CN114630828A - 3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的合成 - Google Patents
3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的合成 Download PDFInfo
- Publication number
- CN114630828A CN114630828A CN202080073868.8A CN202080073868A CN114630828A CN 114630828 A CN114630828 A CN 114630828A CN 202080073868 A CN202080073868 A CN 202080073868A CN 114630828 A CN114630828 A CN 114630828A
- Authority
- CN
- China
- Prior art keywords
- propyl
- methylsulfonyl
- chloro
- trifluoroethyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GTQTUABHRCWVLL-UHFFFAOYSA-N C(CCN1C(=CC2=CC(=CC=C12)Cl)CN1C2=C(N(C1=O)CC(F)(F)F)C=CN=C2)S(=O)(=O)C Chemical compound C(CCN1C(=CC2=CC(=CC=C12)Cl)CN1C2=C(N(C1=O)CC(F)(F)F)C=CN=C2)S(=O)(=O)C GTQTUABHRCWVLL-UHFFFAOYSA-N 0.000 title claims description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 21
- -1 { 5-chloro-1- [3- (methylsulfonyl) propyl ] -1H-indol-2-yl } methyl Chemical group 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 8
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- UMPPWOWKLZZAPK-UHFFFAOYSA-N ClC=1C=C2C=C(N(C2=CC=1)CCCS(=O)(=O)C)C(=O)O Chemical compound ClC=1C=C2C=C(N(C2=CC=1)CCCS(=O)(=O)C)C(=O)O UMPPWOWKLZZAPK-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- QGYMTESOTDSWPR-UHFFFAOYSA-N NC1C=NC=CC1(CC(F)(F)F)N Chemical compound NC1C=NC=CC1(CC(F)(F)F)N QGYMTESOTDSWPR-UHFFFAOYSA-N 0.000 claims description 5
- 229910000085 borane Inorganic materials 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000007822 coupling agent Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- CDHPGNJIWNZIDY-UHFFFAOYSA-N ClC=1C=C2C=C(N(C2=CC=1)CCCS(=O)(=O)C)C(=O)NC=1C=NC=CC=1NCC(F)(F)F Chemical compound ClC=1C=C2C=C(N(C2=CC=1)CCCS(=O)(=O)C)C(=O)NC=1C=NC=CC=1NCC(F)(F)F CDHPGNJIWNZIDY-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 4
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- BNXZHVUCNYMNOS-UHFFFAOYSA-N 1-butylpyrrolidin-2-one Chemical compound CCCCN1CCCC1=O BNXZHVUCNYMNOS-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- MTAMZFNDKNTDQS-UHFFFAOYSA-N CS(CCCN(C(CC1(C(NCC(F)(F)F)=CC=NC1)N)=CC1=C2)C1=CC=C2Cl)(=O)=O Chemical compound CS(CCCN(C(CC1(C(NCC(F)(F)F)=CC=NC1)N)=CC1=C2)C1=CC=C2Cl)(=O)=O MTAMZFNDKNTDQS-UHFFFAOYSA-N 0.000 claims description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 150000004678 hydrides Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006751 