CN105130891A - 一种Ivacaftor的合成方法及其中间体 - Google Patents
一种Ivacaftor的合成方法及其中间体 Download PDFInfo
- Publication number
- CN105130891A CN105130891A CN201510473941.1A CN201510473941A CN105130891A CN 105130891 A CN105130891 A CN 105130891A CN 201510473941 A CN201510473941 A CN 201510473941A CN 105130891 A CN105130891 A CN 105130891A
- Authority
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- Prior art keywords
- compound
- acid
- reaction
- ivacaftor
- solvent
- Prior art date
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- PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960004508 ivacaftor Drugs 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Chemical group 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 70
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- -1 hydrated barta Chemical compound 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000006884 silylation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 201000003883 Cystic fibrosis Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 102000008371 intracellularly ATP-gated chloride channel activity proteins Human genes 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(C)c(c(N)c1)cc(*(C)(C)C)c1OC(OC)=O Chemical compound CC(C)(C)c(c(N)c1)cc(*(C)(C)C)c1OC(OC)=O 0.000 description 2
- ILNJBIQQAIIMEY-UHFFFAOYSA-N OC(C1=CNc(cccc2)c2C1=O)=O Chemical compound OC(C1=CNc(cccc2)c2C1=O)=O ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- BKSDHPHOWDUJNB-UHFFFAOYSA-N 5-amino-2,4-ditert-butylphenol Chemical class CC(C)(C)C1=CC(C(C)(C)C)=C(O)C=C1N BKSDHPHOWDUJNB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZULVUZCOXQBGCY-UHFFFAOYSA-N CC(C)(C)c(c(NC(C1=CNc2ccccc2C1=O)=O)c1)cc(C(C)(C)C)c1OC(NC)=O Chemical compound CC(C)(C)c(c(NC(C1=CNc2ccccc2C1=O)=O)c1)cc(C(C)(C)C)c1OC(NC)=O ZULVUZCOXQBGCY-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical group C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 102100023419 Cystic fibrosis transmembrane conductance regulator Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 208000035467 Pancreatic insufficiency Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- VZDYWEUILIUIDF-UHFFFAOYSA-J cerium(4+);disulfate Chemical compound [Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O VZDYWEUILIUIDF-UHFFFAOYSA-J 0.000 description 1
