reactions, no toxic and explosive materials are used, the route is short, the yield is high, and the cost and the environmental protection advantage are obvious.
In the invention, X1 in the compound of the formula b is selected from I, br and Cl, wherein the activity of a chloro structure is weaker, and the reaction yield is lower; the iodinated structure has the strongest activity, but has higher cost; the bromostructure of the 2- (5-bromopyridin-2-yl) -2, 2-difluoroacetic acid ethyl ester has high reactivity, low price, easy purchase, few reaction byproducts and high yield, and is preferable.
In the invention, X2 in the compound of the formula d is selected from I, br and Cl, wherein the activity of a chloro structure is weaker, and the reaction yield is lower; the iodinated structure has the strongest activity, but has higher cost; the 2, 4-difluoro bromobenzene with the bromo structure has high reactivity, low price, easy purchase, less reaction byproducts and higher yield, and is preferable.
In the invention, X3 in the compound of the formula f is selected from I, br and Cl, wherein the activity of a chloro structure is weaker, and the reaction yield is lower; the iodinated structure has the strongest activity, but has higher cost; the bromostructure 1- (2-bromoethyl) -1H-tetrazole has high reactivity, low price, easy purchase, less reaction byproducts and higher yield, and is preferable.
The catalyst of the Suzuki coupling reaction in the step 1 is a palladium catalyst and an inorganic base catalyst, wherein the palladium catalyst is selected from tetra (triphenylphosphine) palladium (0), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (tricyclohexylphosphine) palladium (0) or bis (tri-O-tolylphosphine) palladium (0), and is preferably tetra (triphenylphosphine) palladium (0); the inorganic base is selected from cesium carbonate, potassium carbonate, sodium carbonate or lithium carbonate, preferably more alkaline cesium carbonate or potassium carbonate, because the water content in the solvent system is less, the inorganic base catalyst needs to be crushed or directly fed by a powdery material so as to increase the conversion efficiency of heterogeneous reaction.
In the invention, the compound of the formula b in the Suzuki coupling reaction in step 1 contains an ethyl ester structure, and only trace water is added to ensure that the reaction is smoothly carried out in order to avoid ester hydrolysis, and meanwhile, the generation of ester hydrolysis byproducts is avoided. In addition, in order to avoid the formation of transesterification by-products of the compounds of formula b, the solvent is selected so as to avoid the use of other alcohol solvents other than ethanol.
In the invention, the Suzuki coupling reaction in step 2 is carried out under the catalysis of organolithium at low temperature, and the organolithium catalyst is selected from n-butyllithium, tert-butyllithium, sec-butyllithium, n-pentyyllithium and neopentyllithium, wherein the n-butyllithium has the strongest activity and lower cost, and is preferable.
In the step 2 coupling reaction, the molar feed ratio of the compound of the formula c to the compound of the formula d is 1:1-1.3:1-1.3, preferably 1:1.1-1.2:1.1-1.2, wherein the main material is a proper excess of the compound of the formula d, the compound of the formula c can be completely reacted, the generation of byproducts is reduced, and the excess material is easy to remove by post-treatment.
The preparation of the single-configuration octreozole by the asymmetric synthesis reaction in the step 3 is the most important characteristic of the patent, wherein the asymmetric reaction catalyst is selected from (R) -1,1' -binaphthol or 3,3' -disubstituted aryl binaphthol, wherein the (R) -1,1' -binaphthol has stronger selectivity, better important reaction effect and low price, and is the first choice. In addition, the Grignard reagent isopropyl magnesium chloride lithium chloride is added for catalytic coupling reaction, and the catalyst is Lewis acid; the isopropyl magnesium chloride lithium chloride firstly activates a compound of a formula f, and then carries out coupling reaction with carbonyl in 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (a compound of a formula e) under the catalysis of an asymmetric synthesis catalyst (R) -1,1' -binaphthol, so as to generate the octreonazole with an absolute single R configuration, which is the biggest bright point of the invention.