Mitsunobu reaction Methods 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 241000725643 Respiratory syncytial virus Species 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- AXUFUWARAAYMCG-UHFFFAOYSA-N 3-methylsulfonylpropyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCCS(C)(=O)=O)C=C1 AXUFUWARAAYMCG-UHFFFAOYSA-N 0.000 description 2
- CZUGFKJYCPYHHV-UHFFFAOYSA-N 3-methylthiopropanol Chemical compound CSCCCO CZUGFKJYCPYHHV-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 description 1
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BZPVREXVOZITPF-UHFFFAOYSA-N 4-methoxy-3-nitropyridine Chemical compound COC1=CC=NC=C1[N+]([O-])=O BZPVREXVOZITPF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical class [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000007929 acylimidazolides Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 1
- 229960004012 amifampridine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LWKIFKYHCJAIAB-UHFFFAOYSA-N ethyl 5-chloro-1h-indole-2-carboxylate Chemical compound ClC1=CC=C2NC(C(=O)OCC)=CC2=C1 LWKIFKYHCJAIAB-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- TXXWBTOATXBWDR-UHFFFAOYSA-N n,n,n',n'-tetramethylhexane-1,6-diamine Chemical compound CN(C)CCCCCCN(C)C TXXWBTOATXBWDR-UHFFFAOYSA-N 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种用于制备RSV抑制化合物3‑({5‑氯‑1‑[3‑(甲基磺酰基)丙基]‑1H‑吲哚‑2‑基}甲基)‑1‑(2,2,2‑三氟乙基)‑10 1,3‑二氢‑2H‑咪唑并[4,5‑c]吡啶‑2‑酮的化学合成路线,并且涉及在多步方法中用作中间体化合物的新化合物。
Description
本发明涉及一种用于制备RSV抑制化合物3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的化学合成路线,并且涉及在多步方法中用作中间体化合物的新化合物。
背景技术
呼吸道合胞病毒是引起幼儿、免疫功能受损的成人和老年人急性下呼吸道感染的主要原因。使用对呼吸道合胞病毒具有特异性的小分子抗病毒药物的干预提供重要的治疗机会,但目前还没有这种化合物被批准。
化合物(1),即,3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮,可以由以下结构表示:
该化合物抑制呼吸道合胞病毒(RSV)的复制,并且已作为化合物P55在WO-2012/080447中描述。
现有技术
WO-2012/080447中披露的化合物合成的一般途径涉及2-羟甲基取代的吲哚与N-取代的2-氧代-咪唑并吡啶之间的光延(Mitsunobu)反应。光延反应虽然在小规模实验室制备中非常有用,但需要在工业过程中不优选的试剂(典型地是过量的偶氮二甲酸二异丙酯和三苯基膦)。那些试剂会产生化学计量量的亚肼基二甲酸二异丙酯(diisopropylhydrazodicarboxylate)和三苯基氧化膦作为副产物,或如果使用替代的偶氮二甲酸酯和膦,则产生类似的副产物。去除那些副产物需要通过色谱法或多次重结晶或再浆化进行精细纯化。那些纯化操作在大规模上是不可取的,因为它们通过消耗溶剂和纯化助剂(例如,硅胶)增加了最终产物的成本,并且还降低了所需产物的产率。此外,在工厂中用于去除反应副产物的延长处理时间,以及反应副产物的处置成本,大大降低了光延反应在工业生产规模上的有用性。
WO-2012/080447中披露的化合物合成的一般途径可以在第11页的方案1中找到,并且如下所描绘:
WO-2012/080447的方案1
