CN88102511A - 吡咯烷衍生物 - Google Patents
吡咯烷衍生物 Download PDFInfo
- Publication number
- CN88102511A CN88102511A CN88102511.9A CN88102511A CN88102511A CN 88102511 A CN88102511 A CN 88102511A CN 88102511 A CN88102511 A CN 88102511A CN 88102511 A CN88102511 A CN 88102511A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- rudimentary
- compound
- carboxyl
- group
- 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
- 150000003235 pyrrolidines Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 150000003839 salts Chemical class 0.000 claims abstract description 127
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 162
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- -1 phenyl amino formyl Chemical group 0.000 claims description 111
- 238000006243 chemical reaction Methods 0.000 claims description 99
- 238000000034 method Methods 0.000 claims description 96
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 230000032050 esterification Effects 0.000 claims description 13
- 238000005886 esterification reaction Methods 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 claims description 7
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 32
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 abstract 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 144
- 239000000243 solution Substances 0.000 description 88
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- 239000000203 mixture Substances 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000002904 solvent Substances 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 238000005406 washing Methods 0.000 description 31
- 229960001701 chloroform Drugs 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 229960001866 silicon dioxide Drugs 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- BZVFPVFIHLNDEB-UHFFFAOYSA-N [Na].C=N.C=N.C=N.C=N Chemical compound [Na].C=N.C=N.C=N.C=N BZVFPVFIHLNDEB-UHFFFAOYSA-N 0.000 description 16
- 238000013375 chromatographic separation Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ACBRDXYEZXNEIR-UHFFFAOYSA-N FC(C(=O)O)(F)F.C=N.C=N.C=N.C=N Chemical compound FC(C(=O)O)(F)F.C=N.C=N.C=N.C=N ACBRDXYEZXNEIR-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003981 vehicle Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 229940086542 triethylamine Drugs 0.000 description 11
- 230000000903 blocking effect Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 239000003513 alkali Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 9
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 8
- 125000005907 alkyl ester group Chemical group 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 231100000989 no adverse effect Toxicity 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 0 CCC(C)CC(*C)N*C Chemical compound CCC(C)CC(*C)N*C 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 150000002466 imines Chemical group 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229910052728 basic metal Inorganic materials 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- RVLHQTNUNYWCIH-UHFFFAOYSA-N pyrrolidin-2-ylidenemethanone Chemical compound O=C=C1CCCN1 RVLHQTNUNYWCIH-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 150000001262 acyl bromides Chemical class 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 150000003818 basic metals Chemical class 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 125000006023 1-pentenyl group Chemical group 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 description 2
- AQOSUYULGIFJLY-UHFFFAOYSA-N C[S-]=O.[Na+] Chemical compound C[S-]=O.[Na+] AQOSUYULGIFJLY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
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- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N isopropyl-benzene Natural products CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 229910000400 magnesium phosphate tribasic Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- JHZWMBRFGLKQSH-UHFFFAOYSA-N methyl $l^{1}-oxidanylformate Chemical compound COC([O])=O JHZWMBRFGLKQSH-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Substances [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- LZWOXEHMQORMLQ-HIFRSBDPSA-N tert-butyl (2s,4r)-2-acetyl-4-[(4-chlorophenyl)sulfonylamino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)[C@H](C(=O)C)C[C@H]1NS(=O)(=O)C1=CC=C(Cl)C=C1 LZWOXEHMQORMLQ-HIFRSBDPSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
Abstract
上式所示的吡咯烷衍生物及其医药上可接受的盐。上述化合物的制备方法及其作为血栓素A2(TXA2)拮抗剂在医药上的应用其中各符号定义见本说明书。
Description
本发明涉及新型吡咯烷衍生物及其医药上可接受的盐。
更具体地讲,本发明涉及的吡咯烷衍生物及其医药上可接受的盐是血栓素A2(TXA2)拮抗剂,因而可用作血栓形成、气喘、肾炎等疾病的治疗药物。
本发明的吡咯烷衍生物可用通式(Ⅰ)表示:
其中
R1是氢或酰基,
R2是酰基,
R3是羧(低级)烷基、被羧基和一个或多个卤原子取代的低级烷基、被护羧(低级)烷基、羧芳基、被护羧芳基、羧基、被护羧基、羟(低级)烷基、亚磺基(低级)烷基、膦酰基(低级)烷基、被护膦酰基(低级)烷基或卤代(低级)烷基,
R7是氢或低级烷基,
根据本发明,上述新吡咯烷衍生物(Ⅰ)可由下列反应式所示的方法制备。
方法1
方法4
方法7
方法10
其中R1、R2、R3、R7、A和R8定义同上,
R4是芳基,
R1 a是亚胺保护基,
R1 b是酰基,
R3 a羧(低级)烷基、羧芳基或羧基,
R3 b是酯化的羧(低级)烷基、酯化的羧芳基或酯化的羧基,
R3 c是被护羧(低级)烷基、被护羧芳基或被护羧基,
Y1是低级亚烷基,
R9是氢、低级烷磺酰基或芳磺酰基,
R10是被护羧基,
Y2是C1-C5亚烷基,
X1是卤素,
R11是氢或膦酰保护基,
R11 a是膦酰保护基,
R7是低级烷基,
X2是卤素。
初始化合物(Ⅱ)是新型化合物,可通过下列合成路线制备。
方法A
方法E
其中R1、R1 a、R1 b、R2、R7和R8定义同上,
R5是低级烷基,
R6是低级烷基,
X3是卤素,
M是碱金属。
目标化合物(Ⅰ)的医药上可接受的适用的盐是普通的无毒盐,包括金属盐如碱金属盐(钠盐、钾盐等)和碱土金属盐(钙盐、镁盐等)、铵盐、有机碱盐(如三甲基胺盐、三乙基胺盐、吡啶盐、甲基吡啶盐、二环己基胺盐、N,N′-二苄基乙二胺盐等)、有机酸盐(如醋酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、甲酸盐、甲苯磺酸盐、三氟乙酸盐等)、无机酸盐(如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等)、与氨基酸成的盐(如精氨酸、天冬氨酸、谷氨酸、赖氨酸等)及类似盐类。
化合物(Ⅰa)-(Ⅰs)、(Ⅱ)、(Ⅱa)、(Ⅳ)、(Ⅵ)、(Ⅷ)、(Ⅸ)、(Ⅸa)、(Ⅹ)、(Ⅹa)、(Ⅹb)、(Ⅹc)、(Ⅺ)和(Ⅺa)的适用的盐与解释化合物(Ⅰ)的医药上可接受的盐时所列举的那些相同。
化合物(Ⅲ)和(ⅩⅢ)的适用的盐与解释化合物(Ⅰ)时所列兴趣的那些碱式盐相同。
化合物(Ⅻ)的适用的盐与解释化合物(Ⅰ)时所列举的那些酸式盐相同。
下面将对本说明书的阐述中所用到的、包括在本发明范围内的各种定义的适当的例子和说明予以详细解释。
除非另有说明,术语“低级”是指含1-6个碳原子。
适用的“酰基”可以包括低级烷酰基(如甲酰、乙酰、丙酰、丁酰、异丁酰、戊酰、异戊酰、新戊酰等基团)、低级烷氧基羰基(如甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、叔丁氧基羰基、戊氧基羰基、叔戊氧基羰基、己氧基羰基等)、低级烷磺酰基(如甲磺酰、乙磺酰、丙磺酰、异丙磺酰、丁磺酰、叔丁磺酰、戊磺酰、叔戊磺酰、己磺酰等基团)、芳磺酰基(如苯磺酰、萘磺酰等基团)、芳酰基(如苯甲酰、萘甲酰等基团)、芳基(低级)烷酰基(如苯乙酰、苯丙酰等基团)、(低级)环烷基(低级)烷酰基(如环己乙酰、环戊乙酰等基团)、芳基(低级)烷氧基羰基(如苄氧基羰基、苯乙氧基羰基等)、芳基氨基甲酰基(如苯基氨基甲酰基、萘基氨基甲酰基等)、杂环磺酰基如单杂环磺酰基(如噻吩磺酰、呋喃磺酰、吡啶磺酰等基团)等;所述酰基可被1-3个适当的取代基取代,如卤素(氯、溴、氟和碘)、低级烷基(甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、叔戊基、己基等)、低级烷氧基(甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基、叔戊氧基、己氧基等)、硝基、单(或二或三)卤代(低级)烷基(氯甲基、溴甲基、氯丙基、1,2-二氯乙基、1,2-二溴乙基、2,2-二氯乙基、三氟甲基、1,2,2-三氯乙基等)或类似基团。
术语“羧(低级)烷基”、“被护羧(低级)烷基”、“酯化羧(低级)烷基”、“羟(低级)烷基”、“亚磺基(低级)烷基”、“膦酰基(低级)烷基”、“被护膦酰基(低级)烷基”、“卤代(低级)烷基”和“低级烷磺酰基”中适用的“低级烷基”和“低级烷基部分”可包括1-6个碳原子的直链或支链烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、叔戊基、己基等。
术语“被护羧(低级)烷基”和“被护羧芳基”中所指的适用“被护羧基”和“被护羧基部分”可以包括氨基甲酰基、酰基氨基甲酰基如低级烷磺酰氨基甲酰基(甲磺酰氨基甲酰、乙磺酰氨基甲酰、丙磺酰氨基甲酰、异丙磺酰氨基甲酰、丁磺酰氨基甲酰、叔丁磺酰氨基甲酰、戊磺酰氨基甲酰、叔戊磺酰氨基甲酰、己磺酰氨基甲酰等基团)、芳磺酰氨基甲酰基(苯磺酰氨基甲酰、萘磺酰氨基甲酰等基团)等;酯化羧基(其中所指的酯可以是下面这些酯:低级烷基酯(如甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯、戊酯、叔戊酯、己酯等)、低级链烯基酯(如乙烯基酯、烯丙基酯等)、低级炔基酯(如乙炔基酯、丙炔基酯等)、单(或二或三)卤代(低级)烷基酯(如2-碘代乙酯、2,2,2-三氯乙酯等)、低级烷基酰氧基(低级)烷基酯(如乙酰氧基甲酯、丙酰氧基甲酯、1-乙酰氧基丙酯、戊酰氧基甲酯、新戊酰氧基甲酯、己酰氧基甲酯、1-乙酰氧基乙酯、2-丙酰氧基乙酯、1-异丁酰氧基乙酯等)、低级烷磺酰(低级)烷基酯(如甲磺酰甲酯、2-甲磺酰乙酯等)、芳基(低级)烷基酯如可被一个或多个适当取代基取代的苯基(低级)烷基酯(苄酯、4-甲氧基苄酯、4-硝基苄酯、苯乙酯、三苯甲酯、二苯甲酯、二(甲氧基苯基)甲酯、3,4-二甲氧基苄酯、4-羟基-3,5-二叔丁基苄酯等)、低级烷氧基羰基氧基(低级)烷基酯(如甲氧基羰基氧基甲酯、乙氧基羰基氧基甲酯、乙氧基羰基氧基乙酯等)、芳酰氧基(低级)烷基酯(如苯甲酰氧基甲酯、苯甲酰氧基乙酯、甲苯酰氧基乙酯等)、可带有一个或多个适当取代基的芳基酯(如苯酯、甲苯酯、叔丁基苯酯、二甲苯酯、
酯、枯烯酯等);及类似基团。
术语“羧芳基”、“酯化羧芳基”、“被护羧芳基”和“芳磺酰基”中所指的“芳基”和“芳基部分”可以包括苯基、萘基等。
术语“被护膦酰基(低级)烷基”中所指的适用“被护膦酰基部分”可以包括二(低级)烷氧基膦酰基(如二甲氧基膦酰基、二乙氧基膦酰基、二丙氧基膦酰基等)及类似基团。
适用的“卤素”包括氯、溴、氟和碘。
适用的“亚胺保护基”包括上述酰基等。
术语“酯化羧基(低级)烷基”和“酯化羧基芳基”中所指的适用“酯化羧基”和“酯化羧基部分”是前文列举的那些。
适用的低级亚烷基包括1-6个碳原子的直链或支链亚烷基,如甲撑、乙撑、三亚甲基、1,2-亚丙基、四亚甲基、乙基乙撑、四亚甲基、五亚甲基、六亚甲基等。
适用的膦酰保护基包括上述低级烷基等。
适用的“碱金属”包括钠、钾等。
目标化合物(Ⅰ)的优选实例如下。
优选的R1是氢、低级烷氧基羰基,苯磺酰,经1-3个选自卤素、硝基、低级烷氧基、单(或二或三)卤代(低级)烷基和低级烷基的取代基取代的苯磺酰,苯基氨基甲酰基,低级烷基磺酰,苯甲酰或噻吩磺酰;
优选的R2是苯磺酰或经1-3个选自卤素、低级烷基、低级烷氧基和单(或二或三)卤代(低级)烷基等的取代基取代的苯磺酰;
优选的R3是羧(低级)烷基、被护羧(低级)烷基〔更优选的是酯化羧(低级)烷基、氨基甲酰(低级)烷基或酰基氨基甲酰(低级)烷基,最优选的是低级烷氧基羰基(低级)烷基、氨基甲酰(低级)烷基、低级烷磺酰氨基甲酰基(低级)烷基或苯磺酰氨基甲酰基(低级)烷基〕、羧苯基、被护羧苯基〔更优选的是酯化羧苯基,最优选的是低级烷氧基羰基苯基〕、羧基、被护羧基〔更优选的是酯化羧基,最优选的是低级烷氧基羰基〕、羟(低级)烷基、亚磺基(低级)烷基、膦酰基(低级)烷基、被护膦酰基(低级)烷基〔更优选的是二(低级)烷氧基膦酰基(低级)烷基〕、卤代(低级)烷基或经羧基和1-3个卤原子取代的低级烷基;
优选的R7是氢或低级烷基;
A是
(其中R8是氢或低级烷基)。
下面将详细介绍制备本发明目标化合物(Ⅰ)和初始化合物(Ⅱ)的方法。