In the step 3 of the invention, excessive main materials can cause the generation of byproducts, a little excessive isopropyl magnesium chloride lithium chloride catalyst is favorable for the reaction, while the asymmetric reaction catalyst (R) -1,1 '-binaphthol only needs 1/10 equivalent of the main materials, the excessive main materials not only increase the cost, but also cause the increase of the byproducts, and the optimized final confirmation of the molar feed ratio of the compound of the formula e, the compound of the formula f, the isopropyl magnesium chloride lithium chloride and the asymmetric reaction catalyst (R) -1,1' -binaphthol is 1:0.9-1.1:1.0-1.5: 0.08 to 0.12, preferably 1:0.95 to 1.05:1.1 to 1.3: 0.09-0.11, can ensure the smooth reaction, simultaneously control the byproducts to the minimum, and obtain the octreonazole with absolute single R configuration, and has lower cost.
The invention provides a novel method for synthesizing the octreonazole, which has the advantages of short route, high yield, environmental protection and the like, has obvious advantages compared with the prior art document and can benefit from the advantages.
The specific implementation method comprises the following steps:
the technical solutions in the embodiments of the present invention will be described in detail in the following embodiments of the present invention, but the following embodiments are only for understanding the present invention, and are not limited to the present invention, which can be implemented in various ways defined and covered by the claims.
The novel synthetic method of octreonazole and the advantages of the method will be further described below in connection with examples 1 and 10 of the present invention.
EXAMPLE 1 Synthesis of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (Compound of formula c) 1
Under nitrogen protection, the compound p- (2, 2-trifluoroethoxy) phenylboronic acid pinacol ester (formula a,151g,0.5 mol), ethyl 2- (5-bromopyridin-2-yl) -2, 2-difluoroacetate (formula b-I,140g,0.5 mol), tetrakis (triphenylphosphine) palladium (0) (28.9 g,25 mmol), powdered anhydrous potassium carbonate (79.5 g,0.75 mol), toluene 1L, 200ml of absolute ethanol and 5ml of water were placed in a three-necked flask, refluxed for 12h, cooled, 1.2L of water and 500ml of ethyl acetate were added, the mixture was stirred and separated, the organic phase was washed with 1L of water, the organic phase was dried, concentrated under reduced pressure to about 1/5 volume, the residue was cooled, filtered, and the filter cake was dried to give the compound of formula c (159 g, yield 85%) Ms M/z.1 (m+1). 1 H NMR(300MHz d 6 -DMSO)：1.23(t，3H),4.18(q，2H),4.50(m，2H)，7.01(d，2H)，7.45(d，1H)，7.73(d，2H)，7.95(d，1H)，8.79(d，1H)。
EXAMPLE 2 Synthesis of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (Compound of formula c)
Under nitrogen protection, the compound p- (2, 2-trifluoroethoxy) phenylboronic acid pinacol ester (formula a,75.5g,0.25 mol), ethyl 2- (5-bromopyridin-2-yl) -2, 2-difluoroacetate (formula b-I,70g,0.25 mol), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride (18.2 g,25 mmol), powdery anhydrous cesium carbonate (122 g,0.375 mol), dimethylformamide 600ml, water 2ml were placed in a three-necked flask, reacted for 8h at a controlled temperature of 80-90 ℃, cooled, 1L of water and ethyl acetate 1.2L were added, the organic phase was washed with 500ml of water, the organic phase was dried, most of the solvent was concentrated under reduced pressure, the residue was added to 200ml of n-hexane, dissolved under reflux, cooled for crystallization, filtered, and the cake was dried to obtain the compound of formula c (67.6 g, 72%) Ms M/z 376.1 (m+1).
EXAMPLE 3 Synthesis of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (Compound of formula c) 3
Under nitrogen protection, the compound p- (2, 2-trifluoroethoxy) phenylboronic acid pinacol ester (formula a,60.4g,0.2 mol), ethyl 2- (5-iodopyridin-2-yl) -2, 2-difluoroacetate (formula b-I,65.4g,0.2 mol), tetrakis (triphenylphosphine) palladium (0) (11.6 g,10 mmol), powdered anhydrous potassium carbonate (31.8 g,0.3 mol), toluene 400ml, absolute ethanol 80ml and water 2ml were placed in a three-neck flask, reflux reacted for 6h, cooled, 480ml of water and ethyl acetate 200ml were added, the mixture was stirred and separated, the organic phase was washed with 400ml of water, the organic phase was dried, concentrated to about 1/5 volume under reduced pressure, the residue was cooled, filtered, and the filter cake was dried to give the compound of formula c (75.1 g, yield 87%), M/z.1 (m+1).
