CN1296494A - 新化合物 - Google Patents
新化合物 Download PDFInfo
- Publication number
- CN1296494A CN1296494A CN99804901A CN99804901A CN1296494A CN 1296494 A CN1296494 A CN 1296494A CN 99804901 A CN99804901 A CN 99804901A CN 99804901 A CN99804901 A CN 99804901A CN 1296494 A CN1296494 A CN 1296494A
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- Prior art keywords
- phenyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 211
- 238000002360 preparation method Methods 0.000 claims abstract description 565
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 51
- 229920001184 polypeptide Polymers 0.000 claims abstract description 22
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 22
- 241001465754 Metazoa Species 0.000 claims abstract description 4
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 392
- -1 Heptyl naphthoyl Chemical group 0.000 claims description 313
- 125000003118 aryl group Chemical group 0.000 claims description 159
- 239000000203 mixture Substances 0.000 claims description 147
- 125000003545 alkoxy group Chemical group 0.000 claims description 129
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 120
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 125000001424 substituent group Chemical group 0.000 claims description 79
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 55
- 125000003435 aroyl group Chemical group 0.000 claims description 47
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 45
- 239000001301 oxygen Substances 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
- 229920006395 saturated elastomer Polymers 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 29
- 125000004193 piperazinyl group Chemical group 0.000 claims description 28
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 22
- 125000005936 piperidyl group Chemical group 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 244000000010 microbial pathogen Species 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 230000000845 anti-microbial effect Effects 0.000 abstract description 7
- 208000015181 infectious disease Diseases 0.000 abstract description 6
- 201000000317 pneumocystosis Diseases 0.000 abstract description 4
- 238000011282 treatment Methods 0.000 abstract description 4
- 241000233870 Pneumocystis Species 0.000 abstract 2
- 229920002498 Beta-glucan Polymers 0.000 abstract 1
- 206010035664 Pneumonia Diseases 0.000 abstract 1
- 230000000843 anti-fungal effect Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 238000001819 mass spectrum Methods 0.000 description 201
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
- 239000011734 sodium Substances 0.000 description 153
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 150
- 239000000243 solution Substances 0.000 description 145
- 238000004458 analytical method Methods 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 134
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 122
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 115
- 239000002585 base Substances 0.000 description 110
- 239000011541 reaction mixture Substances 0.000 description 100
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 229940095102 methyl benzoate Drugs 0.000 description 62
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 61
- 235000019439 ethyl acetate Nutrition 0.000 description 59
- 235000002639 sodium chloride Nutrition 0.000 description 59
- 238000001556 precipitation Methods 0.000 description 58
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 46
- 125000002252 acyl group Chemical group 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 238000005406 washing Methods 0.000 description 44
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- 238000001035 drying Methods 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- 238000006722 reduction reaction Methods 0.000 description 38