方法1
化合物(Ⅰa)或其盐可通过化合物(Ⅱ)或其盐与化合物(Ⅲ)或其盐反应来制备。
此反应通常在普通溶剂中进行,如丙酮、二噁烷、乙腈、氯仿、二氯甲烷、氯化乙烯、四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺、二甲亚砜或其它任何不会对此反应产生不利影响的溶剂。
反应温度要求不严格,此反应通常是在冷却至加热的条件下进行的。
方法2
化合物(Ⅰc)或其盐可以通过化合物(Ⅰb)或其盐进行亚胺保护基消除反应来制备。
所述消除反应可按照常规方法进行,如水解、还原等。水解法包括使用酸或碱等。可根据要消除的保护基团的种类选择这些方法。
在这些方法中,使用了酸的水解法是常用和优选的方法之一,可用来消除诸如取代或未取代的烷氧基羰基(如叔戊氧基羰基、叔丁氧基羰基等)、烷酰基(如甲酰等)、环烷氧基羰基、取代或未取代的芳烷氧基羰基(如苄氧基羰基、取代的苄氧羰基等)等保护基团。
适用的酸包括有机或无机酸,例如甲酸、三氟乙酸、苯磺酸、对-甲苯磺酸、盐酸等,优选的酸是甲酸、三氟乙酸、盐酸等。可根据要消除的保护基团的种类选择适于上述反应的酸。当消除反应是在酸存在下进行时,可以使用溶剂也可不使用溶剂。适用的溶剂包括普通的有机溶剂(如甲醇、乙醇、四氢呋喃等)、水或它们的混合物。
用碱进行的水解最好用来消除酰基,例如卤代烷酰基(如二氯乙酰基、三氟乙酰基等)等。适用的碱包括无机碱如碱金属氢氧化物(氢氧化钠、氢氧化钾等)、碱土金属氢氧化物(氢氧化镁、氢氧化钙等)、碱金属碳酸盐(碳酸钠、碳酸钾、碳酸铯等)、碱土金属碳酸盐(碳酸镁、碳酸钙等)、碱金属碳酸氢盐(碳酸氢钠、碳酸氢钾等)、碱金属醋酸盐(醋酸钠、醋酸钾等)、碱土金属磷酸盐(磷酸镁、磷酸钙等)、碱金属磷酸氢盐(磷酸氢二钠、磷酸氢二钾等)等,还包括有机碱如三烷基胺(三甲胺、三乙胺等)等。使用碱的水解常在水、普通有机溶剂或它们的混合物中进行。在酰基是卤代烷氧基羰基或8-喹啉基氧羰基的情况下,它们是用重金属(如铜、锌等)进行消除的。
还原消除法一般用来消除下列保护基团,如卤代烷氧基羰基(三氯乙氧基羰基等)、取代或未取代的芳烷氧基羰基(苄氧基羰基、取代的苄氧基羰基等)等。适用的还原法包括用碱金属硼氢化物等(如硼氢化钠等)进行还原。
反应温度要求不严格,可以根据亚胺保护基团的种类和上述消除方法适当加以选择,上述反应最好在温和的条件下进行,例如在冷却下,在室温下或在稍稍升温的条件下进行。
方法3
化合物(Ⅰd)或其盐可通过化合物(Ⅰc)或其盐与酰化剂反应来制备。
所述酰化剂包括有机酸(如R1 b-OH,其中R1 b是酰基)或其活性衍生物或其盐。
上述有机酸的适用的活性衍生物可以是其普通衍生物,如酰基卤(酰氯、酰溴等)、酰基叠氮、酸酐、活化酰胺、活化酯、异氰酸酯〔如异氰酸芳基酯(异氰酸苯酯等)等〕。
当用游离酸作酰化剂时,酰化反应最好在普通缩合剂(如N,N′-二环己基碳化二亚胺等)的存在下进行。
上述反应最好在无机或有机碱(如解释方法2时所列举的)的存在下进行。
此反应通常在对反应没有不利影响的溶剂中进行,如甲醇、乙醇、丙醇、二氯甲烷、四氢呋喃、氯仿等。
反应温度要求不严格,此反应可在冷却至加热的条件下进行。
方法4
化合物(Ⅰf)或其盐可通过化合物(Ⅰe)或其盐经酯化反应来制备。在此反应中所用的酯化剂包括那些传统的酯化剂,如醇或其活性等同物(如卤化物、磺酸酯、硫酸酯、重氮化合物等)等。
此反应通常在普通溶剂中进行,如丙酮、二噁烷、醇、氯仿、二氯甲烷、氯化乙烯、四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺、二甲亚砜,或任何其它对反应没有不利影响的溶剂。
反应温度要求不严格,此反应可以在冷却至加热条件下进行。
方法5
化合物(Ⅰg)或其盐可通过将化合物(Ⅰa)或其盐还原来制备。
适于本反应的还原方法包括催化还原。
在催化还原中使用的合适的催化剂是那些传统的还原催化剂,如铂催化剂(铂屑、海绵状铂、铂黑、胶态铂、氧化铂、铂丝等)、钯催化剂(海绵状钯、钯黑、氧化钯、载于碳上的钯、胶态钯、载于硫酸钡上的钯、载于碳酸钡上的钯等)、镍催化剂(还原镍、氧化镍、阮内镍等)、钴催化剂(还原钴、阮内钴等)、铁催化剂(还原铁、阮内铁等)、铜催化剂(还原铜、阮内铜、Ullman铜等)等。
上述反应通常在普通溶剂中进行,如丙酮、二噁烷、醇、四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺、二甲亚砜,或任何其它对反应没有不利影响的溶剂。
反应温度要求不严格,此反应通常可在冷却至加热的条件下进行。
方法6
化合物(Ⅰe)或其盐可通过化合物(Ⅰh)或其盐进行消除羧基保护基团的反应来制备。
本反应是按照传统方法(如水解、还原等)进行的。
在保护基团是酯基的情况下,可通过水解将该保护基团消除。水解最好在碱或酸(包括路易斯酸)的存在下进行。适用的碱包括无机碱和有机碱,如碱金属(钠、钾等)、碱土金属(镁、钙等)、它们的氧化物或碳酸盐或碳酸氢盐、三烷基胺(三甲胺、三乙胺等)等。
适用的酸包括有机酸(如甲酸、乙酸、丙酸、三氯乙酸、三氟乙酸等)和无机酸(如盐酸、氢溴酸、硫酸等)。
还原法最好用于消除这样一些保护基团,如4-硝基苄基、2-碘乙基、2,2,2-三氯乙基等。适于上述消除反应的还原法包括(例如)混合使用金属(如锌、锌汞齐等)或铬化合物盐(如氯化亚铬、乙酸亚铬等)和有机或无机酸(如乙酸、丙酸、盐酸等)进行还原,以及在传统金属催化剂的存在下(如钯-碳等)进行的普通催化还原。
上述反应通常是在溶剂中进行的,如水、醇(甲醇、乙醇等)、二氯甲烷、四氢呋喃或它们的混合物,或任何其它对反应没有不利影响的溶剂。液体碱或酸也可用作溶剂。反应温度要求不严格,此反应通常可在冷却至加温的条件下进行。
方法7
化合物(Ⅰj)或其盐可通过化合物(Ⅻ)或其胺基活性衍生物或其盐与化合物(Ⅰi)或其活性羧基衍生物或其盐反应来制备。
化合物(Ⅰi)的适用的活性羧基衍生物包括酰基卤(如酰氯、酰溴等)、酰基叠氮、酸酐、活化酰胺、活化酯等。
在这个反应中,当化合物(Ⅰi)以游离酸或其盐的形式使用时,反应最好在传统缩合剂(如N,N′-二环己基碳化二亚胺等)的存在下进行。
此反应最好在有机或无机碱(如解释方法2时所列举的那些)存在下进行。
此反应通常在普通溶剂中进行,如丙酮、二噁烷、氯仿、二氯甲烷、氯化乙烯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜,或任何其它对反应没有不利影响的溶剂。
反应温度要求不严格,此反应通常可在冷却至加热条件下进行。
方法8
化合物(Ⅰl)或其盐可通过还原化合物(Ⅰk)或其盐来制备。
此还原反应通常是采用下列还原剂进行的,如氢化二(低级)烷基铝(氢化二异丁基铝等)、氢化铝碱金属(如氢化铝锂、氢化铝钠、氢化铝钾等)等。
此反应通常是在普通溶剂中进行的,如甲苯、四氢呋喃、或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,此反应通常可在冷却或室温下进行。
方法9
化合物(Ⅰn)或其盐可通过化合物(Ⅰm)或其盐与亚硫酸盐反应来制备。
适用的亚硫酸盐包括碱金属亚硫酸盐(如亚硫酸钠盐等)等。
此反应通常在普通溶剂中进行,如水、二甲亚砜,N,N-二甲基甲酰胺、或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,反应通常可在温及加热条件下进行。
方法10
化合物(Ⅰo)或其盐可通过化合物(Ⅰm)或其盐与化合物(ⅩⅢ)或其盐反应来制备。
此反应可在普通溶剂中进行,也可不用溶剂。
反应温度要求不严格,此反应可在加温及加热条件下进行。
方法11
化合物(Ⅰq)或其盐可通过化合物(Ⅰp)或其盐进行消除膦酰基保护基团的反应来制备。此反应可按传统方法进行,如用卤-三(低级)烷基-硅烷(如三甲基溴代硅烷、三甲基碘代硅烷等)等处理化合物(Ⅰp)的方法。
此反应通常在普通溶剂中进行,如二卤代烷(二氯甲烷、二氯乙烷等)、氯仿、四氢呋喃、或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,此反应通常在冷却至加温范围内进行。
方法12
化合物(Ⅰs)或其盐可通过化合物(Ⅰr)或其盐与化合物(ⅩⅣ)反应来制备。
通常此反应即可在普通溶剂中进行,也可不用溶剂。
反应温度要求不严格,此反应通常在冷却至加温范围内进行。
方法A-①
化合物(Ⅵ)或其盐可以通过化合物(Ⅳ)或其盐与化合物(Ⅴ)反应来制备。
此反应通常在普通溶剂中进行,如二氯甲烷,或任何其它对此反应无不利影响的溶剂。
此反应最好在无机或有机碱(如解释方法2时所列举的那些)的存在下进行。
方法A-②
化合物(Ⅷ)或其盐可通过化合物(Ⅵ)或其盐与化合物(Ⅶ)反应来制备。
此反应通常是在普通溶剂中进行的,如二甲亚砜,或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,此反应通常在加温至加热范围内进行。
方法A-③
化合物(Ⅸa)或其盐可通过使化合物(Ⅷ)或其盐氢化来制备。此反应通常是在催化剂(如载于碳上的钯等)的存在下进行。
此反应通常是在普通溶剂中进行的,如醇(甲醇、乙醇等)或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,此反应通常是在冷却至加热范围内进行的。
方法B
化合物(Ⅹ)或其盐可通过化合物(Ⅸ)或其盐与酰化剂反应来制备的。所述酰化剂包括有机酸(如R2-OH,其中R2是酰基)或其活性衍生物或其盐。
上述有机酸的适用的活性衍生物可以是那些普通的活性衍生物,如酰基卤(酰氯、酰溴等)、酰基叠氮、酸酐、活化酰胺、活化酯、异氰酸酯〔如异氰酸芳酯(如异氰酸苯酯等)等〕。
当用游离酸作酰化剂时,酰化反应最好在普通缩合剂(如N,N′-二环己基碳化二亚胺等)的存在下进行。
此反应最好在无机或有机碱(如解释方法2时所列举的那些)存在下进行。
这个反应通常在对其不产生不利影响的溶剂中进行,如甲醇、乙醇、丙醇、二氯甲烷、四氢呋喃、氯仿等。
反应温度要求不严格,此反应通常在冷却至加热条件下进行。
方法C-①
化合物(Ⅹb)或其盐可通过将化合物(Ⅹa)或其盐进行亚胺保护基团消除反应来制备。
这个反应以与方法2基本上相同的方法进行,因而反应条件(如反应温度、溶剂等)可参考所述方法2。
方法C-②
化合物(Ⅹc)或其盐可通过化合物(Ⅹb)或其盐与酰化剂反应来制备。
这个反应以与方法3基本上相同的方式进行,因而反应条件(如反应温度、溶剂、酰化剂等)可参考所述方法3。
方法D
化合物(Ⅱa)或其盐可通过还原化合物(Ⅹ)或其盐来制备。
这个反应以与方法8基本上相同的方式进行,因而反应条件(如反应温度、溶剂、还原剂等)可参考所述方法8。
方法E
化合物(Ⅺa)或其盐可通过还原化合物(Ⅹ)或其盐来制备。
这个反应以与方法8基本上相同的方式进行,因而反应条件(如反应温度、溶剂、还原剂等)可参考所述方法8。
方法F
化合物(Ⅱ)或其盐可通过氧化化合物(Ⅺ)或其盐来制备。
此氧化反应是利用传统氧化剂(如三氧化铬、二甲亚砜等)进行。
此反应通常在普通溶剂中进行,如氯仿、四氢呋喃、二卤代烷(如二氯甲烷、二氯乙烷等)、二甲亚砜、或任何其它对此反应无不利影响的溶剂。
反应温度要求不严格,此反应通常在冷却或室温下进行。
本发明的目标化合物(Ⅰ)及其医药上可接受的盐是血栓素A2(TXA2)拮抗剂,因而可用作诸如血栓形成、气喘、肾炎等疾病的治疗药物。
为了说明,下面给出目标化合物(Ⅰ)的某些生物学数据。
在下列试验中,所用的9,11-偶氮PGH2和9,11-亚甲基环氧PGH2(U46619)在医药学中被称为TXA2拟态剂,并广泛地用于评价试验化合物的TXA2拮抗作用(例如Vide The Journal of Pharmacology and Experimental Therapeutics 234卷,pp435-441页)。
试验化合物
(1)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷。
(2)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷。
试验1(9,11-偶氮PGH2引起的兔血小板凝集的体外试验效果)
(a)试验方法
在体外试验中,将从兔子的颈动脉采集的血置于含0.1体积3.8%柠檬酸钠水溶液的塑料容器中。对血样进行15分钟离心(150g)分离制备富含血小板的血浆(PRP)。按比浊的方法用集合度计(NKK HEMATRAC ER1)研究血小板凝集过程。向225μl PRP添加25μl试验化合物溶液,然后在37℃以1000转/分的转速搅拌2分钟。向此溶液添加5μl9,11-偶氮PGH2(最终浓度为1.0μM)作为凝集诱体。IC50(血小板凝集为50%时的抑制浓度)以图表法测定。
(b)试验结果
试验化合物 | IC50(M) |
(1) | 8.5×10-8 |
(2) | 5.5×10-8 |
试验2(对ex vivo实验中9,11-亚甲基环氧PGH2引起的血小板凝集的作用效果)
(a)试验方法
在ex vivo实验中,使用了禁食过夜重约300g的雄性Hartley品系的豚鼠。从这些动物的腹动脉取血样之前1小时,先让它们口服试验化合物(0.032mg/kg)或介质。按上述方法制备PRP,向250μl PRP中添加5μl的9,11-亚甲基环氧PGH2(U46619,0.5μM)诱发血小板凝集。
(b)试验结果
试验化合物 | 抑制率(%) |
(1) | 94.2 |
(2) | 100 |
目标化合物(Ⅰ)或其医药上可接受的盐通常以普通医药组合物的形式供哺乳动物(包括人类)服用,如胶囊、微胶囊、片剂、颗粒剂、散剂、锭剂、糖浆剂、气雾剂、吸入剂、溶液剂、注射液、悬浮液、乳剂、栓剂、软膏剂等。
本发明的医药组合物可包含各种有机无机载体材料,这些载体是医药上普遍采用的,如赋形剂(如蔗糖、淀粉、甘露醇(mannit)、山梨醇(sorbit)、乳糖、葡萄糖、纤维素、滑石、磷酸钙、碳酸钙等)、结合剂(纤维素、甲基纤维素、羟丙基纤维素、聚丙基吡咯烷酮、明胶、阿拉伯树胶、聚乙二醇、蔗糖、淀粉等)、崩解剂(如淀粉、羧甲基纤维素、羧甲基纤维素钙盐、羟丙基淀粉、乙二醇(sodium glycole)-淀粉钠、碳酸氢钠、磷酰钙、柠檬酸钙等)、润滑剂(如硬脂酸镁、滑石、十二烷基硫酸钠等)、香味剂(如柠檬酸、薄荷醇(mentol)、甘氨酸、桔子粉等)、保存剂(如苯甲酸钠、亚硫酸氢钠、羟苯甲酸甲酯、羟苯甲酸丙酯等)、稳定剂(如柠檬酸、柠檬酸钠、乙酸等)、悬浮剂(如甲基纤维素、聚乙烯基吡咯烷酮、硬脂酸铝等)、分散剂、水溶液稀释剂(如水)、基质蜡(如可可黄油、聚乙二醇、白凡士林等)。
以有效成分计,给药量为每天1-4次,每次0.01-50mg/kg。然而上述剂量根据患者年龄、体重、身体条件或给药方式的不同,要适当的增加或减少。
下列给出的制备方法和实例只是为了更详细地说明本发明。
制备方法1
(1)在冰浴冷却下向(2S,4R)-1-叔丁氧基羰基-4-羟基-2-甲氧基羰吡咯烷(53.4g)的二氯甲烷(500ml)溶液添加三乙胺(36ml)和甲磺酰氯(19.8ml),得到的混合物在相同温度下搅拌3小时。将此溶液依次用稀释的盐酸、碳酸氢钠饱和水溶液和盐水洗涤并用硫酸镁干燥。在真空下蒸除溶剂,剩余物在正己烷中结晶,得到(2S,4R)-1-叔丁氧基羰基-4-甲磺酰氧基-2-甲氧基羰基吡咯烷(56.2g)无色结晶。
熔点:73-75℃
1H-NMR(CDCl3)δppm:1.43(9H x2/3,s),1.47(9H x 1/3,s),2.28(1H,ddd,J=5,8,14Hz),2.63(1H,m),3.05(3H,s),3.7-3.9(2H,m),3.77(3H,s),4.41(2/3H,t,J=8Hz),4.48(1/3H,t,J=8Hz),5.28(1H,m)
按照与制备方法1①相似的方法得到下列化合物。
(2)(2R,4R)-4-甲磺酰氧基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H-NMR(CDCl3)δppm:2.32(ddd,J=4.5,9,13.5Hz,1H),2.58(m,1H),2.84(s,3H),3.79(s,3H),3.7-3.8(m,2H),4.46(t,J=12Hz,1H),5.23(m,1H),7.5-7.7(m,3H),7.9-8.0(m,2H)
(3)(2R,4S)-4-甲磺酰氧基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H-NMR(CDCl3)δppm:2.30(ddd,J=4.5,9,13.5Hz,1H),2.58(m,1H),3.82(s,3H),3.7-3.9(m,2H),3.77(s,3H),4.45(t,J=8Hz,1H),5.23(m,1H),7.5-7.7(m,3H),7.9-8.0(m,2H)
制备方法2
在冰浴冷却和搅拌下向(2S,4S)-1-叔丁氧基羰基-4-羟基-2-甲氧基羰基吡咯烷(20.0g)的二氯甲烷(500ml)溶液添加三乙胺(13.5ml)和甲磺酰氯(7.4ml),并将此混合物在同样温度下搅拌4个小时。依次用稀释的盐酸、碳酸氢钠饱和水溶液和盐水洗涤此溶液,并用硫酸镁干燥。在真空下蒸除溶剂,得到(2S,4S)-1-叔丁氧基羰基-4-甲磺酰氧基-2-甲氧基羰基吡咯烷(27.7g)淡褐色油状物。
1H-NMR(CDCl3)δppm:1.43(s,9x3/5H),1.46(s,9x2/5H),2.53(m,2H),3.03(s,3H),3.76(s,3H),3.80(m,2H),4.4-4.6(m,1H),5.75(m,1H)
制备方法3
(1)将(2S,4R)-1-叔丁氧基羰基-4-甲磺酰氧基-2-甲氧基羰基吡咯烷(32.3g)与苯甲酸钠(28.8g)在二甲亚砜(320ml)中的混合物在90℃搅拌过夜,然后冷却至室温。用乙酸乙酯(600ml)稀释此混合物,并依次用水和盐水洗涤。用硫酸镁干燥有机相,在真空下蒸出溶剂,得到一油状物。将此油状物在正己烷中结晶,得到(2S,4S)-4-苯甲酰氧基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(31.0g)无色结晶。
熔点:89-90℃
1H-NMR(CDCl3)δppm:1.45(s,9/2H),1.48(s,9/2H),2.4-2.7(m,2H),3.68(s,3/2H),3.69(s,3/2H),3.69(m,1H),3.82(m,1H),4.48(dd,J=2,11Hz,1/2H),4.61(dd,J=4,11Hz,1/2H),5.53(m,1H),7.43(t,J=7.5Hz,1H),7.57(t,J=7.5Hz,2H),7.98(d,J=7.5Hz,2H)
按照与制备方法3(1)相似的方法得到下列化合物。