EXAMPLE 4 Synthesis of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (Compound of formula c) 4
Under nitrogen protection, the compound p- (2, 2-trifluoroethoxy) phenylboronic acid pinacol ester (formula a,30.2g,0.1 mol), ethyl 2- (5-chloropyridin-2-yl) -2, 2-difluoroacetate (formula b-I,23.6g,0.1 mol), tetrakis (triphenylphosphine) palladium (0) (11.6 g,10 mmol), powdery anhydrous cesium carbonate (65.2 g,0.2 mol), toluene 200ml, 40ml of absolute ethanol and 1ml of water were placed in a three-necked flask, reflux reacted for 18h, cooled, 240ml of water and 100ml of ethyl acetate were added, the mixture was stirred and separated, the organic phase was washed with 200ml of water, the organic phase was dried, concentrated under reduced pressure to dryness, the residue was added with 100ml of ethyl acetate and 150ml of n-hexane, heated to dissolve, cooled and crystallized, filtered, and the filter cake was dried to obtain the compound of formula c (21.8 g, yield 58%), M/z 376.1 (M+1).
EXAMPLE 5 Synthesis of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (compound of formula e) 1
Tetrahydrofuran (100 mL, manufacturer: pasf) and 2, 4-difluorobromobenzene (formula d-I,44.4g,0.23 mol) are cooled to-75 to-70 ℃ in a 1000mL dry three-port bottle under argon atmosphere, n-BuLi (2.5M n-hexane solution, 92mL,0.23 mol) is dropwise added at-75 to-70 ℃ under temperature control, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) ethyl acetate (formula c,75g,0.2 mol) is dropwise added at-75 to-65 ℃ after dropwise addition, quenching reaction is continued at temperature control for 1h with 1M hydrochloric acid solution (250 mL) and then saturated sodium carbonate solution is used for adjusting ph 7-8, methyl tert-butyl ether is added for extraction twice (300 mL each time), an organic phase is combined, 300mL of purified water is used for washing, and anhydrous phase is used for MgSO 4 Drying, filtering, refluxing the organic phase for 3-4h, concentrating under reduced pressure to dryness, adding n-hexane into the residue to precipitate solid, filtering, recrystallizing the filter cake with absolute ethanol-n-hexane (100 ml/300 ml) to obtain compound of formula e (66.4 g, yield 75%, purity 98.8%), ms M/z 444.1 (M+1), 1 H NMR(300MHz d 6 -DMSO)：5.14(d，2H)，5.70(s，1H)，6.91–6.95(m，1H)，7.21(d，1H)，7.23–7.25(d，2H)，7.23-7.29(m，1H)，7.30(d，1H)，7.53(d，1H)，7.83(d，2H)，8.20–8.22(m，1H)，8.90(d，1H)。
EXAMPLE 6 Synthesis of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (compound of formula e)
Tetrahydrofuran (50 ml, manufacturer: basf) and 2, 4-difluoroiodobenzene (formula d-II,26.4g,0.11 mol) are cooled to-75 to-70 ℃ in a 500ml dry three-port bottle under argon atmosphere, n-BuLi (2.5M n-hexane solution, 44ml,0.11 mol) is dropwise added at-75 to-55 ℃, after that, stirring and cooling are carried out to-75 to-70 ℃, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) ethyl acetate (formula c,37.5g,0.1 mol) is dropwise added at-75 to-65 ℃ in 80ml tetrahydrofuran solution, and after that, stirring is continuously carried out at-75 to-0.5 hQuenching with 1M hydrochloric acid solution (125 mL), adjusting pH 7-8 with saturated sodium carbonate solution, extracting twice with methyl tert-butyl ether (150 mL each time), mixing the organic phases, washing with purified water (150 mL), and washing the organic phase with anhydrous MgSO 4 Drying, filtering, refluxing the organic phase for 3 hours, concentrating under reduced pressure to dryness, adding n-hexane into the residue to precipitate solid, filtering, and recrystallizing the filter cake from absolute ethyl alcohol-n-hexane (50 ml/150 ml) to obtain the compound of formula e (35.9 g, yield 81%, purity 99.1%), ms M/z 444.1 (M+1).