- 239000007858 starting material Substances 0.000 description 37
- 239000007787 solid Substances 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 35
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 34
- 238000009834 vaporization Methods 0.000 description 34
- 230000008016 vaporization Effects 0.000 description 34
- 238000003756 stirring Methods 0.000 description 31
- 239000007864 aqueous solution Substances 0.000 description 30
- 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 29
- CENQUTVRMPTFCN-UHFFFAOYSA-N benzotriazol-1-yl benzoate Chemical compound N1=NC2=CC=CC=C2N1OC(=O)C1=CC=CC=C1 CENQUTVRMPTFCN-UHFFFAOYSA-N 0.000 description 28
- 238000001914 filtration Methods 0.000 description 28
- 239000000843 powder Substances 0.000 description 28
- 239000002253 acid Chemical class 0.000 description 27
- 239000000725 suspension Substances 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 23
- 238000004108 freeze drying Methods 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 238000007738 vacuum evaporation Methods 0.000 description 22
- 239000002904 solvent Substances 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- 239000000499 gel Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 235000015320 potassium carbonate Nutrition 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 17
- GTZOZDOTOWNSJH-UHFFFAOYSA-N [O].CCCCCCC Chemical compound [O].CCCCCCC GTZOZDOTOWNSJH-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 125000003226 pyrazolyl group Chemical group 0.000 description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- SIVRHMWWSUGKLF-UHFFFAOYSA-N OC(=O)C(F)(F)F.CCOC(=O)C1=CC=CC=C1 Chemical compound OC(=O)C(F)(F)F.CCOC(=O)C1=CC=CC=C1 SIVRHMWWSUGKLF-UHFFFAOYSA-N 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 229960001866 silicon dioxide Drugs 0.000 description 12
- 125000006530 (C4-C6) alkyl group Chemical group 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 238000003810 ethyl acetate extraction Methods 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000012546 transfer Methods 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000012545 processing Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
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- 239000003054 catalyst Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 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 6
- DCQIZHCYMGRWAB-UHFFFAOYSA-N 5-decyl-1h-pyrazole Chemical class CCCCCCCCCCC1=CC=NN1 DCQIZHCYMGRWAB-UHFFFAOYSA-N 0.000 description 6
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
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- 125000001624 naphthyl group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 5
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
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- 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 5
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 5
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- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- DGFNGRBBDQUMJZ-UHFFFAOYSA-N FC(C(=O)O)(F)F.C(C1=CC=CC=C1)(=O)OC Chemical compound FC(C(=O)O)(F)F.C(C1=CC=CC=C1)(=O)OC DGFNGRBBDQUMJZ-UHFFFAOYSA-N 0.000 description 4
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 230000001857 anti-mycotic effect Effects 0.000 description 4
- 238000003287 bathing Methods 0.000 description 4
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 4
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Abstract
本发明涉及由通式(Ⅰ)代表的新的多肽化合物或其盐,其中R1、R2、R3和R4如说明书中所定义,它们具有抗微生物活性(尤其是抗真菌活性),对β-1,3-葡聚糖合酶的抑制活性,本发明还涉及其制备方法,涉及含有它们的药用组合物;还涉及用于预防和/或治疗人类或动物感染性疾病包括卡氏肺囊虫感染(如卡氏肺囊虫肺炎)的方法。
Description
技术领域
本发明涉及用作药物的新的多肽化合物及其盐。
背景技术