(2)(2R,4S)-4-苯甲酰氧基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H-NMR(CDCl3)δppm:2.35(ddd,J=4,9.5,14Hz,1H),2.52(dt,J=14,3Hz,1H),3.78(m,1H),3.80(s,3H),3.89(dd,J=3.5,12.5Hz,1H),4.42(dd,J=8,9.5Hz,1H),5.41(m,1H),7.3-7.4(m,5H),7.5-7.6(m,3H),7.8-7.9(m,2H)
制备方法4
(1)向(2S,4S)-4-苯甲酰氧基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(30.0g)在甲醇(600ml)中的溶液添加羰酸钾(11.9g),将此混合物在室温下搅拌1小时。用乙酸乙酯(1l)稀释此溶液并用水洗涤。用盐水洗涤有机相。用氯化钠饱和水相,用氯仿萃取并用盐水洗涤。用硫酸镁干燥混合的有机萃取液,然后在真空下蒸发,得到一油状物。在硅胶柱上以正己烷和乙酸乙酯(1∶1)混合物作洗脱液层析分离此油状物,得到(2S,4S)-1-叔丁氧基羰基-4-羟基-2-甲氧基羰基吡咯烷(20.7g)无色结晶。
熔点:59-62℃
1H-NMR(CDCl3)δppm:1.45(s,9x3/5H),1.47(s,9x2/5H),2.10(m,1H),2.33(m,1H),3.5-3.7(m,3H),3.78(s,3x3/5H),3.80(s,3x2/5H),4.35(m,1H)
按照与制备方法4(1)相似的方法得到下列化合物。
(2)(2R,4S)-4-羟基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H-NMR(CDCl3)δppm:2.12(ddd,J=4.5,9,13.5Hz,1H),2.24(m,1H),3.43(dt,J=11.5,2Hz,1H),3.62(dd,J=4,11.5Hz),3.75(s,3H),4.45(t,J=9Hz,1H),4.47(m,1H),7.5-7.7(m,3H),7.9-8.0(m,2H)
制备方法5
(1)将(2S,4S)-1-叔丁氧基羰基-4-甲磺酰氧基-2-甲氧基羰基吡咯烷(27.7g)与叠氮钠(10.6g)在二甲亚砜(350ml)中的混合物在90℃搅拌过夜,然后用乙酸乙酯(600ml)稀释此溶液。依次用水和盐水洗涤上述溶液,并用硫酸镁干燥。真空下蒸出溶剂,得到(2S,4R)-4-叠氮基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(20.0g)淡褐色油状物。
1H-NMR(CDCl3)δppm:1.41(s,9x2/3H),1.47(s,9x1/3H),2.20(m,1H),2.32(m,1H),3.4-3.7(m,3H),3.76(s,3H),4.20(m,1H),4.36(m,1H)
按照与制备方法5(1)相似的方法得到下列化合物。
(2)(2S,4S)-4-叠氮基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷
1H-NMR(CDCl3)δppm:1.43(s,9x3/5H),1.48(s,9x2/5H),2.14(t,J=4Hz,2/5H),2.21(t,J=4Hz,3/5H),2.47(m,1H),3.50(m,1H),3.73(m,1H),3.76(s,3H),4.14(m,1H),4.33(dd,J=4,9Hz,3/5H),4.43(dd,J=4,9Hz,2/5H)
(3)(2R,4S)-4-叠氮基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H-NMR(CDCl3)δppm:7.23(m,2H),3.47(dd,J=3,12Hz,1H),3.76(dd,J=5,12Hz,1H),4.25(m,1H),4.35(t,J=7Hz,1H),7.5-7.7(m,3H),7.9-8.0(m,2H)
(4)(2R,4R)-4-叠氮基-2-甲氧基羰基-1-苯磺酰基吡咯烷
1H NMR(CDCl3)δppm:2.2-2.4(m,2H),3.35(dd,J=4,11Hz,1H),3.67(dd,J=5.5,11Hz,1H),
3.73(s,3H),4.10(m,1H),4.56(dd,J=4,8.5Hz,1H),7.5-7.7(m,3H),7.9-8.0(m,2H)
制备方法6
(1)在载于碳上的10%钯(20.2g)存在下,于环境压力下将(2S,4R)-4-叠氮基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(112g)的甲醇(870ml)溶液氢化5小时。将催化剂滤除后,在真空下蒸发滤出液,得到(2S,4R)-4-氨基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(93.8g)油状物。
1H-NMR(CDCl3)δppm:1.41(s,9x2/3H),1.46(s,9x1/3H),1.9-2.2(m,2H),3.2-3.4(m,1H),3.6-3.8(m,2H),3.74(s,3H),4.40(m,1H)
按照与制备方法6(1)相似的方法得到下列化合物。
(2)(2S,4S)-4-氨基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷
(3)(2R,4S)-4-氨基-2-甲氧基羰基-1-苯磺酰基吡咯烷
(4)(2R,4R)-4-氨基-2-甲氧基羰基-1-苯磺酰基吡咯烷
制备方法7
用冰浴冷却下向(2S,4R)-4-氨基-1-叔丁氧基羰基-2-甲氧基羰基吡咯烷(6.04g)的二氯甲烷(60ml)溶液添加三乙胺(3.44ml)和对一氯苯磺酰氯(6.26g)。室温下搅拌过夜后,依次用稀释的盐酸、碳酸氢钠饱和水溶液和盐水洗涤上述溶液,并用硫酸镁干燥。在真空下将溶剂蒸出,将剩余物在正己烷中结晶,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(9.13g)淡黄色结晶。
1H-NMR(CDCl3)δppm:1.37(s,9x2/3H),1.40(s,9x1/3H),2.0-2.4(m,2H),3.20(m,1H),3.63(m,1H),3.95(m,1H),4.30(m,1H),5.0-5.2(m,1H),7.52(d,J=10Hz,2H),7.83(d,J=10Hz,2H)
按照与制备方法7(1)相似的方法得到下列化合物。
(2)(2S,4R)-1-叔丁氧基羰基-2-甲氧基羰基-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.40(s,9H),2.0-2.3(m,2H),3.17(dd,J=5,11Hz,1H),3.59(m,1H),3.98(m,1H),4.30(m,1H),4.82(m,1H),7.5-7.7(m,3H),8.8-8.9(m,2H)
(3)(2S,4S)-1-叔丁氧基羰基-2-甲氧基羰基-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.37(s,9H),1.7-1.9(m,1H),2.81(m,1H),3.3-3.5(m,2H),3.74(s,3H),4.03(m,1H),4.20(m,1H),5.93(broad,1H),7.5-7.6(m,3H),7.8-7.9(m,2H)
(4)(2R,4S)-2-甲氧基羰基-1-苯磺酰基-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:2.1-2.2(m,2H),3.18(dd,J=3,12Hz,1H),3.50(dd,J=5,12Hz,1H),
3.99(m,1H),4.42(dd,J=5,8Hz,1H),4.75(d,J=7,1H),7.5-7.7(m,3H),7.8-7.9(m,1H)
(5)(2R,4R)-2-甲氧基羰基-1-苯磺酰基-4-苯磺酰氨基吡咯烷
1H NMR(CDCl3)δppm:1.83(m,1H),2.18(ddd,J=6,10,15Hz,1H),3.2-3.3(m,2H),3.77(s,3H),4.04(m,1H),4.23(dd,J=2,6Hz,1H),5.97(d,J=10Hz,1H),7.4-7.7(m,6H),7.7-7.9(m,4H)
制备方法8
(1)在-78℃向(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(9.01g)的甲苯(70ml)溶液滴加氢化二异丁基铝(61.2mmol)的四氢呋喃(40.8ml)1.5M溶液。混合物在-78℃搅拌1.5小时后,向其中添加酒石酸钾钠饱和水溶液,并将此混合物经硅藻土(Celite)过滤。用乙酸乙酯洗涤得到的固体,用盐水洗涤混合有机相,并用硫酸镁干燥。在真空下蒸发掉溶剂,在硅胶柱上以乙酸乙酯和正己烷(1∶2-2∶1)作为洗脱液将剩余物层析分离,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(5.51g)淡黄色结晶。
熔点:120-122℃
1H-NMR(CDCl3)δppm:1.43(s,9H),2.16(m,2H),3.33(m,1H),3.60(m,1H),3.85(m,1H),4.26(m,1H),4.87(m,1H),7.53(d,J=10Hz,2H),7.82(d,J=10Hz,2H),9.4-9.6(m,1H)
按照与制备方法8(1)相似的方法得到下列化合物。
(2)(2S,4R)-1-叔丁氧基羰基-2-甲酰基-4-苯磺酰氨基吡咯烷
1H-NMR(DMSO-d6)δppm:1.34(s,9x3/5H),1.37(s,9x2/5H),1.94(m,2H),3.17(m,1H),3.38(m,1H),3.67(m,1H),4.15(m,1H),7.6-7.7(m,3H),7.8-7.9(m,2H),8.12(broad 1H),9.36(broad 1H)
(3)(2R,4S)-2-甲酰基-1-苯磺酰基-4-苯磺酰氨基吡咯烷
(4)(2R,4R)-2-甲酰基-1-苯磺酰基-4-苯磺酰氨基吡咯烷
制备方法9
在-25℃向(2S,4S)-1-叔丁氧基羰基-2-甲氧基羰基-4-苯磺酰氨基吡咯烷(10.0g)的甲苯(70ml)溶液滴加二异丁基氢化铝的甲苯(70ml)1.0摩尔溶液,将得到的混合物在同样温度下搅拌4小时。在向此混合物添加氯化铵饱和水溶液后,将混合物在室温下搅拌1小时。将混合物过滤,用乙酸乙酯萃取滤出液。用盐水洗涤有机相,并用硫酸镁干燥。蒸出溶剂得到(2S,4S)-1-叔丁氧基羰基-2-羟甲基-4-苯磺酰氨基吡咯烷(9.44g)无色油状物。
1H-NMR(CDCl3)δppm:1.82(m,1H),2.23(m,1H),3.24(dd,J=3,12Hz,1H),3.47(dd,J=3.5,12Hz,1H),3.53(m,1H),3.8-3.9(m,2H),4.03(dd,J=2.5,11Hz,1H),7.4-7.6(m,3H),7.8-7.9(m,2H)
制备方法10
在冰浴冷却下向吡啶(8.5ml)的二氯甲烷(150ml)溶液添加三氧化铬(5.55g),然后在室温下将此混合物搅拌1小时。向此溶液添加硅藻土和(2S,4S)-1-叔丁氧基羰基-2-羟甲基-4-苯磺酰氨基吡咯烷(3.4g)的二氯甲烷(20ml)溶液,并在室温下将所得的混合物搅拌1小时。用正己烷和乙酸乙酯(1∶1,150ml)稀释后,将上述溶液通过硅胶,并在真空下蒸出溶剂,得到(2S,4S)-1-叔丁氧基羰基-2-甲酰基-4-苯磺酰氨基吡咯烷淡黄色油状物。
实例1
(1)向(4-羧丁基)三苯基溴化鏻(17.3g)的二甲亚砜(45ml)溶液添加甲亚磺酰甲基化钠〔78.0mmol,由氢化钠(3.12g)和二甲亚砜(45ml)制备〕,并在室温下将此溶液搅拌20分钟。向上述溶液添加(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(5.06g)的二甲亚砜(30ml)溶液,所得混合物在室温下搅拌2小时。向上述反应混合物添加水,用乙酸乙酯洗涤此水溶液。用1N盐酸将水相的PH调到2,并用乙酸乙酯萃取。依次用水和盐水洗涤有机相,用硫酸镁干燥。在真空下蒸出溶剂,在硅胶柱上以氯仿和甲醇(40∶1)的混合物作为洗脱液将剩余物层析分离,得到(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷(7.64g)淡褐色油状物。
1H NMR(CDCl3)δppm:1.38(s,9x2/3H),1.39(s,9x1/3H),1.7-1.8(m,2H),2.0-2.2(m,4H),2.3-2.5(m,2H),3.30(m,1H),3.45(dd,J=5,12Hz,1H),3.86(m,1H),4.58(m,1H),5.2-5.5(m,3H),7.52(d,J=10Hz,1H),7.83(d,J=10Hz,1H)
按照与实例1(1)相似的方法得到下列化合物。
(2)(2S,4S)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.38(s,9H),1.5-1.8(m,3H),2.0-2.1(m,3H),2.3-2.4(m,2H),3.08(dd,J=6.5,10.5Hz,1H),3.6-3.8(m,2H),4.44(m,1H),5.2-5.5(m,2H),7.4-7.6(m,3H),7.8-7.9(m,2H)
(3)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.36(s,9H),1.6-1.8(m,3H),2.0-2.2(m,3H),2.3-2.4(m,2H),3.2-3.5(m,2H),3.85(m,1H),4.57(m,1H),5.1-5.5(m,2H),5.72(broad 1H),7.4-7.6(m,3H),7.3-7.4(m,2H)
(4)(2R,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.5-1.8(m,2H),1.9-2.0(m,1H),2.12(m,1H),2.2-2.4(m,2H),3.4-3.5(m,2H),3.68(m,1H),4.45(m,1H),5.2-5.5(m,2H),6.27(d,J=6Hz,1H),7.4-7.6(m,6H),7.6-7.9(m,4H)
(5)(2R,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.4-1.8(m,3H),2.0-2.2(m,3H),2.38(m,2H),3.13(m,1H),3.50(m,2H),4.30(m,1H),4.92(d,J=6.5Hz,1H),5.3-5.5(m,2H),7.4-7.7(m,6H),7.7-7.9(m,4H)
(6)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:149-150℃
1H-NMR(D2O-NaOD)δppm:1.4-1.8(m,3H),1.98(m,3H),2.07(t,J=7.5Hz,2H),2.77(t,J=9Hz,1H),3.28(t,J=9Hz,1H),3.56(m,1H),4.43(m,1H),5.0-5.3(m,2H),7.36(d,J=8Hz,2H),7.4-7.7(m,6H)
(7)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-苯磺酰吡咯烷
(8)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-甲基苯磺酰)吡咯烷
熔点:116-119℃
1H-NMR(CDCl3)δppm:1.6-1.8(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),2.45(s,3H),3.3-3.5(m,2H),3.78(m,1H),4.52(m,1H),5.2-5.6(m,3H),7.3-7.4(m,2H),7.5(m,2H),7.6-7.8(m,4H)
(9)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-三氟甲基苯磺酰)吡咯烷
熔点:152-154℃
1H-NMR(CDCl3)δppm:1.5-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.46(m,1H),3.62(m,1H),3.70(m,1H),4.63(m,1H),5.2-5.3(m,1H),5.4-5.6(m,2H),7.4-7.5(m,2H),7.7-7.8(m,4H),7.9-8.0(m,2H)
(10)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-甲氧基苯磺酰)吡咯烷
熔点:158-160℃
1H-NMR(CDCl3)δppm:1.6-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.3-3.5(m,2H),3.75(m,1H),3.90(s,3H),4.48(m,1H),5.15(d,J=7Hz,1H),5.2-5.5(m,2H),7.00(d,J=9Hz,2H),7.4-7.5(m,2H),7.7-7.8(m,4H)
(11)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-氟苯磺酰)吡咯烷
熔点:78-82℃
1H-NMR(CDCl3)δppm:1.6-1.9(m,3H),2.0-2.2(m,3H),2.3-2.4(m,2H),3.4-3.5(m,2H),3.72(m,1H),4.57(m,1H),5.25(m,1H),5.4-5.6(m,2H),7.1-7.2(m,2H),7.5-7.6(m,2H),7.7-7.9(m,4H)
(12)(2S,4R)-1-(4-溴苯磺酰)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
熔点:116-120℃
1H-NMR(CDCl3)δppm:1.5-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.4-3.5(m,2H),3.75(m,1H),4.57(m,1H),5.25(m,1H),5.4-5.5(m,2H),7.4-7.5(m,2H),7.6-7.7(m,4H),7.7-7.8(m,2H)