如在WO-2012/080447中制备WO-2012/080477的式(I)化合物所用的偶联反应是根据光延反应条件使用偶氮二甲酸二异丙酯和三苯基膦在合适溶剂诸如DMF或THF中进行。使用光延路线会导致无法通过结晶从最终化合物中轻松清除的高水平杂质,从而阻止了此工艺被考虑用于商业生产。光延反应的使用还导致化合物(1)分离为灰色固体,这是不希望的。变色需要通过色谱法去除,这是一种对于大规模生产非优选的纯化技术。
因此,需要改进的以高产率和优异纯度获得化合物(1)的一般合成路线,其避免在工业规模上使用光延条件。本文所述的方法提供了高纯度的结晶中间体和具有适合制造药物产品的纯度的化合物(1)。这种新颖方法的每个化学步骤都是高产的(high yielding),使用廉价、安全和可商购的试剂,具有高原子经济性,并允许通过从反应混合物中结晶进行非常高效的纯化。
发明内容
已经发现了一种用于制备化合物(1)的新颖三步方法,其包括酰胺形成、羰基还原和环化的步骤,而不需要使用光延反应条件。
在第一实施例中,本发明涉及一种用于制备化合物(1)的方法,
该方法包括以下连续步骤
a)使式(a)的5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-甲酸或其反应性官能衍生物,
与式(b)的N4-(2,2,2-三氟乙基)吡啶-3,4-二胺
在偶联剂和任选地碱的存在下、在合适的溶剂中反应;
以得到式(c)的5-氯-1-(3-(甲基磺酰基)丙基)-N-(4-((2,2,2-三氟乙基)氨基)吡啶-3-基)-1H-吲哚-2-甲酰胺;
b)将化合物(c)中的羰基用还原剂还原,以得到式(d)的N3-((5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-基)甲基)-N4-(2,2,2-三氟乙基)吡啶-3,4-二胺;
c)以及使化合物(d)在合适的非质子溶剂中与羰基转移试剂任选地在有机或无机碱的存在下反应,以得到化合物(1)。
在第二实施例中,本发明涉及一种新颖的式(a)化合物,
其为5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-甲酸。
在第三实施例中,本发明涉及一种新颖的式(c)化合物,
其为5-氯-1-(3-(甲基磺酰基)丙基)-N-(4-((2,2,2-三氟乙基)氨基)吡啶-3-基)-1H-吲哚-2-甲酰胺。
在第四实施例中,本发明涉及一种新颖的式(d)化合物,
其为N3-((5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-基)甲基)-N4-(2,2,2-三氟乙基)吡啶-3,4-二胺。
步骤a)是式(a)的甲酸化合物与式(b)的胺之间的公知的酰胺键形成反应,其中所述酰胺键的形成可以通过在偶联剂和任选地碱的存在下、在合适的溶剂中混合化合物(a)和(b)来进行。合适的溶剂是极性非质子溶剂,诸如例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、N-丁基吡咯烷酮、四氢呋喃、2-甲基四氢呋喃、乙腈、丙腈和丁腈。式(a)的甲酸化合物可以按原样使用或可以首先转化为其活化的官能衍生物,例如酰基异脲、酰基咪唑化物(acyl imidazolide)、酰基卤化物或混合酸酐。适宜的酰胺偶联剂是例如,EDC(N-(3-二甲基氨基-丙基)-N′-乙基碳二亚胺盐酸盐)、DIC(N,N′-二异丙基碳二亚胺)、DCC(N,N′-二环己基碳二亚胺)、CDI(1,1'-羰基二咪唑)和T3P(1-丙烷膦酸酐)。适用于酰胺键形成反应的任选的碱是例如,三烷基胺(诸如三乙胺、三丁胺和N,N-二异丙基乙胺)、环胺(诸如DBU(1,8-二氮杂-双环[5.4.0]十一碳-7-烯)和DBN(1,5-二氮杂双环[4.3.0]壬-5-烯))、吡啶类化合物(诸如吡啶、2-和4-甲基吡啶和2,6-二甲基吡啶)和DMAP(4-二甲基氨基-吡啶)。该反应可以适宜地在范围介于室温与反应混合物的回流温度之间的温度下进行。上述转化的一个非常理想的特征是酰胺形成步骤中的高区域选择性:在化合物(a)的甲酸与化合物(b)的仲胺之间没有观察到偶联,从而使化合物(c)的产率和纯度增加。
步骤b)是通过用合适的还原剂处理将式(c)化合物中的羰基转化为亚甲基。合适的还原剂是例如,硅氢化物(诸如Et3SiH和PMHS(聚(甲基氢硅氧烷)))、铝氢化物(诸如Dibal-H(二异丁基氢化铝)和RedAl(双(2-甲氧基-乙氧基)氢化铝钠))和硼氢化物(诸如LiBH4、NaBH4以及硼烷络合物BH3.THF和BH3.Me2S)。硼烷络合物可以适宜地由NaBH4和布朗斯台德酸诸如硫酸或路易斯酸诸如三卤化硼(任选地作为与醚溶剂的络合物)、三氯化铝或碘原位生成。适用于酰胺还原反应的溶剂是醚类,例如四氢呋喃(THF)和2-甲基-四氢呋喃(2-Me-THF)。
在步骤c)中,使用羰基转移试剂诸如例如,CDI、脲、光气、双光气、三光气或氯甲酸酯诸如氯甲酸乙酯或氯甲酸苯酯;在合适的非质子溶剂例如乙酸乙酯、乙腈、丙腈、丁腈、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中将二胺化合物(d)转化为化合物(1),以提供化合物(1)。任选地,添加有机碱,例如三乙胺、三丁胺、N,N-二异丙基-乙胺、环胺(诸如DBU(1,8-二氮杂-双环[5.4.0]-十一碳-7-烯)或DBN(1,5-二氮杂双环[4.3.0]壬-5-烯))、咪唑类(诸如咪唑或N-甲基咪唑)、吡啶类(诸如吡啶、2-或4-甲基吡啶或2,6-二甲基吡啶)、DMAP(4-二甲基氨基吡啶),或无机碱,诸如碳酸钾。