EXAMPLE 7 Synthesis of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (compound of formula e) 3
Tetrahydrofuran (50 mL, manufacturer: pasf) and 2, 4-difluorochlorobenzene (formula d-II,26.4g,0.13 mol) are cooled to-75 to-70 ℃ in a 200mL dry three-port bottle under argon atmosphere, n-BuLi (2.5M n-hexane solution, 23mL,57.5 mmol) is dropwise added at-75 to-70 ℃ under temperature control, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) ethyl acetate (formula c,18.8g,50 mmol) is dropwise added at-75 to-65 ℃ after dropwise addition, saturated sodium carbonate solution is then used for regulating ph 7-8 after dropwise addition of 1M hydrochloric acid solution (70 mL) for quenching for 1h, methyl tert-butyl ether is then added for extraction twice (80 mL each time), the organic phases are combined, the organic phases are washed with purified water, and anhydrous phases are dried with 80mL of water 4 Drying, filtering, refluxing the organic phase for 3 hours, concentrating under reduced pressure to dryness, adding n-hexane into the residue to precipitate solid, filtering, and recrystallizing the filter cake from absolute ethyl alcohol-n-hexane (30 ml/70 ml) to obtain the compound of formula e (16.0 g, yield 72%, purity 97.5%), ms M/z 444.1 (M+1).
EXAMPLE 8 Synthesis of octreonazole 1
1- (2-bromoethyl) -1H-tetrazole (formula f-I,17.7g,0.1 mol) and tetrahydrofuran (90 ml) were added to a 500ml dry three-necked flask under argon atmosphere, cooled to-35℃and 1.3M solution of magnesium chloride in tetrahydrofuran (110 ml,0.12 mol) was added dropwise at-35-15 ℃. After the addition, the temperature is controlled to be between 25 ℃ below zero and 15 ℃ below zero continuously, and stirring reaction is carried out for 1 hour. Cooling to-25 ℃, controlling the temperature to-25 ℃ to-15 ℃, dropwise adding a mixed solution of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridine-2-yl) -ethanone (formula e,44.3g,0.1 mol) and (R) -1,1' -binaphthol (2.9 g,10 mmol) in tetrahydrofuran (150 ml), controlling the temperature to-25 ℃ to-15 ℃ for 1h after the addition, stopping the reaction, adding 10% aqueous solution of citric acid (200 ml) into the reaction solution, regulating ph to 7-8 with saturated sodium carbonate solution, adding ethyl acetate for three times (250 ml each time), merging the organic phase, washing the organic phase with saturated saline water, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding n-hexane (200 ml), stirring and dispersing, filtering, recrystallizing the filter cake with anhydrous ethanol (200 ml) to obtain the titled product (41.1 g, 78%, chemical yield coefficient of the product (98%), purity of the product (38M: 98%), purity of the product (38 m+2M/38 z), 1 HNMR(300MHz d 6 -DMSO)：4.86(q，2H)，5.11(d，2H)，5.68(s，1H)，6.93–6.89(m，1H)，7.19(d，1H)，7.23–7.21(d，2H)，7.27–7.21(m，1H)，7.29(d，1H)，7.52(d，1H)，7.80(d，2H)，8.22–8.20(m，1H)，8.93(d，1H)，9.15(s，1H)。
EXAMPLE 9 Synthesis of octreonazole 2
1- (2-iodoethyl) -1H-tetrazole (formula f-II,11.2g,50 mmol) and tetrahydrofuran (90 ml) were added to a 250ml dry three-necked flask under argon atmosphere, cooled to-35℃and 1.3M lithium magnesium chloride isopropyl chloride in tetrahydrofuran (55 ml,60 mmmol) was added dropwise at-35-15 ℃. After the addition, the temperature is controlled to be between 25 ℃ below zero and 15 ℃ below zero continuously, and stirring reaction is carried out for 0.5h. Cooling to-25 ℃, controlling the temperature to-25 ℃ to-15 ℃, dropwise adding a mixed solution of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridine-2-yl) -ethanone (formula e,22.2g,50 mmol) and tetrahydrofuran (80 ml) of (R) -1,1' -binaphthol (1.5 g,5 mmol), stopping the reaction, adding 10% aqueous solution of citric acid (100 ml) into the reaction solution, regulating ph to 7-8 with saturated sodium carbonate solution, extracting three times (120 ml each time), merging the organic phase, washing the organic phase with 150ml of saturated saline, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 100ml of normal hexane, stirring and dispersing, filtering, and recrystallizing the filter cake with 100ml of anhydrous ethanol to obtain the titled product (21.1 g, chemical 80%, purity of the product is 528.1 m+20.5%).