(13)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-硝基苯磺酰)吡咯烷
熔点:70-73℃
1H-NMR(CDCl3)δppm:1.6-1.9(4H,m),2.03(1H,m),2.21(1H,m),2.3-2.5(2H,m),3.48(1H,m),3.6-3.8(2H,m),4.62(1H,m),5.1-5.3(2H,m),5.55(1H,m),7.4-7.5(2H,m),7.7-7.8(2H,m),7.9-8.0(2H,m),8.3-8.4(2H,m)
(14)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.6-1.8(3H,m),1.9-2.2(3H,m),2.38(2H,m),3.3-3.5(2H,m),3.79(1H,m),4.52(1H,m),5.09(1H,broad),5.2-5.6(2H,m),7.4-7.6(3H,m),7.8-7.9(2H,m)
(15)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-苯磺酰氨基吡咯烷
(16)(2S,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
(17)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯基氨基甲酰基-4-苯磺酰氨基吡咯烷
(18)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-4-羧基-1-丁烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.39(9H,s),1.7-1.9(2H,m),2.3-2.5(4H,m),3.3-3.5(2H,m),3.85(1H,m),4.67(1H,m),5.2-5.5(2H,m),5.88(1H,m),7.50(2H,d,J=8Hz),7.85(2H,d,J=8Hz)
实例2
(1)室温下将(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷(7.63g)在75%含水三氟乙酸(48ml)中的溶液搅拌40分钟,在真空下将溶剂蒸出。向剩余物添加甲苯(50ml),然后在真空下蒸出溶剂,得到(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐(7.85g)褐色油状物。
1H-NMR(CDCl3)δppm:1.70(2H,m),2.0-2.2(4H,m),2.37(2H,t,J=7Hz),3.36(1H,m),3.58(1H,dd,J=5,12Hz),4.06(1H,m),4.60(1H,m),5.45(1H,m),5.85(1H,m),7.68(2H,d,J=9Hz),7.88(2H,d,J=9Hz)
按照与实例2(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷三氟乙酸盐
1H-NMR(D2O)δppm:1.7-1.9(4H,m),2.1-2.3(2H,m),2.3-2.4(2H,m),3.3-3.6(2H,m),4.07(1H,m),4.80(1H,m),4.46(1H,m),5.80(1H,m),7.5-7.7(3H,m),7.8-7.9(2H,m)
(3)(2S,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷三氟乙酸盐
(4)(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:145-147℃
1H-NMR(CDCl3)δppm:1.8-2.1(2H,m),2.85(1H,dd,J=4,11Hz),3.28(1H,dd,J=6,11Hz),3.90(3H,s),3.8-4.0(2H,m),6.20(1H,dd,J=7,16Hz),6.51(1H,d,J=16Hz),7.36(2H,d,J=8.5Hz),7.49(2H,d,J=8.5Hz),7.83(2H,d,J=8.5Hz),7.94(2H,d,J=8.5Hz)
实例3
(1)在冰冷却下向(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-吡咯烷三氟乙酸盐(7.85g)的二氯甲烷(80ml)溶液添加三乙胺(8.98ml)和4-氯苯磺酰氯(3.40g),并将此混合物在同样的温度下搅拌1.5小时。依次用稀释的盐酸和水洗涤上述溶液,用1N氢氧化钠水溶液萃取有机相。用乙酸乙酯洗涤水相,并用3N盐酸将PH调至3。用乙酸乙酯萃取上述水溶液,并依次用水
和盐水洗涤有机相,用硫酸镁干燥。在真空下蒸出溶剂,在硅胶柱上以氯仿作洗脱液将剩余物层析分离,得到(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷(2.03g)淡黄色结晶。
熔点:149-150℃
1H-NMR(D2O-NaOD)δppm:1.4-1.8(m,3H),1.98(m,3H),2.07(t,J=7.5Hz,2H),2.77(t,J=9Hz,1H),3.28(t,J=9Hz,1H),3.56(m,1H),4.43(m,1H),5.0-5.3(m,2H),7.36(d,J=8Hz,2H),7.4-7.7(m,6H)
按照与实例3(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-苯磺酰基吡咯烷
(3)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-甲基苯磺酰基)吡咯烷
熔点:116-119℃
1H-NMR(CDCl3)δppm:1.6-1.8(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),2.45(s,3H),3.3-3.5(m,2H),3.78(m,1H),4.52(m,1H),5.2-5.6(m,3H),7.3-7.4(m,2H),7.5(m,2H),7.6-7.8(m,4H)
(4)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-三氟甲基苯磺酰基)吡咯烷
熔点:152-154℃
1H-NMR(CDCl3)δppm:1.5-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.46(m,1H),3.62(m,1H),3.70(m,1H),4.63(m,1H),5.2-5.3(m,1H),5.4-5.6(m,2H),7.4-7.5(m,2H),7.7-7.8(m,4H),7.9-8.0(m,2H)
(5)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-甲氧基苯磺酰基)吡咯烷
熔点:158-160℃
1H-NMR(CDCl3)δppm:1.6-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.3-3.5(m,2H),3.75(m,1H),3.90(s,3H),4.48(m,1H),5.15(d,J=7Hz,1H),5.2-5.5(m,2H),7.00(d,J=9Hz,2H),7.4-7.5(m,2H),7.7-7.8(m,4H)
(6)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-氟苯磺酰基)吡咯烷
熔点:78-82℃
1H-NMR(CDCl3)δppm:1.6-1.9(m,3H),2.0-2.2(m,3H),2.3-2.4(m,2H),3.4-3.5(m,2H),3.72(m,1H),4.57(m,1H),5.25(m,1H),5.4-5.6(m,2H),7.1-7.2(m,2H),7.5-7.6(m,2H),7.7-7.9(m,4H)
(7)(2S,4R)-1-(4-溴苯磺酰)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
熔点:116-120℃
1H-NMR(CDCl3)δppm:1.5-1.9(m,3H),2.0-2.2(m,3H),2.3-2.5(m,2H),3.4-3.5(m,2H),3.75(m,1H),4.57(m,1H),5.25(m,1H),5.4-5.5(m,2H),7.4-7.5(m,2H),7.6-7.7(m,4H),7.7-7.8(m,2H)
(8)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(4-硝基苯磺酰基)吡咯烷
熔点:70-73℃
1H-NMR(CDCl3)δppm:1.6-1.9(m,4H),2.03(m,1H),2.21(m,1H),2.3-2.5(m,2H),3.48(m,1H),3.6-3.8(m,2H),4.62(m,1H),5.1-5.3(m,2H),5.55(m,1H),7.4-7.5(m,2H),7.7-7.8(m,2H),7.9-8.0(m,2H),8.3-8.4(m,2H)
(9)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.6-1.8(m,3H),1.9-2.2(m,3H),2.38(m,2H),3.3-3.5(m,2H),3.79(m,1H),4.52(m,1H),5.09(broad 1H),5.2-5.6(m,2H),7.4-7.6(m,3H),7.8-7.9(m,2H)
(10)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-苯磺酰氨基吡咯烷
(11)(2S,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
(12)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.38(s,9x2/3H),1.39(s,9x1/3H),1.7-1.8(m,2H),2.0-2.2(m,4H),2.3-2.5(m,2H),3.30(m,1H),3.45(dd,J=5,12Hz,1H),3.86(m,1H),4.58(m,1H),5.2-5.5(m,3H),7.52(d,J=10Hz,1H),7.83(d,J=10Hz,1H)
(13)(2S,4S)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.38(s,9H),1.5-1.8(m,3H),2.0-2.1(m,3H),2.3-2.4(m,2H),3.08(dd,J=6.5,10.5Hz,1H),3.6-3.8(m,2H),4.44(m,1H),5.2-5.5(m,2H),7.4-7.6(m,3H),7.8-7.9(m,2H)
(14)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.36(s,9H),1.6-1.8(m,3H),2.0-2.2(m,3H),2.3-2.4(m,2H),3.2-3.5(m,2H),3.85(m,1H),4.57(m,1H),5.1-5.5(m,2H),5.72(broad 1H),7.4-7.6(m,3H),7.3-7.4(m,2H)
(15)(2R,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.5-1.8(m,2H),1.9-2.0(m,1H),2.12(m,1H),2.2-2.4(m,2H),
3.4-3.5(m,2H),3.68(m,1H),4.45(m,1H),5.2-5.5(m,2H),6.27(d,J=6Hz,1H),7.4-7.6(m,6H),7.6-7.91(m,4H)
(16)(2R,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰-4-苯磺酰氨基吡咯烷
1H-NMR(CDCl3)δppm:1.4-1.8(m,3H),2.0-2.2(m,3H),2.38(m,2H),3.13(m,1H),3.50(m,2H),4.30(m,1H),4.92(d,J=6.5Hz,1H),5.3-5.5(m,2H),7.4-7.7(m,6H),7.7-7.9(m,4H)
(17)(2S,4R)-1-丁磺酰-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:0.91(3H,t,J=7Hz),1.3-1.5(3H,m),1.6-1.9(4H,m),2.1-2.3(3H,m),2.3-2.4(2H,m),2.95(2H,m),3.30(1H,m),3.50(1H,m),4.73(1H,m),5.2-5.4(1H,m),5.4-5.7(1H,m),5.77(1H,d,J=6.5Hz),7.51(2H,d,J=9Hz),7.83(2H,d,J=9Hz)
(18)(2S,4R)-1-苯甲酰-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.7-2.0(4H,m),2.1-2.5(5H,m),3.33(1H,m),3.58(1H,m),3.92(1H,m),5.1-5.4(2H,m),7.3-7.5(7H,m),7.6-7.8(2H,m)
(19)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-甲氧基苯磺酰)-4-苯磺酰氨基吡咯烷
熔点:130-131℃
1H-NMR(D2O-NaOD)δppm:1.3-1.4(4H,m),1.7-2.0(4H,m),2.58(1H,m),3.19(1H,m),3.47(1H,m),3.76(3H,s),4.20(1H,m),4.9-5.2(2H,m),6.9-7.0(2H,m),7.3-7.4(2H,m),7.5-7.6(4H,m)
(20)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-甲基苯磺酰)-4-苯磺酰氨基吡咯烷
(21)(2S,4R)-1-(4-溴苯磺酰)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
(22)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基-1-(4-三氟甲基苯磺酰)吡咯烷
熔点:108-110℃
1H-NMR(D2O-NaOD)δppm:1.5-1.7(3H,m),1.7-1.9(2H,m),1.9-2.2(4H,m),3.34(1H,m),3.49(1H,m),4.43(1H,m),5.3-5.6(2H,m),7.3-7.5(3H,m),7.6-8.0(6H,m)
(23)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-硝基苯磺酰)-4-苯磺酰氨基吡咯烷
熔点:132-134℃
1H-NMR(CDCl3)δppm:1.6-1.9(3H,m),1.9-2.1(2H,m),2.1-2.2(2H,m),2.3-2.4(2H,m),
3.42(1H,m),3.63(1H,m),4.57(1H,m),5.3-5.6(2H,m),7.4-7.6(3H,m),7.7-7.8(2H,m),7.9-8.0(2H,m),8.3-8.4(2H,m)
(24)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氟苯磺酰)-4-苯磺酰氨基吡咯烷
(25)(2S,4R)-1-丁磺酰-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷
(26)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基-1-(2-噻吩磺酰基)吡咯烷
(27)(2S,4R)-2-〔(E和Z)-4-羧基-1-丁烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.6-1.9(2H,m),2.04(1H,m),2.3-2.5(3H,m),3.3-3.5(2H,m),3.77(1H,m),4.68(1H,m),5.23(1H,m),5.3-5.6(1H,m),5.76(1H,m),7.3-7.5(4H,m),7.6-7.9(4H,m)
(28)(2S,4R)-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:168-169℃
1H-NMR(CDCl3)δppm:1.9-2.1(2H,m),3.32(1H,dd,J=4,11Hz),3.49(1H,dd,J=5.5,11Hz),3.92(3H,s),4.47(1H,q,J=7Hz),4.87(1H,d,J=7.5Hz),5.92(1H,dd,J=7.5,16Hz),6.47(1H,d,J=16Hz),7.28(2H,d,J=8.5Hz),7.41(2H,d,J=8.5Hz),7.51(2H,d,J=8.5Hz),7.69(2H,d,J=8.5Hz),7.74(2H,d,J=8.5Hz),7.79(2H,d,J=8.5Hz),7.97(2H,d,J=8.5Hz)
实例4
将(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷(169mg)、三乙胺(0.070ml)和异氰酸苯酯(0.060ml)在甲醇(5ml)中的混合物在室温下搅拌过夜,然后向此溶液添加水。用氯仿萃取上述溶液并用盐水洗涤有机相。此溶液经硫酸镁干燥后,在真空下蒸出溶剂,在硅胶柱上以氯仿和甲醇(40∶1)的混合物作为洗脱液将剩余物层析分离,得到(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯基氨基甲酰基-4-苯磺酰氨基吡咯烷(51mg)油状物。
实例5
(1)在室温下将(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷(300mg)在甲醇(0.5ml)和1N氢氧化钠水溶液混合物中的溶液搅拌30分钟,用二氯甲烷洗涤此溶液。将水相经“Diaion HP 20”色谱柱(商标:由Mitsubishi Chemical Industries制造)进行分离,并用水洗涤。用50%甲醇水溶液进行洗脱,并将洗脱液冻干,得到(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷钠盐(220mg)白色粉末。
熔点:114-121℃(dec.)