化合物(1)可以任选地通过本领域已知的技术诸如柱色谱法或结晶法进一步纯化。
实例1:4-甲基苯磺酸3-(甲基磺酰基)丙酯的合成
在氮气氛下将3-(甲硫基)丙-1-醇(100.00g)溶解在二氯甲烷(500mL)中并添加甲苯磺酰氯(188.50g)。将溶液冷却至0℃;然后添加N,N,N′,N′-四甲基-1,6-己二胺(4.87g)和三乙胺(114.40g)。甲苯磺酰化反应完成后,添加水并将混合物在10℃-15℃的温度下搅拌。相分离后,将有机层用稀HCl水溶液洗涤,并且随后用水洗涤。然后在25℃下将有机层逐滴添加至含有单过硫酸氢钾(OxoneTM)(752.60g)在水(3000mL)中的溶液的容器中并搅拌直至完全氧化。然后将有机层用水洗涤;然后将MTBE(1000mL)逐滴添加至有机层中,并且在添加完成后,将混合物冷却至0℃。然后过滤固体并减压干燥,以得到产物(246.70g,90%产率)。
1H NMR(600MHz,CDCl3)δppm 2.15-2.28(m,2H);2.45(s,3H);2.91(s,3H);3.05-3.17(m,2H);4.17(t,J=5.95Hz,2H);7.37(d,J=8.12Hz,2H);7.78(d,J=8.31Hz,2H)
13C NMR(151MHz,CDCl3)δppm 21.89;22.45;41.39;51.06;68.06;128.22;130.24;132.72;145.50
实例2:N4-(2,2,2-三氟乙基)吡啶-3,4-二胺的合成
将柠檬酸一水合物(295.00g)溶解在水(370.00g)中,并添加4-甲氧基-3-硝基吡啶(179.00g),之后是2,2,2-三氟乙胺(348.00g)。将该混合物在50℃下搅拌直至完成转化。冷却至室温后,添加2-甲基-四氢呋喃(1250mL)并分离各相。将水相用2-甲基四氢呋喃(530mL)再萃取。合并的有机层用7%NaHCO3水溶液(890.00g)和用水(903.00g)洗涤。将有机层浓缩至大约600mL。添加乙醇(1000mL),之后是Pd/C(10%,50%湿的,7.50g)。将混合物在45-50psi(310-345kPa)氢气下氢化直至完成转化,然后冷却至30℃-40℃并经硅藻土(Celite)过滤,并且滤饼用乙醇洗涤。通过常压蒸馏和平行投入2-甲基四氢呋喃,将溶剂转换成纯的2-甲基四氢呋喃,达到大约500mL的体积。将混合物冷却至50℃-55℃并缓慢添加甲苯(1700mL)。添加完成后,将混合物冷却至0℃-5℃,并且然后过滤固体并减压干燥,以得到产物(b)(204.00g,92%产率)。
1H NMR(600MHz,DMSO-d6)δppm 4.03(qd,J=9.50,6.80Hz,2H);4.66(br s,2H);5.88(t,J=6.80Hz,1H);6.60(d,J=5.29Hz,1H);7.62(d,J=5.29Hz,1H);7.71(s,1H)。
13C NMR(151MHz,DMSO-d6);δppm 43.08(q,J=32.9Hz);104.68;125.61(q,J=281.0Hz);131.02;135.30;139.53;139.94
实例3:5-氯-1-(3-(甲基磺酰基;丙基)-1H-吲哚-2-甲酸的合成
将5-氯-1H-吲哚-2-甲酸乙酯(50.00g)、4-甲基苯磺酸3-(甲基磺酰基)丙酯(71.90g)、碳酸钾(61.79g)和四丁基硫酸氢铵(3.79g)在甲苯(500mL)中混合。将混合物加热至70℃直至完成转化,然后缓慢添加水(250mL)并在60℃下分离各相。弃去水层,并添加水(100mL)和50%NaOH水溶液(23.25g);将该混合物在60℃下搅拌直至完成转化。添加水(150mL)并在60℃下分离各相。在50℃下,将所得到的水层的80%部分(285.10g)(另外20%用于其他目的)分批添加至34.5%w/w HCl(34.00g)、水(71mL)和异丙醇(500mL)的混合物中。在水溶液添加25%之后添加引晶(seeding)材料。将混合物在50℃下搅拌4小时,并然后缓慢冷却至15℃。将产物过滤,用水(36mL)和异丙醇(36mL)的混合物洗涤,并减压干燥,以得到产物(a)(52.90g,93%产率)。
1H NMR(600MHz,DMSO-d6)δppm 2.07-2.18(m,2H);2.96(s,3H);3.07-3.14(m,2H);4.67(t,J=7.18Hz,2H);7.24(d,J=0.76Hz,1H);7.35(dd,J=9.06,2.27Hz,1H);7.70(d,J=9.06Hz,1H);7.77(d,J=2.20Hz,1H)。
13C NMR(151MHz,DMSO-d6)δppm 23.31;39.99;42.63;50.92;109.67;112.63;121.33;124.83;125.02;126.39;129.22;137.03;162.44。
实例4:5-氯-1-(3-(甲基磺酰基)丙基)-N-(4-((2,2,2-三氟乙基)氨基)吡啶-3-
基)-1H-吲哚-2-甲酰胺的合成
在20℃和氮气氛下,将5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-甲酸(=化合物(a))(25.00g)和N4-(2,2,2-三氟乙基)吡啶-3,4-二胺(=化合物(b))(15.10g)在乙腈(198mL)中与DMAP(4-二甲基-氨基吡啶)(9.67g)混合。添加EDC(1-乙基-3-(3-二甲基氨基-丙基)碳二亚胺盐酸盐)(30.35g),并且在20℃下30分钟后,将混合物逐渐加热至55℃。再过2小时后,将混合物逐渐加热至73℃并在1小时内添加水(253mL)。30分钟后,添加引晶材料。将混合物逐渐冷却至20℃,2小时后过滤,并且将滤饼用乙腈(24mL)和水(40mL)的混合物洗涤,并减压干燥,以得到产物(c)(35.08g,91%产率)。