- 229910000355 cerium(IV) sulfate Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005357 flat glass Substances 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940005405 kalydeco Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种Ivacaftor的合成方法及其中间体，通过如下式方法实施，本发明合成路线新颖，操作简便，收率高，安全性好，适合工业化生产。还包括如式7或8所示的新型中间体，其中X为氯或溴，R为氢或C1～C5的烷基，优选为氢、甲基或乙基。
Description
技术领域：
本发明涉及一种囊性纤维化治疗药物Ivacaftor的合成方法及其新型中间体，属于有机合成领域。
背景技术：
囊性纤维化(cysticfibrosis,CF)是一种遗传疾病，主要以慢性梗阻性肺部病变、胰腺外分泌功能不足和汗液电解质异常升高为主要特征，是白人中最常见的影响生存寿命的遗传性疾病，由囊性纤维化跨膜传导调节因子(cysticfirbrosistransmembraneconductanceregulator,CFTR)的突变产生。以下式I化合物通用名为Ivacaftor；商品名为Kalydeco；化学名为N-(2,4-二叔丁基-5-羟基苯基)-4-氧代-1,4-二氢喹啉-3-甲酰胺(英文化学名为N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide)是由VertexPharmaceuticals公司开发，2012年1月31日FDA批准上市，用于治疗囊性纤维化的药物。该药物正是通过提高CFTR的作用来达到治疗目的。口服该药可以增加细胞表面CFTR通道的开放时间。体外实验证明该药可以提高G551D—CFTR蛋白的氯离子转运活性，从而在源头上阻断CF的发病。
文献报道的Ivacaftor合成方法中，喹啉酮部分主要通过4-氧代-1,4-二氢喹啉-3-甲酸、酯或酰氯引入，(WO2006002421,WO2010108162CN103044263,CN103787968)；例如：Vertex公司的原研专利WO2006002421，以和2,4-二叔丁基-5-羟基苯胺缩合得到Ivacaftor，该步反应收率仅有8％，且反应用到缩合剂HATU，后处理不易除去。
WO2010108162在原研专利的基础上进行了工艺优化，以4-氧代-1,4-二氢喹啉-3-甲酸和化合物3缩合后脱保护得到Ivacaftor，反应以丙基磷酸酐(T3P)为缩合剂，反应收率得到一定提高，但该缩合剂易引起环境污染，且价格昂贵。
本发明提供了一种新类型的中间体并用以合成Ivacaftor，合成路线新颖，操作简便，收率高，安全性好，环境友好，成本低，有利于工艺化生产。
发明内容
本发明的目的之一是提供了一种具有下面通式(II)的化合物，该化合物为用于制备Ivacaftor的新中间体化合物。
其中X为氯或溴，R为氢或本领域常规保护基，优选的，R为氢、四氢吡喃基(THP)、硅烷基、酰基或酰基烷基醚。更优选的，R为氢、三甲基硅基、甲酰基甲酯或甲酰基乙酯。
本发明的另一个目的为提供了通过化合物II制备Ivacaftor的方法。
R不为氢时，化合物II在有机溶剂中，脱除保护基R，然后在酸性条件下得到Ivacaftor；所述的脱羟基保护基的方法和条件可以为本领域此类反应的常规方法和条件。当R为氢时，化合物II直接在酸性条件下得到Ivacaftor，
所述的酸为无机酸或有机酸，所述无机酸选自盐酸、硫酸、硝酸、磷酸，所述有机酸选自甲酸、乙酸、乙二酸、甲磺酸、苯磺酸，酸与化合物II的摩尔比为10～40：1；所述的溶剂为乙腈、四氢呋喃、二氯甲烷、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜，或者上述溶剂的任意混合；所述的反应时间以检测反应完成为止；所述的反应温度为0-100℃。
所述化合物II通过化合物5与化合物6在碱性条件下反应得到。
所述的化合物6与化合物5的摩尔投料比为1-5:1；所述的碱可以是碳酸钠，碳酸钾，碳酸铯，碳酸氢钠，碳酸氢钾，氢氧化钠，氢氧化钾，氢氧化锂，氢氧化钡等，或二异丙基乙基胺、三乙胺、二异丙胺、三乙烯二胺(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、4-二甲氨基吡啶(DMAP)、吡啶、N-甲基吗啉、四甲基乙二胺、四甲基胍(TMG)，优选为三乙胺；所述碱与化合物5的摩尔投料比为1-10:1，优选为2-4:1；所述的溶剂为四氢呋喃、二氯甲烷、乙腈、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜，或者上述溶剂的任意混合，优选为四氢呋喃。
所述的反应时间以检测反应完成为止，通常反应时间为1-24小时，优选为2-5小时。
所述的反应温度为0-100℃，优选为20-30℃。
所述化合物6参考文献WO2006002421制得。
所述式5化合物由以下步骤制备,化合物3在卤化试剂的作用下，得到化合物5；
所述的卤化试剂为草酰氯、氯化亚砜、三溴化磷、三氯氧磷，优选为氯化亚砜，所述卤化试剂与化合物3的摩尔投料比为2-10:1，优选为4-6:1。
所述的溶剂为二氯甲烷、四氢呋喃、甲苯、氯仿、二氧六环、N,N-二甲基甲酰胺、二甲亚砜，优选为二氯甲烷。
所述的反应时间以检测完成为止，通常为1-24小时，优选为3-6小时。
所述的反应温度为0-100℃，优选为40-60℃。
所述化合物3参考文献WO2006002421制得。
本发明方法的优点主要在于：
1.本发明提供了一条全新的可工业化的路线用于合成Ivacaftor；
2.该合成路线：路线短，收率高，总收率65％；
3.该合成路线：操作简单、环境友好，适合工业生产；