1H-NMR(D2O-NaOD)δppm:1.4-1.7(m,4H),1.9-2.2(m,4H),2.78(m,1H),3.37(m,1H),3.63(m,1H),4.45(m,1H),5.2-5.5(m,2H),7.4-7.8(m,8H)
按照与实例5(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-苯磺酰基吡咯烷钠盐
1H-NMR(D2O)δppm:1.60(m,2H),1.83(m,2H),2.03(m,2H),2.16(t,J=7Hz,2H),3.39(m,1H),3.55(m,1H),3.71(m,1H),4.38(q,J=8.5Hz,1H),5.3-5.6(m,2H),7.6-7.9(m,9H)
(3)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰基-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(D2O)δppm:1.5-1.7(m,2H),1.7-1.8(m,2H),1.9-2.1(m,2H),2.15(m,2H),3.33(m,1H),3.57(m,1H),3.70(m,1H),4.38(m,1H),5.3-5.6(m,2H),7.5-7.9(m,10H)
(4)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(D2O)δppm:1.4-1.6(m,2H),1.74(m,1H),1.89(m,1H),1.9-2.1(m,2H),2.12(m,2H),3.2-3.5(m,2H),3.62(m,1H),4.42(m,1H),5.1-5.3(m,1H),5.3-5.6(m,1H),7.4-7.7(m,9H)
(5)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯基氨基甲酰基-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(D2O)δppm:1.5-1.7(m,2H),1.78(m,1H),2.0-2.2(m,5H),3.28(dd,J=5,11Hz,1H),
3.57(dd,J=6,11Hz,1H),3.88(m,1H),4.72(m,1H),5.3-5.6(m,2H),7.1-7.3(m,3H),7.3-7.4(m,2H),7.5-7.6(m,3H),7.8-7.9(m,2H)
(6)(2S,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰基-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(CDCl3)δppm:1.4-1.7(m,4H),2.0-2.2(m,4H),2.9-3.2(m,3H),3.37(dd,J=6,12Hz),4.28(m,1H),5.4-5.5(m,2H),7.6-7.8(m,10H)
(7)(2R,4S)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰基-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(D2O)δppm:1.5-1.7(m,2H),1.81(m,1H),2.03(m,1H),2.1-2.2(m,2H),3.40(m,1H),3.56(dd,J=4.5,11.5Hz,1H),3.7(m,1H),4.38(m,1H),5.3-5.6(m,2H),7.5-7.9(m,10H)
(8)(2R,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-苯磺酰基-4-苯磺酰氨基吡咯烷钠盐
1H-NMR(D2O)δppm:1.4-1.7(m,4H),2.0-2.2(m,4H),2.9-3.2(m,2H),3.37(m,1H),4.28(m,1H),5.4-5.6(m,2H),7.5-7.8(m,10H)
(9)(2S,4R)-1-丁磺酰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷钠盐
1H-NMR(D2O)δppm:0.92(3H,t,J=7Hz),1.4-1.5(3H,m),1.5-1.8(4H,m),2.0-2.2(5H,m),3.0-3.2(2H,m),3.4-3.5(2H,m),3.83(1H,m),4.65(1H,m),5.3-5.7(2H,m),7.61(2H,d,J=9Hz),7.84(2H,d,J=9Hz)
(10)(2S,4R)-1-苯甲酰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷钠盐
1H-NMR(D2O)δppm:1.1-1.4(1H,m),1.6-1.8(1H,m),1.90(1H,m),2.06(1H,m),2.1-2.3(3H,m),3.02(1H,m),3.5-3.7(1H,m),3.98(1H,m),4.7-5.1(2H,m),5.37(1H,m),5.5-5.7(1H,m),7.3-7.5(5H,m),7.62(2H,m),7.90(2H,m)
(11)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-甲苯磺酰基)-4-苯磺酰氨基吡咯烷钠盐
熔点:109-113℃
1H-NMR(D2O)δppm:1.5-1.7(3H,m),1.7-1.9(2H,m),1.9-2.1(2H,m),2.1-2.2(2H,m),2.47(3H,s),3.53(1H,m),3.68(1H,m),4.33(1H,m),5.3-5.6(2H,m),7.4-7.8(9H,m)
(12)(2S,4R)-1-(4-溴苯磺酰基)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷钠盐
熔点:108-112℃
1H-NMR(D2O)δppm:1.4-1.7(3H,m),1.8-2.2(6H,m),3.51(1H,m),3.64(1H,m),4.37(1H,m),5.3-5.6(2H,m),7.6-7.9(5H,m)
(13)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氟苯磺酰基)-4-苯磺酰氨基吡咯烷钠盐
熔点:94-98℃
1H-NMR(D2O)δppm:1.3-1.6(4H,m),1.72(1H,m),1.8-2.1(3H,m),2.70(1H,m),3.22(1H,m),3.47(1H,m),4.36(1H,m),5.3-5.7(2H,m),7.3-7.4(5H,m),7.5-7.6(2H,m),7.7-7.8(2H,m)
(14)(2S,4R)-1-丁磺酰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷钠盐
熔点:96-98℃
1H-NMR(D2O)δppm:0.78(3H,t,J=7Hz),1.2-1.4(2H,m),1.4-1.7(5H,m),1.8-2.1(5H,m),2.86(1H,m),3.03(2H,m),3.24(1H,m),3.56(1H,m),4.50(1H,m),5.2-5.4(2H,m),7.4-7.5(3H,m),7.6-7.7(2H,m)
(15)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基-1-(2-噻吩磺酰基)吡咯烷钠盐
熔点:110-112℃
1H-NMR(D2O)δppm:1.5-1.7(3H,m),1.8-2.0(2H,m),2.0-2.2(4H,m),3.45(1H,m),3.61(1H,m),4.47(1H,m),5.3-5.6(2H,m),7.31(1H,m),7.6-7.8(6H,m),7.92(1H,m)
(16)(2S,4R)-2-〔(E和Z)-4-羧基-1-丁烯基〕-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷钠盐
熔点:60-64℃
1H-NMR(D2O)δppm:1.6-1.8(2H,m),2.0-2.4(4H,m),3.18(1H,m),3.5-3.7(2H,m),4.14(1H,m),4.8-5.0(1H,m),5.1-5.4(1H,m),7.2-7.4(4H,m),7.6-7.9(4H,m)
实例6
将按照与实例3(1)相似的方法处理(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕盐-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐(8.14g)所得到的粗(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷,在硅胶(Wakogel C300,由Wako Pure Chemical industries Ltd.生产,200g)柱上以氯仿作为洗脱液进行层析分离。
从初洗脱物中得到(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(2.50g)
熔点:150.5-151.5℃
1H-NMR(CDCl3)δppm:1.5-1.8(m,3H),2.03(m,1H),2.1-2.2(m,2H),2.41(t,J=6.5Hz,2H),3.4-3.5(m,2H),3.74(m,1H),4.56(q,J=7Hz,1H),5.25(dd,J=10.5,9Hz,1H),5.48(dt,J=10.5,7.5Hz,1H),7.4-7.5(m,4H),7.7-7.8(m,4H)
从第二次洗脱物得到(2S,4R)-2-〔(E)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(650mg)。
熔点:111-113℃
1H-NMR(CDCl3)δppm:1.6-1.8(m,2H),1.8-1.9(m,2H),1.9-2.1(m,2H),2.31(t,J=7.5Hz,2H),3.22(dd,J=5,10Hz,1H),3.42(dd,J=5.5,10Hz,1H),3.83(m,1H),4.23(q,J=6Hz,1H),5.17(dd,J=7.5,15.5Hz,1H),5.53(dt,J=15.5,6.5Hz,1H),7.4-7.5(m,4H),7.65-7.8(m,4H)
实例7
将按照与实例3(1)相似的方法处理(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-苯磺酰氨基吡咯烷三氟乙酸盐(29.9g)所得的粗(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-苯磺酰氨基吡咯烷,在硅胶(Wakogel C300,700g)柱上以氯仿为洗脱液进行层析分离。
从初洗脱物中得到(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-苯磺酰氨基吡咯烷(10.5g)。
熔点:121-123℃
1H-NMR(CDCl3+CD3OD)δppm:1.5-1.8(m,3H),1.92(m,1H),2.11(q,J=6.5Hz,2H),2.33(t,J=6.5Hz,2H),3.4-3.6(m,2H),3.68(m,1H),4.46(q,J=8Hz,1H),5.37(dd,J=10.5,10Hz,1H),5.45(dt,J=10.5,7Hz,1H),7.5-7.7(m,5H),7.7-7.9(m,4H)
从第二次洗脱物中得到(2S,4R)-2-〔(E)-5-羧基-戊烯基〕-1-(4-氯苯磺酰基)-4-苯磺酰氨基吡咯烷(1.55g)。
熔点:155-156℃
1H-NMR(CDCl3+CD3OD)δppm:1.6-1.7(m,2H),1.7-1.8(m,2H),1.9-2.1(m,2H),2.28(t,J=7.5Hz,2H),3.18(dd,J=5.5,10.5Hz,1H),3.47(m,1H),3.76(m,1H),4.28(q,J=6.5Hz,1H),5.20(dd,J=8,15.5Hz,1H),5.54(dt,J=15.5,6.5Hz,1H),7.4-7.6(m,5H),7.6-7.7(m,2H),7.75-7.85(m,2H)
实例8
在0℃向(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(330mg)的乙酸乙酯(15ml)溶液添加重氮甲烷的乙醚溶液,在同样温度下将此混合物搅拌10分钟。在真空下蒸出溶剂,用正己烷将剩余物凝固,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(E和Z)-5-甲氧基羰基-1-戊烯基〕吡咯烷(321mg)白色粉末。
熔点:87-89℃
1H-NMR(CDCl3)δppm:1.5-1.9(3H,m),1.9-2.1(3H,m),2.2-2.4(2H,m),3.43(2H,m),3.71(1H,m),4.50(1H,m),4.96(1H,d,J=6.5Hz),5.2-5.6(2H,m),7.4-7.5(4H,m),7.6-7.8(4H,m)
实例9
在载于碳上的10%钯存在下在适当压力(2个大气压)下将(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(400mg)的甲醇(15ml)溶液氢化7小时。去除催化剂后,在真空下蒸出溶剂,用乙醚将剩余物凝固化,得到(2R,4R)-2-(5-羧戊基)-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)吡咯烷(164mg)白色粉末。
熔点:124-125℃
1H-NMR(CDCl3)δppm:1.2-1.4(4H,m),1.5-1.7(3H,m),1.7-1.9(3H,m),2.35(2H,t,J=7.5Hz),3.09(1H,m),3.38(1H,m),3.6-3.9(2H,m),7.4-7.6(4H,m),7.7-7.9(4H,m)
实例10
在冰浴冷却下分批向三苯-(4-甲氧基羰基苯基)氯化鏻(88.49g)在四氢呋喃(500ml)中的悬浮液添加氢化钠(4.75g),并在冰浴下将此混合物搅拌1小时。
在冰浴下向所得到的黄色悬浮液滴加(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(70.0g)在四氢呋喃(200ml)中的溶液,同样在冰浴下将此混合物搅拌1小时。向上述混合物添加氯化铵饱和水溶液(50ml)和乙酸乙酯(1.5l),依次用水和盐水洗涤此溶液。用硫酸镁干燥有机层,在真空下蒸出溶剂,得到粗(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(E和Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷产物。此粗产物在以正己烷和乙酸乙酯(4∶1-2∶1)混合物为洗脱液的硅胶(1kg)柱上层析分离,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(Z异构体,15.98g,极性小)白色粉末和(2S,4R)-1-叔丁氧基羰-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(E异构体,21.94g,极性较大)白色粉末。
Z异构体
熔点:178-179℃
1H-NMR(CDCl3)δppm:1.29(9H,s),1.8-2.3(2H,m),3.26(1H,m),3.51(1H,dd,J=6,11Hz),3.89(1H,m),3.93(3H,s),4.78(1H,m),5.10(1H,m),5.60(1H,dd,J=9,11.5Hz),6.48(1H,d,J=11.5Hz),7.2-7.4(2H,m),7.48(2H,d,J=8.5Hz),7.82(2H,d,J=8.5Hz),8.02(2H,d,J=8.5Hz)
E异构体
熔点:164-165℃
1H-NMR(CDCl3)δppm:1.39(9H,s),1.9-2.2(2H,m),3.24(1H,dd,J=5,11Hz),3.55(1H,dd,J=6,11.5Hz),3.91(3H,s),3.8-4.0(1H,m),4.49(1H,m),4.91(1H,m),6.12(1H,dd,J=6.5,15.5Hz),7.37(2H,d,J=8.5Hz),7.50(2H,d,J=8.5Hz),7.82(2H,d,J=8.5Hz),7.97(2H,d,J=8.5Hz)
实例11
按照与实例10相似的方法得到下列化合物。
(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:154-156℃
1H-NMR(CDCl3)δppm:1.28(9H,s),1.8-2.1(2H,m),3.30(1H,dd,J=5,12Hz),3.56(1H,dd,J=6,12Hz),3.89(1H,m),3.93(3H,s),4.79(1H,m),4.93(1H,d,J=7Hz),5.58(1H,dd,J=9,12.5Hz),6.48(1H,d,J=12.5Hz),7.3-7.5(4H,m),7.83(2H,d,J=8.5Hz),7.92(2H,m)
(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:126-128℃
1H-NMR(CDCl3)δppm:1.40(9H,s),1.8-2.1(2H,m),3.24(1H,dd,J=5.5,11Hz),3.57(1H,dd,J=6,11Hz),3.92(3H,s),3.97(1H,m),4.49(1H,m),4.88(1H,m),6.09(1H,dd,J=6.5,16Hz),6.43(1H,d,J=16Hz),7.49(1H,t,J=7.5Hz),7.4-7.6(3H,m),7.33(2H,d,J=8.5Hz),7.92(1H,d,J=7Hz),8.03(1H,s)
实例12
(1)将(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(15.5g)在90%含水三氟乙酸(100ml)中的溶液在室温下搅拌30分钟,并在真空下蒸出溶剂。将剩余物悬浮在氯仿(200ml)中,用碳酸氢钠饱和水溶液将其PH调至8。分离有机相,用盐水洗涤,硫酸镁干燥。在真空下蒸出溶剂,滤集剩余固体,得到(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(11.9g)白色粉末。
熔点:189-190℃
1H-NMR(CDCl3)δppm:1.7-2.2(2H,m),2.66(1H,dd,J=4.5,11.5Hz),3.18(1H,dd,J=6,11.5Hz),3.88(1H,m),3.93(3H,s),4.08(1H,m),5.61(1H,dd,J=9.5,11.5Hz),6.52(1H,d,J=11.5Hz),7.28(2H,d,J=8.5Hz),7.49(1H,d,J=8.5Hz),7.80(1H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz)
按照与实例12(1)相似的方法得到下列化合物。
(2)(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
1H-NMR(CDCl3)δppm:1.75(1H,dd,J=7.5,14Hz),1.91(1H,m),2.74(1H,dd,J=5,12Hz),3.26(1H,dd,J=6,12Hz),3.90(1H,m),3.92(3H,s),4.13(1H,m),5.62(1H,dd,J=9.5,12Hz),6.51(1H,d,J=12Hz),7.3-7.5(5H,m),7.7-8.0(3H,m)
(3)(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
1H-NMR(CDCl3)δppm:1.8-2.0(2H,m),2.93(1H,dd,J=4.5,11.5Hz),3.32(1H,dd,J=6,11.5Hz),3.90(1H,m),3.93(3H,s),4.05(1H,m),6.28(1H,dd,J=7.5,16.5Hz),6.52(1H,d,J=16.5Hz),7.36(1H,t,J=7.5Hz),7.4-7.5(3H,m),7.7-7.9(3H,m),8.00(1H,m)
实例13
(1)在冰浴冷却下向(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(11.5g)在二氯甲烷(200ml)中的悬浮液添加三乙胺(3.80ml)和4-氯苯磺酰氯(5.77g),并在室温下将此混合物搅拌1小时。依次用稀释的盐酸、碳酸氢钠饱和水溶液和盐水洗涤上述溶液,并用硫酸镁干燥。在真空下蒸出溶剂,滤集剩余固体,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(15.71g)白色粉末。
熔点:171-172℃
1H-NMR(CDCl3)δppm:1.8-2.1(2H,m),3.30(1H,dd,J=4,11Hz),3.53(1H,dd,J=5.5,11Hz),3.81(1H,m),3.97(3H,s),4.53(1H,m),5.58(1H,dd,J=9,11.5Hz),6.43(1H,d,J=11.5Hz),7.25(2H,d,J=8.5Hz),7.33(2H,d,J=8.5Hz),7.45(2H,d,J=8.5Hz),7.50(2H,d,J=8.5Hz),7.75(2H,d,J=8.5Hz),8.04(2H,d,J=8.5Hz)
按照与实例13(1)相似的方法得到下列化合物。
(2)(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:203-204℃
1H-NMR(DMSO-d6)δppm:1.8-1.9(2H,m),3.23(1H,dd,J=4.5,11Hz),3.50(1H,dd,J=5.5,11Hz),3.65(1H,m),3.89(3H,s),4.40(1H,m),5.68(1H,dd,J=9,11.5Hz),6.54(1H,d,J=11.5Hz),7.4-8.0(12H,m)
(3)(2S,4R)-1-(4-氯苯磺酰)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-(3-甲氧基羰基苯基)乙烯基〕吡咯烷
熔点:138-139℃
1H-NMR(DMSO-d6)δppm:1.7-1.9(2H,m),3.13(1H,dd,J=5,9.5Hz),3.53(1H,dd,J=6.5,9.5Hz),3.78(1H,m),4.33(1H,m),6.23(1H,dd,J=7.5,16Hz),6.57(1H,d,J=16Hz),7.4-8.0(12H,m)
实例14
(1)在50℃下将(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-2-(4-甲氧基羰基苯基)乙烯基〕吡咯烷(15.0g)在甲醇(100ml)和1N氢氧化钠水溶液(75ml)混合物中的溶液搅拌4小时,在真空下将挥发性溶剂蒸出。用浓盐酸将剩余水溶液的PH调至1。滤集白色沉淀并用水洗涤,得到(2S,4R)-2-〔(Z)-2-(4-羧苯基)乙烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(14.50g)白色粉末。
熔点:206-208℃(dec.)
1H-NMR(DMSO-d6)δppm:1.8-2.0(2H,m),3.31(1H,dd,J=3.5,10.5Hz),3.51(1H,dd,J=5.5,10.5Hz),4.40(1H,m),5.68(1H,dd,J=9.5,11.5Hz),6.54(1H,d,J=11.5Hz),7.32(2H,d,J=8Hz),7.40(2H,d,J=8Hz),7.47(2H,d,J=8Hz),7.67(2H,d,J=8Hz),7.78(2H,d,J=8Hz),7.95(2H,d,J=8Hz)
按照与实例14(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E)-2-(4-羧苯基)乙烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:168-171℃(dec.)