1H NMR(600MHz,DMSO-d6)1H NMR(600MHz,DMSO-d6)δppm 2.13-2.23(m,2H);2.95(s,3H);3.08-3.19(m,2H);4.00-4.11(m,2H)4.65(br t,J=7.18Hz,2H);6.66(br t,J=6.61Hz,1H);6.89(d,J=6.04Hz,1H);7.34(dd,J=8.88,2.08Hz,1H);7.44(s,1H);7.71(d,J=8.69Hz,1H);7.82(d,J=1.51Hz,1H);8.10(s,1H);8.13(d,J=5.67Hz,1H);9.89(s,1H)。
13C NMR(151MHz,DMSO-d6)δppm 23.29;39.99;42.79;42.88(q,J=33.2Hz);51.01;105.81;105.85;112.33;119.22;120.90;125.50(q,J=282.1Hz);124.11;124.96;126.65;132.42;136.30;148.16;148.43;149.23;161.09。
实例5:N3-((5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-基)甲基)-N4-(2,2,2-三
氟乙基)吡啶-3,4-二胺的合成
将化合物(c)(45.00g)悬浮在THF(450mL)中并且在连续添加THF的情况下蒸馏溶剂直至水含量为<0.05%w/w。然后添加NaBH4(10.45g),之后缓慢添加BF3.THF(51.51g)。完成转化后,缓慢投入甲醇(460mL)。将溶剂蒸馏并转换成纯的2-甲基四氢呋喃(约700mL)。添加水(340mL)和50%NaOH水溶液(8.6mL)。将混合物在52℃下搅拌16-24小时,同时连续添加50%NaOH水溶液以保持pH值在9.5与10.5之间。相分离后,将有机层在52℃下用水(368mL)洗涤。然后通过在大气压下蒸馏将有机相共沸干燥并浓缩至约300mL的体积。将混合物逐渐冷却至15℃,8小时后过滤,用2-甲基四氢呋喃洗涤并减压干燥,以得到产物(d)(33.8g,77%产率)。
1H NMR(600MHz,DMSO-d6)δppm 2.12(dd,J=7.60Hz,2H);2.94(s,3H);3.17(t,J=7.81Hz,2H);4.01-4.10(m,2H);4.35(t,J=7.45Hz,2H);4.51(d,J=5.27Hz,2H);5.09(t,J=5.18Hz,1H);6.07(t,J=6.63Hz,1H);6.50(s,1H);6.67(d,J=5.27Hz,1H);7.14(dd,J=8.83,1.91Hz,1H);7.55(d,J=8.90Hz,1H);7.57(d,J=2.00Hz,1H);7.73(d,J=5.45Hz,1H);7.82(s,1H)。
13C NMR(151MHz,DMSO-d6)δppm 23.48;40.35;40.57;41.97;43.65(q,J=32.7Hz);51.38;101.45;104.78;111.68;119.61;121.41;126.10(q,J=282.3Hz);124.45;128.83;131.23;132.55;135.69;139.75;140.82;141.24。
实例6:化合物(1)的合成
将化合物(d)(38.00g)和羰基二咪唑(26.00g)悬浮在乙腈(480mL)中并将混合物加热至75℃直至完成转化。添加乙腈(480mL),将混合物冷却至60℃,并且添加引晶材料,之后是水(2.90g)。通过在约10℃下减压蒸馏将混合物浓缩至约350mL的最终体积。将浆液过滤,用乙腈洗涤并减压干燥,以得到产物化合物(1)(36.00g,90%产率)。
通过从2-丁酮和水(90:10v/v,10体积)的混合物中结晶来进一步纯化化合物(1)。
1H NMR(500MHz,DMSO-d6)δppm 1.95(m,2H);2.98(s,3H);3.15(t,J=7.90Hz,2H);4.38(t,J=7.90Hz,2H);4.89(q,J=9.30Hz,2H);5.40(s,2H);6.48(s,1H);7.17(dd,J=8.70,2.30Hz,1H);7.44(d,J=5.30Hz,1H);7.55(d,J=9.10Hz,1H);7.57(d,J=1.90Hz,1H);8.31(d,J=5.30Hz,1H);8.49(s,1H)。
13C NMR(125MHz,DMSO-d6)δppm 22.95;37.55;41.60;40.20;42.07(q,J=34.0Hz);50.82;101.91;104.59;111.56;119.56;121.70;124.32(q,J=279.9Hz);124.31;126.19;128.04;129.96;134.98;135.28;135.57;143.26;152.44。
熔点(DSC):216℃。
Claims (14)
1.一种用于制备3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的方法,