4.公开了一种新的合成Ivacaftor的中间体II，其中X为氯或溴，R为氢或C1-C5的烷基，优选为氢、甲基或乙基；
5.为类似化合物的合成提供方法学参考。
本方法是一条全新的可工业化的合成路线。同时，该路线对开发新的囊性纤维化治疗药物具有很好的方法学意义。
具体实施例：
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件进行。
实施例中所用的原料或试剂除特别说明之外，均市售可得。
实施例中所述的室温均指20-35℃。除非特别指出，所述的试剂不经纯化直接使用。所有溶剂均购自商业化供应商，例如奥德里奇(Aldrich)，并且不经处理就可使用。反应通过TLC分析和/或通过LC-MS分析，通过起始材料的消耗来判断反应的终止。分析用的薄层层析(TLC)是在预涂覆硅胶60F2540.25毫米板的玻璃板(EMD化学品公司(EMDChemicals))上进行的，用UV光(254nm)和/或硅胶上的碘显象，和/或与TLC染色物如醇制磷钼酸、水合茚三酮溶液、高锰酸钾溶液或硫酸高铈溶液一起加热。
1H-NMR谱是在万瑞安-默丘利-VX400(VarianMercury-VX400)仪上，在400MHz操作下记录的。
本发明中使用的缩写具有本领域常规含义，如：DCM表示二氯甲烷，DMF表示N,N-二甲基甲酰胺。
实施例1
500mL三口瓶中加入化合物3(15g，79.37mmol,1.0eq)和二氯甲烷(300.0ml)，室温搅拌下滴加SOCl2(47.2g，396.8mmol,5.0eq)，然后滴加DMF(1.7g，24mmol，0.3eq)。将反应液升温至40-45℃，在40-45℃下反应3小时，反应液浓缩得到黄色固体，将50.0mL乙腈加入到烧瓶中，搅拌1小时，过滤，固体烘干得淡黄色粉末状固体19g(纯度95％，直接用于下一步)。
1HNMR(400MHz,DMSO):δ＝9.22(s,1H),8.6(d,1H),8.05(d,1H),7.89(t,1H),7.76(t,1H)ppm。
实施例2
500mL三口瓶中加入化合物5-1(10g,44.25mmol,1.0eq)、化合物6-1(12.35g,44.25mmol,1.0eq)和四氢呋喃(200mL)，滴加三乙胺(8.94g,88.5mmol,2.0eq)，该反应体系在室温下反应2小时。加入H2O(100.0mL)，用1NHCl调pH值至3-4，乙酸乙酯萃取(100.0mL)，有机相用饱和食盐水洗一次、干燥、浓缩，加入二氯甲烷(20mL)，搅拌30min，过滤、烘干，得到化合物7-1为类白色固体(16.9g，收率：81％，纯度：97％)。
1HNMR(400MHz,DMSO):δ＝10.20(s,1H),9.02(s,1H),8.33(d,1H),8.20(d,1H),7.96(t,1H),7.86(t,1H),7.41(s,1H),7.21(s,1H),3.85(s,3H),1.40(s,9H),1.31(s,9H)ppm；ESI/MS:m/z＝469(M+H)+.
实施例3
250mL反应瓶中加入化合物7-1(10g,21mmol,1eq)和THF(50mL)，搅拌下加入2NNaOH(63.0mL,126mmol,6.0eq),该反应体系在室温下反应2小时，加H2O(150ml)，用乙酸乙酯萃取两次(75mL×2)，有机相干燥、浓缩，得到化合物8-1为类白色固体(8g，收率：91％，纯度：94％)，直接用于下一步。
1HNMR(400MHz，DMSO)δ＝9.99(s,1H),9.94(s,1H),8.86(s,1H),8.34(d,1H)，8.15(d,1H),7.94(m,1H),7.85(m,1H),7.18(s,1H),6.74(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝411(M+H)+.
实施例4
1L三口瓶中加入化合物8-1(8g，20mmol,1eq)和乙腈(25.0mL)，滴加1NHCl(400mL，20eq)，反应液升温至75-85℃，反应6小时。降温，用乙酸乙酯萃取2次(150mL×2)，干燥有机相，浓缩得到黄色油状物，加入乙腈(15mL)搅拌30min，过滤、烘干，得到Ivacaftor为白色固体(6.7g，收率：88％，纯度：98.1％)。
1HNMR(400MHz，DMSO):δ＝12.88(s,1H),11.77(s,1H),9.17(s,1H),8.83(d,1H),8.28(d,1H),7.79(t,1H),7.71(t,1H),7.48(t,1H),7.12(s,1H),7.06(s,1H),1.34(s,18H)ppm；ESI/MS:m/z＝393(M+H)+.
实施例5
250mL三口瓶中加入化合物5-1(6.8g，30.1mmol，1eq)和四氢呋喃(70mL)，加入三乙胺(6.1g，60.2mmol，2.0eq)，将化合物6-2(7.3g，33.1mmol，1.1eq)溶于四氢呋喃(70.0ml)中缓慢滴加到反应体系，室温下反应2小时。加入H2O(150.0ml)，用1NHCl调pH值至3-4，用乙酸乙酯萃取两次(200mL×2)，合并有机相，干燥、浓缩，得到红色固体。加入DCM(20mL)，搅拌30min，过滤、烘干，得化合物8-1为类白色固体(8.8g，收率：62％，纯度：95.1％)。
1HNMR(400MHz，DMSO)δ＝9.99(s,1H),9.94(s,1H),8.86(s,1H),8.34(d,1H)，8.15(d,1H),7.94(m,1H),7.85(m,1H),7.18(s,1H),6.74(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝411(M+H)+.