1H-NMR(DMSO-d6)δppm:1.7-1.9(2H,m),3.08(1H,dd,J=6,11Hz),3.46(1H,m),3.78(1H,m),4.32(1H,m),6.30(1H,dd,J=7,16Hz),6.53(1H,d,J=16Hz),7.47(2H,d,J=8.5Hz),7.6-7.7(4H,m),7.7-7.8(4H,m),7.88(2H,d,J=8.5Hz),8.00(1H,d,J=6Hz)
(3)(2S,4R)-2-〔(Z)-2-(3-羧苯基)乙烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:127-130℃
1H-NMR(DMSO-d6)δppm:1.8-1.9(2H,m),3.23(1H,dd,J=4.5,10.5Hz),3.50(1H,dd,J=5,10.5Hz),3.63(1H,m),4.41(1H,m),5.67(1H,dd,J=9.5,12Hz),6.54(1H,d,J=12Hz),7.4-8.0(12H,m)
(4)(2S,4R)-2-〔(E)-2-(3-羧苯基)乙烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:119-121℃
1H-NMR(DMSO-d6)δppm:1.7-1.9(2H,m),3.12(1H,dd,J=5,9.5Hz),3.50(1H,dd,J=6.5,9.5Hz),3.79(1H,m),4.31(1H,m),6.23(1H,dd,J=7.5,16Hz),6.57(1H,d,J=16Hz),7.4-8.0(12H,m)
实例15
(1)将水合L-赖氨酸(4.01g)和(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(12.0g)的混合物溶于热水(9ml)和热乙醇(170ml)混合物中,并将此溶液冷却至室温。滤集沉淀物(白色结晶),用乙醇洗涤,真空干燥后得到(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷的L-赖氨酸盐(13.4g)白色结晶。
熔点:176-178℃
1H-NMR(D2O-NaOD)δppm:1.2-1.4(5H,m),1.5-1.7(5H,m),1.98(2H,m),2.09(2H,t,J=7.5Hz),2.53(2H,t,J=7.5Hz),2.77(1H,t,J=8.5Hz),3.18(1H,t,J=7Hz),3.31(1H,m),3.59(1H,m),4.44(1H,m),5.1-5.4(2H,m),7.4-7.7(8H,m)
按照与实例15(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷的L-精氨酸盐
熔点:139-145℃
1H-NMR(D2O-NaOD)δppm:1.4-1.7(8H,m),1.96(2H,m),2.09(2H,t,J=7.5Hz),2.74(1H,t,J=9Hz),3.07(2H,m),3.20(1H,m),3.32(1H,m),3.60(1H,m),4.42(1H,m),5.1-5.4(2H,m),7.4-7.7(8H,m)
制备方法11
在-78℃向(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(5.0g)在无水四氢呋喃(50ml)中的溶液添加溴化甲基镁(10.8ml,在乙醚中的3M溶液),在同样的温度下将此溶液搅拌3小时。用氯化铵饱和水溶液骤冷后,用乙酸乙酯萃取上述混合物,依次用水和盐水洗涤有机相。有机相经硫酸镁干燥后,在真空下将溶剂蒸出,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(R和S)-1-羟乙基〕吡咯烷(5.2g)油状物。
1H-NMR(CDCl3)δppm:1.0-1.1(3H,m),1.41(9H,s),1.8-2.0(2H,m),3.3-3.4(2H,m),3.6-4.0(3H,m),5.40(1H,m),7.52(2H,d,J=8.5Hz),7.84(2H,d,J=8.5Hz)
制备方法12
在-78℃向草酰氯(1.57ml)在二氯甲烷(120ml)中的溶液添加二甲亚砜(1.46ml)。将此混合物在同样温度下搅拌10分钟后,在-78℃向其中添加(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(R和S)-1-羟乙基〕吡咯烷(5.20g)的二氯甲烷(15ml)溶液,并将得到的混合物在同样温度下搅拌15分钟。向此溶液添加三乙胺(6.75ml),将得到的混合物在-78℃搅拌1小时。依次用水和盐水洗涤溶液此溶液,并用硫酸镁干燥。在真空下将溶剂蒸出,剩余物在以正己烷和乙酸乙酯(2∶1)混合物为洗脱液的硅胶柱上进行层析分离,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-乙酰基吡咯烷(3.19g)
1H-NMR(CDCl3)δppm:1.40(9H,s),1.9-2.1(2H,m),2.15(3H,s),2.31(1H,m),3.32(1H,m),3.57(1H,m),3.84(1H,broad),4.42(1H,m),5.45(1/3H,d,J=7Hz),5.59(2/3H,d,J=7Hz),7.53(2H,d,J=8.5Hz),7.82(2H,d,J=8.5Hz)
制备方法13
在室温下将(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(20g)在90%含水三氟乙酸中的溶液搅拌30分钟,然后在真空下蒸出溶剂。将剩余物溶于氯仿和甲醇(500ml,3∶1)的混合物,依次用碳酸氢钠饱和水溶液和盐水洗涤上述溶液。用硫酸镁干燥有机层,并在真空下蒸出溶剂。用乙醚使剩余物固化,得到(2S,4R)-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(10.7g)。
1H-NMR(CDCl3)δppm:2.07(1H,d,J=8Hz),2.10(1H,d,J=8Hz),2.74(1H,dd,J=3,11Hz),3.09(1H,dd,J=5.5,11Hz),3.72(3H,s),3.8-3.9(2H,m),7.48(2H,d,J=8.5Hz),7.82(2H,d,J=8.5Hz)
制备方法14
在冰浴冷却下向(2S,4R)-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(10.0g)在二氯甲烷(200ml)中的溶液添加三乙胺(4.8ml)和4-氯苯磺酰氯(6.62g),并将此混合物在冰浴中搅拌3小时。用稀释的盐酸、碳酸氢钠饱和水溶液和盐水洗涤上述溶液,用硫酸镁干燥。在真空下蒸出溶剂,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-甲氧基羰基吡咯烷(11.5g)。
1H-NMR(CDCl3)δppm:2.14(2H,t,J=7Hz),3.22(1H,dd,J=4.5,10Hz),3.45(1H,dd,J=5,10Hz),3.69(3H,s),3.93(1H,m),4.47(1H,t,J=7Hz),7.45-7.55(4H,m),7.7-7.8(4H,m)
制备方法15
按照与制备方法7(1)相似的方法得到下列化合物。
(1)(2S,4R)-1-叔丁氧基羰基-4-(4-甲基苯磺酰氨基)-2-甲氧基羰基吡咯烷
1H-NMR(CDCl3)δppm:1.40(9H,s),2.1-2.3(2H,m),2.45(3H,s),3.19(1H,m),3.60(1H,dd,J=6,11Hz),3.71(3H,s),3.94(1H,m),4.30(1H,m),5.20(1H,m),7.34(2H,d,J=8Hz),7.77(2H,d,J=8Hz)
(2)(2S,4R)-1-叔丁氧基羰基-2-甲氧基羰基-4-(4-甲氧基苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.48(9H,s),2.1-2.3(2H,m),3.18(1H,m),3.59(1H,dd,J=6,11Hz),3.70(3H,s),3.88(3H,s),3.90(1H,m),4.28(1H,m),5.40(1H,m),6.98(2H,d,J=8Hz),7.80(1H,d,J=8Hz)
(3)(2S,4R)-1-叔丁氧基羰基-2-甲氧基羰基-4-(4-三氟甲基苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.39(9H,s),2.0-2.2(2H,m),2.30(1H,m),3.2-3.4(1H,m),3.73(3H,s),3.98(1H,m),4.33(1H,m),7.82(2H,d,J=8Hz),8.04(2H,d,J=8.0Hz)
制备方法16
按照与制备方法8(1)相似的方法得到下列化合物。
(1)(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷
(2)(2S,4R)-1-叔丁氧基羰基-2-甲酰基-4-(4-甲基苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.40(9H,s),2.13(1H,m),2.47(3H,s),3.32(1H,m),3.57(1H,m),3.82(1H,m),4.25(1H,m),5.10(1H,m),7.34(2H,d,J=8Hz),7.75(2H,d,J=8Hz),9.50(1H,broad)
(3)(2S,4R)-1-叔丁氧基羰基-2-甲酰基-4-(4-甲氧基苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.42(9H,s),1.88(1H,m),2.12(1H,m),3.15(1H,m),3.7-4.0(2H,m),3.88(3H,s),4.93(1H,m),5.38(1H,m),7.02(2H,d,J=8Hz),7.25-7.35(2H,m),9.44(1H,broad)
(4)(2S,4R)-1-叔丁氧基羰基-2-甲酰基-4-(4-三氟甲基苯磺酰氨基)吡咯烷
实例16
在室温下将(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(1.00g)与乙氧基羰基甲撑三苯基正磷(1.50g)在二氯甲烷(20ml)中的混合物搅拌2小时,然后在真空下蒸出溶剂。在以正己烷和乙酸乙酯(2∶1)混合物为洗脱液的硅胶柱上将剩余的油状物层析分离,得到(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(E)-2-乙氧基羰基乙烯基〕吡咯烷(1.15g)油状物。
1H-NMR(CDCl3)δppm:1.30(3H,t,J=7.5Hz),1.38(9H,s),1.98(1H,m),2.15(1H,m),3.22(1H,m),3.53(1H,m),3.85(1H,m),4.20(2H,q,J=7.5Hz),4.46(1H,m),4.92(1H,m),5.80(1H,d,J=15.5Hz),6.73(1H,dd,J=6,15.5Hz),7.52(2H,d,J=8.5Hz),7.81(2H,d,J=8.5Hz)
实例17
在室温下将被氯化氢饱和的(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷(1.14g)在甲醇(20ml)中的溶液搅拌过夜,然后在真空下将溶剂蒸出。将剩余物溶于氯仿,并依次用碳酸氢钠饱和水溶液和盐水洗涤此溶液。用硫酸镁干燥上述溶液,在真空下蒸出溶剂,得到(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E和Z)-5-甲氧基羰基-1-戊烯基〕吡咯烷(908mg)油状物。
1H-NMR(CDCl3)δppm:1.6-1.9(4H,m),2.07(2H,m),2.29(2H,m),2.73(1H,m),3.22(1H,m),3.66(3x1/3H,s),3.68(3x2/3H,s),3.85(1H,m),4.03(1H,m),5.2-5.6(2H,m),7.4-7.6(2H,m),7.8-7.9(2H,m)
实例18
在室温下将(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-〔(E)-2-乙氧基羰基乙烯基〕吡咯烷(1.10g)在90%含水三氟乙酸(10ml)中的溶液搅拌1小时,然后在真空下蒸出溶剂。将剩余物溶于乙酸乙酯,并依次用碳酸氢钠饱和水溶液和盐水洗涤此溶液。用硫酸镁干燥有机相,在真空下将溶剂蒸出,得到(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-乙氧基羰基乙烯基〕吡咯烷(596mg)油状物。
实例19
按照与实例3(1)相似的方法得到下列化合物。
(1)(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E和Z)-5-甲氧基羰基-1-戊烯基〕-1-(2-噻吩磺酰基)吡咯烷
1H-NMR(CDCl3)δppm:1.6-1.9(4H,m),1.9-2.2(2H,m),2.33(2H,m),3.37(1H,dd,J=3,12.5Hz),3.59(1H,dd,J=5,12.5Hz),3.67(3x1/3H,s),3.69(3x2/3H,s),3.79(1H,m),4.22(1x1/3H,q,J=7Hz),4.52(1x2/3H,q,J=7Hz),4.62(1x1/3H,d,J=7Hz),4.78(1x2/3H,d,J=6Hz),5.3-5.7(2H,m),7.1-7.2(1H,m),7.5-7.7(4H,m),7.7-7.8(2H,m)
(2)(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(E)-2-乙氧基羰基乙烯基〕吡咯烷
1H-NMR(CDCl3)δppm:1.28(3H,t,J=7Hz),1.9-2.1(2H,m),3.23(1H,dd,J=5,11Hz),3.50(1H,dd,J=5.5,11Hz),3.85(1H,m),4.18(1H,q,J=7Hz),4.43(1H,q,J=6Hz),4.85(1H,d,J=9.5Hz),5.90(1H,d,J=15Hz),6.62(1H,dd,J=6,15Hz),7.51(2H,d,J=8.5Hz),7.52(2H,d,J=8.5Hz),7.73(2H,d,J=8.5Hz),7.79(2H,d,J=8.5Hz)
(3)(2S,4R)-2-〔(E和Z)-5-羧基-1-甲基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基〕吡咯烷
熔点:106-110℃
1H-NMR(CDCl3)δppm:1.59(3H,s),1.6-1.8(2H,m),1.84(1H,m),2.0-2.2(3H,m),2.38(2H,t,J=7.0Hz),3.18(1H,m),3.42(1H,m),3.74(1H,m),4.45(1H,t,J=7.0Hz),5.22(1H,m),5.40(1H,d,J=7.0Hz),7.4-7.5(4H,m),7.65-7.8(4H,m)
实例20
(1)向溴化(4-羧基-4-甲基戊基)三苯基鏻(3.83g)在二甲亚砜(21ml)中的溶液添加甲基亚磺酰甲基钠〔19.5mmol,由氢化钠(468mg)和二甲亚砜(17ml)制备〕,在室温下将此溶液搅拌30分钟。再向上述溶液添加(2S,4R)-1-叔丁氧基羰基-4-(4-氯苯磺酰氨基)-2-甲酰基吡咯烷(1.0g)〔在二甲亚砜(3.0ml)中〕,在室温下将此混合物搅拌1小时。添加水(50ml)后,用乙酸乙酯洗涤此溶液,并用1N盐酸将水层的PH调至1。用乙酸乙酯萃取上述水层溶液,并依次用水和盐水洗涤有机相。用硫酸镁干燥上述溶液,在真空下将溶剂蒸出,得到(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-5-甲基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷油状物。
按照与实例20(1)相似的方法得到下列化合物。
(2)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-6-羧基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.40(9H,s),1.4-1.5(2H,m),1.6-1.8(3H,m),1.9-2.1(3H,m),2.3-2.4(2H,m),3.39(1H,m),3.86(1H,m),4.58(1H,m),5.3-5.5(2H,m),7.50(2H,m),7.81(2H,m)
(3)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
(4)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-甲基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
1H-NMR(CDCl3)δppm:1.34(9H,s),1.5(3H,m),1.6-1.8(3H,m),2.0-2.2(3H,m),2.3-2.4(2H,m),3.39(1H,m),3.78(2H,m),4.50(1H,m),5.1-5.3(1H,m),7.49(2H,d,J=8.5Hz),7.83(2H,d,J=8.5Hz)
(5)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-甲基苯磺酰氨基)吡咯烷
(6)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-甲氧基苯磺酰氨基)吡咯烷
(7)(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-三氟甲基苯磺酰氨基)吡咯烷
实例21
(1)将由实例20(1)得到的(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-5-甲基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷溶于75%三氟乙酸水溶液(8ml),并将此溶液在室温下搅拌1小时。在真空下蒸出溶剂,得到(2S,4R)-2-〔(E和Z)-5-羧基-5-甲基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐油状物。
按照与实例21(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E和Z)-6-羧基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐
(3)(2S,4R)-2-〔(E和Z)-5-羧基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐
(4)(2S,4R)-2-〔(E和Z)-5-羧基-1-甲基-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐
(5)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-甲基苯磺酰氨基)吡咯烷三氟乙酸盐
(6)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-甲氧基苯磺酰氨基)吡咯烷三氟乙酸盐
(7)(2S,4R)-2-〔(E和Z)-5-羧基-1-戊烯基〕-4-(4-三氟甲基苯磺酰氨基)吡咯烷三氟乙酸盐
实例22
(1)在冰浴冷却下向由实例21(1)得到的(2S,4R)-2-〔(E和Z)-5-羧基-5-甲基-1-己烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐和二氯甲烷(13ml)的混合物添加三乙胺(2.0ml)和4-氯苯磺酰氯(380mg),并将此混合物在同样的温度下搅拌1小时。在加入1N盐酸后,用二氯甲烷萃取上述溶液,并依次用水和盐水洗涤有机层,用硫酸镁干燥。在真空下蒸出溶剂,剩余物在以氯仿为洗脱液的硅胶(Wako gel C-300)柱上进行层析分离,得到(2S,4R)-2-〔(Z)-5-羧基-5-甲基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷。
熔点:159-160℃
1H-NMR(CD3OD)δppm:1.20(3H,s),1.22(3H,s),1.5-1.8(5H,m),2.0-2.2(2H,m),3.43(1H,m),3.64(1H,m),4.43(1H,q,J=8Hz),5.2-5.4(2H,m),7.57(2H,d,J=7.5Hz),7.61(2H,d,J=7.5Hz),7.77(2H,d,J=7.5Hz),7.78(2H,d,J=7.5Hz)
按照与实例22(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(Z)-6-羧基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:112-114℃
1H-NMR(CDCl3+CD3OD)δppm:1.3-1.5(2H,m),1.5-1.8(4H,m),1.93(1H,m),2.09(2H,q,J=7.5Hz),2.32(2H,t,J=7.5Hz),3.41(1H,m),3.74(1H,m),4.52(1H,q,J=8.5Hz),
5.50(1H,dd,J=8.5,10Hz),5.42(dt,J=7.5,10Hz),7.50(4H,d,J=8Hz),7.71(2H,d,J=8Hz),7.78(2H,d,J=8Hz)
(3)(2S,4R)-2-〔(Z)-5-羧基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:159-160℃
1H-NMR(CDCl3+CD3OD)δppm:1.12(3x1/3H,d,J=6.5Hz),1.13(3x2/3H,d,J=6.5Hz),1.3-1.5(2H,m),1.6-1.8(2H,m),1.87(1H,m),1.9-2.1(2H,m),2.34(1H,m),3.3-3.5(2H,m),4.42(1H,q,J=8Hz),5.13(1H,m),5.34(1H,m),7.35-7.45(4H,m),7.6-7.7(4H,m)
(4)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-甲基苯磺酰氨基)吡咯烷
熔点:98-101℃
1H-NMR(CDCl3)δppm:1.5-1.8(5H,m),1.98(1H,m),2.1-2.2(2H,m),2.43(3H,s),3.4-3.5(2H,m),3.69(1H,m),4.52(1H,q,J=7.5Hz),5.2-5.5(3H,m),7.32(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.68(2H,d,J=8Hz),7.75(2H,d,J=8Hz)
(5)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-甲氧基苯磺酰氨基)吡咯烷
熔点:90℃
1H-NMR(CDCl3)δppm:1.5-1.8(3H,m),2.02(1H,m),2.17(2H,q,J=7.5Hz),2.49(2H,t,J=6.5Hz),3.4-3.5(2H,m),3.66(1H,m),3.88(3H,s),4.50(1H,q,J=7Hz),5.2-5.5(3H,m),6.98(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.75(4H,d,J=8Hz)
(6)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-三氟甲基苯磺酰氨基)吡咯烷
熔点:140-141℃
1H-NMR(CDCl3)δppm:1.5-1.8(3H,m),2.05(1H,m),2.18(2H,q,J=7.5Hz),2.40(2H,t,J=6.5Hz),3.41(dd,J=4.5,11Hz),3.53(1H,dd,J=3,11Hz),3.79(1H,m),4.65(1H,q,J=7Hz),5.22(1H,dd,J=11,10Hz),5.44(1H,dt,J=11,7.5Hz),5.78(1H,d,J=6.5Hz),7.45(2H,d,J=8Hz),7.72(2H,d,J=8Hz),7.89(2H,d,J=8Hz),7.98(2H,d,J=8Hz)
实例23
在-78℃向甲醇(20ml)中添加亚硫酰氯(0.32ml),并在同样温度下将此溶液搅拌30分钟。向此溶液添加(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(2.0g),在室温下将此混合物搅拌2小时。在真空下蒸出溶剂后,将剩余物溶于氯仿中,并依次用碳酸氢钠饱和水溶液和盐水洗涤。用硫酸镁干燥有机层,在真空下蒸出溶剂。用乙醚将剩余物凝固化,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-甲氧基羰基-1-戊烯基〕吡咯烷(2.0g)。
熔点:95-96℃
1H-NMR(CDCl3)δppm:1.5-1.9(3H,m),1.95-2.15(3H,m),2.32(2H,t,J=7.5Hz),3.40-3.45(2H,m),3.67(3H,s),3.81(1H,m),4.48(1H,q,J=8Hz),4.94(1H,d,J=7.5Hz),5.23(1H,t,J=10.5Hz),5.46(1H,m),7.4-7.5(4H,m),7.6-7.8(4H,m)
实例24
按照与实例9相似的方法得到下列化合物。
(1)(2R,4R)-2-〔2-(4-羧苯基)乙基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:180-182℃(dec.)
