CN114478373A - 一种氨基磺酸酯的制备方法 - Google Patents
一种氨基磺酸酯的制备方法 Download PDFInfo
- Publication number
- CN114478373A CN114478373A CN202011254756.0A CN202011254756A CN114478373A CN 114478373 A CN114478373 A CN 114478373A CN 202011254756 A CN202011254756 A CN 202011254756A CN 114478373 A CN114478373 A CN 114478373A
- Authority
- CN
- China
- Prior art keywords
- substituted
- unsubstituted
- group
- reagent
- alkyl
- 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
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 230000004048 modification Effects 0.000 claims abstract description 7
- 238000012986 modification Methods 0.000 claims abstract description 7
- -1 Carbonyl Chemical group 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 239000000126 substance Substances 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 238000005849 sulfamoylation reaction Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 229940126062 Compound A Drugs 0.000 claims description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 37
- 239000006227 byproduct Substances 0.000 abstract description 13
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 52
- 238000003786 synthesis reaction Methods 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 238000001914 filtration Methods 0.000 description 25
- 238000001035 drying Methods 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 150000003254 radicals Chemical class 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 150000003333 secondary alcohols Chemical class 0.000 description 5
- 238000005694 sulfonylation reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- MPUQHZXIXSTTDU-QXGSTGNESA-N sulfamic acid [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7-pyrrolo[2,3-d]pyrimidinyl]-2-hydroxycyclopentyl]methyl ester Chemical compound C1[C@H](O)[C@H](COS(=O)(=O)N)C[C@H]1N1C2=NC=NC(N[C@@H]3C4=CC=CC=C4CC3)=C2C=C1 MPUQHZXIXSTTDU-QXGSTGNESA-N 0.000 description 4
- 230000006103 sulfonylation Effects 0.000 description 4
- RXWNCMHRJCOWDK-UHFFFAOYSA-N 2-naphthalen-1-ylethanol Chemical compound C1=CC=C2C(CCO)=CC=CC2=C1 RXWNCMHRJCOWDK-UHFFFAOYSA-N 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 150000003138 primary alcohols Chemical class 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical group NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- NPFYZDNDJHZQKY-UHFFFAOYSA-N 4-Hydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=CC=C1 NPFYZDNDJHZQKY-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 150000007960 acetonitrile Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 1
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- WYTRYIUQUDTGSX-UHFFFAOYSA-N 1-phenylpropan-2-ol Chemical compound CC(O)CC1=CC=CC=C1 WYTRYIUQUDTGSX-UHFFFAOYSA-N 0.000 description 1
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 1
- ZLHVIYHWWQYJID-UHFFFAOYSA-N 4'-hydroxyflavanone Chemical compound C1=CC(O)=CC=C1C1OC2=CC=CC=C2C(=O)C1 ZLHVIYHWWQYJID-UHFFFAOYSA-N 0.000 description 1
- BOTGCZBEERTTDQ-UHFFFAOYSA-N 4-Methoxy-1-naphthol Chemical compound C1=CC=C2C(OC)=CC=C(O)C2=C1 BOTGCZBEERTTDQ-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- XXSCONYSQQLHTH-UHFFFAOYSA-N 9h-fluoren-9-ylmethanol Chemical compound C1=CC=C2C(CO)C3=CC=CC=C3C2=C1 XXSCONYSQQLHTH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 1