实施例6
500mL三口瓶中加入化合物3(20g，0.106mol,1.0eq)和二氯甲烷(300mL)，室温搅拌下滴加PBr3(57g，0.212mol，2eq)，然后滴加DMF(1.5g，21mmol，0.2eq)，将反应液升温至40-45℃，在40-45℃下反应3小时，降温，反应液滴加三乙胺(21.4g)，搅拌30min，过滤，滤液浓缩得到黄色固体，将40.0mL乙腈加入装固体的烧瓶中，搅拌1小时，过滤，固体烘干得化合物5-2为淡黄色粉末状固体35g(纯度92％，直接用于下一步)。
1HNMR(400MHz,DMSO):δ＝9.17(s,1H),8.57(d,1H),8.03(d,1H),7.86(t,1H),7.73(t,1H)ppm。
实施例7
500mL三口瓶中加入化合物5-2(35g，0.106mol，1.0eq)、化合物6-3(31g，0.106mol，1.0eq)和四氢呋喃(350mL)，滴加二异丙胺(21.4g，0.212mol，2.0eq)，该反应体系在室温下反应2小时。加入H2O(1000mL)，用1NHCl调pH值至3-4，乙酸乙酯萃取(300mL×2)，有机相用饱和食盐水洗一次、干燥、浓缩，加入二氯甲烷(20mL)，搅拌30min，过滤、烘干，得到化合物7-2为类白色固体(29g，收率：52％，纯度：99％)。
1HNMR(400MHz，DMSO):δ＝10.12(s,1H),8.98(s,1H),8.31(d,1H),8.18(d,1H),7.94(t,1H),7.86(t,1H),7.41(s,1H),7.21(s,1H),4.21(m,2H),1.40(s,9H),1.31(s,9H),1.27(t,3H)ppm；ESI/MS:m/z＝527(M+H)+.
实施例8
500mL反应瓶中加入化合物7-2(29g,55mmol)和THF(150mL)，搅拌下加入2NNaOH(165mL,330mmol,6.0eq),该反应体系在室温下反应2小时，加H2O(250ml)，用乙酸乙酯萃取两次(150mL×2)，有机相干燥、浓缩，得到化合物8-2为类白色固体(22g，收率：88％，纯度：94.6％)，直接用于下一步。
1HNMR(400MHz，DMSO)δ＝10.02(s,1H),9.97(s,1H),8.91(s,1H),8.43(d,1H)，8.20(d,1H),7.90(m,1H),7.81(m,1H),7.16(s,1H),6.73(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝455(M+H)+.
实施例9
1L三口瓶中加入化合物8-2(22g，48mmol)和乙腈(100mL)，滴加1NHCl(480mL，10eq)，反应液升温至75-85℃，反应6小时。降温，用乙酸乙酯萃取2次(200mL×2)，干燥有机相，浓缩得到黄色油状物，加入乙腈(30mL)搅拌30min，过滤、烘干，得到Ivacaftor为白色固体(16.5g，收率：87％，纯度：97.5％)。
1HNMR(400MHz，DMSO):δ＝12.88(s,1H),11.77(s,1H),9.17(s,1H),8.83(d,1H),8.28(d,1H),7.79(t,1H),7.71(t,1H),7.48(t,1H),7.12(s,1H),7.06(s,1H),1.34(s,18H)ppm；ESI/MS:m/z＝393(M+H)+.
实施例10
1L三口瓶中加入化合物5-2(35g，0.106mol，1.0eq)和四氢呋喃(350mL)，加入三乙胺(21.4g，0.212mol，2.0eq)，将化合物6-2(23.5g，0.106mol，1eq)溶于四氢呋喃(100mL)中缓慢滴加到反应体系，室温下反应2小时。加入H2O(1L)，用1NHCl调pH值至3-4，用乙酸乙酯萃取两次(400mL×2)，合并有机相，干燥、浓缩，得到红色固体。加入DCM(20mL)，搅拌30min，过滤、烘干，得化合物8-2为类白色固体(28.5g，收率：59％，纯度：95.4％)。
1HNMR(400MHz，DMSO)δ＝10.02(s,1H),9.97(s,1H),8.91(s,1H),8.43(d,1H)，8.20(d,1H),7.90(m,1H),7.81(m,1H),7.16(s,1H),6.73(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝455(M+H)+.