1H-NMR(CDCl3)δppm:1.6-1.9(2H,m),2.21(1H,m),2.5-2.8(2H,m),3.08(1H,dd,J=6,11Hz),3.4-3.8(4H,m),7.18(2H,d,J=8.5Hz),7.4-7.5(4H,m),7.61(2H,d,J=8.5Hz),7.73(2H,d,J=8.5Hz),7.97(2H,d,J=8.5Hz)
(2)(2R,4R)-2-〔2-(3-羧苯基)乙基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:206-207℃
1H-NMR(DMSO-d6)δppm:1.54(1H,m),1.7-1.85(2H,m),2.05(1H,m),2.55-2.7(2H,m),
3.02(1H,m),3.3-3.7(3H,m),7.45(2H,d,J=8Hz),7.65-7.85(6H,m),12.93(1H,broad)
实例25
(1)在室温下将(2S,4R)-4-(4-氯苯磺酰氨基)-2-〔(E和Z)-5-甲氧基羰基-1-戊烯基〕-1-(2-噻吩磺酰基)吡咯烷(890mg)在甲醇和1N氢氧化钠水溶液(2ml)混合物中的溶液搅拌过夜。用1N盐酸将上述溶液的PH调至2,并用氯仿萃取。用盐水洗涤有机相溶液,并用硫酸镁干燥。在真空下蒸出溶剂,在以氯仿为洗脱液的硅胶(Wako gel C-300)柱上将剩余物层析分离,得到(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(2-噻吩磺酰基)吡咯烷(242mg)白色粉末。
熔点:115-116℃
1H-NMR(CDCl3+CD3OD)δppm:1.5-2.0(4H,m),2.15(2H,q,J=7Hz),2.33(2H,t,J=7.5Hz),3.3-3.6(2H,m),3.68(1H,m),4.52(1H,q,J=8Hz),5.3-5.5(2H,m),7.17(1H,dd,J=3,5Hz),7.50(2H,d,J=8.5Hz),7.60(1H,m),7.66(1H,m),7.75(2H,d,J=8.5Hz)
按照与实例25(1)相似的方法得到下列化合物。
(2)(2S,4R)-2-〔(E)-2-羧基乙烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:76-81℃
1H-NMR(CDCl3+CD3OD)δppm:1.88(2H,t,J=6Hz),3.23(1H,dd,J=5.5,11Hz),3.51(1H,dd,
J=6,11Hz),3.74(1H,m),4.38(1H,q,J=6.5Hz),5.91(1H,d,J=16Hz),6.65(1H,dd,J=6.5,16Hz),7.45-7.55(4H,m),7.7-7.8(4H,m)
(3)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-〔N-(4-氯苯磺酰)-N-甲氨基〕吡咯烷
熔点:90-92℃
1H-NMR(CDCl3)δppm:1.6-1.8(3H,m),2.02(1H,dt,J=8.5,12.5Hz),2.18(2H,q,J=7.5Hz),2.37(2H,t,J=8Hz),2.68(3H,s),3.13(1H,dd,J=7.5H,10Hz),3.37(1H,dd,J=7.5,10Hz),4.5-4.7(2H,m),5.22(1H,t,J=10.5Hz),5.40(1H,dt,J=7.5,10.5Hz),7.45-7.55(4H,m),7.65-7.75(4H,m)
实例26
(1)向(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(547mg)、苯磺酰胺(157mg)和4-二甲氨基吡啶(122mg)在二氯甲烷(10ml)中的溶液添加N,N′-二环己基碳化二亚胺(206mg),并将此混合物在室温下搅拌过夜。滤除不溶物质后,在真空中蒸发滤出液,将剩余物在以氯仿和甲醇(40∶1)混合物为洗脱液的硅胶柱上层析分离,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-{N-(苯磺酰)氨基甲酰基}-1-戊烯基〕吡咯烷(478mg)。
熔点:150-152℃
1H-NMR(CDCl3+CD3OD)δppm:1.55-1.75(3H,m),1.88(1H,m),2.09(2H,q,J=7.5Hz),2.27
(2H,q,J=7.5Hz),3.36(1H,m),3.50(1H,m),3.64(1H,m),4.45(1H,q,J=7.5Hz),5.2-5.4(2H,m),7.45-7.65(7H,m),7.7-7.8(4H,m),8.0-8.1(2H,m)
按照与实例26(1)相似的方法得到下列化合物。
(2)(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-{N-(甲磺酰)氨基甲酰基}-1-戊烯基〕吡咯烷
熔点:123-124℃
1H-NMR(CDCl3+CD3OD)δppm:1.6-1.8(3H,m),1.95(1H,m),2.17(2H,q,J=7.5Hz),2.33(2H,t,J=7.5Hz),3.27(3H,s),3.4-3.55(2H,m),3.68(1H,m),4.52(1H,q,J=7.5Hz),5.2-5.5(2H,m),7.5-7.6(4H,m),7.85-7.95(4H,m)
实例27
在室温下将(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(500mg)、N-羟基琥珀酰亚胺(105mg)和N,N′-二环己基碳化二亚胺(188mg)在四氢呋喃(20ml)中的混合物搅拌过夜。过滤后,在真空下将滤出液蒸浓,得到一种油状活性酯。
将上述活性酯和28%氢氧化铵(1.0ml)在四氢呋喃(10ml)中的混合物在室温下搅拌30分钟,然后将氯仿(30ml)和甲醇(10ml)的混合物加入上述溶液。依次用水和盐水洗涤该溶液,并用硫酸镁干燥。在真空下蒸出溶剂,用乙醚使剩余物固化,得到(2S,4R)-2-〔(Z)-5-氨基甲酰基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(447mg)。
熔点:142-143℃
1H-NMR(CDCl3)δppm:1.6-1.8(3H,m),1.93(1H,m),2.13(2H,q,J=7.5Hz),2.25(2H,t,J=7.5Hz),3.4-3.55(2H,m),3.62(1H,m),4.53(1H,q,J=8Hz),5.30(1H,t,J=10Hz),5.48(1H,dt,J=7.5,10Hz),7.45-7.55(4H,m),7.75-7.85(4H,m)
实例28
在冰浴冷却下向(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-甲氧基羰基-1-戊烯基〕吡咯烷(500mg)在无水四氢呋喃(20ml)中的溶液添加氢化铝锂(34mg)。在冰浴下将此混合物搅拌30分钟后,向其中添加含水四氢呋喃,并通过硅藻土(Celite)将此混合物过滤。依次用水和盐水洗涤滤出液,经硫酸镁干燥。在真空下蒸出溶剂,用乙醚使剩余物凝固化,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-6-羟基-1-己烯基〕吡咯烷(350mg)。
熔点:108-109℃
1H-NMR(CDCl3)δppm:1.4-1.6(4H,m),1.77(1H,m),2.0-2.2(3H,m),3.4(2H,d,J=4Hz),3.67(2H,t,J=6.5Hz),3.85(1H,m),4.66(1H,q,J=7.5Hz),5.13(1H,t,J=11Hz),5.42(1H,dt,J=11,7.5Hz),5.76(1H,d,J=7.5Hz),7.50(2H,d,J=8.5Hz),7.52(2H,d,J=8.5Hz),7.73(2H,d,J=8.5Hz),7.80(2H,d,J=8.5Hz)
实例29
在0℃将(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(839mg)在亚硫酰氯(5.0ml)中的溶液搅拌1小时,然后在真空下蒸发此溶液,得到一种油状酰氯。在回流下向N-氧化巯基吡啶(242mg)和4-二甲氨基吡啶(19mg)在一溴三氯甲烷(15ml)中的混合物添加上述酰氯在一溴三氯甲烷(9ml)中的混合物,并将此溶液回流2小时。然后在真空下蒸出溶剂,剩余的油状物在以氯仿为洗脱液的硅胶柱上进行层析分离,得到(2S,4R)-2-〔(Z)-5-溴-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(555mg)油状物。
1H-NMR(CDCl3)δppm:1.7-2.0(4H,m),2.22(2H,q,J=7Hz),3.3-3.5(4H,m),3.83(1H,m),4.61(1H,q,J=8.5Hz),5.15-5.45(3H,m),7.4-7.5(4H,m),7.7-7.8(4H,m)
实例30
将(2S,4R)-2-〔(Z)-5-溴-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(527mg)和亚硫酸钠(630mg)在水(2.3ml)中的混合物回流9小时,然后使此溶液通过一个Diaion HP 20柱。用水淋洗此柱,并用甲醇洗脱产物。蒸出目标馏分并将其冻干,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-亚磺基-1-戊烯基)吡咯烷钠盐(350mg)粉末。
1H-NMR(CD3OD)δppm:1.7-2.0(4H,m),2.1-2.3(2H,m),2.79(2H,t,J=7.5Hz),3.45-3.55
(2H,m),3.60(1H,m),4.42(1H,q,J=7.0Hz),5.3-5.4(2H,m),7.5-7.65(4H,m),7.7-7.85(4H,m)
实例31
按照与实例20(1)相似的方法得到下列化合物。
(2S,4R)-1-叔丁氧基羰基-2-〔(E和Z)-5-羧基-5,5-二氟-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷
实例32
按照与实例21(1)相似的方法得到下列化合物。
(2S,4R)-2-〔(E和Z)-5-羧基-5,5-二氟-1-戊烯基〕-4-(4-氯苯磺酰氨基)吡咯烷三氟乙酸盐
实例33
按照与实例22(1)相似的方法得到下列化合物。
(2S,4R)-2-〔(Z)-5-羧基-5,5-二氟-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:145-147℃
1H-NMR(CDCl3+CD3OD)δppm:1.5-1.7(2H,m),1.8-2.2(4H,m),3.3-3.4(2H,m),3.52(1H,m),4.41(1H,q,J=8.5Hz),5.1-5.4(2H,m),7.35-7.45(4H,m),7.6-7.7(4H,m)
实例34
将(2S,4R)-2-〔(Z)-5-溴-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(200mg)和亚磷酸三乙酯(5.0ml)的混合物回流3小时,然后在真空下进行蒸馏,得到一种油状物。此油状物在硅胶柱上以氯仿为洗脱液进行层析分离,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-二乙氧基磷酰基-1-戊烯基〕吡咯烷(164mg)油状物。
1H-NMR(CDCl3)δppm:1.2-1.4(6H,m),1.65-1.85(4H,m),2.0-2.3(4H,m),3.48(2H,m),3.68(1H,m),4.0-4.2(4H,m),4.57(1H,q,J=6.5Hz),5.2-5.5(2H,m),6.50(1H,d,J=6Hz),7.4-7.5(4H,m),7.7-7.8(4H,m)
实例35
向(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-二乙氧基磷酰基-1-戊烯基〕吡咯烷(146mg)在二氯甲烷(5.0ml)中的溶液添加三甲基溴硅烷(0.1ml),并在室温下将此混合物搅拌3小时。将此混合物蒸干后,将剩余物溶于丙酮(5ml),并向其中添加水(20μl)。在室温下将所得的混合物搅拌1小时,然后在真空下蒸出溶剂。用氯仿和水的混合物将剩余物凝固,得到(2S,4R)-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)-2-〔(Z)-5-膦酰基-1-戊烯基〕吡咯烷(70mg)粉末。
1H-NMR(CD3OD)δppm:1.6-1.9(6H,m),2.1-2.3(2H,m),3.4-3.5(2H,m),3.63(1H,m),4.42(1H,q,J=7.0Hz),5.25-5.45(2H,m),7.5-7.6(4H,m),7.7-7.8(4H,m)
实例36
向(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷(274mg)溶液添加氢化钠(60mg)和碘甲烷(0.1ml),并将此混合物在室温下搅拌5小时。用乙酸乙酯稀释此溶液,并依次用水和盐水洗涤。用硫酸镁干燥此有机溶液,然后在真空下蒸馏。剩余物在硅胶柱上以正己烷和乙酸乙酯(3∶1)混合物为洗脱液进行层析分离,得到(2S,4R)-1-(4-氯苯磺酰)-4-〔N-(4-氯苯磺酰基)-N-甲氨基〕-2-〔(Z)-5-甲氧基羰基-1-戊烯基〕吡咯烷(220mg)油状物。
1H-NMR(CDCl3)δppm:1.6-1.8(3H,m),2.02(1H,m),2.05(2H,q,J=7.5Hz),2.33(2H,t,J=8Hz),2.69(3H,s),3.15(1H,dd,J=7.5,10Hz),3.37(1H,dd,J=7.5,10Hz),3.68(3H,s),4.5-4.8(2H,m),5.70(1H,t,J=10.5Hz),5.41(1H,dt,J=7.5,10.5Hz),7.4-7.6(4H,m),7.6-7.8(4H,m)
实例37
按照与实例1(1)、10和20(1)相似的方法得到下列化合物。
(1)(2S,4R)-2-〔(Z)-5-羧基-5-甲基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:159-160℃
1H-NMR(CD3OD)δppm:1.20(3H,s),1.22(3H,s),1.5-1.8(5H,m),2.0-2.2(2H,m),3.43(1H,m),3.64(1H,m),4.43(1H,q,J=8Hz),5.2-5.4(2H,m),7.57(2H,d,J=7.5Hz),7.61(2H,d,J=7.5Hz),7.77(2H,d,J=7.5Hz),7.78(2H,d,J=7.5Hz)
(2)(2S,4R)-2-〔(Z)-6-羧基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:112-114℃
1H-NMR(CDCl3+CD3OD)δppm:1.3-1.5(2H,m),1.5-1.8(4H,m),1.93(1H,m),2.09(2H,q,J=7.5Hz),2.32(2H,t,J=7.5Hz),3.41(1H,m),3.74(1H,m),4.52(1H,q,J=8.5Hz),5.50(1H,dd,J=8.5,10Hz),5.42(dt,J=7.5,10Hz),7.50(4H,d,J=8Hz),7.71(2H,d,J=8Hz),7.78(2H,d,J=8Hz)
(3)(2S,4R)-2-〔(Z)-5-羧基-1-己烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:159-160℃
1H-NMR(CDCl3+CD3OD)δppm:1.12(3x1/3H,d,J=6.5Hz),1.13(3x2/3H,d,J=6.5Hz),1.3-1.5(2H,m),1.6-1.8(2H,m),1.87(1H,m),1.9-2.1(2H,m),2.34(1H,m),3.3-3.5(2H,m),4.42(1H,q,J=8Hz),5.13(1H,m),5.34(1H,m),7.35-7.45(4H,m),7.6-7.7(4H,m)
(4)(2S,4R)-2-〔(E和Z)-5-羧基-1-甲基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:106-110℃
1H-NMR(CDCl3)δppm:1.59(3H,s),1.6-1.8(2H,m),1.84(1H,m),2.0-2.2(3H,m),2.38(2H,t,J=7.0Hz),3.18(1H,m),3.42(1H,m),3.74(1H,m),4.45(1H,t,J=7.0Hz),5.22(1H,m),5.40(1H,d,J=7.0Hz),7.4-7.5(4H,m),7.65-7.8(4H,m)
(5)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-甲苯磺酰氨基)吡咯烷
熔点:98-101℃
1H-NMR(CDCl3)δppm:1.5-1.8(5H,m),1.98(1H,m),2.1-2.2(2H,m),2.43(3H,s),3.4-3.5(2H,m),3.69(1H,m),4.52(1H,q,J=7.5Hz),5.2-5.5(3H,m),7.32(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.68(2H,d,J=8Hz),7.75(2H,d,J=8Hz)
(6)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-甲氧基苯磺酰氨基)吡咯烷
熔点:90℃
1H-NMR(CDCl3)δppm:1.5-1.8(3H,m),2.02(1H,m),2.17(2H,q,J=7.5Hz),2.49(2H,t,J=6.5Hz),3.4-3.5(2H,m),3.66(1H,m),3.88(3H,s),4.50(1H,q,J=7Hz),5.2-5.5(3H,m),6.98(2H,d,J=8Hz),7.50(2H,d,J=8Hz),7.75(4H,d,J=8Hz)