美国专利第5376634和WO96/11210公开了多肽化合物及其药学上可接受的盐,其具有抗微生物活性(尤其是抗真菌活性)。
本发明的公开
本发明涉及新的多肽化合物及其盐。
更具体地说,本发明涉及新的多肽化合物及其盐,它们具有抗微生物活性(尤其是抗真菌活性,其中真菌可包括曲霉属、隐球酵母属、假丝酵母属、毛霉属、放线菌属、组织孢浆菌属、皮真菌属、鳞斑霉属、镰孢属等),对β-1,3-葡聚糖合酶的抑制活性,还期望它们用于人类或动物卡氏肺囊虫感染(如卡氏肺囊虫肺炎)的预防和/或治疗,本发明还涉及其制备方法,涉及含有它们的药用组合物,还涉及用于人类或动物包括卡氏肺囊虫感染(如卡氏肺囊虫肺炎)的感染性疾病的预防和/或治疗的方法。
可具有一个或多个合适取代基的芳基氨基(低级)链烷酰基,
由可具有一个或多个合适取代基的杂环基取代的芳酰基,
由具有高级烷基的芳基取代的芳酰基,
由具有低级烷基的芳基取代的芳酰基,
由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基,
由具有一个或多个合适取代基的不饱和的稠合杂环基取代的低级链烷酰基,
由具有一个或多个合适取代基的吡啶基取代的低级链烷酰基,
氨基保护基团,
庚基萘酰基,
己基萘酰基,
由具有一个或多个合适取代基的杂环氨基甲酰基取代的芳酰基,
由具有一个或多个合适取代基的环(低级)烷基取代的低级链烷酰基,
由具有杂环基(带有一个或多个合适的取代基)的噻吩基取代的低级链烷酰基,或
由具有一个或多个合适取代基的杂环基取代的低级链烯酰基,R2为氢或羟基,R3为羟基、羟基磺酰基氧基或低级烷氧基,和R4为羟基或低级烷氧基。
通过如下反应图式所示方法可以制备新的式[Ⅰ]多肽化合物及其盐。
方法1
通过如下反应图式所示方法可以制备式[Ⅱ]和[Ⅳ]原料化合物或其盐。
方法B
方法C其中R2、R3和R4如上所定义,R1 a为可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基,
由可具有一个或多个合适的取代基的杂环基取代的芳酰基,
由具有高级烷基的芳基取代的芳酰基,
由具有低级烷基的芳基取代的芳酰基,
由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基,
由具有一个或多个合适的取代基的、不饱和的稠合杂环基取代的低级链烷酰基,
由具有一个或多个合适的取代基的吡啶基取代的低级链烷酰基,
氨基保护基团,
庚基萘酰基,
己基萘酰基,
由具有一个或多个合适取代基的杂环氨基甲酰基取代的芳酰基,
由具有一个或多个合适取代基的环(低级)烷基取代的低级链烷酰基,
由具有杂环基(带有一个或多个合适的取代基)的噻吩基取代的低级链烷酰基,或
由具有一个或多个合适取代基的杂环基取代的低级链烯酰基,R3 a为低级烷氧基,及R4 a为羟基或低级烷氧基。
新的式[Ⅰ]多肽化合物的合适的盐是药学上可接受的且通常无毒性的盐,可包括与碱的盐或酸加成盐,例如与无机碱的盐,如碱金属盐(如钠盐、钾盐等)、碱土金属的盐(如钙盐、镁盐等)、铵盐;与有机碱成的盐,例如,有机胺盐(如三乙胺盐、二异丙基乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐等);无机酸加成盐(如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等);有机羧酸磺酸加成盐(如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、富马酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等);与碱性或酸性氨基酸(如精氨酸、天冬氨酸、谷氨酸等)成的盐。
上述及随后将要描述的本说明书中各种定义的合适的例子和说明(本发明打算包括在其范围内)详细解释如下:
除非另有条件,术语“低级”指具有1-6个碳原子的基团。
除非另有条件,术语“高级”指具有7-20个碳原子的基团。
“一个或多个”的合适的例子可以是1-6个,其中优选1-3个。
“低级链烷酰基”的合适的例子可包括直链或支链的基团,例如,甲酰基、乙酰基、2-甲基乙酰基、2,2-二甲基乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、2,2-二甲基丙酰基、己酰基等。
在R1和R1 a中的“合适的取代基”的合适的例子可包括高级烷氧基、具有一个或多个高级烷氧基的芳基、高级烷基、低级烷基、具有一个或多个低级烷氧基的芳基、可以具有一个或多个高级烷氧基的杂环基、具有一个或多个环(低级)烷基的芳基、具有一个或多个低级烷氧基(高级)烷氧基的芳基、具有一个或多个杂环基的芳基、具有一个或多个环(低级)烷基的环(低级)烷基、由可具有一个或多个低级烷氧基的芳基取代的芳基、由可具有一个或多个高级烷氧基的芳基取代的芳基、由可具有一个或多个带杂环基的低级烷氧基的芳基取代的芳基、具有一个或多个低级烷氧基(低级)烷氧基的芳基、可具有一个或多个高级烷基的杂环基、由可具有一个或多个芳氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级链烯基氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(高级)烷氧基的芳基取代的芳基、由可具有一个或多个杂环基(低级)烷氧基的芳基取代的芳基、可具有一个或多个芳氧基(低级)烷氧基的芳基、可具有一个或多个杂环基的杂环基、可具有一个或多个环(低级)烷氧基的芳基、可具有一个或多个具低级烷氧基的杂环基的芳基、可具有一个或多个具环(低级)烷氧基的杂环基的芳基、可具有一个或多个具芳基(低级)烷氧基的杂环基的芳基、可具有一个或多个具环(低级)烷基的杂环基的芳基、可具有一个或多个具芳基的杂环基的芳基、可具有一个或多个具低级烷氧基的芳基的杂环基、可具有一个或多个具高级烷氧基(低级)烷基的芳基的杂环基、可具有一个或多个具低级烷氧基(低级)烷氧基的芳基的杂环基、可具有一个或多个具环(低级)烷基的芳基的杂环基、可具有一个或多个具杂环基的芳基的杂环基、可具有一个或多个由具芳基的杂环基(低级)烷基取代的芳基的杂环基、可具有一个或多个具芳基的杂环基的杂环基、由可具有一个或多个环(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基(低级)烷基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个杂环基的芳基取代的芳基、具有一个或多个环(低级)烷氧基的芳基、具有一个或多个低级烷氧基(高级)烷硫基的芳基、具有一个或多个具杂环基的低级烷氧基的芳基、可具有一个或多个低级烷基的环(低级)烷基、可具有一个或多个芳基的环(低级)烷基、芳基等。
“低级烷氧基”的合适的例子可包括直链或支链烷氧基,例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、叔戊氧基、新戊氧基、己氧基、异己氧基等,其中优选的基团可以是甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基和异己氧基。
“高级烷氧基”的合适的例子可包括直链或支链烷氧基,例如,庚氧基、辛氧基、3,5-二甲基辛氧基、3,7-二甲基辛氧基、壬氧基、癸氧基、十一氧基、十二氧基、十三氧基、十四氧基、十六氧基、十七氧基、十八氧基、十九氧基、二十氧基等,其中优选的烷氧基可以是(C7-C14)烷氧基,更优选的烷氧基可以是庚氧基和辛氧基。
“低级烷基”的合适的例子可包括具有1-6个碳原子的直链或支链烷基,例如,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、新戊基、己基、异己基等,其中优选的低级烷基可以是甲基、戊基、己基和异己基等。
“高级烷基”的合适的例子可包括具有7-20个碳原子的直链或支链高级烷基,例如,庚基、辛基、3,5-二甲基辛基、3,7-二甲基辛基、壬基、癸基、十一基、十二基、十三基、十四基、十五基、十六基、十七基、十八基、十九基、二十基等,其中优选的烷基可以是(C7-C14)烷基,更优选的烷基可以是庚基、辛基、壬基和癸基。
“芳基”和“芳”部分的合适的例子可包括具有低级烷基的苯基(如苯基、_基、二甲苯基、甲苯基等)、萘基、蒽基、2,3-二氢化茚基等,其中优选的基团可以是苯基和萘基,及该“芳基”和“芳”部分可以带有卤素或低级烷氧基。
“芳酰基”的合适的例子可包括苯甲酰基、甲苯甲酰基、萘甲酰基、蒽基羰基等,其中优选的基团为苯甲酰基和萘甲酰基,而且这种“芳酰基”可具有低级烷基。
“杂环基”和“杂环”部分的合适的例子可包括:
含有1-4个氮原子的不饱和3-8元(更优选5或6元)杂单环基,例如,吡咯基、吡咯啉基、咪唑基、吡唑基、吡啶基、二氢吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基(如4H-1,2,4-三唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基等)、四唑基(如1H-四唑基、2H-四唑基等)等;
含有1-4个氮原子的饱和3-8元(更优选5或6元)杂单环基,例如,吡咯烷基、咪唑烷基、哌啶基、哌嗪基等;
含有1-4个氮原子的不饱和、稠合杂环基,例如,吲哚基、异吲哚基、二氢吲哚基、中氮茚基、苯并咪唑基、喹啉基、异喹啉基、吲唑基、苯并三唑基等;
含有1-2个氧原子和1-3个氮原子的不饱和3-8元(更优选5或6元)杂单环基,例如,噁唑基、异噁唑基、噁二唑基(如1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基等)等;
含有1或2个氧原子和1-3个氮原子的饱和3-8元(更优选5或6元)杂单环基,例如,吗啉基、悉尼酮基、吗啉代等;
含有1或2个氧原子和1-3个氮原子的不饱和、稠合杂环基,例如,苯并噁唑基、苯并噁二唑基等;
含有1或2个硫原子和1-3个氮原子的不饱和3-8元(更优选5或6元)杂单环基,例如,噻唑基、异噻唑基、噻二唑基(如1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基等)、二氢噻嗪基等;
含有1或2个硫原子和1-3个氮原子的饱和3-8元(更优选5或6元)杂单环基,例如,噻唑烷基、硫代吗啉基、硫代吗啉代等;
含有1或2个硫原子的不饱和3-8元(更优选5或6元)杂单环基,例如,噻吩基、dihydrodithiinyl、dihydrodithionyl等;
含有1或2个硫原子和1-3个氮原子的不饱和、稠合杂环基,例如,苯并噻唑基、苯并噻二唑基、咪唑并噻二唑基等;
含有氧原子的不饱和3-8元(更优选5或6元)杂单环基,例如,呋喃基等;
含有氧原子的饱和3-8元(更优选5或6元)杂单环基,例如,四氢呋喃基、四氢吡喃基等;
含有氧原子和1或2个硫原子的不饱和3-8元(更优选5或6元)杂单环基,例如,二氢氧硫杂环己二烯基等;
含有1或2个硫原子的不饱和、稠合杂环基,例如,苯并噻吩基、benzodithiinyl等;
含有氧原子和1或2个硫原子的不饱和、稠合杂环基,例如,苯并氧硫杂环己二烯基等,这种“杂环基”和“杂环”部分可以有低级烷基或环(低级)烷基。
“低级链烯基氧基”的合适的例子可包括乙烯基氧基、1-(或2-)丙烯基氧基、1-(或2-或3-)丁烯基氧基、1-(或2-或3-或4-)戊烯基氧基、1-(或2-或3-或4-或5-)己烯基氧基等,其中优选的基团为可以是(C2-C6)链烯基氧基,最优选的基团可以是2-丙烯基氧基。
“环(低级)烷基”的合适的例子可包括环丙基、环丁基、环戊基、环己基等,其中优选的基团可以是环(C4-C6)烷基,最优选的基团可以是环己基,此种“环(低级)烷基”可具有低级烷基。
适合的“氨基保护基团”可包括如下解释的酰基,常规保护基团如可具有1-3个合适的取代基的芳(低级)烷基(如苄基、苯乙基、1-苯基乙基、二苯甲基、三苯甲基等)、[5-(低级)烷基-2-氧代-1,3-二氧杂环戊-4-基](低级)烷基[如(5-甲基-2-氧代-1,3-二氧杂环戊-4-基)甲基等]等。
合适的“酰基基团”和“酰基”可包括衍生自羧酸、碳酸、氨基甲酸、磺酸等的脂族酰基、芳族酰基、芳脂族酰基和杂环-脂族酰基。
所述“酰基”的合适的例子可说明如下。
脂族酰基,例如低级或高级链烷酰基(甲酰基、乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、2,2-二甲基丙酰基、己酰基、庚酰基、辛酰基、壬酰基、癸酰基、十一酰基、十二酰基、十三酰基、十四酰基、十五酰基、十六酰基、十七酰基、十八酰基、十九酰基、二十酰基等);低级或高级烷氧基羰基(如甲氧基羰基、乙氧基羰基、叔丁氧基羰基、叔戊氧基羰基、庚氧基羰基等);
低级或高级烷基磺酰基(甲基磺酰基、乙基磺酰基等);
低级或高级烷氧基磺酰基(如甲氧基磺酰基、乙氧基磺酰基等)等;
芳族酰基,例如芳酰基(如苯甲酰基、甲苯酰基、萘酰基等),芳(低级)链烷酰基[如苯基(C1-C6)链烷酰基(如苯基乙酰基、苯基丙酰基、苯基丁酰基、苯基异丁酰基、苯基戊酰基、苯基己酰基等)、萘基(C1-C6)链烷酰基(如萘基乙酰基、萘基丙酰基、萘基丁酰基等)等],芳(低级)链烯酰基[如苯基(C3-C6)链烯酰基(如苯基丙烯酰基、苯基丁烯酰基、苯基异丁烯酰基、苯基戊烯酰基、苯基己烯酰基等)、萘基(C3-C6)链烯酰基(如萘基丙烯酰基、萘基丁烯酰基等)等],芳(低级)烷氧基羰基[如苯基(C1-C6)烷氧基羰基(如苄氧基羰基等)、芴基(C1-C6)烷氧基羰基(如芴基甲氧基羰基等)等],芳氧基羰基(如苯氧基羰基、萘氧基羰基等);
芳氧基(低级)链烷酰基(如苯氧基乙酰基、苯氧基丙酰基等);
芳基氨基甲酰基(如苯基氨基甲酰基等);
芳基硫代氨基甲酰基(如苯基硫代氨基甲酰基等);
芳基乙醛酰基(如苯基乙醛酰基、萘基乙醛酰基等);
可具有1-4个低级烷基的芳基磺酰基(如苯磺酰基、对-甲苯磺酰基等)等;
杂环酰基如杂环羰基、杂环(低级)链烷酰基(如杂环乙酰基、杂环丙酰基、杂环丁酰基、杂环戊酰基、杂环己酰基等)、杂环(低级)链烯酰基(如杂环丙烯酰基、杂环丁烯酰基、杂环戊烯酰基、杂环己烯酰基等)、杂环乙醛酰基等;其中术语“杂环羰基”、“杂环(低级)链烷酰基”、“杂环(低级)链烯酰基”和“杂环乙醛酰基”中的合适的“杂环”部分可指上述的“杂环”部分,其中优选的基团可以是芳(低级)烷氧基羰基并更优选的基团可以是苯基(C1-C4)烷氧基羰基和芴基(C1-C4)烷氧基羰基,最优选的基团可以是苄氧基羰基和芴基甲氧基羰基。
术语“可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基”的“芳基氨基”部分的合适的例子可以是苯基氨基、_基氨基、甲苯基氨基、萘基氨基、蒽基氨基等,其中优选的基团可以是萘基氨基。
术语“可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基”中的“低级链烷酰基”部分的合适的例子可指上述的”低级链烷酰基”,其中优选的基团可以是甲酰基。
术语“可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基”中的“合适的取代基”部分的合适的例子可指上述的“合适的取代基”,其中优选的取代基可以是高级烷氧基,最优选的取代基可以是庚氧基。
“可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基”的合适的例子可以是具有高级烷氧基的萘基氨基羰基,其中优选的基团可以是具有庚氧基的萘基氨基羰基。
术语“由可具有一个或多个合适的取代基的杂环基取代的芳酰基”中的“芳酰基”部分的合适的例子可指上述的“芳酰基”,其中优选的芳酰基可以是苯甲酰基。
术语“由可具有一个或多个合适的取代基的杂环基取代的芳酰基”的“杂环基”部分的合适的例子可指上述的“杂环基”,其中优选的杂环基可以是含有1-4个氮原子的饱和3-8元杂单环基、含有1或2个硫原子和1-3个氮原子的不饱和3-8元杂单环基、含有1或2个氧原子和1-3个氮原子的不饱和3-8元杂单环基和含有1或2个硫原子和1-3个氮原子的不饱和、稠合杂环基,更优选的杂环基可以是哌嗪基、噻二唑基、噁二唑基、咪唑并噻二唑基和异噁唑基。
术语“由可具有一个或多个合适的取代基的杂环基取代的芳酰基”的“合适的取代基”部分的合适的例子可指上述的“合适的取代基”,其中优选的取代基可以是具有一个或多个高级烷氧基的芳基、具有一个或多个低级烷氧基的芳基、具有一个或多个环(低级)烷基的芳基、具有一个或多个低级烷氧基(高级)烷氧基的芳基、具有一个或多个杂环基的芳基、具有一个或多个环(低级)烷基的环(低级)烷基、由可具有一个或多个低级烷氧基的芳基取代的芳基、由可具有一个或多个高级烷氧基的芳基取代的芳基、由可具有一个或多个具杂环基的低级烷氧基的芳基取代的芳基、具有一个或多个低级烷氧基(低级)烷氧基的芳基、可具有一个或多个高级烷基的杂环基、由可具有一个或多个芳氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级链烯基氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(高级)烷氧基的芳基取代的芳基、由可具有一个或多个杂环基(低级)烷氧基的芳基取代的芳基(其中杂环基可具有一个或多个低级烷基)、可具有一个或多个芳氧基(低级)烷氧基的芳基、可具有一个或多个杂环基的杂环基、可具有一个或多个环(低级)烷氧基的芳基、可具有一个或多个具低级烷氧基的杂环基的芳基、可具有一个或多个具环(低级)烷氧基的杂环基的芳基、可具有一个或多个具芳基(低级)烷氧基的