- 229910003844 NSO2 Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- QGXBDMJGAMFCBF-LUJOEAJASA-N epiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-LUJOEAJASA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229960002330 methocarbamol Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 229950010588 pevonedistat Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/18—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- 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
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
本发明涉及一种氨基磺酸酯的制备方法。具体地，本发明公开了一种氨基磺酰化试剂，具有廉价易得、溶解度好、高稳定性等优点。使用所述试剂可高选择性地实现对羟基的氨基磺酰化修饰，反应条件温和，操作简单，可放大量。所得产物具有收率高、副产物少、纯度高等优势。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体地涉及氨基磺酸酯化合物的高效制备及其在药物分子合成上的应用。
背景技术
氨基磺酸酯具有独特的化学和生物学性质，在有机化学、药物化学等领域都有重要的应用。在合成反应中，氨基磺酸酯既是交叉偶联反应前体(J.Am.Chem.Soc.2009,131,17748)，又是碳氢活化体系中氨基供体(Org.Lett.2020,22,168)。另一方面，作为药效基团，氨基磺酸酯是磺酸酯和磷酸酯的等排类似物，在生理环境下为电中性，独特的相互作用模式使其在药物分子中常常作为调整生物活性和生物利用度的重要基团(J.Med.Chem.2003,46,2197)。
到目前为止，从醇/酚出发直接制备氨基磺酰酯的合成方法还非常有限。最常见的策略是以氨基磺酰氯(H2NSO2Cl)为亲电试剂的取代反应，然而H2NSO2Cl却存在价格贵(百灵威售价：12903元/100g)、不稳定、多羟基选择性差的缺点。
2012年，Zhu课题组开发了一种氨基磺酰化试剂t-Bu/DABCO Burgess-typeReagent，并应用到了NAE抑制剂MLN4924的合成工艺上。但该试剂在高溶解性的大极性溶剂(如DMAc、DMF)中稳定性差，而在能稳定存在的溶剂(如MeCN)中却表现出很差的溶解性，经NMR测试其在室温下氘代乙腈中的饱和溶解浓度为0.06mol/L，这使得大规模反应时搅拌困难，且不得不加热，(ACS Symposium Series，2016,1240,13-62.)这制约了该磺酰化反应的可操作性、底物普适性和选择性。另一方面，该试剂须使用0.2eq～0.4eq的HCl作为添加剂来促进反应的进行，这导致与醇反应时存在氯代副产物(Org.Lett.2020,14,2626)。
2020年，Leahy和Miller等人报道了N-甲基咪唑催化的以活泼氨基磺酸酯PCPS为试剂的磺酰化反应。然而该试剂有较大的毒性，毒性来源于分解物五氯苯酚，大鼠经口急毒测试LD50＝50mg/kg。另外其官能团兼容性较差，且制备是仍需要使用过量的H2NSO2Cl。(Org.Lett.2020,22,168)。
对于含有多羟基的复杂分子的氨基磺酰化反应，选择性是需要考察的重要方向。例如，在NAE抑制剂MLN4924的合成中，后期对于伯醇和仲醇的选择性氨基磺酰化是抑制剂制备过程中的难点和关键步骤。Zhu课题组使用t-Bu/DABCO Burgess-type Reagent作为反应试剂时(Org.Process Res.Dev.2015,19,1299)，原料转化率仅有63％，且与伯醇氨基磺酰化产物相伴也得到了相当比例的仲醇取代副产物以及双羟基取代副产物(52:7:3)。Leahy和Miller等人利用活泼氨基磺酸酯PCPS为氨基磺酰化试剂时，仅以38％的收率得到目标产物，(Org.Lett.2020,22,168)且伴随得到大量仲醇取代和双取代副产物(4.7:1.0:1.1)。
基于以上背景，开发一种高效实用的新型氨基磺酰化试剂，并探索出条件温和、操作便捷、选择性高、官能团兼容性好的氨基磺酸酯制备方法具有重要的意义。
发明内容
本发明的目的在于提供一种廉价易得，高效稳定的磺酰化试剂，并开发其在氨基磺酸酯合成上的应用。
本发明的第一方面，提供了一种氨基磺酰化试剂，所述试剂包含式I所示化合物和式II所示化合物，
其中，R1选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C6-10芳基、取代或未取代的C6-10芳基-(CH2)m-、取代或未取代的芴基-(CH2)m-；
各m独立地选自下组：0、1、2、3、4、5；
R2-R6各自独立地选自下组：H、取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C1-10酰胺基、取代或未取代的C1-10羰基、卤素、取代或未取代的苯基、取代或未取代的C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、醛基、酯基、羧基、C1-10烷基、C1-10氟烷基、C1-10环烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基；
所述试剂中，所述式I所示化合物和所述式II所示化合物的摩尔比为1：0.5-1.5。
在另一优选例中，所述式I所示化合物和所述式II所示化合物的摩尔比为1:1。
在另一优选例中，R1选自下组：C1-10烷基、C2-10烯基、C2-10炔基、C6-10芳基、C6-10芳基-(CH2)m-、芴基-(CH2)m-；
m为1；
R2-R6各自独立地选自下组：H、C1-10烷基、C2-10烯基、C2-10炔基、C1-10酰胺基、C1-10羰基、卤素、苯基、C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基。
在另一优选例中，R1选自下组：C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C6-10芳基-(CH2)m-、芴基-(CH2)m-。
在另一优选例中，R2-R6各自独立地选自下组：H、C1-6烷基。
在另一优选例中，m＝1。
在另一优选例中，式I所示化合物和式II所示化合物中，各R2-R6相同。
在另一优选例中，所述试剂选自下组：
本发明的第二方面，提供了一种本发明第一方面所述试剂的制备方法，包括步骤：
1)将化合物A与R1OH反应，得到化合物B；
2)将化合物B与化合物C反应，得到试剂D，即本发明第一方面所述试剂；
其中，R1-R6如本发明第一方面所定义。
在另一优选例中，步骤2)中，化合物C与R1OH的摩尔比为2-4。
在另一优选例中，步骤1)中，R1OH和化合物A的摩尔比为1-1.5，优选1.1。
在另一优选例中，步骤2)中，化合物C与R1OH的摩尔比为2-2.5。
本发明的第三方面，提供了一种本发明第一方面所述试剂的用途，用于制备氨基磺酸酯。
本发明的第四方面，提供了一种氨基磺酸酯的制备方法，包括步骤：
i)将化合物E与本发明第一方面所述试剂反应，得到化合物F，即氨基磺酸酯；
其中，
R选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、羧基、C1-10烷基、C1-10亚烷基、
取代的C1-10亚烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基、苯氧基、苯基-(C＝O)-、＝O、
萘基；
R1如本发明第一方面所定义。
在另一优选例中，所述苯并基团具有选自下组的结构：
本发明的第五方面，提供了一种药物分子氨基磺酰化的方法，包括步骤：
使用本发明第一方面所述氨基磺酰化试剂对前体药物进行单羟基修饰，以得到氨基磺酰化的药物分子；
所述前体药物包含2-10个羟基。
在另一优选例中，所述前体药物包含2-6个羟基，较佳地2-4个，更佳地2个。
在另一优选例中，所述方法中，本发明第一方面所述氨基磺酰化试剂与所述前体药物的摩尔比为2-5，较佳地2-3。
在另一优选例中，所述方法在选自下组的溶剂中进行：乙腈、二氯甲烷、或其组合。
在另一优选例中，所述氨基磺酰化的药物分子具有选自下组的结构：
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种溶解性好、稳定性好、廉价易得、无氯代副产物、反应易操作、条件温和、底物普适性好、便于药物后期修饰、多羟基选择性好的新型的氨基磺酰化试剂，并将所述氨基磺酰化试剂应用到了多羟基复杂分子的氨基磺酰化，具有多羟基选择性好、总收率高、副产物少、纯度高等优势。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C1-10烷基”具有类似含义。
在本发明中，术语“C2-6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。术语“C2-10烯基”具有类似含义。
在本发明中，术语“C2-6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。术语“C2-10炔基”具有类似含义。
在本发明中，术语“C1-6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。术语“C1-10烷氧基”具有类似含义。
在本发明中，术语“C1-10酰胺基”是指具有1-10个碳原子的含有一个酰胺键的一级、二级或三级酰胺。
在本发明中，术语“C1-10羰基”是指具有1-10个碳原子的含有一个碳氧双键的羰基。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-10芳基”。术语“C6-10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语“多个”指1、2、3、4、5或6个。其他类似术语具有类似含义。
氨基磺酰化试剂及其制备
本发明人开发了一种新型氨基磺酰化试剂(D)，在稳定存在的溶剂(如DCM，MeCN)中表现出良好的溶解性，经NMR测试其在室温下氘代乙腈中的饱和溶解浓度为0.35mol/L，且无需添加剂、无氯代副产物，可由廉价易得原料(氯磺酰异氰酸酯百灵威售价：251元/100g)方便制备。与醇/酚的氨基磺酰化反应操作简单、底物范围广、可大量合成，已成功应用于多种药物分子的后期结构修饰。与此同时，对于多羟基复杂化合物体现出了良好的选择性，以MLN4924的合成为例，该方法可以以两步84％的总收率高效制备目标化合物，且几乎无仲醇取代及双取代副产物，使得纯化更加方便。
现有氨基磺酰化试剂和本发明氨基磺酰化试剂的特点概述如下表1所示。
表1
本发明所述氨基磺酰化试剂是如下制备的：
将反应物氯磺酰异氰酸酯(A)与醇试剂R1OH用溶剂混合，氮气保护下反应，后加入2倍量(取代)吡啶(C)，反应后经重结晶、快速过滤、干燥后得试剂D。其中：
1)R1为叔丁基、苄基、烯丙基、芴甲基。
2)R2～R6独立地选自下组：氢、取代或未取代的C1-10烷基、C2-10烯基、C2-10炔基、C1-10酰胺基、C1-10羰基、卤素、取代或未取代的苯基、C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基。
3)式D中，n为1.5～0.5，通常为1.0。
4)步骤1和步骤2的溶剂选自下组：四氢呋喃、二甲基乙二醚、1,4-二氧六环、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈。
5)步骤1中，醇试剂与反应物A的摩尔比为1.0-2.0:1，优选1.1倍量。反应温度为0-30℃，优选0℃。反应时间为0.1-5小时，优选1小时。
6)步骤2中，反应物C与反应物A的摩尔比为2.0-4.0:1，优选2.2倍量。反应温度为0-30℃，优选0℃。逐渐升温到室温(25-40℃)。反应时间为0.1-48小时，优选3小时。
氨基磺酸酯及其制备
采用本发明所述氨基磺酰化试剂通过如下路线制备了氨基磺酸酯：
将反应底物醇/酚(E)与氨基磺酰化试剂(D)用溶剂混合反应，后处理后柱层析纯化，得产物F。其中：
1)R选自下组：取代或未取代的C1-10烷基、C2-10烯基、C2-10炔基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团。
2)步骤3中，反应物D与醇/酚试剂的摩尔比为1.0-5.0:1。反应温度为0-30℃，通常为室温。反应时间为0.1-48小时。
3)步骤3的溶剂选自下组：四氢呋喃、二甲基乙二醚、1,4-二氧六环、二氯甲烷、1,2-二氯乙烷、乙腈。
与现有技术相比，本发明具有以下主要优点：
(1)所述氨基磺酰化试剂具有如下优点：溶解性好、稳定性好、廉价易得、无氯代副产物、反应易操作、条件温和、底物普适性好、便于药物后期修饰；
(2)使用所述氨基磺酰化试剂对多羟基复杂分子进行氨基磺酰化的反应具有多羟基选择性好、总收率高、副产物少、纯度高等优势。
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，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1：氨基磺酰化试剂D1的制备。
氮气保护条件下，向250mL的反应瓶中加入叔丁醇(44mmol，3260mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入吡啶(88mmol，6960mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D1，无需纯化，收率92％。1H NMR(400MHz,CDCl3)δ8.92(dd,J＝6.6,1.5Hz,4H),8.48(tt,J＝7.8,1.6Hz,2H),8.01(dd,J＝7.8,6.6Hz,4H),7.40(s,1H),1.41(s,9H).
实施例2：氨基磺酰化试剂D2的制备。
氮气保护条件下，向250mL的反应瓶中加入叔丁醇(44mmol，3260mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入4-甲基吡啶(88mmol，8195mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D2，无需纯化，收率90％。1H NMR(400MHz,CDCl3)δ8.71(d,J＝6.6Hz,4H),7.73(d,J＝6.2Hz,4H),2.65(s,6H),1.41(s,9H).
实施例3：氨基磺酰化试剂D3的制备。
氮气保护条件下，向250mL的反应瓶中加入9-芴甲醇(44mmol，8634mg)，干燥的甲苯60mL，冰浴降温至0℃，滴加氯磺酰异氰酸酯(40mmol，5660mg)，0℃下搅拌一小时，滴加入吡啶(88mmol，6960mg)后，升至室温继续搅拌3小时，有白色固体析出。快速抽滤，用乙醚洗一遍，固体转移至100mL烧瓶中，真空干燥20分钟后得白色固体产物D1，无需纯化，收率85％。1H NMR(400MHz,CDCl3)δ8.85(d,J＝5.3Hz,4H),8.39(t,J＝7.8Hz,2H),7.92(dd,J＝7.5,6.7Hz,4H),7.76–7.66(m,2H),7.64–7.53(m,2H),7.35(t,J＝7.5Hz,2H),7.26(t,J＝7.3Hz,2H),4.40–4.10(m,3H).
实施例4：氨基磺酸酯F1的合成。
向10mL的反应瓶中加入苯乙醇(0.2mmol，24.4mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F1，无色油状物，50mg，收率84％。1H NMR(400MHz,Chloroform-d)δ7.32–7.19(m,5H),4.47(t,J＝7.1Hz,2H),3.03(t,J＝7.1Hz,2H),1.43(s,9H).
实施例5：氨基磺酸酯F2的合成。
向10mL的反应瓶中加入1-苯基-2-丙醇(0.2mmol，27.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F2，无色油状物，56.8mg，收率90％。1H NMR(400MHz,Chloroform-d)δ7.36–7.03(m,5H),5.05(q,J＝6.4Hz,1H),3.12(dd,J＝13.6,5.2Hz,1H),2.87(dd,J＝13.6,7.9Hz,1H),1.46(s,9H),1.32(d,J＝6.2Hz,3H).
实施例6：氨基磺酸酯F3的合成。
方法1)：向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F3，白色固体，56.2mg，收率80％。
方法2)：向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D2(0.4mmol，160mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F3，白色固体，52.7mg，收率75％。
1H NMR(400MHz,Chloroform-d)δ7.83–7.73(m,3H),7.65(t,J＝1.3Hz,1H),7.50–7.40(m,2H),7.32(dd,J＝8.5,1.8Hz,1H),4.57(t,J＝7.1Hz,2H),3.20(t,J＝7.1Hz,2H),1.39(s,9H).
实施例7：氨基磺酸酯F4的合成。
向10mL的反应瓶中加入2-萘酚(0.2mmol，28.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F4，白色固体，48.5mg，收率75％。1H NMR(400MHz,Chloroform-d)δ7.78–7.71(m,4H),7.46–7.39(m,3H),1.40(s,9H).
实施例8：氨基磺酸酯F5的合成。
向10mL的反应瓶中加入4-甲氧基-1-萘酚(0.2mmol，34.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F5，白色固体，58.0mg，收率82％。1H NMR(400MHz,Methanol-d4)δ8.29–8.17(m,2H),7.58–7.38(m,3H),6.85(d,J＝8.5Hz,1H),3.99(s,3H),1.40(s,9H).
实施例9：氨基磺酸酯F6的合成。
向10mL的反应瓶中加入4-苯氧基苯酚(0.2mmol，37.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F6，无色油状物，61.4mg，收率84％。1H NMR(400MHz,CDCl3)δ7.38(dd,J＝8.6,7.5Hz,2H),7.27(d,J＝9.1Hz,2H),7.17(t,J＝7.4Hz,1H),7.07–6.99(m,4H),1.54(s,9H).
实施例10：氨基磺酸酯F7的合成。
向10mL的反应瓶中加入4-溴苯酚(0.2mmol，34.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F7，白色固体，47.9mg，收率68％。1H NMR(400MHz,Methanol-d4)δ7.52(d,J＝8.9Hz,2H),7.22(d,J＝8.9Hz,2H),1.45(s,9H).
实施例11：氨基磺酸酯F8的合成。
向10mL的反应瓶中加入4-叔丁基苯酚(0.2mmol，30.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F8，无色油状物，48.1mg，收率73％。1H NMR(400MHz,Chloroform-d)δ7.36(d,J＝8.8Hz,2H),7.20(d,J＝8.8Hz,2H),1.46(s,9H),1.29(s,9H).
实施例12：氨基磺酸酯F9的合成。
向10mL的反应瓶中加入对氰基苯酚(0.2mmol，23.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F9，白色固体，44.7mg，收率75％。1H NMR(400MHz,CD3OD)δ7.84(d,J＝8.9Hz,2H),7.46(d,J＝8.9Hz,2H),1.46(s,9H).
实施例13：氨基磺酸酯F10的合成。
向10mL的反应瓶中加入4-羟基-二苯甲酮(0.2mmol，39.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F10，无色油状物，46.8mg，收率62％。1H NMR(400MHz,Chloroform-d)δ7.72(dd,J＝21.5,8.0Hz,4H),7.55(t,J＝7.6Hz,1H),7.46–7.33(m,4H),1.41(s,9H).
实施例14：氨基磺酸酯F11的合成。
向10mL的反应瓶中加入雌酚酮(0.2mmol，54.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F11，无色油状物，75.5mg，收率84％。1H NMR(400MHz,Chloroform-d)δ7.22(d,J＝8.6Hz,1H),7.03(d,J＝8.7Hz,1H),6.98(s,1H),2.86–2.82(m,2H),2.48(dd,J＝19.0,8.6Hz,1H),2.38–2.29(m,1H),2.26–1.92(m,5H),1.88(d,J＝9.4Hz,1H),1.63–1.33(m,14H),0.83(s,3H).
实施例15：氨基磺酸酯F12的合成。
向10mL的反应瓶中加入睾酮(0.2mmol，57.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F12，无色油状物，69.2mg，收率74％。1H NMR(400MHz,Chloroform-d)δ5.72(s,1H),4.51(dd,J＝9.2,7.7Hz,1H),2.43–2.33(m,3H),2.31–2.14(m,3H),2.05–1.88(m,3H),1.83(ddd,J＝9.9,4.9,2.9Hz,2H),1.73–1.61(m,3H),1.57(ddd,J＝14.2,7.5,3.7Hz,2H),1.47(s,9H),1.41–1.33(m,2H),1.17(s,3H),1.07–0.97(m,1H),0.87(s,3H).
实施例16：氨基磺酸酯F13的合成。
向10mL的反应瓶中加入表雄酮(0.2mmol，58.0mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F13，无色油状物，85.5mg，收率91％。1H NMR(400MHz,Chloroform-d)δ4.68(dq,J＝10.8,5.5,5.0Hz,1H),2.49–2.35(m,1H),2.09(m,1H),2.02(m,2H),1.95–1.88(m,1H),1.84–1.74(m,5H),1.73–1.67(m,1H),1.54(m,4H),1.48(s,9H),1.34–1.30(m,2H),1.22(m,3H),1.01(m,2H),0.83(d,J＝2.6Hz,6H).
实施例17：氨基磺酸酯F14的合成。
向10mL的反应瓶中加入二氢胆固醇(0.2mmol，77.7mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F14，无色油状物，90.9mg，收率80％。1H NMR(400MHz,Chloroform-d)δ4.70(dt,J＝11.5,6.0Hz,1H),1.97(m,2H),1.85–1.70(m,5H),1.70–1.56(m,5H),1.50(s,9H),1.41–1.29(m,6H),1.17–0.97(m,12H),0.91–0.83(m,12H),0.65(d,J＝5.8Hz,4H).
实施例18：氨基磺酸酯F15的合成。
向10mL的反应瓶中加入盐酸普萘洛尔(0.2mmol，59.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F15，白色固体，66.7mg，收率76％。1H NMR(400MHz,dmso)δ9.07(s,2H),8.29(d,J＝8.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.53(dd,J＝15.7,7.6Hz,3H),7.42(t,J＝7.9Hz,1H),6.97(d,J＝7.6Hz,1H),5.12–5.01(m,1H),4.36(ddd,J＝24.1,10.6,4.8Hz,2H),3.51–3.37(m,3H),1.37(s,9H),1.31(dd,J＝12.3,6.4Hz,6H).
实施例19：氨基磺酸酯F16的合成。
向10mL的反应瓶中加入艾地苯醌(0.2mmol，67.6mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F16，黄色油状物，72.5mg，收率70％。1H NMR(400MHz,Chloroform-d)δ4.30(t,J＝6.5Hz,2H),3.96(d,J＝1.7Hz,6H),2.41(t,J＝7.4Hz,2H),1.98(s,3H),1.72(dd,J＝8.3,6.5Hz,2H),1.47(s,9H),1.41–1.22(m,14H).
实施例20：氨基磺酸酯F17的合成。
向10mL的反应瓶中加入托吡卡胺(0.2mmol，56.8mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F17，白色固体，60.3mg，收率65％。1H NMR(400MHz,CD3OD)δ8.41(d,J＝5.8Hz,2H),7.44–7.25(m,5H),7.19(dd,J＝24.0,6.0Hz,2H),4.76(td,J＝9.4,7.2Hz,1H),4.71–4.62(m,2H),4.56(dd,J＝9.4,5.0Hz,1H),4.32–4.15(m,1H),3.48(dtd,J＝36.6,14.2,7.2Hz,2H),1.43(d,J＝5.2Hz,9H),1.05(dt,J＝20.6,7.1Hz,3H).
实施例21：氨基磺酸酯F18的合成。
向10mL的反应瓶中加入甲硝唑(0.2mmol，34.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F18，白色固体，51.9mg，收率74％。1H NMR(400MHz,CD3OD)δ7.98(s,1H),4.74–4.70(m,2H),4.65–4.61(m,2H),2.51(s,3H),1.38(s,9H).
实施例22：氨基磺酸酯F19的合成。
向10mL的反应瓶中加入美索巴莫(0.2mmol，48.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F19，无色油状物，50.4mg，收率60％。1H NMR(400MHz,CDCl3)δ6.96–6.72(m,4H),5.51(s,2H),5.14–5.05(m,1H),4.40(ddd,J＝18.3,12.4,4.7Hz,2H),4.25–4.19(m,1H),4.13(dd,J＝10.6,5.6Hz,1H),3.82(s,3H),1.29(s,9H).
实施例23：氨基磺酸酯F20的合成。
向10mL的反应瓶中加入4'-羟基黄烷酮(0.2mmol，48.0mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F20，无色油状物，76.3mg，收率91％。1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.9Hz,1H),7.54–7.39(m,3H),7.38–7.31(m,2H),7.08–6.92(m,2H),5.40(d,J＝12.5Hz,1H),3.06–2.72(m,2H),1.45(s,9H).
实施例24：氨基磺酸酯F21的合成。
向10mL的反应瓶中加入丙泊酚(0.2mmol，35.7mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F21，无色油状物，55.8mg，收率78％。1H NMR(400MHz,Methanol-d4)δ7.19(m,3H),3.52(m,2H),1.52(s,9H),1.21(d,J＝6.9Hz,12H).
实施例25：氨基磺酸酯F22的合成。
向10mL的反应瓶中加入CBZ-L-酪氨酸甲酯(0.2mmol，65.9mg)、氨基磺酰化试剂D1(0.6mmol，224mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F22，无色油状物，71.2mg，收率70％。1H NMR(400MHz,CDCl3)δ7.36–7.25(m,5H),7.18(d,J＝8.3Hz,2H),7.05(d,J＝8.1Hz,2H),5.44(d,J＝8.2Hz,1H),5.04(s,2H),4.58(dd,J＝13.4,6.0Hz,1H),3.66(s,3H),3.01(ddd,J＝20.3,13.7,6.1Hz,2H),1.40(s,9H).
实施例26：氨基磺酸酯F23的合成。
向10mL的反应瓶中加入2-萘乙醇(0.2mmol，34.2mg)、氨基磺酰化试剂D3(0.4mmol，198.4mg)、干燥的二氯甲烷2mL，室温下搅拌3小时。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、0.5M HCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，硅胶柱层析分离得产物F23，无色油状物，62.5mg，收率66％。1H NMR(400MHz,CDCl3)δ7.61(t,J＝5.7Hz,3H),7.55(t,J＝7.5Hz,2H),7.43(d,J＝7.8Hz,3H),7.30(dd,J＝6.2,3.3Hz,2H),7.27–7.22(m,2H),7.12(t,J＝7.0Hz,3H),4.41(t,J＝7.1Hz,2H),4.19(d,J＝6.9Hz,2H),3.98(t,J＝7.0Hz,1H),2.99(t,J＝7.0Hz,2H).
实施例27：Pevonedistat的合成。
向10mL的反应瓶中加入底物原料E1(0.2mmol，73.2mg)、氨基磺酰化试剂D1(0.4mmol，150mg)、干燥的乙腈1.5mL，干燥的二氯甲烷1.5mL，室温下搅拌1小时后，补加D1(0.1mmol，37.4mg)，继续搅拌1小时，TLC监控原料反应完全。加入12M浓盐酸0.5mL，室温搅拌1小时后，加饱和碳酸氢钠水溶液调pH到中性。加入50mL乙酸乙酯，先后用饱和碳酸氢钠溶液、饱和NaCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后，HPLC分析伯醇氨基磺酰化产物、剩余原料、仲醇取代副产物以及双羟基取代副产物的比例为：20:1：0.15:1)，反应选择性明显优于已报到方法。硅胶柱层析分离得产物G1，白色固体，74.5mg，收率84％。1HNMR(600MHz,MeOD)δ8.17(s,1H),7.25(t,J＝6.2Hz,2H),7.22–7.12(m,3H),6.63(d,J＝3.6Hz,1H),5.85(t,J＝7.7Hz,1H),5.45(qd,J＝8.8,5.0Hz,1H),4.49(t,J＝3.6Hz,1H),4.38(dd,J＝9.7,7.6Hz,1H),4.20(dd,J＝9.7,7.4Hz,1H),3.05(ddd,J＝15.6,8.7,3.2Hz,1H),2.97–2.88(m,1H),2.84–2.75(m,1H),2.63(dtd,J＝11.1,7.8,3.3Hz,1H),2.34(ddd,J＝13.5,7.9,1.1Hz,1H),2.25(ddd,J＝19.6,11.3,7.0Hz,2H),2.08–1.97(m,2H).
实施例28：三唑并嘧啶类NAE抑制剂G2的合成。
向250mL的反应瓶中加入底物原料E2(2.0mmol，792mg)、干燥的乙腈15mL，室温下缓慢滴加氨基磺酰化试剂D1(5.0mmol，1870mg)的乙腈溶液(25mL，0.2M)，室温下搅拌5小时。加入12M浓盐酸5mL，室温搅拌1小时后，加饱和碳酸氢钠水溶液调pH到中性。加入250mL乙酸乙酯，先后用饱和碳酸氢钠溶液、饱和NaCl溶液萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩后得黄色油状物粗品760mg。加入100mL乙醚，室温搅拌3小时，有灰白色固体析出，过滤，固体用乙酸乙酯溶解、活性炭吸附、重结晶后得产物G2，白色固体，570mg，收率60％。1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),7.36–7.14(m,4H),6.00(d,J＝5.4Hz,1H),5.61(s,1H),4.57(s,1H),4.44–4.31(m,2H),4.23(dd,J＝9.8,7.3Hz,1H),3.38(d,J＝7.9Hz,3H),3.17(qd,J＝16.4,4.3Hz,2H),2.91(s,1H),2.61(dt,J＝12.7,5.7Hz,1H),2.46(ddd,J＝12.7,7.8,4.5Hz,1H),2.33(t,J＝7.2Hz,2H).MS(ESI)：[M+H]+m/z 476.4
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范围。
Claims (10)
1.一种氨基磺酰化试剂，其特征在于，所述试剂包含式I所示化合物和式II所示化合物，
其中，R1选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C6-10芳基、取代或未取代的C6-10芳基-(CH2)m-、取代或未取代的芴基-(CH2)m-；
各m独立地选自下组：0、1、2、3、4、5；
R2-R6各自独立地选自下组：H、取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的C1-10酰胺基、取代或未取代的C1-10羰基、卤素、取代或未取代的苯基、取代或未取代的C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、醛基、酯基、羧基、C1-10烷基、C1-10氟烷基、C1-10环烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基；
所述试剂中，所述式I所示化合物和所述式II所示化合物的摩尔比为1：0.5-1.5。
2.如权利要求1所述的试剂，其特征在于，
R1选自下组：C1-10烷基、C2-10烯基、C2-10炔基、C6-10芳基、C6-10芳基-(CH2)m-、芴基-(CH2)m-；
m为1；
R2-R6各自独立地选自下组：H、C1-10烷基、C2-10烯基、C2-10炔基、C1-10酰胺基、C1-10羰基、卤素、苯基、C1-10烷氧基、-COOC1-10烷基、-S-C1-10烷基、-C＝COOC1-10烷基、硝基、氰基、羟基、羧基。
3.如权利要求1所述的试剂，其特征在于，式I所示化合物和式II所示化合物中，各R2-R6相同。
4.如权利要求1所述的试剂，其特征在于，所述试剂选自下组：
5.一种权利要求1所述试剂的制备方法，其特征在于，包括步骤：
1)将化合物A与R1OH反应，得到化合物B；
2)将化合物B与化合物C反应，得到试剂D，即权利要求1所述试剂；
其中，R1-R6如权利要求1所定义。
6.如权利要求5所述的方法，其特征在于，步骤2)中，化合物C与R1OH的摩尔比为2-4。
7.一种权利要求1所述试剂的用途，其特征在于，用于制备氨基磺酸酯。
8.一种氨基磺酸酯的制备方法，其特征在于，包括步骤：
i)将化合物E与权利要求1所述试剂反应，得到化合物F，即氨基磺酸酯；
其中，
R选自下组：取代或未取代的C1-10烷基、取代或未取代的C2-10烯基、取代或未取代的C2-10炔基、取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、取代或未取代的吡咯基、取代或未取代的萘基、取代或未取代的蒽基、取代或未取代的苯并基团；
所述取代指被选自下组的一个或多个取代基取代：卤素、羟基、硝基、氰基、羧基、C1-10烷基、C1-10亚烷基、
取代的C1-10亚烷基、C1-10烷氧基、C2-10烯基、C2-10炔基、苯基、苯氧基、苯基-(C＝O)-、＝O、
萘基；
R1如权利要求1所定义。
9.一种药物分子氨基磺酰化的方法，其特征在于，包括步骤：
使用权利要求1所述氨基磺酰化试剂对前体药物进行单羟基修饰，以得到氨基磺酰化的药物分子；
所述前体药物包含2-10个羟基。
10.如权利要求9所述的方法，其特征在于，所述氨基磺酰化的药物分子具有选自下组的结构：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011254756.0A CN114478373B (zh) | 2020-11-11 | 2020-11-11 | 一种氨基磺酸酯的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011254756.0A CN114478373B (zh) | 2020-11-11 | 2020-11-11 | 一种氨基磺酸酯的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114478373A true CN114478373A (zh) | 2022-05-13 |
| CN114478373B CN114478373B (zh) | 2023-11-17 |
Family
ID=81491381
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011254756.0A Active CN114478373B (zh) | 2020-11-11 | 2020-11-11 | 一种氨基磺酸酯的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114478373B (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001002349A (ja) * | 1999-06-18 | 2001-01-09 | Mitsubishi Electric Corp | エレベーターのかご装置 |
-
2020
- 2020-11-11 CN CN202011254756.0A patent/CN114478373B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001002349A (ja) * | 1999-06-18 | 2001-01-09 | Mitsubishi Electric Corp | エレベーターのかご装置 |
Non-Patent Citations (1)
| Title |
|---|
| LOÏC PANTAINE: "Efficient Synthesis of Unsymmetrical Sulfamides via a Lossen-Like Rearrangement By: Pantaine, Loic", ADVANCED SYNTHESIS & CATALYSIS, vol. 358, pages 2012 - 2016 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114478373B (zh) | 2023-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101269568B1 (ko) | 루테늄 착물 리간드, 루테늄 착물, 고정 루테늄 착물 촉매및 그의 제조방법과 용도 | |
| Ollevier et al. | An efficient method for the ring opening of epoxides with aromatic amines catalyzed by bismuth trichloride | |
| US20070078273A1 (en) | Process for preparing 5-methyl-2-furfural | |
| CN107235923B (zh) | 一类3-芳基喹喔啉酮衍生物的制备方法 | |
| CN110938077A (zh) | 合成Avapritinib的方法 | |
| CN101684075A (zh) | 一种金属络合物配体、金属络合物及其制备方法和应用、高分子聚合物及其制备方法和应用 | |
| CN106986804A (zh) | 用于单卤代甲基基团转移的基于锍离子的亲电试剂、其制备和用途 | |
| Kadoh et al. | Enhanced structural variety of nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation of benzylic C–H bonds | |
| CN113214129A (zh) | 一种磺酰自由基引发的1,6-二烯类化合物碘化/磺酰化反应方法 | |
| CN112920066A (zh) | 一种α-取代-α-氨基酸酯类化合物及其制备方法 | |
| Chen et al. | MnBr2 catalyzed regiospecific oxidative Mizoroki-Heck type reaction | |
| CN114634482A (zh) | 一种重氮二氟甲基化试剂及其合成方法和应用 | |
| Mendoza et al. | Trialkylsilyl triflimides as easily tunable organocatalysts for allylation and benzylation of silyl carbon nucleophiles with non-genotoxic reagents | |
| CN114478373A (zh) | 一种氨基磺酸酯的制备方法 | |
| CN109232334A (zh) | 一种甲硫基甲酯的合成方法 | |
| CN110790809A (zh) | 一种醋酸阿比特龙的制备方法 | |
| US5637722A (en) | Ester syntheses and transesterifiable xanthate reactants therefor | |
| Zhou et al. | Oxidative cross-coupling of allyl (trimethyl) silanes with aryl boronic acids by palladium catalysis | |
| JP4163113B2 (ja) | 新規化合物及びその製造方法 | |
| CN108440395A (zh) | 一种米力农杂质的制备方法 | |
| JPH04234358A (ja) | ２，６−ジ−ｔ−ブチル−４−メルカプト−フェノールの製造方法 | |
| CN1307165C (zh) | 4－甲基－5－甲酰噻唑的制造方法 | |
| JP2008100951A (ja) | ２−シクロペンタデセノンの製造方法 | |
| He et al. | Bicyclic Organophosphorus Amides. Nucleophilic Cleavage of 1-Oxo-2, 3-benzo-10-phenyl-4, 7, 10-triaza-1λ 5-phosphabicyclo [5.3. 0] decane and its p-Anisyl Analogues | |
| KR100834711B1 (ko) | 엔-아실-5'-데옥시-5-플루오로시티딘 유도체의 제조 방법 |
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 |