该方法包括以下连续步骤
a)使式(a)的5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-甲酸或其反应性官能衍生物,
与式(b)的N4-(2,2,2-三氟乙基)吡啶-3,4-二胺
在偶联剂和任选地碱的存在下、在合适的溶剂中反应;
以得到式(c)的5-氯-1-(3-(甲基磺酰基)丙基)-N-(4-((2,2,2-三氟乙基)氨基)吡啶-3-基)-1H-吲哚-2-甲酰胺;
b)将化合物(c)中的羰基用还原剂还原,以得到式(d)的N3-((5-氯-1-(3-(甲基磺酰基)丙基)-1H-吲哚-2-基)甲基)-N4-(2,2,2-三氟乙基)-吡啶-3,4-二胺;
c)以及使化合物(d)在合适的非质子溶剂中与羰基转移试剂任选地在有机或无机碱的存在下反应,以得到3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮。
2.如权利要求1所述的方法,其中,在步骤a)中,该合适的溶剂是极性非质子溶剂。
3.如权利要求2所述的方法,其中,该极性非质子溶剂选自二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、N-丁基吡咯烷酮、四氢呋喃、2-甲基四氢呋喃、乙腈、丙腈和丁腈。
4.如权利要求1所述的方法,其中,在步骤a)中,该偶联剂选自EDC(N-(3-二甲基氨基-丙基)-N′-乙基碳二亚胺盐酸盐)、DIC(N,N′-二异丙基碳二亚胺)、DCC(N,N′-二环己基碳二亚胺)、CDI(1,1'-羰基二咪唑)或T3P(1-丙烷膦酸酐)。
5.如权利要求1所述的方法,其中,在步骤a)中,该碱为三烷基胺、环胺或吡啶类化合物。
6.如权利要求5所述的方法,其中,该碱选自三乙胺、三丁胺、N,N-二异丙基乙胺、DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)、吡啶、2-或4-甲基吡啶、2,6-二甲基吡啶或DMAP(4-二甲基氨基吡啶)。
7.如权利要求1所述的方法,其中,在步骤b)中,该还原剂为硼或硅或铝的氢化物或硼烷络合物。
8.如权利要求7所述的方法,其中,该还原剂选自Et3SiH、聚(甲基氢硅氧烷)、二异丁基氢化铝、双(2-甲氧基-乙氧基)-氢化铝钠)、LiBH4、NaBH4、BH3.THF和BH3.Me2S。
9.如权利要求1所述的方法,其中,在步骤c)中,该羰基转移试剂选自CDI、光气、三光气、氯甲酸乙酯或氯甲酸苯酯。
10.如权利要求1所述的方法,其中,在步骤c)中,该合适的非质子溶剂选自乙酸乙酯、乙腈、丙腈、丁腈、四氢呋喃、2-甲基-四氢呋喃、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺或N-甲基吡咯烷酮。
11.如权利要求10所述的方法,其中,该任选的有机或无机碱选自三乙胺、三丁胺、N,N-二异丙基乙胺、DBU(1,8-二氮杂-双环[5.4.0]十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)、吡啶、2-或4-甲基吡啶或2,6-二甲基吡啶或DMAP(4-二甲基氨基吡啶)、或碳酸钾。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019114254 | 2019-10-30 | ||
CNPCT/CN2019/114254 | 2019-10-30 | ||
PCT/EP2020/080381 WO2021083998A1 (en) | 2019-10-30 | 2020-10-29 | Synthesis of 3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1h-indol-2 yl} methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2h-imidazo[4,5-c]pyridin-2-one |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114630828A true CN114630828A (zh) | 2022-06-14 |
CN114630828B CN114630828B (zh) | 2023-10-31 |
Family
ID=73059849
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080073868.8A Active CN114630828B (zh) | 2019-10-30 | 2020-10-29 | 一种rsv抑制化合物的合成 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20240109894A1 (zh) |
EP (1) | EP4051662B1 (zh) |
JP (1) | JP2023500214A (zh) |
KR (1) | KR20220091465A (zh) |
CN (1) | CN114630828B (zh) |
AU (1) | AU2020372633A1 (zh) |
BR (1) | BR112022008152A2 (zh) |
CA (1) | CA3152302A1 (zh) |
CL (1) | CL2022001092A1 (zh) |