杂环基的芳基、可具有一个或多个具环(低级)烷基的杂环基的芳基、可具有一个或多个具芳基的杂环基的芳基、可具有一个或多个具低级烷氧基的芳基的杂环基、可具有一个或多个具高级烷氧基(低级)烷基的芳基的杂环基、可具有一个或多个具低级烷氧基(低级)烷氧基的芳基的杂环基、可具有一个或多个具环(低级)烷基的芳基的杂环基、可具有一个或多个具杂环基的芳基的杂环基、可具有一个或多个由具芳基的杂环基(低级)烷基取代的芳基的杂环基、可具有一个或多个具芳基的杂环基的杂环基、由可具有一个或多个环(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基(低级)烷基的芳基取代的芳基、由可具有一个或多个低级烷氧基(低级)烷氧基(低级)烷氧基的芳基取代的芳基、由可具有一个或多个杂环基的芳基取代的芳基、具有一个或多个环(低级)烷氧基的芳基、具有一个或多个低级烷氧基(高级)烷硫基的芳基、具有一个或多个具杂环基的低级烷氧基的芳基、可具有一个或多个低级烷基的环(低级)烷基、可具有一个或多个芳基的环(低级)烷基、芳基,其中优选的基团可以是具有(C7-C14)烷氧基的苯基、具有(C4-C6)烷氧基的苯基、具有环(C4-C6)烷基的苯基、具有(C1-C4)烷氧基(C7-C14)烷氧基的苯基、具有含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有环(C4-C6)烷基的环(C4-C6)烷基、由具有(C1-C6)烷氧基的苯基取代的苯基、由具有(C7-C14)烷氧基的苯基取代的苯基、由具有(C1-C4)烷氧基(具有含有1-4个氮原子的饱和3-8元杂单环基)的苯基取代的苯基、具有(C1-C4)烷氧基(C4-C6)烷氧基的苯基、具有(C7-C14)烷基的含有1-4个氮原子的饱和3-8元杂单环基、由具有苯氧基(C1-C4)烷氧基的苯基取代的苯基、由具有(C3-C6)链烯基氧基的苯基取代的苯基、由具有(C1-C4)烷氧基(C7-C14)烷氧基的苯基取代的苯基、由具有(C1-C4)烷氧基(具有含有1或2个氧原子和1-3个氮原子及具有1-4个(C1-C4)烷基的饱和3-8元杂单环基)的苯基取代的苯基、具有苯氧基-(C1-C4)烷氧基的苯基、具有(C1-C4)烷氧基(C7-C14)烷氧基的苯基、具有含有1-4个氮原子的饱和3-8元杂单环基的含有1-4个氮原子的不饱和3-8元杂单环基、具有带有(C1-C4)烷氧基的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有带有环(C4-C6)烷氧基的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有带有苯基(C1-C4)烷氧基的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有带有环(C4-C6)烷基的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有由环(C4-C6)烷基(具有二(C4-C6)烷基)取代的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有由环(C4-C6)烷基(具有(C1-C4)烷基)取代的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有由(C1-C4)烷氧基和具有卤素的苯基取代的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有由苯基取代的含有1-4个氮原子的饱和3-8元杂单环基的苯基、具有由具(C1-C6)烷氧基的苯基取代的含有1或2个硫原子和1-3个氮原子的不饱和3-8元杂单环基的苯基、具有带(C1-C6)烷氧基的苯基的含有1-4个氮原子的不饱和3-8元杂单环基、具有带(C7-C14)烷氧基(C1-C6)烷基的苯基的含有1-4个氮原子的不饱和3-8元杂单环基、具有带(C4-C6)烷基的苯基的含有1-4个氮原子的饱和3-8元杂单环基、具有含1-4个氮原子的饱和3-8元杂单环基的苯基的含有1-4个氮原子的不饱和3-8元杂单环基、具有由(C1-C6)烷基(具有带苯基的含有1-4个氮原子的饱和3-8元杂单环基)取代的苯基的含有1-4个氮原子的不饱和3-8元杂单环基、具有带苯基的含有1-4个氮原子的饱和3-8元杂单环基的含有1-4个氮原子的不饱和3-8元杂单环基、由具有环(C4-C6)烷氧基的苯基取代的苯基、由具有(C1-C6)烷氧基(C1-C6)烷基的苯基取代的苯基、由具有(C1-C6)烷氧基(C1-C6)烷氧基的苯基取代的苯基、由具有(C1-C6)烷氧基(C1-C6)烷氧基(C1-C6)烷基的苯基取代的苯基、由具有(C1-C6)烷氧基(C1-C6)烷氧基(C1-C6)烷氧基的苯基取代的苯基、由具有带环(C4-C6)烷基的含有1-4个氮原子的饱和3-8元杂单环基的苯基取代的苯基、具有由环(C4-C6)烷基(具有二(C1-C4)烷基)取代的含有1-4个氮原子的饱和3-8元杂单环基的苯基取代的苯基、具有环(C4-C6)烷氧基的苯基、具有(C1-C6)烷氧基(C7-C14)烷硫基的苯基、具有含1-4个氮原子的饱和3-8元杂单环基的(C1-C6)烷氧基的苯基、具有(C1-C6)烷氧基(具有含1或2个氧原子和1-3个氮原子的饱和3-8元杂单环基)的苯基、具有带二(C1-C4)的含有1或2个氧原子和1-3个氮原子的饱和3-8元杂单环基的(C1-C6)烷氧基的苯基、具有含1或2个硫原子和1-3个氮原子的饱和3-8元杂单环基的(C1-C6)烷氧基的苯基、具有(C1-C6)烷基的环(C4-C6)烷基、具有苯基的环(C4-C6)烷基、2,3-二氢化茚基、由含有1或2个氧原子和1-3个氮原子的饱和3-8元杂单环基取代的苯基、由具有(C1-C6)烷基的含有1-4个氮原子的饱和3-8元杂单环基取代的苯基、由带二(C1-C4)烷基的含有1或2个氧原子和1-3个氮原子的饱和3-8元杂单环基取代的苯基及由含1或2个硫原子和1-3个氮原子的饱和3-8元杂单环基取代的苯基,最优选的基团可以是具有辛氧基的苯基、具有己氧基的苯基、具有环己基的苯基、具有哌啶基的苯基、具有环己基的环己基、具有甲氧基辛氧基的苯基、具有甲氧基庚氧基的苯基、具有丁氧基的苯基、具有戊氧基的苯基、由具有甲氧基的苯基取代的苯基、由具有丙氧基的苯基取代的苯基、由具有丁氧基的苯基取代的苯基、由具有戊氧基的苯基取代的苯基、由具有己氧基的苯基取代的苯基、由具有庚氧基的苯基取代的苯基、由具有带哌啶基的丙氧基的苯基取代的苯基、具有甲氧基己氧基的苯基、具有癸氧基的异噁唑基、由具有苯氧基丙氧基的苯基取代的苯基、由具有丙氧基的苯基取代的苯基、由具有苯氧基丁氧基的苯基取代的苯基、由具有甲氧基辛氧基的苯基取代的苯基、由具有带二甲基的丙氧基的苯基取代的苯基、具有苯氧基丙氧基的苯基、具有苯氧基丁氧基的苯基、具有苯氧基戊氧基的苯基、具有甲氧基戊氧基的苯基、具有甲氧基庚氧基的苯基、具有哌啶基的吡啶基、具有环己氧基的苯基、具有带丙氧基的哌啶基的苯基、具有带环己基的哌啶基的苯基、具有带苯基甲氧基的哌啶基的苯基、具有带环己基的哌嗪基的苯基、具有由具二甲基的环己基取代的哌嗪基的苯基、具有由具甲基的环己基取代的哌嗪基的苯基、具有由甲氧基和氯代苯基取代的哌啶基的苯基、具有由苯基取代的哌啶基的苯基、具有由苯基取代的哌嗪基的苯基、具有由戊氧基苯基取代的噻二唑基的苯基、具有己氧基苯基的吡唑基、具有庚氧基甲基苯基的吡唑基、具有带环己基的苯基的哌嗪基、具有带哌啶基的苯基的吡唑基、具有带吡咯烷基的苯基的吡唑基、具有由具有苯基的哌嗪基甲基取代的苯基的吡唑基、具有带苯基的哌啶基的吡啶基、由具有环己基氧基的苯基取代的苯基、由具有乙氧基甲基的苯基取代的苯基、由具有乙氧基丙氧基的苯基取代的苯基、由具有乙氧基乙氧基的苯基取代的苯基、由具有甲氧基丙氧基的苯基取代的苯基、由具有甲氧基乙氧基的苯基取代的苯基、由具有甲氧基戊氧基的苯基取代的苯基、由具有甲氧基乙氧基甲基的苯基取代的苯基、由具有甲氧基乙氧基乙氧基的苯基取代的苯基、由具有哌嗪基(具有环己基)的苯基取代的苯基、由具有吗啉基(具有二甲基)的苯基取代的苯基、具有环己氧基的苯基、具有甲氧基庚硫基的苯基、具有哌啶子基丁氧基的苯基、具有哌啶子基戊氧基的苯基、具有哌啶子基己氧基的苯基、具有吗啉代戊氧基的苯基、具有吗啉代戊氧基(具有二甲基)的苯基、具有吗啉代己氧基(具有二甲基)的苯基、具有硫代吗啉代戊氧基的苯基、具有戊基的环己基、具有苯基的环己基、2,3-二氢化茚基、具有哌啶基的苯基、具有吗啉基的苯基、具有硫代吗啉代的苯基、由具有甲氧基丁氧基的苯基取代的苯基、由具有乙基的哌嗪基取代的苯基,及由具有二甲基的吗啉基取代的苯基。