实施例11
500mL三口瓶中加入化合物5-1(10g,44.25mmol,1.0eq)、化合物6-4(13.51g,44.25mmol,1.0eq)和四氢呋喃(200mL)，滴加三乙胺(8.94g,88.5mmol,2.0eq)，该反应体系在室温下反应2小时。加入H2O(100.0mL)，乙酸乙酯萃取(100.0mL)，有机相用饱和食盐水洗一次、干燥、浓缩，加入二氯甲烷(20mL)，搅拌30min，过滤、烘干，得到化合物7-4为类白色固体(18.1g，收率：83％，纯度：97.6％)。
1HNMR(400MHz,DMSO):δ＝10.10(s,1H),9.01(s,1H),8.31(d,1H),8.23(d,1H),7.92(t,1H),7.85(t,1H),7.43(s,1H),7.20(s,1H),5.84(t,1H),3.55-3.65(m,2H),1.87-2.01(m,2H),1.57-1.63(m,2H),1.45-1.55(m,2H),1.40(s,9H),1.31(s,9H)ppm；ESI/MS:m/z＝495(M+H)+.
实施例12
250mL反应瓶中加入化合物7-4(18.1g,36.6mmol,1eq)和甲醇(60mL)，搅拌下加入三氟乙酸(25.0g,219.6mmol,6.0eq),该反应体系在室温下反应2小时，加碳酸钠的水溶液，调节pH至8-9，用乙酸乙酯萃取两次(75mL×2)，有机相干燥、浓缩，得到化合物8-1为类白色固体(13.4g，收率：89.4％，纯度：95.7％)，直接用于下一步。
1HNMR(400MHz，DMSO)δ＝9.99(s,1H),9.94(s,1H),8.86(s,1H),8.34(d,1H)，8.15(d,1H),7.94(m,1H),7.85(m,1H),7.18(s,1H),6.74(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝411(M+H)+.
实施例13
500mL三口瓶中加入化合物5-1(10g,44.25mmol,1.0eq)、化合物6-5(13g,44.25mmol,1.0eq)和四氢呋喃(200mL)，滴加三乙胺(8.94g,88.5mmol,2.0eq)，该反应体系在室温下反应2小时。加入H2O(100.0mL)，乙酸乙酯萃取(100.0mL)，有机相用饱和食盐水洗一次、干燥、浓缩，加入二氯甲烷(20mL)，搅拌30min，过滤、烘干，得到化合物7-5为类白色固体(18.3g，收率：86％，纯度：96.9％)。
1HNMR(400MHz,DMSO):δ＝10.15(s,1H),9.00(s,1H),8.43(d,1H),8.25(d,1H),7.90(t,1H),7.81(t,1H),7.37(s,1H),7.16(s,1H),1.40(s,9H),1.31(s,9H)，0.26(s,9H)ppm；ESI/MS:m/z＝483(M+H)+.
实施例14
250mL反应瓶中加入化合物7-5(18.3g,38mmol,1eq)和甲醇(60mL)，搅拌下加入四正丁基氟化铵(20g,76mmol,2.0eq),该反应体系在室温下反应2小时，加200mL水溶液，调节pH至8-9，用乙酸乙酯萃取两次(75mL×2)，有机相干燥、浓缩，得到化合物8-1为类白色固体(13.5g，收率：86.7％，纯度：94.2％)，直接用于下一步。
1HNMR(400MHz，DMSO)δ＝9.99(s,1H),9.94(s,1H),8.86(s,1H),8.34(d,1H)，8.15(d,1H),7.94(m,1H),7.85(m,1H),7.18(s,1H),6.74(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝411(M+H)+.
实施例15
500mL三口瓶中加入化合物5-1(10g,44.25mmol,1.0eq)、化合物6-6(11.6g,44.25mmol,1.0eq)和四氢呋喃(200mL)，滴加三乙胺(8.94g,88.5mmol,2.0eq)，该反应体系在室温下反应2小时。加入H2O(100.0mL)，乙酸乙酯萃取(100.0mL)，有机相用饱和食盐水洗一次、干燥、浓缩，加入二氯甲烷(20mL)，搅拌30min，过滤、烘干，得到化合物7-6为类白色固体(16.5g，收率：82.5％，纯度：97.2％)。
1HNMR(400MHz,DMSO):δ＝10.18(s,1H),9.06(s,1H),8.31(d,1H),8.22(d,1H),7.94(t,1H),7.81(t,1H),7.51(s,1H),7.48(s,1H),2.28(s,3H),1.40(s,9H),1.31(s,9H)ppm；ESI/MS:m/z＝453(M+H)+.