IL (1) | IL292526A (zh) |
MX (1) | MX2022005257A (zh) |
WO (1) | WO2021083998A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022184606A1 (en) * | 2021-03-01 | 2022-09-09 | Janssen Sciences Ireland Unlimited Company | Synthesis of rilematovir |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103347875A (zh) * | 2010-12-16 | 2013-10-09 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的吲哚类 |
CN104540817A (zh) * | 2012-06-15 | 2015-04-22 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的用杂环取代的1,3-二氢-2h-苯并咪唑-2-酮衍生物 |
CN104903313A (zh) * | 2012-10-16 | 2015-09-09 | 爱尔兰詹森科学公司 | Rsv抗病毒化合物 |
CN108601774A (zh) * | 2016-02-03 | 2018-09-28 | 爱尔兰詹森科学公司 | 用于治疗rsv的组合产品 |
WO2019058271A1 (en) * | 2017-09-19 | 2019-03-28 | Lupin Limited | PROCESS FOR THE PREPARATION OF ELUXADOLINE |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012080477A1 (en) | 2010-12-17 | 2012-06-21 | Philip Morris Products S.A. | Container having interactive surface elements including design element |
-
2020
- 2020-10-29 MX MX2022005257A patent/MX2022005257A/es unknown
- 2020-10-29 CA CA3152302A patent/CA3152302A1/en active Pending
- 2020-10-29 EP EP20800823.5A patent/EP4051662B1/en active Active
- 2020-10-29 CN CN202080073868.8A patent/CN114630828B/zh active Active
- 2020-10-29 WO PCT/EP2020/080381 patent/WO2021083998A1/en active Application Filing
- 2020-10-29 US US17/754,591 patent/US20240109894A1/en active Pending
- 2020-10-29 BR BR112022008152A patent/BR112022008152A2/pt not_active Application Discontinuation
- 2020-10-29 IL IL292526A patent/IL292526A/en unknown
- 2020-10-29 JP JP2022522048A patent/JP2023500214A/ja active Pending
- 2020-10-29 AU AU2020372633A patent/AU2020372633A1/en active Pending
- 2020-10-29 KR KR1020227011160A patent/KR20220091465A/ko unknown
-
2022
- 2022-04-28 CL CL2022001092A patent/CL2022001092A1/es unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103347875A (zh) * | 2010-12-16 | 2013-10-09 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的吲哚类 |
CN104540817A (zh) * | 2012-06-15 | 2015-04-22 | 爱尔兰詹森研发公司 | 作为呼吸道合胞病毒抗病毒剂的用杂环取代的1,3-二氢-2h-苯并咪唑-2-酮衍生物 |
CN104903313A (zh) * | 2012-10-16 | 2015-09-09 | 爱尔兰詹森科学公司 | Rsv抗病毒化合物 |
CN108601774A (zh) * | 2016-02-03 | 2018-09-28 | 爱尔兰詹森科学公司 | 用于治疗rsv的组合产品 |
WO2019058271A1 (en) * | 2017-09-19 | 2019-03-28 | Lupin Limited | PROCESS FOR THE PREPARATION OF ELUXADOLINE |
Also Published As