“可具有一个或多个合适的取代基的杂环基取代的芳酰基”的合适的例子可以为由具有苯基(具有辛氧基)的哌嗪基取代的苯甲酰基、由具有苯基(具有己氧基)的哌嗪基取代的苯甲酰基、由具有苯基(具有己氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有己氧基)的噁二唑基取代的苯甲酰基、由具有苯基(具有环己基)的哌嗪基取代的苯甲酰基、由具有苯基(具有甲氧基辛氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有哌啶基)的噻二唑基取代的苯甲酰基、由具有环己基(具有环己基)的哌嗪基取代的苯甲酰基、由具有苯基(具有甲氧基辛氧基)的哌嗪基取代的苯甲酰基、由具有苯基(具有甲氧基庚氧基)的哌嗪基取代的苯甲酰基、由具有苯基(具有丁氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有丙氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有丁氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有戊氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有己氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有庚氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有由苯基(具有带哌啶基的丙氧基)取代的苯基的噁二唑基取代的苯甲酰基、由具有苯基(具有甲氧基己氧基)的噻二唑基取代的苯甲酰基、由具有吡唑基(具有癸基)的噁二唑基取代的苯甲酰基、由具有吡唑基(具有癸基)的噻二唑基取代的苯甲酰基、由具有苯基(由具有苯氧基丙氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由带有丙氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(具有甲氧基己氧基)的噻二唑基取代的苯甲酰基、由具有苯基(由具有苯氧基丁氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基辛氧基的苯基取代)的噁二唑基取代的苯甲酰基、由具有由苯基(具有带二甲基吗啉基的丙氧基)取代的苯基的噁二唑基取代的苯甲酰基、由具有苯基(具有苯氧基丁氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有苯氧基戊氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有苯氧基丙氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有甲氧基戊氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有甲氧基庚氧基)的噻二唑基取代的苯甲酰基、由具有吡啶基(具有哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有环己氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有戊氧基)的异噁唑基取代的苯甲酰基、由具有苯基(具有带丙氧基的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有带环己氧基的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有带苯基甲氧基的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有带环己基的哌嗪基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有由具有二甲基的环己基取代的哌嗪基)的噻二唑基取代的苯甲酰基、由具有苯基(具有带环己基的哌嗪基)的噻二唑基取代的苯甲酰基、由具有苯基(具有由具有甲基的环己基取代的哌嗪基)的噻二唑基取代的苯甲酰基、由具有苯基(具有由甲氧基和氯代苯基取代的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有由苯基取代的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(具有由苯基取代的哌嗪基)的噻二唑基取代的苯甲酰基、由具有苯基(具有由戊氧基苯基取代的噻二唑基)的噻二唑基取代的苯甲酰基、由具有吡唑基(具有己氧基苯基)的噻二唑基取代的苯甲酰基、由具有吡唑基(具有庚氧基甲基苯基)的噻二唑基取代的苯甲酰基、由具有哌嗪基(具有带环己基的苯基)的哌啶基取代的苯甲酰基、由具有吡唑基(具有带哌啶基的苯基)的噻二唑基取代的苯甲酰基、由具有吡唑基(具有带吡咯烷基的苯基)的噻二唑基取代的苯甲酰基、由具有吡唑基(具有由具有苯基的哌嗪基甲基取代的苯基)的噻二唑基取代的苯甲酰基、由具有吡啶基(具有带苯基的哌啶基)的噻二唑基取代的苯甲酰基、由具有苯基(由具有环己氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有乙氧基甲基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有乙氧基丙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有乙氧基乙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基丙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基乙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基戊氧基的苯基取代)的哌嗪基取代的苯甲酰基、由具有苯基(由具有甲氧基乙氧基甲基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基乙氧基乙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有带环己基的哌嗪基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有带二甲基的吗啉基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(具有环己氧基)的噁二唑基取代的苯甲酰基、由具有苯基(具有环己氧基)的噻二唑基取代的苯甲酰基、由具有苯基(具有环己氧基)的哌嗪基取代的苯甲酰基、由具有苯基(具有甲氧基庚硫基)的哌嗪基取代的苯甲酰基、由具有苯基(具有哌啶子基丁氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有哌啶子基戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有哌啶子基己氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有吗啉代戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有带二甲基的吗啉代戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有带二甲基的吗啉代己氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有硫代吗啉代戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有环己基(具有戊基)的哌嗪基取代的苯甲酰基、由具有环己基(具有苯基)的哌嗪基取代的苯甲酰基、由具有2,3-二氢化茚基的哌嗪基取代的苯甲酰基、由具有苯基(具有带乙基的哌嗪基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有丁氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有甲氧基戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有环己基)的哌嗪基取代的苯甲酰基、由具有苯基(具有甲氧基己氧基)的噻二唑基取代的二甲基苯甲酰基、由具有苯基(由具有丁氧基的苯基取代)的噁二唑基取代的萘甲酰基、由具有苯基(具有甲氧基己氧基)的噻二唑基取代的萘甲酰基、由具有苯基(具有戊氧基)的噻唑基取代的苯甲酰基、由具有苯基(具有己氧基)的噻唑基取代的苯甲酰基、由具有苯基(具有庚氧基)的噻唑基取代的苯甲酰基、由具有苯基(由具有丙氧基的苯基