EXAMPLE 10 Synthesis of octreonazole 3
1- (2-chloroethyl) -1H-tetrazole (formula f-III,29.1g,0.22 mol) and tetrahydrofuran 180ml were added to a 1L dry three-necked flask under argon atmosphere, cooled to-35℃and 1.3M solution of isopropyl magnesium chloride in lithium tetrahydrofuran (138 ml,0.26 mol) was added dropwise at-35℃to-15 ℃. After the addition, the temperature is controlled to be between 25 ℃ below zero and 15 ℃ below zero continuously, and stirring reaction is carried out for 1.5 hours. Cooling to-25 ℃, controlling the temperature to-25 ℃ to-15 ℃, dropwise adding a mixed solution of 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (formula e,88.6g,0.2 mol) and (R) -1,1' -binaphthol (5.8 g,20 mmol) in tetrahydrofuran (300 ml), stopping the reaction, adding 10% aqueous solution of citric acid (400 ml) into the reaction solution, adjusting ph to 7-8 with saturated sodium carbonate solution, extracting three times (500 ml each time), combining the organic phases with saturated saline water (600 ml), washing the organic phases with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding 400ml of normal hexane, stirring and dispersing the residue, filtering, and recrystallizing the filter cake with 300ml of anhydrous ethanol twice to obtain the title product of octconazole (71.7%, 97% pure chemical purity (97 m+97.380m), purity of which is 97.38m+1).
Compared with the method for synthesizing the octreonazole provided by the comparative example, the examples 1-10 of the invention have the advantages of shorter route, higher yield, reduced health damage to production operators and more friendly environment.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A preparation method of an antifungal drug, namely, octreonazole, which is characterized in that the method comprises the following steps:
step 1, (2, 2-trifluoro ethoxy) phenylboronic acid pinacol ester (compound of formula a) and a compound of formula b are subjected to Suzuki coupling reaction to obtain 2, 2-difluoro-2- (5- (4- (2, 2-trifluoro ethoxy) phenyl) pyridin-2-yl) ethyl acetate (compound of formula c);
step 2, coupling reaction of ethyl 2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) acetate (compound of formula c) with a compound of formula d to give 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (compound of formula e);
step 3, carrying out asymmetric synthesis reaction on 1- (2, 4-difluorophenyl) -2, 2-difluoro-2- (5- (4- (2, 2-trifluoroethoxy) phenyl) pyridin-2-yl) -ethanone (a compound of formula e) and a compound of formula f to obtain the octreonazole;
wherein the method comprises the steps of
X in the compound of formula b 1 Selected from I, br and Cl, preferably Br;
x in the compound of formula d 2 Selected from I, br and Cl, preferably Br;
x in the compound of formula f 3 Selected from I, br and Cl, preferably Br.
2. The preparation method according to claim 1, wherein the step 1 coupling reaction catalyst is a palladium catalyst and an inorganic base catalyst, wherein the palladium catalyst is selected from the group consisting of tetrakis (triphenylphosphine) palladium (0), (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (tricyclohexylphosphine) palladium (0) and bis (tri-O-tolylphosphine) palladium (0), preferably tetrakis (triphenylphosphine) palladium (0); the inorganic base is selected from cesium carbonate, potassium carbonate, sodium carbonate or lithium carbonate, preferably cesium carbonate or potassium carbonate.
3. The preparation method according to claim 1, wherein the step 2 coupling reaction catalyst is an organolithium, wherein the organolithium catalyst is selected from n-butyllithium, t-butyllithium, sec-butyllithium, n-pentyyllithium or neopentyllithium, preferably n-butyllithium.
4. The synthetic method according to claim 1, wherein the asymmetric synthesis reaction of step 3 requires the addition of an asymmetric reaction catalyst selected from (R) -1,1' -binaphthol or 3,3' -disubstituted arylbinaphthol, preferably (R) -1,1' -binaphthol.
5. The method according to claim 1, wherein the step 2 coupling reaction catalyst is isopropyl magnesium chloride lithium chloride.
6. The method according to claim 1, 4, 5, wherein the step 2 is carried out by reacting the compound of formula e, the compound of formula f, the isopropyl magnesium chloride lithium chloride and the asymmetric reaction catalyst in a molar ratio of 1:0.9-1.1:1.0-1.5: 0.08 to 0.12, preferably 1:0.95 to 1.05:1.1 to 1.3:0.09 to 0.11.
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