实施例16
500mL反应瓶中加入化合物7-6(16.5g,36.5mmol,1.0eq)和THF(150mL)，搅拌下加入2NNaOH(110mL,0.219mmol,6.0eq),该反应体系在室温下反应2小时，加H2O(250ml)，用乙酸乙酯萃取两次(150mL×2)，有机相干燥、浓缩，得到化合物8-1为类白色固体(12.8g，收率：85.4％，纯度：97.2％)，直接用于下一步。
1HNMR(400MHz，DMSO)δ＝9.99(s,1H),9.94(s,1H),8.86(s,1H),8.34(d,1H)，8.15(d,1H),7.94(m,1H),7.85(m,1H),7.18(s,1H),6.74(s,1H),1.34(s,18H)ppm,ESI/MS:m/z＝411(M+H)+.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的。
Claims (10)
1.一种Ivacaftor的制备方法，其特征在于，该方法以化合物II为原料，R不为氢时，化合物II在有机溶剂中，脱除保护基R，然后在酸性条件下得到Ivacaftor；当R为氢时，化合物II直接在酸性条件下得到Ivacaftor，
其中X为氯或溴，R为氢或本领域常规羟基保护基，所述脱除保护基方法为本领域常规脱保护基方法。
2.根据权利要求1所述的方法，其特征在于，所述的酸为无机酸或有机酸，所述无机酸选自盐酸、硫酸、硝酸、磷酸，所述有机酸选自甲酸、乙酸、乙二酸、甲磺酸、苯磺酸，酸与化合物II的摩尔比为10～40：1；所述的溶剂为乙腈、四氢呋喃、二氯甲烷、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜，或者上述溶剂的任意混合；所述的反应时间以检测反应完成为止；所述的反应温度为0-100℃。
3.根据权利要求1所述的方法，其特征在于，化合物II由如下步骤制备：化合物5与化合物6在碱性条件下反应得到化合物II，
4.如权利要求3所述的方法，其特征在于，所述的化合物6与化合物5的摩尔投料比为1～5:1；所述的碱可以是碳酸钠，碳酸钾，碳酸铯，碳酸氢钠，碳酸氢钾，氢氧化钠，氢氧化钾，氢氧化锂，氢氧化钡，或二异丙基乙基胺、三乙胺、二异丙胺、三乙烯二胺(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、4-二甲氨基吡啶(DMAP)、吡啶、N-甲基吗啉、四甲基乙二胺、四甲基胍(TMG)；所述碱与化合物5的摩尔投料比为1～10:1；所述的溶剂为四氢呋喃、二氯甲烷、乙腈、二氧六环、2-甲基四氢呋喃、甲苯、N,N-二甲基甲酰胺、甲基叔丁基醚、乙醚、二甲亚砜，或者上述溶剂的任意混合；所述的反应时间以检测反应完成为止；所述的反应温度为0-100℃。
5.根据权利要求3所述的方法，其特征在于，化合物5由以下步骤制备：化合物3在卤化试剂的作用下，得到化合物5。
6.根据权利要求5所述的方法，其特征在于，所述的卤化试剂选自草酰氯、氯化亚砜、三溴化磷、三氯氧磷；所述卤化试剂与化合物3的摩尔投料比为2～10:1；所述的溶剂为二氯甲烷、四氢呋喃、甲苯、氯仿、二氧六环、N,N-二甲基甲酰胺、二甲亚砜；所述的反应时间以检测完成为止，通常为1～24小时，所述的反应温度为0～100℃。
7.根据权利要求5所述的方法，其特征在于，所述的卤化试剂为氯化亚砜，其与化合物3的摩尔投料比为4～6:1；所述的溶剂为二氯甲烷；所述的反应时间为3～6小时；所述的反应温度为40～60℃。
8.根据权利要求5所述的方法，其特征在于，所述的卤化试剂为氯化亚砜，其与化合物3的摩尔投料比为4～6:1；所述的溶剂为二氯甲烷；所述的反应时间为3～6小时；所述的反应温度为40～60℃。
9.一种如下式II所示的中间体化合物，
其中X为氯或溴，R定义如权利要求1。
10.如权利要求9所述化合物，其中R选自氢、THP、硅烷基、酰基或酰基烷基醚。
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