取代)的噻唑基取代的苯甲酰基、由具有苯基(具有甲氧基己氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有甲氧基庚氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有甲氧基辛氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有吗啉代)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有二甲基吗啉代)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有硫代吗啉代)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有戊氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有己氧基)的咪唑并噻二唑基取代的苯甲酰基、由具有苯基(具有环己基)的噻二唑基取代的苯甲酰基、由具有苯基(具有环己基)的噁二唑基取代的萘甲酰基、由具有苯基(由具有丙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有乙氧基的苯基取代)的噻二唑基取代的苯甲酰基、由具有苯基(由具有甲氧基丁氧基的苯基取代)的噻二唑基取代的苯甲酰基,及由具有苯基(由具有丁氧基的苯基取代)的噻二唑基取代的苯甲酰基。
术语“由具有高级烷基的芳基取代的芳酰基”中的“芳酰基”部分的合适的例子可指上述的“芳酰基”,其中优选的芳酰基可以是苯甲酰基。
术语“由具有高级烷基的芳基取代的芳酰基”中的“芳基”部分的合适的例子可指上述的“芳基”,其中优选的芳基可以是苯基。
术语“由具有高级烷基的芳基取代的芳酰基”中的“高级烷基”部分的合适的例子可指上述的“高级烷基”,其中优选的高级烷基可以是(C7-C14)烷基,更优选的高级烷基可以是庚基。
“由具有高级烷基的芳基取代的芳酰基”中的合适的例子可以是由具有(C7-C14)烷基的苯基取代的苯甲酰基,其中优选的例子可以是由具有庚基的苯基取代的苯甲酰基。
术语“由具有低级烷基的芳基取代的芳酰基”中的“芳酰基”部分的合适的例子可指上述的“芳酰基”,其中优选的芳酰基可以是苯甲酰基。
术语“由具有低级烷基的芳基取代的芳酰基”中的“芳基”部分的合适的例子可指上述的“芳基”,其中优选的芳基可以是苯基。
术语“由具有低级烷基的芳基取代的芳酰基”中的“低级烷基”部分的合适的例子可指上述的“低级烷基”,其中优选的低级烷基可以是(C4-C6)烷基,更优选的低级烷基可以是己基。
“由具有低级烷基的芳基取代的芳酰基”中的合适的例子可以是由具有(C4-C6)烷基的苯基取代的苯甲酰基,其中优选的例子可以是由具有己基的苯基取代的苯甲酰基。
术语“由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基”中的“芳基”部分的合适的例子可指上述的“芳基”,其中优选的芳基可以是苯基。
术语“由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基”中的“(C2-C6)链烷酰基”部分的合适的例子可以上乙酰基、丙酰基、丁酰基等,其中优选的链烷酰基可以是(C2-C4)链烷酰基,更优选的链烷酰基可以是丙酰基。
术语“由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基”中的“低级烷基”部分的合适的例子可指上述的“低级烷基”,其中优选的低级烷基可以是(C4-C6)烷基”,更优选的低级烷基可以是戊基。
“由具有低级烷基的芳基取代的芳基(C2-C6)链烷酰基”中的合适的例子可以是由具有戊基的苯基取代的苯基丙酰基。
术语“由可具有一个或多个合适的取代基的不饱和的、稠合杂环基取代的低级链烷酰基”中的“低级链烷酰基”的合适的例子可以指上述的“低级链烷酰基”,其中优选的基团可以是(C1-C3)链烷酰基,更优选甲酰基。
术语“由可具有一个或多个合适的取代基的不饱和的稠合杂环基取代的低级链烷酰基”中的“不饱和的稠合杂环基”的合适的例子可以指上述的“杂环基”,其中优选的杂环基可以是含有1或2个氧原子和1-3个氮原子的不饱和的稠合杂环基,更优选苯并噁唑基。
术语“由可具有一个或多个合适的取代基的不饱和的稠合杂环基取代的低级链烷酰基”中的“合适的取代基”部分的合适的例子可以是可具有一个或多个高级烷氧基的杂环基和可具有一个或多个低级烷氧基的芳基,其中优选的取代基可以是具有(C7-C14)烷氧基的含有1-4个氮原子的不饱和3-8元杂单环基和具有(C4-C6)烷氧基的苯基,更优选为具有辛氧基的吡啶基和具有己氧基的苯基。
“由可具有一个或多个合适的取代基的不饱和的稠合杂环基取代的低级链烷酰基”的合适的例子可以是具有吡啶基(具有(C7-C14)烷氧基)的苯并噁唑基羰基和具有苯基(具有(C4-C6)烷氧基)的苯并噁唑基羰基,其中优选的基团可以是具有吡啶基(具有辛氧基)的苯并噁唑基羰基和具有苯基(具有己氧基)的苯并噁唑基羰基。
术语“由可具有一个或多个合适的取代基的吡啶基取代的低级链烷酰基”中的“低级链烷酰基”的合适的例子可以指上述的“低级链烷酰基”,其中优选的基团可以是(C1-C3)链烷酰基,更优选甲酰基。
术语“由可具有一个或多个合适的取代基的吡啶基取代的低级链烷酰基”中的“合适的取代基”部分的合适的例子可以是上述的“合适的取代基”,其中优选的取代基可以是高级烷氧基,更优选的取代基为(C7-C14)烷氧基,最优选庚氧基和辛氧基。
术语“由可具有一个或多个合适的取代基的吡啶基取代的低级链烷酰基”的合适的例子可以是具有(C7-C14)烷氧基的吡啶基羰基,其中优选的基团可以是具有辛氧基的吡啶基羰基和具有庚氧基的吡啶基羰基。
术语“由可具有一个或多个合适的取代基的杂环基氨基甲酰基取代的芳酰基”中的“芳酰基”的合适的例子可以指上述的“芳酰基”,其中优选的芳酰基可以是苯甲酰基。
术语“由可具有一个或多个合适的取代基的杂环基氨基甲酰基取代的芳酰基”中的“杂环基”的合适的例子可以指上述的“杂环基”部分,其中优选的杂环基可以是含有1或2个硫原子和1-3个氮原子的不饱和3-8元杂单环基,更优选为噻二唑基。
术语“由可具有一个或多个合适的取代基的杂环基氨基甲酰基取代的芳酰基”中的“合适的取代基”部分的合适的例子可以指上述的“合适的取代基”,其中优选的取代基可以是具有(C1-C6)烷氧基的苯基,更优选为具有戊氧基的苯基。
术语“由可具有一个或多个合适的取代基的杂环基氨基甲酰基取代的芳酰基”的合适的例子可以是由具有苯基(具有戊氧基)的噻二唑基氨基甲酰基取代的苯甲酰基。
术语“由可具有一个或多个合适的取代基的环(低级)烷基取代的低级链烷酰基”中的“低级链烷酰基”的合适的例子可以指上述的“低级链烷酰基”,其中优选的基团可以是甲酰基。
术语“由可具有一个或多个合适的取代基的环(低级)烷基取代的低级链烷酰基”中的“环(低级)烷基”部分的合适的例子可以指上述的“环(低级)烷基”,其中优选的基团可以是环己基。
术语“由可具有一个或多个合适的取代基的环(低级)烷基取代的低级链烷酰基”中的“合适的取代基”部分的合适的例子可以是上述的“合适的取代基”,其中优选的取代基可以是具有一个或多个芳基(具有低级烷氧基(低级)烷氧基)的杂环基,更优选的取代基可以是具有苯基(具有甲氧基己氧基)的噻二唑基。
术语“由可具有带一个或多个合适的取代基的杂环基的噻吩基取代的低级链烷酰基”中的“低级链烷酰基”的合适的例子可以指上述的“低级链烷酰基”,其中优选的基团可以是甲酰基。
术语“由可具有带一个或多个合适的取代基的杂环基的噻吩基取代的低级链烷酰基”中的“杂环基”部分的合适的例子可以指上述的“杂环基”,其中优选的杂环基可以是含有1或2个氧原子和1-3个氮原子的不饱和3-8元杂单环基,更优选为噁二唑基。
术语“由可具有带一个或多个合适的取代基的杂环基的噻吩基取代的低级链烷酰基”中的“合适的取代基”部分的合适的例子可以是上述的“合适的取代基”,其中优选的取代基可以是由具有一个或多个低级烷氧基的芳基取代的芳基,更优选的取代基可以是具有戊氧基的苯基取代的苯基。
术语“由可具有一个或多个合适的取代基的杂环基取代的低级链烯酰基”中的“低级链烯酰基”的合适的例子可以是丙烯酰基、丁烯酰基、戊烯酰基、己烯酰基、2,4-己二烯酰基等,其中优选的基团可以是2,4-己二烯酰基。
术语“由可具有一个或多个合适的取代基的杂环基取代的低级链烯酰基”中的“杂环基”部分的合适的例子可以指上述的“杂环基”,其中优选的杂环基可以是含有1或2个硫原子和1-3个氮原子的不饱和3-8元杂单环基,更优选为噻二唑基。
术语“由可具有一个或多个合适的取代基的杂环基取代的低级链烯酰基”中的“合适的取代基”部分的合适的例子可以是上述的“合适的取代基”,其中优选的取代基可以是具有低级烷氧基(低级)烷氧基的芳基,更优选的取代基可以是具有甲氧基己氧基的苯基。