Publication number | Publication date |
---|---|
EP4051662A1 (en) | 2022-09-07 |
IL292526A (en) | 2022-06-01 |
EP4051662B1 (en) | 2024-02-07 |
WO2021083998A1 (en) | 2021-05-06 |
JP2023500214A (ja) | 2023-01-05 |
BR112022008152A2 (pt) | 2022-09-27 |
MX2022005257A (es) | 2022-06-09 |
CA3152302A1 (en) | 2021-05-06 |
US20240109894A1 (en) | 2024-04-04 |
KR20220091465A (ko) | 2022-06-30 |
CN114630828B (zh) | 2023-10-31 |
AU2020372633A1 (en) | 2022-04-21 |
CL2022001092A1 (es) | 2022-11-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW200459B (zh) | ||
TWI658042B (zh) | 雜環化合物的合成 | |
US8399491B2 (en) | Derivatives of indole-2-carboxamides and of azaindole-2-carboxamides substituted with a silanyl group, preparation thereof and therapeutic use thereof | |
ES2564133T3 (es) | Procedimientos e intermediarios para fabricar un inhibidor de JAK | |
JP6691115B2 (ja) | コパンリシブおよびそれの二塩酸塩の合成 | |
KR20100017069A (ko) | 아고멜라틴의 합성 방법 | |
JP2007522213A (ja) | 置換されたトリアゾール化合物の製造方法 | |
CN114630828B (zh) | 一种rsv抑制化合物的合成 | |
ES2962961T3 (es) | Procedimiento de preparación de n-(5-((4-(4-(dimetilamino)metil)-3-fenil-1h-pirazol-1-il)pirimidin-2-il)amino)-4-metoxi-2-morfolinofenil)acrilamida haciendo reaccionar la amina correspondiente con un cloruro de 3-halo-propionilo | |
ES2270144T3 (es) | Procedimiento para la obtencion de compuestos de zolmitriptan. | |
CN108623602B (zh) | 一种制备和纯化依鲁替尼的方法 | |
JP2017502009A (ja) | シロドシン及びその中間体の製造方法 | |
EP3911660B1 (en) | Process for preparation of 2-amino-5-hydroxy propiophenone | |
WO2002014277A1 (fr) | Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci | |
WO2022042577A1 (zh) | 一种吡咯并嘧啶化合物的制备方法 | |
CA2604890A1 (en) | Pyrimidine derivatives and their use for the treatment of cancer | |
US11078163B2 (en) | Processes for the synthesis of substituted urea compounds | |
US20080009628A1 (en) | One-Pot Condensation-Reduction Methods for Preparing Substituted Allylic Alcohols | |
WO2022184606A1 (en) | Synthesis of rilematovir | |
KR101752449B1 (ko) | 솔리페나신 또는 그 염의 결정형 제조방법, 이에 사용되는 신규 중간체 및 그 제조방법 | |
JP7309725B2 (ja) | 2環性ヘテロ芳香環誘導体 | |
Yue et al. | Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives | |
TW202311275A (zh) | 烷基矽烷氧取代苄基化合物之製造方法 | |
CN112961160A (zh) | 一种西地那非的改良合成工艺 | |
JP6780958B2 (ja) | 結晶構造を有する1−(3−カルボキシピリジル−2−)−2−フェニル−4−メチルピペラジン及びその製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |