CN113661166A - 用于合成二氮杂二环[6.2.0]癸烷相关化合物的方法 - Google Patents
用于合成二氮杂二环[6.2.0]癸烷相关化合物的方法 Download PDFInfo
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- CN113661166A CN113661166A CN202080017679.9A CN202080017679A CN113661166A CN 113661166 A CN113661166 A CN 113661166A CN 202080017679 A CN202080017679 A CN 202080017679A CN 113661166 A CN113661166 A CN 113661166A
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- Prior art keywords
- alkyl
- compound
- formula
- pharmaceutically acceptable
- nitrogen
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 110
- 238000000034 method Methods 0.000 title claims abstract description 64
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 230000008569 process Effects 0.000 title claims description 19
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- AOPMQYDIROQTMY-UHFFFAOYSA-N 1,2-diazabicyclo[6.2.0]decane Chemical compound N12NCCCCCC2CC1 AOPMQYDIROQTMY-UHFFFAOYSA-N 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 150000002596 lactones Chemical class 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 77
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 59
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 32
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- -1 sulfinyl imine Chemical class 0.000 claims description 26
- 125000002950 monocyclic group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 239000001301 oxygen Chemical group 0.000 claims description 24
- 239000000543 intermediate Substances 0.000 claims description 22
- 125000004434 sulfur atom Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Chemical group 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002500 ions Chemical class 0.000 claims description 8
- 239000012038 nucleophile Substances 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical group C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 4
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001721 carbon Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012069 chiral reagent Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical group [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000005543 phthalimide group Chemical group 0.000 claims 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 54
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012267 brine Substances 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000012043 crude product Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- VKRCTZCBMKVHCK-RTOKGZNSSA-N (8R,9S,10S)-10-[(dimethylamino)methyl]-N-(4-methoxyphenyl)-9-[4-(2-phenylethynyl)phenyl]-1,6-diazabicyclo[6.2.0]decane-6-carboxamide Chemical compound CN(C)C[C@@H]1[C@@H]([C@@H]2CN(CCCCN12)C(=O)NC1=CC=C(C=C1)OC)C1=CC=C(C=C1)C#CC1=CC=CC=C1 VKRCTZCBMKVHCK-RTOKGZNSSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 238000005447 aza-Wittig reaction Methods 0.000 description 5
- 239000012456 homogeneous solution Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- DLEIRQMIYDUVBY-OWOJBTEDSA-N (e)-3-(4-bromophenyl)prop-2-en-1-ol Chemical compound OC\C=C\C1=CC=C(Br)C=C1 DLEIRQMIYDUVBY-OWOJBTEDSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 4
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 4
- ZMXDDKWLCZADIW-YYWVXINBSA-N N,N-dimethylformamide-d7 Chemical compound [2H]C(=O)N(C([2H])([2H])[2H])C([2H])([2H])[2H] ZMXDDKWLCZADIW-YYWVXINBSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 201000004792 malaria Diseases 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- MFKOGXVHZUSUAF-QPJJXVBHSA-N methyl (e)-3-(4-bromophenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(Br)C=C1 MFKOGXVHZUSUAF-QPJJXVBHSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 238000007248 oxidative elimination reaction Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- CPDDDTNAMBSPRN-ZZXKWVIFSA-N (e)-3-(4-bromophenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=C(Br)C=C1 CPDDDTNAMBSPRN-ZZXKWVIFSA-N 0.000 description 2
- 150000000180 1,2-diols Chemical class 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- YOZFZNNDFOOJMQ-UHFFFAOYSA-N 1-bromo-4-(3-bromoprop-1-enyl)benzene Chemical compound BrCC=CC1=CC=C(Br)C=C1 YOZFZNNDFOOJMQ-UHFFFAOYSA-N 0.000 description 2
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 238000005821 Claisen rearrangement reaction Methods 0.000 description 2
- 208000008953 Cryptosporidiosis Diseases 0.000 description 2
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- IFAXXCBMQJNCCF-UHFFFAOYSA-N N-(trifluoroacetyl)glycine Chemical compound OC(=O)CNC(=O)C(F)(F)F IFAXXCBMQJNCCF-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 102000002798 Phenylalanine-tRNA Ligase Human genes 0.000 description 2
- 108010004478 Phenylalanine-tRNA Ligase Proteins 0.000 description 2
- 241000224016 Plasmodium Species 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 125000000532 dioxanyl group Chemical group 0.000 description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000005657 iodolactonization reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000003328 mesylation reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- OFXSXYCSPVKZPF-UHFFFAOYSA-N methoxyperoxymethane Chemical class COOOC OFXSXYCSPVKZPF-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- VZOPRCCTKLAGPN-ZFJVMAEJSA-L potassium;sodium;(2r,3r)-2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VZOPRCCTKLAGPN-ZFJVMAEJSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
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- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- 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
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/12—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
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- C—CHEMISTRY; METALLURGY
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Abstract
本申请提供一种合成二氮杂二环[6.2.0]癸烷化合物的方法。该合成通过立体选择性合成手性内酯、再通过一系列化学选择性反应形成氮杂环丁烷来进行。通过双环化而形成了二氮杂二环[6.2.0]癸烷相关的化合物。
Description
政府支持的声明
本发明是在美国国防部同行审查医学研究计划所资助的政府支持(资金编号:W81XWH-16-1-0719)下完成的。政府享有本发明的某些权利。
相关申请的交叉引用
本申请要求提交于2019年1月9目的美国临时专利申请号62/790,340的优先权,其通过引用并入本文。
技术领域
本发明涉及用于生产1,6-二氮杂二环[6.2.0]癸烷的以立体化学界定的合成。
背景技术
疟疾是由疟原虫属的原生动物寄生虫引起的传染病。疟疾难以被根治的原因在于,疟原虫复杂的生命周期和寄生虫抗药性的出现。多样性导向合成(DOS)已被用于鉴别抗疟化合物。例如,已鉴别出了苯丙氨酰-tRNA合成酶抑制剂(phenylalanyl-tRNAsynthetase inhibitor)BRD7929。BRD7929在寄生虫生命周期的所有阶段均表现出活性。
BRD7929的化学名为(8R,9S,10S)-10-[(二甲氨基)甲基]-N-(4-甲氧基苯基)-9-[4-(2-苯基乙炔基)苯基]-1,6-二氮杂二环[6.2.0]癸烷-6-甲酰胺,其被报道于美国专利申请公开号US2016/0289235中,该文献通过引用并入本文。BRD7929具有下述结构:
同样地,下述结构所示的化合物(式XIV、或化合物22)也被鉴别为可用于治疗及/或预防由寄生虫传播的疾病,包括疟疾和隐孢子虫病:
参见WO2018/175385,该文献被援引并以其全文并入本文中。
同样据称可用于对抗由寄生虫传播的疾病(包括例如疟疾和隐孢子虫病)的疗法中的追加的相关化合物及其合成可见于WO2018/175385;Lowe,J.T.等,Synthesis andprofiling of a diverse collection of azetidine-based scaffolds for thedevelopment of CNS-focused lead-like libraries,J.Org.Chem.77,7187-7211(2012);Maetani,M.等,Synthesis of a Bicyclic Azetidine with In Vivo AntimalarialActivity Enabled by Stereospecific,Directed C(sp3)-H Arylation,J.A.C.S.139,11300-11306(2017);和Kato,N.等,Diversity-oriented synthesis yields novelmultistage antimalarial inhibitors,Nature 538,344-349(2016)中,所有上述文献均被援引并以其全文并入本文中。
与制备用于和治疗寄生虫疾病的化合物相关的追加文献包括下述文献:WO2015070204、WO2015002755、WO2016172631和US2018/0194768;其均被援引并以其全文并入本文中。
然而,冗长、低产率及/或昂贵的合成路线限制了这一化合物的应用。已知BRD7929、式XIV和相关化合物具有治疗价值,改进用于其生产的合成路线能够提供该类化合物进一步的药物化学探索同时降低其生产成本,从而使这些治疗剂的开发及/或广泛供应更加可行。因此,需要改进用于制备这些潜在抗疟化合物的合成。
发明内容
一个实施方式涉及一种形成式I所示固体化合物的方法:
在另一个实施方式中,P1选自由-C(O)CF3、-C(O)OC(CH3)3和-C(O)OCH2Ph组成的组。
在另一个实施方式中,P1是-C(O)CF3。
在另一个实施方式中,反应中,所述碱是二异丙基胺锂,并且在ZnCl2的存在下进行。
在另一个实施方式中,手性试剂是(R)-(+)-1-苯乙胺。
在另一个形成式I所示化合物的实施方式中,R1是-I、-Cl、-Br、或
R2是C(O)R3;R3是-O烷基;并且P1是氮保护基团。所述方法包括使式III的反应物与手性亚磺酰亚胺反应,
其中,X1是卤素原子。
在另一个实施方式中,R4是-C(CH3)3并且,R5是-CH2CH3。
在另一个实施方式中,反应在Zn的存在下进行。
另一个实施方式可涉及形成式IV所示化合物的方法:
形成式V的内酯,
其中,R2是C(O)R3;R3是-OH、-O烷基、-O-;当R3是-O-时,阳抗衡离子与式I离子缔合;并且,P1是氮保护基团;将式V的内酯还原为式VI的化合物:
将共价连接至式VI的不饱和碳的醇基转化为离去基团形成中间体,所述中间体与氮亲核试剂反应产生式IV的化合物。
在一个实施方式中,氮亲核试剂是邻苯二甲酰亚胺。
在另一个实施方式中,式V的内酯通过在极性溶剂中使式I的化合物与卤素的正电性源反应而形成。
在另一个实施方式中,卤素的正电性源是I2,并且,极性溶剂是CH3CN的水性混合物。本领域技术人员容易认识到可以使用的多种极性溶剂,包括但不限于水、THF的水溶液、DMF的水溶液、或者其它极性质子或极性非质子的水混溶溶剂。
在另一个实施方式中,式V的内酯通过如下方式形成:在极性溶剂中使式I的化合物与I2反应以形成第一产物,以及,使第一产物与NaN3反应形成式V的化合物。
在另一个实施方式中,还原用NaBH4来实施。
在另一个实施方式中,离去基团是甲磺酸基(mesylate groups),并且,中间体由下述结构中的一者或两者所示:
在另一个实施方式中,P1从-C(O)CF3转化为下述结构:
在另一个实施方式中,R1是-Br,R2是-C(O)OCH2CH3,并且,P1是-S(O)C(CH3)3。
在另一个实施方式中,式V的内酯通过如下方式形成:在极性溶剂中使式I的化合物与卤化物的正电性源反应形成第一产物,以及,使第一产物与NaN3反应形成式V的化合物。
在另一个实施方式中,式V的内酯被NaBH4还原形成下述化合物:
在另一个实施方式中,离去基团是甲磺酸基,并且,中间体由下述结构中的一者或两者所示:
另一个实施方式可涉及一种制备式VIII的结构所示化合物的方法:
式VIII中,R1是-I、-Cl、-Br、或R6和R7独立地相同或不同,且选自-H、烷基、-O烷基,或者其中R6和R7与它们所连接的原子一起形成环;R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系;R10是-H、直链或支链烷基、-C(O)烷基、-C(O)O-烷基、-C(O)NH-烷基、-C(O)芳基、-C(O)O-芳基、-C(O)NH-芳基、-C(O)杂芳基、-C(O)O-杂芳基和-C(O)N-杂芳基;其中烷基、芳基和杂芳基被一个或多个卤素、氧、氮、或硫原子任选地取代。方法包括使式IV所示化合物与经取代的γ-羟醛(substitutedγ-hydroxyaldehyde)反应,以及,实现双环化
在一个实施方式中,γ-羟醛由下述结构所示:
其中R11是-H或氧保护基团;并且,R12是-H或-CH2OH。
在另一个实施方式中,γ-羟醛是
并且,经由下述中间体制备式VIII的化合物:
在另一个实施方式中,方法进一步包括氧化和经由下述中间体制备式VIII的化合物:
在另一个实施方式中,方法进一步包括还原、双环化和经由下述中间体制备式VIII的化合物:
在另一个实施方式中,方法进一步包括还原和经由下述中间体制备式VIII的化合物:
在另一个实施方式中,式XIII的化合物与4-甲氧基苯基异氰酸酯反应,并且,式VIII的化合物为如下述结构所示:
本发明的另一目的涉及一种形成式IV所示化合物的方法,
在一个实施方式中,离去基团是甲磺酸基,并且,中间体由下述结构中的一者或两者所示,
在另一个实施方式中,氮亲核试剂是邻苯二甲酰亚胺。
本发明的一个有益发现是用以制备经取代的氮杂环丁烷的化学选择性串联工艺。这可能是首例优先于氧离去基团置换的、定制型(tailored)亲核氮丙啶开环或者首例之一,其强调了环应变能释放在控制化学反应活性中的重要性。本发明的另一个有益发现是应用氮杂-维蒂希(aza-Wittig)/还原串(sequence),直接从叠氮基-醛构建八元环。
另一个实施方式涉及式I所示化合物:
另一个实施方式涉及式IV所示化合物:
另一个实施方式涉及式V所示化合物:
另一个实施方式涉及式VI所示化合物:
另一个实施方式涉及式VII所示化合物:
另一个实施方式涉及式VIIb所示化合物:
另一个实施方式涉及式VIII所示化合物:
式VIII中,R1是-I、-Cl、-Br、或R6和R7独立地相同或不同,且选自-H、烷基、-O烷基,或者其中R6和R7与它们所连接的原子一起形成环;R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系;和R10是-H、直链或支链烷基、-C(O)烷基、-C(O)O-烷基、-C(O)NH-烷基、-C(O)芳基、-C(O)O-芳基、-C(O)NH-芳基、-C(O)杂芳基、-C(O)O-杂芳基和-C(O)N-杂芳基,其中所述烷基、芳基和杂芳基被一个或多个氢、卤素、氧、氮、或硫原子取代。
另一个实施方式涉及式X所示化合物:
式X中,R1是-I、-Cl、-Br、或并且,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个氢、卤素、氧、氮、或硫原子取代。
另一个实施方式涉及式XI所示化合物:
式XI中,R1是-I、-Cl、-Br、或并且,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个氢、卤素、氧、氮、或硫原子取代。
另一个实施方式涉及式XII所示化合物:
式XII中,R1是-I、-Cl、-Br、或并且,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个卤素、氢、氧、氮、或硫原子取代。
另一个实施方式涉及式XIII所示化合物:
式XIII中,R1是-I、-Cl、-Br、或并且,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个卤素、氢、氧、氮、或硫原子取代。
另一个实施方式涉及式XV所示化合物:
Z是选自下述任一者的四元含氮杂环:
P1和P2相同或不同,并且是氮保护基团或-H;
R6和R7独立地相同或不同,且选自-H、烷基、-O烷基,或者其中R6和R7与它们所连接的原子一起形成环;R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系;和R10是-H、直链或支链烷基、-C(O)烷基、-C(O)O-烷基、-C(O)NH-烷基、-C(O)芳基、-C(O)O-芳基、-C(O)NH-芳基、-C(O)杂芳基、-C(O)O-杂芳基和-C(O)N-杂芳基,其中烷基、芳基和杂芳基被一个或多个卤素、氢、氧、氮、或硫原子取代;
R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;
R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;
R8和R9独立地相同或不同,并且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;和
R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中所述烷基被一个或多个卤素、氢、氧、氮、或硫原子任选地取代.
另一个实施方式涉及式XV所示化合物:
其中在式XV中,Z选自下述中的一者:
R2是C(O)R3;R3是-O-,并且,阳抗衡离子与式XVI离子缔合,或R3是-OH;并且,P1是氮保护基团或-H;
P1是氮保护基团或-H;
P1是氮保护基团或-H;
P1是氮保护基团或-H;和
P1是氮保护基团或-H;
或者其药学上可接受的盐。
本文提供的化合物,包括但不限于式I、IV、V、VI、VII、VIIb、VIII、X、XI、XII、XIII和XV的化合物,可作为药学上可接受的盐提供。如本文中使用的“药学上可接受的盐”在本公开文本中指化合物的酸加成盐或碱加成盐。药学上可接受的盐是保留了母体化合物的活性且对施用其的受试者和在其所施用的环境中不产生任何不必要的有害影响或不理想影响的任意盐。药学上可接受的盐包括但不限于金属络合物以及无机酸和羧酸的盐。药学上可接受的盐还包括例如铝、钙、铁、镁、锰的金属盐和络盐(complex salts)。此外,药学上可接受的盐包括但不限于下述酸式盐,例如乙酸盐、天冬氨酸盐、烷基磺酸盐、芳基磺酸盐、醋氧乙基(axetil)盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、重硫酸(bisulfuric)盐、酒石酸氢盐、丁酸盐、乙二胺四乙酸钙盐、樟脑磺酸(camsylic)盐、碳酸盐、氯苯甲酸盐、柠檬酸盐、乙二胺四乙酸盐、乙二磺酸(edisylic)盐、丙酸酯十二烷基硫酸(estolic)盐、乙基磺酸(esyl)盐、乙磺酸(esylic)盐、甲酸盐、富马酸盐、葡庚糖酸(gluceptic)盐、葡萄糖酸(gluconic)盐、谷氨酸盐、甘醇酸(glycolic)盐、羟乙酰基氨苯胂酸(glycolylarsanilic)盐、环己磺酸(hexamic)盐、己基间苯二酸盐(hexylresorcinoic)盐、海巴明(hydrabamic)盐、氢溴酸盐、盐酸盐、氢碘酸盐、羟基萘甲酸盐、羟基乙磺酸(isethionic)盐、乳酸盐、乳糖酸盐、马来酸盐、苹果酸盐、丙二酸盐、杏仁酸盐、甲磺酸盐、甲基硝酸盐、甲基硫酸盐、粘酸盐、粘康酸(muconic)盐、萘磺酸(napsylic)盐、硝酸盐、草酸盐、对硝基甲磺酸盐、帕莫酸盐、泛酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、邻苯二甲酸盐、聚半乳糖醛酸盐、丙酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、氨基磺酸盐、对氨基苯磺酸盐、磺酸盐、硫酸盐、单宁酸盐、酒石酸盐、茶氯酸(teoclic)盐、甲苯磺酸盐等。药学上可接受的盐可源于氨基酸,包括但不限于半胱氨酸。生产作为盐的化合物的方法是本领域技术人员已知的(参见例如,Stahl等,Handbook ofPharmaceutical Salts:Properties,Selection,and Use,Wiley-VCH;Verlag HelveticaChimica Acta,Zurich,2002;Berge等,J.Pharm.Sci.66:1,1977)。
本发明的其它方面和优点根据下述说明、附图和所附权利要求是显而易见的。
附图说明
图1:图1示出化合物5的ORTEP投影。
图2:图2示出化合物32的ORTEP投影。
具体实施方式
虽然本文中使用的术语被认为可被本领域普通技术人员充分理解,但为了便于解释本文公开的主题,仍在本文中对定义进行了阐述。
除非另外定义,本文中使用的所有技术和科学术语均具有与本文公开的主题所属领域的普通技术人员的通常理解相同的含义。尽管与本文所述的方法、装置和材料相似或等价的任意方法、装置和材料均可用于实践或测试当前公开的主题,本文仍描述了代表性的方法、装置和材料。
本文使用的所有方法组合或工艺步骤均能够以任意顺序执行,除非在做出所引用组合的上下文中另外说明或明确暗示了相反内容。
本公开文本的方法和装置(包括其组成部分)可包括本文所述实施方式的基本要素和限定,以及本文所述或其他有用的任何附加的或任选的组成部分或限定;或者由本文所述实施方式的基本要素和限定,以及本文所述或其他有用的任何附加的或任选的组成部分或限定组成;或者基本由本文所述实施方式的基本要素和限定,以及本文所述或其他有用的任何追加的或任选的组成部分或限定组成。
除非另外指出,说明书和权利要求中用于表述物理尺寸、成分数量、性质(如反应条件)等的所有数字在所有情况下均应理解为被术语“约”修饰。因此,除非被相反地指出,本说明书和权利要求中提及的数值参数是能够根据当前公开的主题想要获得的理想性质而改变的近似值。
术语“烷基”包括支链、直链和环状的、经取代或未经取代的饱和脂肪族烃基。烷基可包含约1个至约24个碳原子(“C1~C24”)、约7个至约24个碳原子(“C7~C24”)、约8个至约24个碳原子(“C8~C24”)、或约9个至约24个碳原子(“C9-C24”)。烷基还可包含约1个至约8个碳原子(“C1~C8”)、约1个至约6个碳原子(“C1~C6”)或者约1个至约3个碳原子(“C1~C3”)。C1~C6烷基的示例包括但不限于,甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、环丙基甲基和新己基的基团(radical)。
术语“芳基”包括6至14元单环、双环或三环芳族烃环体系。芳基的示例包括苯基和萘基。
术语“杂芳基”包括5至14元的芳族杂环,其具有至少一个选自氮、氧和硫的杂原子,并含有至少1个碳原子,包括单环、双环和三环环系。代表性的杂芳基是三唑基、四唑基、恶二唑基(oxadiazolyl)、吡啶基、呋喃基、苯并呋喃基(benzofuranyl)、苯硫基(thiopheny1)、苯并苯硫基(benzothiophenyl)、喹啉基(quinolinyl)、吡咯基、吲哚基、恶唑基(oxazolyl)、苯并恶唑基(benzoxazolyl)、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异恶唑基、吡唑基、异噻唑基、哒嗪基、嘧啶基(pyrimidinyl)、吡嗪基、三嗪基、噌啉基(cinnolinyl)、酞嗪基、喹唑啉基、间二氮杂苯基(pyrimidyl)、氧杂环丁基(oxetanyl)、氮杂环庚烷基(azepinyl)、哌嗪基、吗啉基、二恶烷基(dioxanyl)、硫杂环丁基(thietanyl)和恶唑基。
氧保护基团包括但不限于例如,苄基或经取代的苄基、甲硅烷基或经取代的甲硅烷基、乙酰基或其它酯保护基团、甲氧基甲基或其它甲氧基醚(methoxy ethers)。本领域技术人员会认识到其它可接受的保护基团,如鉴别于Greene’s Protective Groups inOrganic Synthesis,Fifth ed.,Peter G.M.Wuts,John Wiley&Sons,Inc.(2014)中的保护基团,该文献通过引用全文并入本文中。
本领域技术人员会认识到根据本发明的实施方式可以使用的多种氮保护基团。还参见Greene’s Protective Groups in Organic Synthesis,Fifth ed.,该文献通过引用全文并入本文中。有用的氮保护基团可包括,例如但不限于9-芴基甲基氨基甲酸酯(9-fluorenylmethyl carbamate);叔丁基氨基甲酸酯(t-butyl carbamate);2-硝基苯磺酰基(2-nitrobenzenesulfonyl);4-硝基苯磺酰基(4-nitrobenzenesulfonyl);苄基氨基甲酸酯(benzyl carbamate);乙酰胺;三氟乙酰胺;邻苯二甲酰亚胺;苄胺;三苯基甲胺;亚苄基胺(benzylideneamine);和对甲苯磺酰胺。
缩写。XPhos-Pd-G3(XPhos G3)是(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II),XPhos-G3-环钯配合物(Sigma-Aldrich)。戴斯-马丁试剂(Dess Martin periodinane)是1,1,1-三(乙酰氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮(Sigma-Aldrich)。MTBE是甲基叔丁基醚。如本文所使用的,“Ns”或“nosyl”指2-硝基苯磺酰基;“Ms”或“mesyl”指甲磺酰基;和“TFA”指三氟乙酰基。
虽然任意给出的权利要求中仅呈现了某些立体异构体,本领域技术人员将理解,通过制造适当的对应手性起始原料或中间体,能够制备对映异构体或其它立体异构体。
如果描述的结构和示出所述结构的命名之间存在差异,以描述的结构为准。此外,如果结构或者部分结构的立体化学没有用例如粗线或虚线标注,所述结构或者部分结构意在涵盖其所有的立体异构体。
路线A合成
酯化4-溴肉桂酸生成((E)-3-(4-溴苯基)丙烯酸甲酯)1
将氯化亚砜(176mL,2422mmol)滴加至4-溴肉桂酸(500g,2202mmol)在甲醇(3000mL)中的白色悬浮液中,历时20分钟,期间反应温度保持在低于40℃。然后,将混合物加热至回流1小时,期间逐渐均质化。使溶液缓慢至室温以生成白色悬浮液。将其过滤并用冷甲醇洗涤滤饼两次,生成为白色固体的1。将滤液浓缩至原始体积的一半并再次过滤,用冷甲醇洗涤滤饼。将所述工序再重复两次生成追加的1(合并为523g,产率98%)。
1H NMR(400MHz,CDCl3)δ7.62(d,J=16.0Hz,1H),7.52(d,J=8.2Hz,2H),7.38(d,J=8.6Hz,2H),6.43(d,J=16.0Hz,1H),3.81(s,3H);13C NMR(75MHz,CDCl3)δ167.1,143.4,133.2,132.1,129.4,124.5,118.5,51.8。
1的菌头反应(Sonogashira reaction)生成((E)-3-(4-(苯基乙炔基)苯基)丙烯酸甲酯)2
将1(285g,1180mmol)溶解于二异丙胺(2500ml)中生成澄清、均质的溶液。向其中鼓入氮气30分钟后,添加碘化亚铜(I)(0.169g,0.885mmol)、二(氰基苯)氯化钯(II)(0.453g,1.18mmol)和三叔丁基膦四氟硼酸盐(0.685g,2.36mmol)。将混合物加热至80℃,之后分批添加苯乙炔(136mL,1239mmol)以首先引发反应,如内部温度升高至回流和形成沉淀所示,然后保持放热反应的回流。在完成添加后,将混合物于80℃追加搅拌1小时,然后使其缓慢地达到50℃,此时用水(2000mL)淬灭反应。边搅拌混合物边使其达到室温,然后过滤。用水(200mL×3)洗涤滤饼,然后于40℃真空干燥,生成为白色固体的2(296g,96%),其根据NMR谱是纯的。
1H NMR(400MHz,CDCl3)δ7.69(d,J=16.0Hz,1H),7.56-7.50(m,6H),7.38-7.35(m,3H),6.46(d,J=16.0Hz,1H),3.83(s,3H);13C NMR(75MHz,CDCl3)δ167.2,143.9,134.1,132.0,131.6,128.5,128.4,128.0,125.2,122.9,118.4,91.6,89.0,51.7。
还原2生成((E)-3-(4-(苯基乙炔基)苯基)丙-2-烯-1-醇)3
将2(210g,801mmol)在二氯甲烷(3150mmol)中的澄清、无色溶液在干冰-丙酮浴中冷却至-78℃,期间所述溶液转变为白色悬浮液。缓慢添加二异丁基氢化铝的溶液(在甲苯中25wt.%,934g,1641mmol)后,历时12小时使混合物缓慢达到-20℃。用酒石酸钾钠四水合物(926g,3282mmol)在水(4200mL)中的溶液小心淬灭反应,将混合物于室温搅拌12小时。分离两相,并且用二氯甲烷(1700mL×4)萃取水相。将合并的有机相经过无水硫酸钠干燥并浓缩生成为白色固体的3(184g,98%),其根据NMR谱是纯的。
1H NMR(400MHz,CDCl3)δ7.55-7.48(m,4H),7.39-7.34(m,5H),6.63(d,J=16.1Hz,1H),6.41(dt,J=16.0,5.4Hz,1H),4.36(dd,J=5.5,1.6Hz,2H);13C NMR(75MHz,CDCl3)δ136.6,131.8,131.6,130.4,129.5,128.3,128.3,126.4,123.2,122.4,90.1,89.4,63.6。
用N-(三氟乙酰基)甘氨酸酯化3生成((E)-3-(4-(苯基乙炔基)苯基)烯丙基(2,2,2-三氟乙酰基)甘氨酸酯)4
将3(184g,785mmol)、N-(三氟乙酰基)甘氨酸(136g,793mmol)和4-(二甲氨基)吡啶(9.59g,78.5mmol)的混合物加入二氯甲烷(1840mL)中生成黄色悬浮液。将其在冰浴中冷却至10℃,此时分批加入N,N’-二异丙基碳二亚胺(128mL,825mmol),同时保持内部温度低于15℃。使混合物缓慢达到室温,并搅拌过夜。过滤混合物,并用二氯甲烷(50mL×3)洗涤滤饼。将滤液加入乙酸乙酯/甲基叔丁基醚(1∶1,3680mL)的混合溶剂中,用碳酸氢钠水溶液(400mL×2)和盐水(brine)(400mL)洗涤。将有机相经过无水硫酸钠干燥并浓缩。将残余物在异丙醇中结晶生成为白色固体的4(240g,79%)。
1H NMR(400MHz,CDCl3)δ7.56-7.50(m,4H),7.40-7.34(m,5H),6.90(br s,1H),6.6.69(d,J=15.6Hz,1H),6.31(dt,J=16.0,6.6Hz,1H),4.88(dd,J=6.6,1.1Hz,2H),4.19(d,J=5.0Hz,1H);13C NMR(75MHz,CDCl3)δ168.0,135.5,134.9,131.9,131.6,128.4,126.6,123.3,123.1,122.5,90.5,89.1,66.6,41.4。
克莱森重排(Claisen rearrangement)4并使用(R)-(+)-1-苯乙胺进行手性拆分生成((R)-1-苯基乙烷-1-氨(2S,3S)-3-(4-(苯基乙炔基)苯基)-2-(2,2,2-三氟乙酰氨基)4-戊烯酸)5
二异丙基氨基锂(LDA)的制备:将二异丙胺(22.8mL,160mmol)在四氢呋喃(130mL)中的溶液在冰浴中冷却,并且用正丁基锂的溶液(己烷中2.5M,62.0mL,155mmol)缓慢地进行处理,同时保持内部温度低于20℃。去除冰浴并于室温搅拌混合物30分钟。
在单独的容器中,将4(20.0g,51.6mmol)在四氢呋喃(140mL)中的溶液在干冰-丙酮浴中冷却生成黄色悬浮液。将其用氯化锌的溶液(2-甲基四氢呋喃中1.9M,40.8mL,77.4mmol)处理,同时保持内部温度低于-60度。向该混合物中缓慢添加LDA溶液,同时保持内部温度低于-65℃,期间所述混合物在所述添加快结束时转变为深蓝色均质溶液。将反应混合物保持于所述温度60分钟。去除冷却浴,并使反应混合物缓慢达到室温,期间其转变为深橙色。用盐酸(1M,336mL,336mmol)淬灭反应,期间内部温度升至35℃。将两相分离并用甲基叔丁基醚(160mL×2)萃取水相。将合并的有机相浓缩并将残余物加入甲基叔丁基醚(160mL)中。加热混合物至回流温度生成大致澄清的溶液。将其用(R)-(+)-1-苯乙胺(12.5g,103mmol)处理生成澄清的溶液,从中很快开始形成沉淀。利用搅拌,使混合物缓慢达到室温,然后在冰浴中冷却。过滤产物,用甲基叔丁基醚(20mL×2)洗涤,并真空干燥生成为白色固体的5(10.7g,产率40.8%,对映体比例(e.r.)=16.8:1)。
1H NMR(400MHz,MeOH-d4)δ7.52-7.49(m,2H),7.46-7.39(m,7H),7.39-7.34(m,3H),7.28(d,J=8.2Hz,2H),6.24-6.14(m,1H),5.13-5.09(m,2H),4.70(d,8.2Hz,1H),4.44(q,J=7.0Hz,1H),3.86(t,J=8.2Hz,1H),1.63(d,J=7.0Hz,3H);13C NMR(75MHz,MeOH-d4)δ175.5,142.2,140.1,139.1,132.7,132.6,130.5,130.3,130.0,129.7,129.5,127.7,124.9,123.2,117.4,90.2,90.1,61.0,54.3,52.5,21.0。
5的碘内酯化反应和用叠氮化钠取代生成(N-((3S,4S,5S)-5-(叠氮基甲基)-2-氧代-4-(4-(苯基乙炔基)苯基)四氢呋喃-3-基)-2,2,2-三氟乙酰胺)7
将5(30.9g,60.8mmol)在乙腈(494mL)和水(124mL)中的白色乳状悬浮液冷却至0℃并用碘(30.8g)处理生成深红色溶液,于所述温度搅拌1小时。通过用硫代硫酸钠(28.8g,182mmol)处理混合物并搅拌10分钟使反应淬灭,期间转变为浅黄色。将混合物加入甲基叔丁基醚(500mL)中并将两相分离。将有机相用1M盐酸(150mL)和盐水(150mL)洗涤。将水相用甲基叔丁基醚反萃取。合并的有机相经过无水硫酸钠干燥和浓缩生成为红色胶状物的粗产物(2,2,2-三氟-N-((3S,4S,5S)-5-(碘甲基)-2-氧代-4-(4-(苯基乙炔基)苯基)四氢呋喃-3-基)乙酰胺)6。
将上述粗产物6加入N,N-二甲基甲酰胺(185mL)中并用叠氮化钠(15.8g,243mmol)处理。将混合物于室温搅拌12小时,然后加热至45℃并追加搅拌12小时。将混合物加入甲基叔丁基醚(400mL)中,并用水(300mL)和盐水(300mL)洗涤。将水相用甲基叔丁基醚(300mL×2)反萃取。将合并的有机相经过无水硫酸钠干燥并浓缩。用正庚烷(100mL)中的50%乙酸乙酯进行洗脱,使粗产物通过硅胶短垫(130g)。浓缩滤液生成为浅黄色泡沫状固体的7,其不经纯化而使用。
从叠氨基内酯((2S,3S,4S)-2-氨基-5-叠氮基-3-(4-(苯基乙炔基)苯基)戊烷-1,4-二醇)7制备氨基二醇9
将上述粗产物7(26.0g,60.8mmol)加入乙醇(260mL)中生成无色溶液。将其在冰浴中冷却并用硼氢化钠(2.76g,73.0mmol)进行处理。将混合物于该温度搅拌2小时生成白色悬浮液。去除冰浴然后使混合物达到室温(rt),之后使其成为45℃直至停止形成气泡且混合物变得均质。将溶液用碳酸钾(25.2g,182mmol)和水(13mL)进行处理,并且于该温度搅拌24小时。将混合物浓缩并将残余物加入二氯甲烷(390mL)中。将其用硅藻土(26g)处理并通过硅藻土垫过滤,用二氯甲烷(260mL×2)冲洗。将滤液浓缩生成橙色固体,用在二氯甲烷中的20%甲醇(用1%氨水溶液调制,2000mL)进行洗脱,使其通过硅胶垫(160g)进行过滤。将滤液浓缩并将残余物进行结晶(在乙酸异丙酯/异丙醇=3∶1中,将母液浓缩并于乙腈,然后乙酸乙酯中进一步结晶)生成为白色固体的9(7.01g)。另一部分9是作为母液中的粗产物而获得的(7.84g,基于9.8g具有ELSD示出为80%纯度的浓缩物,合并5的73%产率)。
1H NMR(400MHz,MeOH-d4)δ7.53-7.49(m,4H),7.40-7.36(m,3H),7.30(d,J=8.2Hz,2H),4.31(ddd,J=9.8,6.2,2.7Hz,1H),3.49-3.45(m,1H),3.40(dd,J=10.6,6.3Hz,1H),3.33-3.32(m,1H),3.29(dd,J=10.5,7.4Hz,1H),3.15(dd,J=12.7,3.0Hz,1H),3.03(dd,J=12.5,6.6Hz,1H),3.00(dd,J=9.7,3.5Hz,1H);13C NMR(75MHz,MeOH-d4)δ138.4,131.2,131.1,129.4,128.1,128.0,123.1,122.0,88.9,88.4,70.8,64.4,55.6,52.4,50.1。
9的一锅(One-pot)N-硝基苯磺酰化(N-Nosylation)和双-O-甲烷磺酰化(bis-O-mesylation);串联N-亲核取代生成氮杂环丁烷(2-(((2S,3S,4R)-4-(叠氮基甲基)-1-((2-硝基苯基)磺酰基)-3-(4-(苯基乙炔基)苯基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)12
将9(2.00g,5.95mmol)和三乙胺(4.97mL,35.7mmol)在二氯甲烷(20mL)中的悬浮液在冰浴中冷却,用2-硝基苯磺酰氯(1.98g,8.92mmol)在二氯甲烷(10mL)中的溶液进行处理,同时保持内部温度低于6℃。将混合物于该温度搅拌30分钟,期间变得均质。然后用甲磺酰氯(1.39mL,17.8mmol)处理溶液并且于该温度搅拌30分钟。用氢氧化钠水溶液(1M,100mL)淬灭反应并且将混合物加入乙酸乙酯(300mL)中。将有机相分离,用盐水(50mL)洗涤,浓缩生成由双-甲磺酸酯(bis-mesylate)11和氮丙啶中间体组成的粗产物。
将上述粗产物加入N,N-二甲基甲酰胺(20mL)中,用碳酸钾(2.47g,17.8mmol)、邻苯二甲酰亚胺钾(1.65g,8.92mmol)进行处理,于室温搅拌60小时。将反应混合物加入乙酸乙酯(400mL)中,用水(100mL)、盐水(100mL)洗涤并进行浓缩。将残余物加入异丙醇(30mL)中并煮沸生成均质溶液,利用搅拌,使其缓慢达到室温,期间产物沉淀。将产物过滤,用异丙醇(10mL×2)洗涤,真空干燥生成为米白色固体的12(3.14g,产率83%)。
1H NMR(400MHz,CDCl3)δ8.15(dd,J=7.8,1.5Hz,1H),7.85-7.75(m,4H),7.72-7.69(m,3H),7.61(d,J=8.6Hz,2H),7.57-7.54(m,2H),7.45(d,J=8.2Hz,2H),7.39-7.35(m,3H),4.93(dt,J=8.2,6.7Hz,1H),4.55(dt,J=9.3,3.9Hz,1H),4.23(dd,J=14.4,6.2Hz,1H),3.79(t,J=8.6Hz,1H),3.75(dd,J=14.4,6.6Hz,1H),3.71(dd,J=12.9,5.1Hz,1H),3.60(dd,J=12.8,9.3Hz,1H);13C NMR(75MHz,CDCl3)δ167.6,149.3,134.8,134.0,132.6,132.2,132.0,131.8,131.7,131.6,130.5,128.4,128.3,127.4,124.3,123.5,123.3,123.1,90.4,88.8,62.5,61.9,48.7,42.4,37.5。
通过12的去保护和还原胺化制备(2-(((2S,3S,4R)-4-(叠氮基甲基)-1-(((4S,5R)-5-((R)-1,2-二羟乙基)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)-3-(4-(苯基乙炔基)苯基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)15
将12(5.84g,9.23mmol)和1-十二烷基硫醇(2.65mL,11.1mmol)在四氢呋喃(70mL)中的澄清、无色溶液在冰浴中冷却至内部温度为4℃。滴加叔丁醇钾(在THF中1M,11.1mL,11.1mmol)的溶液,同时保持内部温度低于10℃,期间混合物转变为深红色。去除冰浴并使混合物达到室温。将混合物于该温度搅拌1小时,然后用碳酸氢钠水溶液(100mL)使其淬灭并将其加入乙酸乙酯(200mL)中。将两相分离并将水相用乙酸乙酯(150mL×3)进行萃取。将合并的有机相经过无水硫酸钠干燥,然后浓缩生成为黄色胶状物的粗产物13。
将粗产物13与14(2.11g,11.1mmol)合并,并加入甲醇(70mL)中生成黄色溶液,将所述溶液用乙酸(2.64mL,46.2mmol)和氰基硼氢化钠(0.696g,11.1mmol)进行处理。将溶液于室温搅拌24小时,然后用追加的乙酸(2.64mL,46.2mmol)和氰基硼氢化钠(0.300g,4.78mmol)进行处理。12小时后,添加第三部分的氰基硼氢化钠(0.300g,4.78mmol)并将混合物追加搅拌6小时。将反应混合物加入乙酸乙酯(200mL)中并用1M氢氧化钠(100mL)洗涤。将水相分离并用乙酸乙酯(200mL)进行反萃取。将合并的有机相用盐水(100mL)洗涤并进行浓缩。将残余物通过先用二氯甲烷(700mL)再用乙酸乙酯(700mL)冲洗的硅胶(140g)柱进行过滤。将乙酸乙酯滤液进行浓缩生成为浅黄色泡沫状固体的15(5.34g,93%),其不经进一步纯化而使用。
氧化裂解15的1,2-二醇生成((4S,5S)-5-(((2R,3S,4S)-2-(叠氮基甲基)-4-((1,3-二氧代异吲哚啉-2-基)甲基)-3-(4-(苯基乙炔基)苯基)氮杂环丁烷-1-基)甲基)-2,2-二甲基-1,3-二氧戊环-4-甲醛)16
将15(5.34g,8.59mm01)在四氢呋喃(64mL)和水(6.4mL)中的澄清、无色溶液用高碘酸钠(2.76g,12.9mmol)进行处理。将混合物于室温搅拌2小时,期间其转变为白色、乳状悬浮液。将其加入乙酸乙酯(500mL)中,并依次用硫代硫酸钠水溶液(50mL)和盐水(50mL)进行洗涤。将有机相分离并且经过无水硫酸钠干燥。浓缩生成为白色泡沫状固体的16,其不经纯化而使用。
相继使用氮杂-维蒂希反应和还原将16转化为(2-(((3aR,6aR,7R,8S,10aS)-2,2-二甲基-7-(4-(苯基乙炔基)苯基)八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-8-基)甲基)异吲哚啉-1,3-二酮)18
将上述粗产物16加入甲醇(30mL)中生成澄清、无色溶液。历时8小时于室温将其缓慢添加至被搅拌的、三苯基膦(2.70g,10.3mmol)在甲醇(50mL)中的白色悬浮液中,期间混合物转变为无色、均质的溶液。将溶液于该温度进一步搅拌6小时,然后添加乙酸(2.46mL,43.0mmol)和氰基硼氢化钠(0.648g,10.3mmol)。将混合物于该温度搅拌4小时,然后进行浓缩。将残余物加入乙酸乙酯(400mL)中,用1M氢氧化钠(40mL)和盐水(40mL)进行洗涤。将有机相经过无水硫酸钠干燥并浓缩生成为无色胶状物的粗产物18。
将18转化为((3aR,6aR,7S,8S,10aS)-8-((1,3-二氧代异吲哚啉-2-基)甲基)-N-(4-甲氧基苯基)-2,2-二甲基-7-(4-(苯基乙炔基)苯基)八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-5-甲酰胺)19
将上述粗产物18加入二氯甲烷(57mL)中并用4-甲氧基苯基异氰酸酯(1.34mL,10.3mmol)进行处理。将混合物保持于室温30分钟,然后进行浓缩。将残余物在异丙醇/乙腈(1∶1,100mL)的混合溶剂中结晶生成为白色固体的19(1.60g)。将母液浓缩并使用硅胶柱色谱(用在庚烷中的50~60%乙酸乙酯进行洗脱)进行纯化生成追加的19(1.0g,合并12的43%产率)。
1H NMR(400MHz,DMF-d7)δ8.44(s,1H),7.88(s,4H),7.74(d,J=8.2Hz,2H),7.64-7.61(m,4H),7.51-7.44(m,3H),7.37-7.33(m,2H),6.87-6.83(m,2H),4.50-4.47(m,1H),4.34-4.29(m,1H),4.08(br dd,J=16.0,5.0Hz,1H),3.97(br dd,J=16.0,2.8Hz,1H),3.87-3.65(m,6H),3.75(s,3H),3.52(dd,J=14.0,4.6Hz,1H),3.48(s,1H),3.10(br t,J=2.1Hz,1H),1.39(s,3H),1.37(s,3H);13C NMR(75MHz,DMF-d7)δ168.9,163.3,157.5,156.1,138.5,135.5,135.0,133.1,132.6,132.4,132.3,129.9,129.8,124.1,124.1,122.4,122.1,114.8,108.1,90.5,90.5,78.9,77.4,68.0,66.5,59.0,56.1,50.7,47.4,45.0,39.7,28.9,26.3。
水解19的邻苯二甲酰亚胺生成((3aR,6aR,7S,8S,10aS)-8-(氨基甲基)-N-(4-甲氧基苯基)-2,2-二甲基-7-(4-(苯基乙炔基)苯基)八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-5-甲酰胺)20
将19(2.30g,3.30mmol)在甲醇(23mL)中的白色悬浮液用乙醇胺(ethanolamine)(2.00mL,33.0mmol)进行处理。将混合物于55℃搅拌12小时,然后回流12小时,期间其转变为均质溶液。将其用乙醇胺(1.50mL,24.8mmol)处理并回流24小时。将溶液浓缩生成无色胶状物,将其加入二氯甲烷(300mL)中,用(50mL×2)、盐水(50mL)洗涤,并且经过无水硫酸钠干燥。将其浓缩生成为白色蜡状固体的粗产物20,其不经纯化而使用。
20的还原胺化和去除丙缩酮生成((3S,4R,8R,9S,10S)-10-((二甲氨基)甲基)-3,4-二羟基-N-(4-甲氧基苯基)-9-(4-(苯基乙炔基)苯基)-1,6-二氮杂二环[6.2.0]癸烷-6-甲酰胺)22
将上述粗产物20加入甲醇(18.7mL)中生成悬浮液,将其用甲醛(37%,3.69mmol,49.5mmol)、乙酸(1.13mL,19.8mmol)和氰基硼氢化钠(0.622g,9.90mmol)进行处理。将混合物于室温搅拌2小时,然后加入乙酸乙酯(150mL)中,用碳酸氢钠水溶液(10mL)、盐水(10mL)洗涤,经过无水硫酸钠干燥并浓缩。用在二氯甲烷中的15%甲醇进行洗脱,使残余物通过硅胶垫,并浓缩生成为无色胶状物的粗产物((3aR,6aR,7S,8S,10aS)-8-((二甲氨基)甲基)-N-(4-甲氧基苯基)-2,2-二甲基-7-(4-(苯基乙炔基)苯基)八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-5-甲酰胺)21,其不经进一步纯化而使用。
将上述粗产物21加入四氢呋喃(14mL)和1M盐酸(14mL,14mmol)的混合溶剂中生成无色溶液,于50℃搅拌12小时。将其加入乙酸乙酯(300mL)中,用1M氢氧化钠(50mL)、盐水(50mL)洗涤,经过无水硫酸钠干燥,并浓缩。用在二氯甲烷中的20~30%甲醇(用7M氨水的0.1%甲醇溶液调制)进行洗脱,使残余物通过硅胶柱色谱进行纯化生成为白色蜡状固体的22(0.86g,52%)。
1H NMR(400MHz,MeOH-d4)δ7.56-7.51(m,6H),7.42-7.36(m,3H),7.16(d,J=9.0Hz,2H),6.84(d,J=8.9Hz,2H),4.19(dd,J=15.6,6.6Hz,1H),4.14-4.1O(m,1H),3.83-3.78(m,2H),3.76(s,3H),3.65(dd,J=14.4,7.6Hz,1H),3.60(br t,J=7.1Hz,1H),3.40(br t,J=8.8Hz,1H),3.30(d,J=10.5Hz,1H),2.84(dd,J=13.5,9.2Hz,1H),2.75(dt,J=15.2,3.0Hz,1H),2.55(dd,J=13.3,8.6Hz,1H),2.45(dd,J=13.3,2.4Hz,1H),2.05(s,6H);13C NMR(75MHz,MeOH-d4)δ160.2,157.3,138.7,134.2,132.7,132.5,132.3,129.7,129.6,124.8,123.5,123.3,115.1,90.5,90.2,77.0,74.0,71.3,66.8,58.2,57.7,56.0,53.0,52.1,46.9,46.0
路线B合成
还原4-溴肉桂酸甲酯1生成4-溴肉桂醇23
向3L三颈圆底烧瓶装入4-溴肉桂酸甲酯(1,100g,414mmol)和二氯甲烷(1.1L)生成澄清溶液。将其在干冰-丙酮浴中冷却生成乳状混合物。将其用二异丁基氢化铝的溶液(在甲苯中25wt%,586mL,871mmol)(浅绿色溶液)进行处理。使混合物缓慢达到-5℃并在冰浴中小心地用酒石酸钾钠四水合物(351g,1.24mol)在水(800mL)中的溶液使其淬灭。将混合物于室温搅拌过夜,用水(2L)处理,并用甲基叔丁基醚(1L×3)萃取。将合并的有机相经过无水硫酸钠干燥并浓缩生成为白色固体的4-溴肉桂醇(23,87.5g,99%)。
1H NMR(400MHz,CDCl3)δ7.46-7.44(m,2H),7.27-7.25(m,2H),6.58(d,J=16.0Hz,1H),6.37(dt,J=15.6,5.5Hz,1H),4.33(dd,J=5.8,1.5Hz,2H)
溴化4-溴肉桂醇23生成4-溴肉桂基溴24
向5L三颈圆底烧瓶装入4-溴肉桂醇(23,329g,1.54mol)和乙醚(3L)。使用冰浴将其冷却至5℃,期间溶液变得轻微浑浊。将三溴化磷在乙醚(200mL)中的溶液(72.6mL,772mmol)滴加至该混合物,同时保持内部温度低于12℃,从而在添加结束时生成大致澄清的溶液。将混合物在冰浴中搅拌1小时,然后通过缓慢添加碳酸氢钠(133g,1.57mol)在水(1.5L)中的溶液使其淬灭。将有机相分离并且用盐水(300mL)洗涤。将水相用甲基叔丁基醚(1L×2)萃取。将合并的有机相经过无水硫酸钠干燥并浓缩生成为白色固体的、纯的24(404g,95%)。
1H NMR(400MHz,CDCl3)δ7.48-7.45(m,2H),7.25-7.24(m,2H),6.59(d,J=15.6Hz,1H),6.40(dt,J=15.6,7.4Hz,1H),4.15(dt,J=7.8,0.7Hz,2H)
制备((S,E)-2-((叔丁基亚磺酰基)亚氨基)乙酸乙酸酯)25
25的锌介导巴豆酰化生成((2S,3S)-3-(4-溴苯基)-2-(((S)-叔丁基亚磺酰基)氨基)4-戊烯酸乙酯)26
向5L三颈圆底烧瓶装入4-溴肉桂基溴(24,175g,6363mmol),25(87g,424mmol)和N,N-二甲基甲酰胺(1.3L)。边搅拌边向溶液中充入氮气30分钟。在保持内部温度低于48度的同时,分批加入锌粉(Zinc dust)(55.4g,848mmol)。混合物最初变成绿色,然后在添加快结束时变成棕色。将其于环境温度搅拌2小时,然后用水(1.3L)淬灭反应。将混合物通过硅藻土垫过滤,用甲基叔丁基醚冲洗。将滤液加入水(1.3L)中并将水相用甲基叔丁基醚(870mL×2)萃取。将合并的有机相浓缩并将浓缩物通过硅藻土垫过滤,用少量的甲基叔丁基醚冲洗。将滤液浓缩并将残余物通过硅胶柱色谱(用在庚烷中的乙酸乙酯进行洗脱)进行纯化,生成为浅黄色油状物的26(111g,65.2%)。
1H NMR(400MHz,CDCl3)δ7.44-7.40(m,2H),7.05-7.03(m,2H),6.05-5.96(m,1H),5.17-5.11(m,2H),4.20-4.12(m,3H),3.91(d,J=9.4Hz,1H),3.67(t,J=7.8Hz,1H),1.25(s,3H)
将亚磺酰胺26转化为((2S,3S)-3-(4-溴苯基)-2-((2-硝基苯基)亚磺酰氨基)4-戊烯酸乙酯)27
将26(2.48g,5.30mmol)在四氢呋喃(21mL)中的溶液用浓缩氯化氢(Concentratedhydrogen chloride)(37%,2.18mL,26.5mmol)处理并于室温搅拌2小时。先用碳酸氢钠水溶液(20mL),再用固体碳酸氢钠淬灭反应,直至混合物不再呈酸性。将混合物用甲基叔丁基醚(200mL×3)萃取,经过无水硫酸钠干燥,并浓缩生成粘稠的黄色油状物。
将其加入二氯甲烷(16mL)中,用2-硝基苯磺酰氯(1.29g,5.83mmol)和三乙胺(1.11mL,7.95mmol)进行处理生成橙色溶液,将所述溶液于室温搅拌过夜。将混合物加入甲基叔丁基醚(200mL)中并用1M氢氧化钠(30mL)洗涤。将水相用甲基叔丁基醚(50mL)进行萃取。将合并的有机相经过无水硫酸钠进行干燥并浓缩。将残余物通过用在正庚烷中的15~40%乙酸乙酯进行洗脱的硅胶柱色谱进行纯化,生成为浅黄色胶状物的27(2.29g,89%)。
1H NMR(400MHz,MeOH-d4)δ7.50-7.32(m,3H),7.23-7.19(m,2H),7.10-7.07(m,2H),5.97-5.88(m,1H),5.01(dd,J=17.0,1.0Hz,1H),4.95(dd,J=10.1,1.3Hz,1H),4.06(d,J=10.5Hz,1H),4.03-3.92(m,2H),3.58(t,J=9.8Hz,1H),1.76(t,J=7.0Hz,3H)
27的碘内酯化反应和叠氮基取代以得到(N-((3S,4S,5S)-5-(叠氮基甲基)-4-(4-溴苯基)-2-氧代四氢呋喃-3-基)-2-硝基苯磺酰胺)29
将27(10.0g,20.7mmol)在乙腈(80mL)和水(3.2mL)中的溶液用碘(10.5g,41.3mmol)处理生成深红色溶液,将其于室温搅拌直至耗尽所有起始原料。将反应用过量的硫代硫酸钠水溶液淬灭并于室温搅拌直至混合物变为浅黄色。将混合物加入甲基叔丁基醚中,用盐水洗涤,经过无水硫酸钠干燥并浓缩,生成为白色固体的粗产物(N-((3S,4S,5S)-4-(4-溴苯基)-5-(碘甲基)-2-氧代四氢呋喃-3-基)-2-硝基苯磺酰胺)28(12g)。
1H NMR(400MHz,CDCl3)δ7.89(dd,J=8.1,1.4Hz,1H),7.81(dd,J=8.0,1.4Hz,1H),7.72(dt,J=7.8,1.5Hz,1H),7.62(dt,J=7.8,1.2Hz,1H),7.44-7.41(m,2H),7.15-7.12(m,2H),6.25(d,9.0 Hz,1H),4.81(dd,J=12.1,9.0Hz,1H),4.27-4.22(m,1H),3.48-3.41(m,2H),3.24(dd,J=11.9,4.9Hz,1H)
将粗产物28加入N,N-二甲基甲酰胺(65mL)中并用叠氮化钠(2.02g,31.0mmol)进行处理,生成黄色悬浮液,将其于室温搅拌过夜。将混合物加入甲基叔丁基醚中,用水、盐水洗涤,经过无水硫酸钠干燥并浓缩。将残余物使用硅胶柱色谱(用在庚烷中的乙酸乙酯洗脱)进行纯化,生成为白色固体的29(7.90g,77%)。
1H NMR(400MHz,CDCl3)δ7.84(dd,J=8.0,0.9Hz,1H),7.75(dd,J=7.8,1.2Hz,1H),7.69(dt,J=7.6,1.3Hz,1H),7.57(dt,J=7.6,1.2Hz,1H),7.34(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,2H),6.46(d,J=9.0Hz,1H),4.79(dd,J=12.1,9.0Hz,1H),4.58-4.53(m,1H),3.63-3.53(m,2H),3.38(dd,J=13.9,4.9Hz,1H)
还原29生成(N-((2S,3S,4S)-5-叠氮基-3-(4-溴苯基)-1,4-二羟基戊-2-基)-2-硝基苯磺酰胺)30
将29(9.10g,18.3mmol)在乙醇(80mL)中的黄色溶液用硼氢化钠(1.04g,27.5mmol)分批处理,期间混合物转变成深紫色。将反应于室温搅拌1小时,然后将其用1M的HCl淬灭。将混合物加入甲基叔丁基醚中,用水、盐水洗涤,经过无水硫酸钠干燥并浓缩。将残余物使用硅胶柱色谱(用在庚烷中的50~80%乙酸乙酯进行洗脱)进行纯化,生成为白色固体的30(8.20g,89%)。
1H NMR(400MHz,CDCl3)δ8.17-8.15(m,1H),7.92-7.89(m,1H),7.80-7.75(m,2H),7.48(d,J=8.6Hz,2H),7.10(d,J=8.2Hz,2H),5.45(d,J=9.0Hz,1H),4.41-4.37(m,1H),4.16-4.11(m,1H),3.72(brs,1H),3.44(dd,J=11.4,5.5Hz,1H),3.30(dd,J=11.3,7.0Hz,1H),3.23(dd,J=12.9,2.7Hz,1H),3.00-2.91(m,2H)
通过双-甲烷磺酰化(bis-mesylation)和串联N-亲核取代将30转化为氮杂环丁烷(2-(((2S,3S,4R)-4-(叠氮基甲基)-3-(4-溴苯基)-1-((2-硝基苯基)磺酰基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)32
将30(5.37g,10.7mmol)和三乙胺(5.98mL,42.9mmol)在二氯甲烷(50mL)中的溶液冷却至0℃并用甲磺酰氯(2.08mL,26.8mmol)逐滴处理。将浅黄色浑浊的混合物于该温度搅拌2小时,然后用碳酸氢钠水溶液淬灭反应。将混合物用乙酸乙酯萃取,用水和盐水洗涤。将有机相经过无水硫酸钠干燥并浓缩,生成包含31和氮丙啶中间体的粗产物。
将残余物加入N,N-二甲基甲酰胺(35mL)中,用碳酸钾(4.45g,32.2mmol)、邻苯二甲酰亚胺钾(2.39g,12.9mmol)进行处理,并于室温搅拌84小时。将混合物加入乙酸乙酯中,用水、盐水洗涤,经过无水硫酸钠干燥并浓缩。将残余物使用硅胶柱色谱(用在庚烷中的乙酸乙酯进行洗脱)进行纯化,生成为白色固体的32(4.92g,75%)。
1H NMR(400MHz,CDCl3)δ8.14(dd,J=7.9,1.6Hz,1H),7.83-7.70(m,7H),7.58(d,J=8.6Hz,2H),7.33(d,J=8.2Hz,2H),4.91(dd,J=14.9,6.7Hz,1H),4.56-4.50(m,1H),4.18(dd,J=17.7,6.0Hz,1H),3.77-3.68(m,3H),3.55(dd,J=12.7,9.6Hz,1H)
通过去保护和还原胺化将32转化为(2-(((2S,3S,4R)-4-(叠氮基甲基)-3-(4-溴苯基)-1-(((4S,5R)-5-((R)-1,2-二羟乙基)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)35
将32(1.35g,2.21mmol)和1-十二烷基硫醇(0.635mL,2.65mmol)在四氢呋喃(10mL)中的溶液用叔丁醇钾(在四氢呋喃中1M,2.65mL,2.65mmol)的溶液于室温逐滴处理,然后搅拌5小时。将混合物加入乙酸乙酯中,用盐水洗涤,经过无水硫酸钠干燥并浓缩,生成为黄色胶状物的粗产物(2-(((2S,3S,4R)-4-(叠氮基甲基)-3-(4-溴苯基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)33。
将粗产物33(0.469g,1.10mmol)和((3aR,6R,6aR)-6-(羟甲基)-2,2-二甲基四氢呋喃并[3,4-d][1,3]二氧杂环戊烷-4-醇)34(0.29g,1.53mmol)的混合物加入甲醇(5mL)中,用乙酸(0.315mL,5.50mmol)、氰基硼氢化钠(0.104g,1.65mmol)进行处理并于室温搅拌直至完成反应。将混合物加入乙酸乙酯中,用1M氢氧化钠、盐水进行洗涤,经过无水硫酸钠干燥并浓缩。将残余物使用硅胶柱色谱(用在二氯甲烷中的甲醇进行洗脱)进行纯化,生成为无色油状物的35(365mg,55%)。
1H NMR(400MHz,CDCl3)δ7.77-7.74(m,2H),7.71-7.67(m,2H),7.52(d,J=8.2Hz,2H),7.19(d,J=8.6Hz,2H),6.11(brs,1H),4.53-4.48(m,1H),4.31(dd,J=9.3,6.2Hz,1H),3.93-3.75(m,7H),3.58(dd,J=13.9,7.3Hz,1H),3.51-3.46(m,1H),3.32-3.24(m,2H),2.77(dd,J=12.5,3.9Hz,1H),2.49(brs,1H),1.41(s,3H),1.33(s,3H)
用((3aR,6aR)-2,2-二甲基四氢呋喃并[3,4-d][1,3]二氧杂环戊烷-4-醇)36还原胺化33生成(2-(((2S,3S,4R)-4-(叠氮基甲基)-3-(4-溴苯基)-1-(((4S,5R)-5-(羟甲基)-2,2-二甲基-1,3-二氧戊环-4-基)甲基)氮杂环丁烷-2-基)甲基)异吲哚啉-1,3-二酮)37
将粗产物35(2.72g,6.38mmol)和36(1.53g,9.57mmol)加入甲醇(40mL)、乙酸(1.83mL,31.9mmol)中,并用氰基硼氢化钠(0.601g,9.57mmol)进行处理。将混合物于室温搅拌直至完成反应。将混合物加入甲基叔丁基醚(500mL)中,用1M氢氧化钠(50mL)和盐水(50mL)进行洗涤。将水相用甲基叔丁基醚(100mL×2)进行反萃取。将合并的有机相经过无水硫酸钠干燥并浓缩。用在二氯甲烷中的甲醇进行洗脱,将残余物用硅胶柱色谱(用70mM的氨水调制)进行纯化,生成为白色泡沫状固体的37(2.34g,64%)。
1H NMR(400MHz,CDCl3)δ7.75-7.71(m,2H),7.68-7.64(m,2H),7.48-7.45(m,2H),7.23-7.21(m,2H),4.43-4.34(m,2H),4.01(brs,1H),3.81-3.66(m,6H),3.50(dd,J=13.7,6.6Hz,1H),3.42(dd,J=12.7,6.5Hz,1H),3.21(dd,12.7,6.5Hz,1H),3.08(dd,12.9,7.8Hz,1H),2.76(dd,J=12.9,5.1Hz,1H),1.41(s,3H),1.31(s,3H)
氧化裂解35生成((4S,5S)-5-(((2R,3S,4S)-2-(叠氮基甲基)-3-(4-溴苯基)-4-((1,3-二氧代异吲哚啉-2-基)甲基)氮杂环丁烷-1-基)甲基)-2,2-二甲基-1,3-二氧戊环-4-甲醛)38
将35(2-73g,4.55mmol)在四氢呋喃(33mL)和水(3.6mL)中的溶液用高碘酸钠(1.46g,6.82mmol)进行处理并于室温搅拌2小时,生成白色悬浮液。将混合物加入甲基叔丁基醚(500mL)中,用硫代硫酸钠水溶液(100mL)和碳酸氢钠水溶液(100mL)进行洗涤。合并的水相用甲基叔丁基醚(150mL×2)进行反萃取。将合并的有机相经过无水硫酸钠干燥并浓缩,生成为无色胶状物的38,其不经纯化而使用。
1H NMR(400MHz,CDCl3)δ9.79(d,J=2.7Hz,1H),7.78-7.75(m,2H),7.71-7.68(m,2H),7.52-7.49(m,2H),7.31-7.29(m,2H),4.54-4.51(m,1H),4.47-4.44(m,2H),3.79-3.3.61(m,4H),3.46-3.40(m,2H),3.21-3.19(m,1H),2.96(dd,J=13.7,4.7Hz,1H),2.80(dd,J=13.7,5.5Hz,1H),1.60(s,3H),1.41(s,3H)
氧化37生成38
将37(900mg,1.58mmol)在二氯甲烷(10mL)中的溶液用戴斯-马丁试剂(DessMartin periodinane)(803mg,1.89mmol)进行处理并于室温搅拌3小时。将混合物加入乙酸乙酯中,用硫代硫酸钠水溶液、1M氢氧化钠、盐水进行洗涤,经过无水硫酸钠干燥,并浓缩生成为无色胶状物的38,其不经纯化而使用。
氮杂-维蒂希反应38并后续还原生成(2-(((3aR,6aR,7R,8S,10aS)-7-(4-溴苯基)-2,2-二甲基八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-8-基)甲基)异吲哚啉-1,3-二酮)40
向三苯基膦(1.79g,6.82mmol)在甲醇(13mL)中的悬浮液历时12小时地缓慢添加粗产物38在甲醇(39mL)和四氢呋喃(7.8mL)中的溶液,生成澄清溶液。再追加3小时后,将溶液用乙酸(0.78mL,13.6mmol)和氰基硼氢化钠(0.343g,5.46mmol)进行处理,并搅拌3小时。将混合物加入甲基叔丁基醚中,用1M氢氧化钠、盐水进行洗涤,经过无水硫酸钠干燥并浓缩。将残余物通过利用乙酸乙酯洗脱的硅胶柱色谱进行纯化,生成为白色固体的40(1.88g,79%)。
1H NMR(400MHz,CDCl3)δ7.81-7.77(m,2H),7.71-7.64(m,2H),7.46-7.44(m,2H),7.40-7.38(m,2H),4.87(brs,3H),4.39-4.34(m,1H),4.28-4.24(m,1H),3.75(dd,J=14.0,5.5Hz,1H),3.70-3.65(m,1H),3.60-3.55(m,2H),3.47(dd,J=14.2,5.3Hz,1H),3.28(dd,J=Hz,1H),3.27(dd,J=14.6,9.8Hz,1H),3.08(dd,J=14.7,2.2Hz,1H),2.90(dd,J=13.2,4.3Hz,1H),2.79(dd,J=13.6,8.6Hz,1H),2.71-2.60(m,2H),1.36(s,3H),1.32(s,3H)
将40转化为((3aR,6aR,7S,8S,10aS)-7-(4-溴苯基)-8-((1,3-二氧代异吲哚啉-2-基)甲基)-N-(4-甲氧基苯基)-2,2-二甲基八氢-5H-氮杂环丁烷并[1,2-a][1,3]二氧杂环戊烯并[4,5-f][1,4]二氮杂环辛四烯-5-甲酰胺)41
将40(70mg,0.133mmol)在二氯甲烷(1.5mL)中的溶液用4-甲氧基苯基异氰酸酯(0.026mL,0.199mmol)、三乙胺(0.028mL,0.199mL)进行处理,并且保持于室温2小时。将混合物浓缩,并使用硅胶柱色谱(用在庚烷中的~60%乙酸乙酯进行洗脱)将残余物进行纯化,生成为白色固体的41(67mg,75%)。
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.85-7.80(m,2H),7.73-7.69(m,2H),7.51-7.45(m,4H),7.23-7.19(m,2H),6.85-6.80(m,2H),4.38(d,J=16.8Hz,1H),4.29(brs,2H),4.16-4.10(m,1H),3.86-3.77(m,2H),3.77(s,3H),3.65-3.47(m,4H),2.79-2.73(m,1H),2.64-2.61(m,2H),1.44(s,3H),1.41(s,3H)
水解丙缩酮41生成((3S,4R,8R,9S,10S)-9-(4-溴苯基)-10-((1,3-二氧代异吲哚啉-2-基)甲基)-3,4-二羟基-N-(4-甲氧基苯基)-1,6-二氮杂二环[6.2.0]癸烷-6-甲酰胺)42
将41(5.0mg,0.0074mmol)在四氢呋喃(1mL)和1M的HCl(1mL)中的溶液于50℃搅拌3小时。将溶液浓缩并将残余物通过反向制备型HPLC进行纯化,生成为白色固体的42(3.8mg,81%)。
1H NMR(400MHz,CD3OD)δ7.79-7.73(m,4H),7.52-7.46(m,4H),7.11-7.07(m,2H),6.80-6.76(m,2H),4.14(dd,J=15.5,6.5Hz,1H),4.08-4.07(m,1H),3.82-3.68(m,4H),3.71(s,3H),3.33-3.27(m,2H),2.82-2.73(m,2H),2.82-2.73(m,2H),2.67-2.63(m,1H)
42可根据前述工序转化为化合物22。参见例如,WO2018/175385的53~55页,其通过引用全文并入本文中。该工艺以简要的方式显示如下:
通过X射线晶体学验证化合物5和32的结构。图1和图2中分别提供了化合物5和32的ORTEP投影。ORTEP是橡树岭热椭球图(Oak Ridge Thermal Ellipsoid Plot)的缩写,是对由X射线衍射所确定的分子结构的示意。
下面示出了可与上述工序组合使用或独立使用的其他工序。
使用巯基乙酸水解12的o-硝基苯基磺酰胺生成13
于室温将12(1.0w/w,1.0eq)、甲醇(12v/w)和四氢呋喃(4v/w)装入反应器。分别一次性地加入巯基乙酸(0.221v/w,0.291w/w,2.0eq)和碳酸钾(0.874w/w,4.0eq)。加热混合物至内部温度50℃并搅拌34、时。使用反应的等分试样的LCMS/UV监控12的完全消耗。将反应混合物倒入独立容器(Separatory vessel)中以乙酸乙酯(25v/w)和水(18v/w)进行萃取。用乙酸乙酯(12v/w)反萃取水相两次。合并有机相,先用碳酸氢钠水溶液(12v/w),再用50%盐水(12v/w)进行洗涤。将有机相用无水硫酸钠干燥。过滤有机相并使用旋转蒸发仪于清扫真空(House vacuum)(Tbath=37℃)进行浓缩,生成为黄色胶状物的粗产物13(~0.8v/w,当量比(quant.))。
反应体积:17v/w
后处理体积:65v/w
预期产率(%):当量(quantitative)
最大规模:20g的12
1H NMR(400MHz,CDCl3)7.84-7.82(m,2H),7.72-7.67(m,2H),7.62-7.52(m,6H),7.39-7.32(m,3H),4.50(dt,J=7.6,4.5Hz,1H),4.25(dd,J=14.1,7.0Hz,1H),3.91(dd,J=14.3,7.8Hz,1H),3.79(t,J=7.6Hz,1H),3.53(dd,J=14.2,4.4Hz,1H),3.35(dd,J=12.6,7.1Hz,1H),3.20(dd,J=12.6,6.6Hz,1H);13C NMR(75MHz,CDCl3)168.2,135.6,134.3,134.0,132.0,131.6,131.6,130.6,128.4,128.3,123.3,122.5,89.9,89.2,57.5,57.2,52.0,46.7,40.2
使用14还原胺化13生成15·HCl(15的HCl盐)
将粗产物13(如上所述制备,1.0w/w,1.0eq)、14(0.850w/w,2.0eq)和乙醇(10v/w)装入反应器。于室温向该混合物先后一次性地加入酸式酸(acidic acid)(0.640v/w,0.671w/w,5.0eq)和氰基硼氢化钠(0.281w/w,2.0eq)1。于室温搅拌混合物12~18小时。使用反应的等分试样的LCMS/UV监控13的完全消耗。先使用饱和碳酸氢钠水溶液(18v/w),再使用乙酸乙酯(35v/w)对反应进行淬灭2,于室温搅拌混合物10分钟。使用独立容器分离两相,将水相用乙酸乙酯(15v/w)反萃取两次。合并有机相,用盐水(18v/w)洗涤,并用无水硫酸钠干燥。过滤然后使用旋转蒸发仪于清扫真空(Tbath=37℃)浓缩有机相。将残余物放入乙酸乙酯(35v/w)中并通过硅胶短柱(Plug of silica gel)过滤去除不溶物。冰浴冷却澄清的滤液3,历时10分钟地缓慢添加4M的HCl-二氧六环溶液(0.071v/w,1.05eq)。冰浴上搅拌白色悬浮液10分钟,然后停止搅拌并保持混合物静止20分钟使白色固体沉淀4。以澄清上清液在先,白色固体的悬浮液在后的顺序过滤混合物。将滤饼用乙酸乙酯洗涤。在清扫真空干燥炉中于40℃干燥滤饼,生成为白色固体的15·HCl(0.813w/w,55%)。
预期产率(%):>55%
最大量:20g的12
1H NMR(400MHz,MeOH-d4)7.83-7.78(m,4H),7.57-7.51(m,6H),7.40-7.38(m,3H),5.4208(dt,J=9.7,6.6Hz,1H),4.93-4.85(m,1H),4.59(dd,8.5,6.5Hz,1H),4.45-4.34(m,2H),4.21(dd,J=8.7,6.4Hz,1H),4.14-3.94(m,3H),3.76(d,J=9.0Hz,1H),3.69-3.58(m,4H),1.48(s,3H),1.08(s,3H);13C NMR(75MHz,MeOH-d4)
168.9,135.7,133.1,133.1,132.6,132.5,131.9,131.8,129.8,129.6,125.2,124.4,124.2,111.6,91.5,89.2,77.5,74.4,71.0,69.2,68.9,65.0,59.3,43.7,37.5,28.1,25.2
使用高碘酸钠氧化裂解1,2-二醇15·HCl
将化合物15·HCl(1.0w/w,1.0eq)、四氢呋喃(15v/w,13.2w/w)和水(5v/w,5w/w)装入反应器。一次性添加高碘酸钠(0.650w/w,2.0eq)。于室温搅拌混合物1~2小时。使用反应混合物的等分试样的LCMS/UV监控15的完全消耗。将混合物倒入乙酸乙酯(36v/w,32.4w/w),先用碳酸氢钠水溶液(12v/w)再用盐水(12v/w)进行洗涤。将有机相经过无水硫酸钠干燥并过滤。使用旋转蒸发仪于清扫真空(Tbath=37℃)浓缩滤液,生成为无色油状物的粗产物16(~0.9w/w,当量比)。
预期产率(%):100%
最大量:8.3g的15·HCl
1H NMR(400MHz,CDCl3)9.82(d,J=2.8Hz,1H),7.79-7.76(m,2H),7.71-7.67(m,2H),7.58-7.53(m,4H),7.44-7.42(m,2H),7.39-7.35(m,3H),4.55(dd,J=11.9,5.8Hz,1H),4.48(dd,J=7.2,2.8Hz,1H),3.82-3.67(m,3H),3.50-3.41(m,2H),3.27-3.22(m,1H),2.98(dd,J=13.6,4.7Hz,1H),2.82(dd,J=13.6,5.7Hz,1H),1.61(s,3H),1.42(s,3H);13CNMR(75MHz,CDCl3)199.9,167.8,135.3,134.0,131.8,131.7,131.6,130.6,128.3,128.2,123.3,123.2,122.4,110.9,89.8,89.2,81.4,66.7,66.4,56.9,50.2,44.2,38.1,27.3,22.7
串联施陶丁格/氮杂-维蒂希/还原(Tandem Staudinger/aza-Wittig/reduction)将16转化为18·HCl
将三苯基膦(0.128w/w,1.2eq)和乙醇(7v/w,5.52w/w)装入反应器。于室温向该混合物历时1.5小时地缓慢添加粗产物16(如上述制备,1.0w/w,1.0eq)在乙醇(10v/w,7.89w/w)和四氢呋喃(5v/w,4.40w/w)中的溶液。于室温进一步搅拌反应混合物12小时并使用反应混合物的等分试样的LCMS/UV监控16的完全消耗。于室温分别一次性地添加氰基硼氢化钠(0.128w/w,1.2eq)和乙酸(0.291v/w,0.306w/w,3.0eq)1。于该温度搅拌混合物0.5~1小时并使用反应混合物的等分试样的LCMS/UV监控亚胺中间体(未显示)的完全消耗。用碳酸氢钠水溶液(30v/w)淬灭反应并用乙酸乙酯(30v/w)萃取。用乙酸乙酯(12v/w)进一步萃取水相两次。合并有机相,用盐水(12v/w)洗涤并经过无水硫酸钠干燥。过滤有机相并使用旋转蒸发仪于清扫真空(Tbath=37℃)浓缩。将残余物加入乙酸乙酯(35v/w)中并过滤去除不溶物。冰浴冷却溶液。边搅拌,边历时10分钟地缓慢添加4M的HCl-二氧六环溶液(0.054v/w,0.065w/w,1.05eq)。冰浴上进一步搅拌得到的白色悬浮液10分钟,然后停止搅拌并将混合物保持静止20分钟使白色固体沉淀2。过滤混合物并用乙酸乙酯洗涤滤饼。在清扫真空干燥炉中于40℃干燥滤饼,生成为白色固体的18·HCl(0.81w/w,82%)。
预期产率(%):80%
最大量:8.3g的18·HCl
1)追加的光谱数据
化合物18:1H NMR(400MHz,CDCl3)7.82-7.78(m,2H),7.71-7.65(m,2H),7.55-7.49(m,6H),7.38-7.31(m,3H),4.40-4.35(m,1H),4.23-4.19(m,1H),3.79(dd,J=14.2,5.5Hz,1H),3.70(dd,J=11.7,6.0Hz,1H),3.51(dd,J=14.2,5.2Hz,1H),3.28(dd,J=14.6,8.5Hz,1H),3.09(dd,J=14.6,2.4Hz,1H),2.87-2.68(m,3H),2.59(brd,J=13.3Hz,1H),1.74(brs,1H),1.39(s,3H),1.33(s,3H);13C NMR(75MHz,CDCl3)167.9,136.6,133.9,131.9,131.5,131.2,130.8,128.3,128.1,123.3,123.2,121.8,106.8,89.5,89.3,77.7,68.2,65.1,57.7,48.7,45.5,44.7,38.5,27.8,25.1
化合物21:1H NMR(400MHz,CDCl3)8.32(brs,1H),7.56-7.53(m,2H),7.52-7.50(m,2H),7.45-7.43(m,2H),7.39-7.33(m,3H),7.25-7.21(m,2H),6.85-6.82(m,2H),4.36(dd,J=16.8,2.7Hz,1H),4.30-4.28(m,1H),4.23-4.18(m,1H),4.13-4.09(m,1H),3.78(s,3H),3.69-3.65(m,1H),3.63-3.54(m,3H),2.79(brd,J=8.0Hz,2H),2.63(dd,J=13.7,10.5Hz,1H),2.44(dd,J=13.3,8.2Hz,1H),2.34(dd,J=13.1,3.7Hz,1H),2.05(s,6H),1.52(s,3H),1.44(s,3H);13C NMR(75MHz,CDCl3)156.9,155.2,136.9,133.1,131.5,131.1,130.7,128.3,128.2,123.2,121.6,121.0,114.1,107.7,89.6,89.1,78.2,77.0,68.2,66.2,57.9,57.4,55.5,51.5,45.6,44.7,28.4,26.1
虽然本发明的实施方式是按照具体的示例性实施方式和实施例进行的描述,但是可以理解,本文公开的实施方式仅出于说明性目的,本领域技术人员可以在不背离以下权利要求所述的发明主旨和范围的条件下,进行各种修饰和变更。
Claims (47)
3.如权利要求2所述的方法,其中,P1选自由-C(O)CF3、-C(O)OC(CH3)3和-C(O)OCH2Ph组成的组。
4.如权利要求3所述的方法,其中,P1是-C(O)CF3。
5.如权利要求4所述的方法,其中,反应中,所述碱是二异丙基胺锂,并且,在ZnCl2的存在下进行。
6.如权利要求5所述的方法,其中,所述手性试剂是(R)-(+)-1-苯乙胺。
9.如权利要求8所述的方法,其中,R4是-C(CH3)3,并且,R5是-CH2CH3。
10.如权利要求9所述的方法,其中,所述反应在Zn的存在下进行。
12.如权利要求11所述的方法,其中,所述氮亲核试剂是邻苯二甲酰亚胺。
14.如权利要求13所述的方法,其中,所述式V的内酯通过在极性溶剂中使式I的化合物与卤素的正电性源反应而形成。
15.如权利要求14所述的方法,其中,所述卤素的正电性源是I2,并且,所述极性溶剂是CH3CN的水性混合物。
16.如权利要求13所述的方法,其中,所述式V的内酯通过如下方式形成:在极性溶剂中使式I的化合物与I2反应形成第一产物,以及,使所述第一产物与NaN3反应形成式V的化合物。
17.如权利要求16所述的方法,其中,所述还原用NaBH4来实施。
20.如权利要求11所述的方法,其中,R1是-Br,R2是-C(O)OCH2CH3,并且,P1是-S(O)C(CH3)3。
22.如权利要求21所述的方法,其中,所述式V的内酯通过如下方式形成:在极性溶剂中使式I的化合物与卤化物的正电性源反应形成第一产物,以及,使所述第一产物与NaN3反应形成式V的化合物。
25.一种制备下述结构所示化合物的方法,
其中,
R1是-I、-Cl、-Br、或
R6和R7独立地相同或不同,且选自-H、-烷基、-O烷基,或者,其中R6和R7与它们所连接的原子一起形成环;
R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系;
R10是-H、直链或支链烷基、-C(O)烷基、-C(O)O-烷基、-C(O)NH-烷基、-C(O)芳基、-C(O)O-芳基、-C(O)NH-芳基、-C(O)杂芳基、-C(O)O-杂芳基和-C(O)N-杂芳基;
其中所述烷基、芳基和杂芳基被一个或多个卤素、氧、氮、或硫原子任选地取代;
所述方法包括使式IV所示化合物与经取代的γ-羟醛反应,以及,实现双环化,
34.如权利要求33所述的方法,其中,所述氮亲核试剂是邻苯二甲酰亚胺。
35.式XV的化合物:
其中,Z是选自下组的经取代的四元含氮杂环,所述组由下述构成:
其中,P1和P2相同或不同,并且是氮保护基团或-H;
其中,R6和R7独立地相同或不同,且选自-H、烷基、-O烷基,或者其中R6和R7与它们所连接的原子一起形成环;R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系;并且,R10是-H、直链或支链烷基、-C(O)烷基、-C(O)O-烷基、-C(O)NH-烷基、-C(O)芳基、-C(O)O-芳基、-C(O)NH-芳基、-C(O)杂芳基、-C(O)O-杂芳基和-C(O)N-杂芳基,其中所述烷基、芳基和杂芳基被一个或多个卤素、氢、氧、氮、或硫原子取代;
其中,R8和R9独立地相同或不同,并且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中所述烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;
其中,R8和R9独立地相同或不同,并且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中所述烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;
其中,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中所述烷基被一个或多个卤素、氢、氧、氮、或硫原子取代;和
其中,R8和R9独立地相同或不同,且选自-H、-烷基、-C(O)烷基、-S(O)2烷基,或者R8和R9与它们所连接的N一起形成单环或双环体系,其中所述烷基被一个或多个卤素、氢、氧、氮、或硫原子任选地取代。
37.如权利要求35所述的化合物或药学上可接受的盐,其中,所述化合物是式VIII的化合物或其药学上可接受的盐:
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