(7)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-三氟甲基苯磺酰氨基)吡咯烷
熔点:140-141℃
1H-NMR(CDCl3)δppm:1.5-1.8(3H,m),2.05(1H,m),2.18(2H,q,J=7.5Hz),2.40(2H,t,J=6.5Hz),3.41(dd,J=4.5,11Hz),3.53(1H,
dd,J=3,11Hz),3.79(1H,m),4.65(1H,q,J=7Hz),5.22(1H,dd,J=11,10Hz),5.44(1H,dt,J=11,7.5Hz),5.78(1H,d,J=6.5Hz),7.45(2H,d,J=8Hz),7.72(2H,d,J=8Hz),7.89(2H,d,J=8Hz),7.98(2H,d,J=8Hz)
(8)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-4-(4-氯苯磺酰氨基)-1-(2-噻吩磺酰基)吡咯烷
熔点:115-116℃
1H-NMR(CDCl3+CD3OD)δppm:1.5-2.0(4H,m),2.15(2H,q,J=7Hz),2.33(2H,t,J=7.5Hz),3.3-3.6(2H,m),3.68(1H,m),4.52(1H,q,J=8Hz),5.3-5.5(2H,m),7.17(1H,dd,J=3,5Hz),7.50(2H,d,J=8.5Hz),7.60(1H,m),7.66(1H,m),7.75(2H,d,J=8.5Hz)
(9)(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-〔N-(4-氯苯磺酰基)-N-甲氨基〕吡咯烷
熔点:90-92℃
1H-NMR(CDCl3)δppm:1.6-1.8(3H,m),2.02(1H,dt,J=8.5,12.5Hz),2.18(2H,q,J=7.5Hz),2.37(2H,t,J=8Hz),2.68(3H,s),3.13(1H,dd,J=7.5,10Hz),3.37(1H,dd,J=7.5,10Hz),4.5-4.7(2H,m),5.22(1H,t,J=10.5Hz),5.40(1H,dt,J=7.5,10.5Hz),7.45-7.55(4H,m),7.65-7.75(4H,m)
(10)(2S,4R)-2-〔(Z)-5-羧基-5,5-二氟-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷
熔点:145-147℃
1H-NMR(CDCl3+CD3OD)δppm:1.5-1.7(2H,m),1.8-2.2(4H,m),3.3-3.4(2H,m),3.52(1H,m),4.41(1H,q,J=8.5Hz),5.1-5.4(2H,m),7.35-7.45(4H,m),7.6-7.7(4H,m)
Claims (13)
2、权利要求1所述的化合物,其中
R1是氢、低级烷氧基羰基、苯磺酰基、被1-3个选自卤素、硝基、低级烷氧基、单(或二或三)卤代(低级)烷基和低级烷基的取代基取代的苯磺酰基、苯基氨基甲酰基、低级烷磺酰基、苯甲酰基或噻吩磺酰基;
R2是苯磺酰基或经1-3个选自卤素、低级烷基、低级烷氧基和单(或二或三)卤代(低级)烷基的取代基取代的苯磺酰基;R3是羧(低级)烷基、被羧基和1-3个卤原子取代的低级烷基、酯化羧(低级)烷基、氨基甲酰基(低级)烷基、酰基氨基甲酰基(低级)烷基、羧苯基、酯化羧苯基、羧基、酯化羧基、羧(低级)烷基、亚磺基(低级)烷基、膦酰基(低级)烷基、二(低级)烷氧基磷酰基(低级)烷基或卤代(低级)烷基。
3、权利要求2所述的化合物,其中
R3是羧(低级)烷基、被羧基和一个或两个卤原子取代的低级烷基、低级烷氧基羰基(低级)烷基、氨基甲酰基(低级)烷基、低级烷磺酰氨基甲酰基(低级)烷基、苯磺酰氨基甲酰基(低级)烷基、羧苯基、低级烷氧基羰基苯基、羧基、低级烷氧基羰基、羟(低级)烷基、亚磺基(低级)烷基、膦酰基(低级)烷基、二(低级)烷氧基磷酰基(低级)烷基或卤代(低级)烷基。
4、权利要求3所述的化合物,其中
R1是氢、低级烷氧基羰基、苯磺酰基、被一个选自卤素、硝基、低级烷氧基、单(或二或三)卤代(低级)烷基和低级烷基的取代基取代的苯磺酰基、苯基氨基甲酰基、低级烷磺酰基、苯甲酰基或噻吩磺酰基;
R2是苯磺酰基或被一个选自卤素、低级烷基、低级烷氧基和单(或二或三)卤代(低级)烷基的取代基取代的苯磺酰基。
6、权利要求5所述的化合物,其中
R1是被一个卤原子取代的苯磺酰基,
R2是被一个卤原子取代的苯磺酰基,
R7是氢,
A是-CH=CH-。
7、权利要求6所述的化合物,它是(2S,4R)-2-〔(Z)-5-羧基-1-戊烯基〕-1-(4-氯苯磺酰基)-4-(4-氯苯磺酰氨基)吡咯烷。
8、一种制备下述通式表示的化合物或其盐的方法:
其中R1是氢或酰基,
R2是酰基,
R3是羧(低级)烷基、被羧基和一个或多个卤原子取代的低级烷基、被护羧(低级)烷基、羧芳基、被护羧芳基、羧基、被护羧基、羟(低级)烷基、亚磺基(低级)烷基、膦酰基(低级)烷基、被护膦酰基(低级)烷基或卤代(低级)烷基,
R7是氢或低级烷基,
此方法包括
(1)将下式所示化合物或其盐与式(R4)3-P=CH-R3所示化合物或其盐反应,
其中R1、R2、R3、R7和R8定义同上,R4是芳基,得到下式所示化合物或其盐
其中R1、R2、R3、R7和R8定义同上,或者
(2)下式所示化合物或其盐经亚胺基保护基消除反应,
其中R2、R3、R7和A定义同上,
R1 a是亚胺基保护基,
得到下式所示化合物或其盐,
其中R2、R3、R7和A定义同上,或者
(3)将下式所示化合物或其盐与一酰化剂反应
其中R2、R3、R7和A定义同上,
得到下式所示化合物或其盐,
其中R2、R3、R7和A定义同上,
R1 b是酰基,或者
(4)使下式所示化合物或其盐经酯化反应,
其中R1、R2、R7和A定义同上,
R3 a是羧(低级)烷基、羧芳基或羧基,
得下式所示化合物或其盐,
其中R1、R2、R7和A定义同上,
R3 a是酯化羧(低级)烷基、酯化羧芳基或酯化羧基,或者
(5)还原下式所示化合物或其盐
其中R1、R2、R3、R7和R8定义同上,
得到下式所示化合物或其盐,
其中R1、R2、R3、R7和R8定义同上,或者
(6)使下式所示化合物或其盐经羧基保护基消除反应,
其中R1、R2、R7和A定义同上,
R3 c是被护羧(低级)烷基、被护羧芳基或被护羧基,
得到下式所示化合物:
其中R1、R2、R3 a、R7和A定义同上,或者
(7)使式R9-NH2所示化合物(其中R9是氢,低级烷磺酰基或芳磺酰基)或其活性氨基衍生物或其盐与下式所示化合物或其活性羧基衍生物或其盐反应,
其中R1、R2、R7和A定义同上,
Y1是低级亚烷基,
得到下式所示化合物或其盐
其中R1、R2、R7、R9、A和Y1定义同上,或者
(8)还原下式所示化合物或其盐
其中R1、R2、R7和A定义同上,
R10是被护羧基,
Y2是C1-C5亚烷基,
得下式所示化合物或其盐,
其中R1、R2、R7、A和Y2定义同上,或者
(9)使下式所示化合物或其盐与亚硫酸盐反应,
其中R1、R2、R7、A和Y1定义同上,
X1是卤素,
得下式所示化合物或其盐,
其中R1、R2、R7、A和Y1定义同上,或者
(10)使下式所示化合物或其盐与式P(-O-R11)3所示化合物(R11是氢或膦酰保护基)或其盐反应,
其中R1、R2、R7、A、Y1和X1定义同上,
得到下式所示化合物或其盐,
其中R1、R2、R7、R11、A和Y1定义同上,或者
(11)使下式所示化合物或其盐经膦酰保护基消除反应,
其中R1、R2、R7、A和Y1定义同上,
R11 a是膦酰保护基,
得到下式所示化合物或其盐,
其中R1、R2、R7、A和Y1定义同上,或者
(12)使下式所示化合物或其盐与式R7 a-X2(R7 a是低级烷基,X2是卤素)所示化合物反应
其中R1、R2、R3和A定义同上,
得下式所示化合物或其盐
其中R1、R2、R3、R7 a和A定义同上。
11、一种药物组合物,包括作为有效组分的权利要求1的化合物及与其混用的医药上可接受的载体。
12、一种治疗血柱形成、气喘、肾炎等疾病的方法,包括给人或动物服用权利要求1的化合物。
13、使用权利要求1的化合物治疗血栓形成、气喘、肾炎等疾病。
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US5130323A (en) * | 1988-10-31 | 1992-07-14 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
US5264453A (en) * | 1988-10-31 | 1993-11-23 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
FR2685325B1 (fr) * | 1991-12-20 | 1994-02-04 | Adir Cie | Nouveaux derives de pyrrolidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2687146B1 (fr) * | 1992-02-12 | 1994-04-01 | Adir Cie | Nouveaux derives de pyrrolidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
HUT70217A (en) * | 1992-07-02 | 1995-09-28 | Fujisawa Pharmaceutical Co | Process for producing pyrrolidine derivative and salt thereof |
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US3577440A (en) * | 1968-12-23 | 1971-05-04 | Robins Co Inc A H | 1-substituted-3-amido-pyrrolidines |
US4282243A (en) * | 1972-04-03 | 1981-08-04 | A. H. Robins Company, Inc. | Optical isomers of 4-amino-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide |
US4210660A (en) * | 1978-12-20 | 1980-07-01 | Yamanouchi Pharmaceutical Co., Ltd. | Benzamide derivatives |
DE3165669D1 (en) * | 1980-06-23 | 1984-09-27 | Squibb & Sons Inc | Azido, imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids having hypotensive activity |
GB8509703D0 (en) * | 1985-04-16 | 1985-05-22 | Fujisawa Pharmaceutical Co | Pyrrolidine derivatives |
US4785119A (en) * | 1985-10-11 | 1988-11-15 | Tokyo Kasei Kogyo Co., Ltd. | 3-aminopyrrolidine compound and process for preparation thereof |
JPH07108898B2 (ja) * | 1986-08-20 | 1995-11-22 | 大日本製薬株式会社 | 3−アミノピロリジン誘導体およびその塩の製造法 |
US5130323A (en) * | 1988-10-31 | 1992-07-14 | Fujisawa Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
-
1988
- 1988-04-26 ES ES88106637T patent/ES2054729T3/es not_active Expired - Lifetime
- 1988-04-26 IL IL86173A patent/IL86173A/xx not_active IP Right Cessation
- 1988-04-26 EP EP88106637A patent/EP0289911B1/en not_active Expired - Lifetime
- 1988-04-26 DE DE88106637T patent/DE3881755T2/de not_active Expired - Fee Related
- 1988-04-26 PH PH36844A patent/PH24950A/en unknown
- 1988-04-26 JP JP63107305A patent/JPS63295553A/ja active Granted
- 1988-04-27 IE IE126088A patent/IE62862B1/en not_active IP Right Cessation
- 1988-04-28 DK DK233888A patent/DK233888A/da not_active Application Discontinuation
- 1988-04-28 US US07/187,240 patent/US4916152A/en not_active Expired - Fee Related
- 1988-04-29 CA CA000565552A patent/CA1329391C/en not_active Expired - Fee Related
- 1988-04-29 AU AU15348/88A patent/AU613360B2/en not_active Ceased
- 1988-04-29 FI FI882015A patent/FI88716C/fi not_active IP Right Cessation
- 1988-04-29 AR AR88310720A patent/AR247879A1/es active
- 1988-04-29 PT PT87359A patent/PT87359B/pt not_active IP Right Cessation
- 1988-04-29 NO NO881884A patent/NO173330C/no unknown
- 1988-04-29 HU HU882232A patent/HU208671B/hu not_active IP Right Cessation
- 1988-04-30 KR KR1019880005091A patent/KR970005190B1/ko not_active IP Right Cessation
- 1988-04-30 CN CN88102511A patent/CN1020899C/zh not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109912487A (zh) * | 2019-03-25 | 2019-06-21 | 山东理工大学 | 一种合成1-对甲苯磺酰基-2-乙烯基-1氢-吡咯的方法 |
CN109912487B (zh) * | 2019-03-25 | 2023-01-10 | 山东理工大学 | 一种合成1-对甲苯磺酰基-2-乙烯基-1氢-吡咯的方法 |
Also Published As
Publication number | Publication date |
---|---|
FI88716C (fi) | 1993-06-28 |
CN1020899C (zh) | 1993-05-26 |
US4916152A (en) | 1990-04-10 |
DE3881755D1 (de) | 1993-07-22 |
JPS63295553A (ja) | 1988-12-01 |
KR880013889A (ko) | 1988-12-22 |
IL86173A0 (en) | 1988-11-15 |
FI88716B (fi) | 1993-03-15 |
AU1534888A (en) | 1988-11-03 |
IE62862B1 (en) | 1995-03-08 |
NO881884L (no) | 1988-11-02 |
PT87359B (pt) | 1992-08-31 |
HUT48579A (en) | 1989-06-28 |
FI882015A0 (fi) | 1988-04-29 |
AU613360B2 (en) | 1991-08-01 |
IL86173A (en) | 1992-02-16 |
DK233888D0 (da) | 1988-04-28 |
EP0289911A3 (en) | 1989-08-16 |
KR970005190B1 (ko) | 1997-04-14 |
JPH0546335B2 (zh) | 1993-07-13 |
DE3881755T2 (de) | 1993-10-21 |
CA1329391C (en) | 1994-05-10 |
EP0289911A2 (en) | 1988-11-09 |
NO881884D0 (no) | 1988-04-29 |
IE881260L (en) | 1988-11-01 |
HU208671B (en) | 1993-12-28 |
ES2054729T3 (es) | 1994-08-16 |
FI882015A (fi) | 1988-11-02 |
PH24950A (en) | 1990-12-26 |
AR247879A1 (es) | 1995-04-28 |
NO173330C (no) | 1993-12-01 |
NO173330B (no) | 1993-08-23 |
PT87359A (pt) | 1989-05-31 |
DK233888A (da) | 1988-11-02 |
EP0289911B1 (en) | 1993-06-16 |
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