制备本发明的目标多肽化合物[Ⅰ]和原料化合物[Ⅱ]或其盐的方法详述如下。
方法1
目标多肽化合物[Ⅰa]或其盐可通过使化合物[Ⅰb]或其在氨基上的反应性衍生物或其盐与化合物[Ⅲ]或其在羧基上的反应性衍生物或其盐反应来制备。
化合物[Ⅲ]的羧基上的合适的反应性衍生物可包括酰卤、酸酐、活化的酰胺、活化的酯等。反应性衍生物的合适例子可以是酰氯、酰基叠氮、与酸的混合酸酐,所述酸有例如取代的磷酸[如二烷基磷酸、苯基磷酸、二苯基磷酸、二苄基磷酸、卤化磷酸等]、二烷基亚磷酸、亚硫酸、硫代硫酸、硫酸、磺酸[如甲磺酸等]、脂族羧酸[如乙酸、丙酸、丁酸、异丁酸、pivaric acid、戊酸、异戊酸、2-乙基丁酸、三氯乙酸等],或芳族羧酸[如苯甲酸等],对称的酸酐,用咪唑活化的酰胺、4-取代咪唑、二甲基吡唑、三唑、四唑或1-羟基-1H-苯并三唑,或活化的酯[如氰基甲酯、甲氧基甲酯、二甲基亚氨基甲基
酯、乙烯基酯、炔丙基酯、对-硝基苯酯、2,4-二硝基苯酯、三氯苯酯、五氯戊酯、甲磺酰基苯酯、苯基偶氮基苯酯、苯基硫代酸酯、对-硝基苯基硫代酸酯、对-甲苯基硫代酸酯、羧甲基硫代酸酯、吡喃基酯、吡啶基酯、哌啶基酯、8-喹啉基硫代酸酯等]或与N-羟基化合物[如N,N-二甲基羟基胺、1-羟基-2-(1H)-吡啶酮、N-羟基琥珀酰亚胺、N-羟基苯邻二甲酰亚胺、1-羟基-1H-苯并三唑等]的酯等。根据打算用的化合物[Ⅲ],可从中任选所述反应性衍生物。
化合物[Ⅲ]及其反应性衍生物的合适的盐可以指对目标多肽化合物[Ⅰ]中所例举的那些。
该反应通常在常规溶剂,例如水、醇[如甲醇、乙醇等]、丙酮、二氧六环、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、吡啶或其对该反应无不利影响的任何其它有机溶剂中进行。也可使用这些常规溶剂与水的混合物。
在该反应中,当化合物[Ⅲ]以游离酸形式或其盐形式使用时,该反应优选在如下的常规缩合剂存在下进行:例如,N,N’-二环己基碳二亚胺;N-环己基-N’-吗啉代乙基碳二亚胺;N-环己基-N’-(4-二乙基氨基环己基)碳二亚胺;N,N’-二乙基碳二亚胺;N,N’-二异丙基碳二亚胺;N-乙基-N’-(3-二甲基氨基丙基)碳二亚胺;N,N-羰基双-(2-甲基咪唑);五亚甲基乙烯酮-N-环己基亚胺;二苯基乙烯酮-N-环己基亚胺,乙氧基乙炔;1-烷氧基-2-氯乙烯;亚磷酸三烷基酯;多磷酸乙酯;多磷酸异丙酯;三氯氧化磷(磷酰氯);三氯化磷,亚硫酰氯;草酰氯;氯代甲酸低级烷基酯[如氯代甲酸乙酯、氯代甲酸异丙酯等];三苯膦;2-乙基-7-羟基苯并异噁唑鎓盐;2-乙基-5-(间-磺基苯基)异噁唑鎓氢氧化物分子内盐;1-(对-氯代苯磺酰基氧基)-6-氯代-1H-苯并三唑;通过N,N-二甲基甲酰胺与亚硫酰氯、光气、三氯甲基氯代甲酸酯、三氯氧化磷、甲磺酰氯等反应制备的所谓Vilsmeier试剂等。
该反应也可在无机或有机碱如碱金属碳酸盐、碱金属碳酸氢盐、三(低级)烷基胺、吡啶、二(低级)烷基氨基吡啶(如4-二甲基氨基吡啶等)、N-(低级)烷基吗啉、N,N-二(低级)烷基苄胺等存在下进行。
反应温度不是很重要的,该反应通常在冷却至温热下进行。
方法2
目标化合物[Ⅰa]或其盐可通过还原化合物[Ⅱ]或其盐制备。
化合物[Ⅰa]和[Ⅱ]的合适的盐可以与对化合物[Ⅰ]所例举的那些相同。
该反应可用常规的方式,即化学还原或催化还原来进行。
用于化学还原的合适的还原剂为金属[如锡、锌、铁等]或金属化合物[如氯化铬、乙酸铬等]和有机酸或无机酸[如甲酸、乙酸、丙酸、三氟乙酸、对-甲苯磺酸、盐酸、氢溴酸、氢负离子转移试剂如氢化铝化合物(氢化铝锂、氢化三-叔-丁氧基铝酸锂等)、硼氢化物(如硼氢化钠、氰基硼氢化钠等)等]。
用于催化还原的合适的催化剂为常规催化剂,例如铂催化剂[如铂片、海棉铂、铂黑、胶态铂、氧化铂、铂丝等]、钯催化剂[如海绵钯、钯黑、氧化钯、披钯炭、胶态钯、披钯硫酸钡、披钯碳酸钡等]、镍催化剂[如还原镍、氧化镍、阮内镍等]、钴催化剂[如还原钴、阮内钴等]、铁催化剂[如还原铁、阮内铁等]、铜催化剂[如还原铜、阮内铜、Ullman铜等]等。
该方法的反应通常在溶剂例如水、醇[如甲醇、乙醇、丙醇等]、乙酸、乙醚、二氧六环、四氢呋喃、二氯甲烷等或其混合物中进行。
该反应最好在温和的条件下,例如在冷却至温热下进行。
在该反应中,R2的“羟基”可被还原为“氢”,这包括在本发明范围内。
方法3
目标化合物[Ⅰb]或其盐可通过还原反应还原原料化合物[Ⅳ]或其盐制备。
该反应可以与方法2基本相同的方式进行,因此,该反应的反应模式和反应条件[如溶剂、反应温度等]应参照方法2中所解释的那些。
方法A
目标化合物[Ⅱ]或其盐可通过使原料化合物[Ⅳ]或其在氨基上的反应性衍生物或其盐与化合物[Ⅲ]或其在羧基上的反应性衍生物或其盐反应来制备。
该反应可以与方法1基本相同的方式进行,因此,该反应的反应模式和反应条件[如溶剂、反应温度等]应参照方法1中所解释的那些。
方法B
化合物[Ⅳb]或其盐可通过使化合物[Ⅳa]或其在磺酸基团上的反应性衍生物或其盐经磺酸基团的水解反应来制备。
所述水解优选在碱或酸包括Lewis酸存在下进行。
合适的碱包括无机碱和有机碱,例如碱金属[如钠、钾等]、碱土金属[如镁、钙等]、它们的氢氧化物或碳酸盐或碳酸氢盐、三烷基胺[如三甲胺、三乙胺等]、甲基吡啶、1,5-二氮杂双环[4.3.0]-壬-5-烯等。
合适的酸可包括有机酸[如甲酸、乙酸、丙酸、三氯乙酸、三氟乙酸等],及无机酸[如盐酸、氢溴酸、硫酸、氢氯酸、氢溴酸等]。
使用Lewis酸如三卤乙酸(例如三氯乙酸、三氟乙酸等)等的消除反应优选在阳离子捕获剂(如苯甲醚、酚等)存在下进行。
该反应通常在常规溶剂,例如水、醇[如甲醇、乙醇、异丙醇等]、四氢呋喃、二氧六环、甲苯、二氯甲烷、氯化乙烯、氯仿、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或对该反应无不利影响的任何其它有机溶剂,或其混合物中进行。
反应温度不是很重要的,该反应通常在冷却至温热下进行。
原料化合物[Ⅳa]是已知的化合物。它可通过EP 0462531 A2中公开的发酵和合成方法制备。
方法C
化合物[Ⅳc]或其盐可通过使化合物[Ⅳb]或其在羟基上的反应性衍生物或其盐与重氮化合物[如重氮甲烷、苯基重氮甲烷、二苯基重氮甲烷、三甲基甲硅烷基重氮甲烷、β-重氮丙酸等]或其盐经羟基的烷基化反应来制备。
该反应通常在溶剂例如水、醇[如甲醇、乙醇等]、苯、N,N-二甲基甲酰胺、四氢呋喃、甲苯、二氯甲烷、氯化乙烯、氯仿、二氧六环、乙醚、乙腈或对该反应无不利影响的其它溶剂,或其混合物中进行。
反应温度不是很重要的,该反应通常在冷却至加热下进行。
所述反应通常在酸包括Lewis酸存在下进行。
合适的酸可包括有机酸[如甲酸、乙酸、丙酸、三氯乙酸、三氟乙酸等],及无机酸[如盐酸、氢溴酸、硫酸、氯化氢、溴化氢、卤化锌(如氯化锌、溴化锌等)等]等。
该反应也可在无机碱和有机碱存在下进行,这些碱有例如碱金属[如钠、钾等]、碱金属的氢氧化物[如氢氧化钠、氢氧化钾等]、碱金属碳酸氢盐[如碳酸氢钠、碳酸氢钾等]、碱金属碳酸盐[如碳酸钠、碳酸钾等]、三(低级)烷基胺[如三甲胺、三乙胺、二异丙基乙胺等]、碱金属氢化物[如氢化钠等]、碱金属(低级)醇盐[如甲醇钠、乙醇钠等]、吡啶、二甲基吡啶、甲基吡啶、二甲基氨基吡啶、N-(低级)烷基吗啉、N,N-二(低级)烷基苄胺、N,N-二(低级)烷基苯胺等。
当碱、酸和/或原料化合物为液体时,它们也可用作溶剂。
通过以上方法1-3和方法A-C获得的化合物可经常规方法如研磨、重结晶、柱层析、高效液相色谱(HPLC)、再沉淀、脱盐树脂柱层析等分离和纯化。
通过以上方法1-3和方法A-C获得的化合物可作为其水合物获得,它的水合物包括在本发明范围内。
应该注意到,由于不对称碳原子和双键的原因,每一目标化合物(Ⅰ)可包括一种或多种立体异构体,例如旋光异构体和几何异构体,所有这些异构体及其混合物均包括在本发明范围内。
目标化合物(Ⅰ)或其盐包括溶剂合化合物[如包合化合物(如水合物等)]。
目标化合物(Ⅰ)或其盐包括结晶形式和非结晶形式。
应该理解,本发明化合物可包括前药形式。
在此引用的专利申请和公开出版物通过引用结合到本文中。
本申请以在澳大利亚递交的申请号PP1728/98和申请号PP3138/98为基础,其内容通过引用结合到本文中。
多肽的生物学性质
本发明的化合物[Ⅰ]
为显示本发明的多肽化合物[Ⅰ]的用途,代表性的化合物的生物学数据解释如下。
实验(抗微生物活性)
下文将公开的实施例12的目标化合物的体外抗微生物活性通过如下所述的微量稀释测定法测定。
实验方法:
根据National Committee for Clinical Laboratory Standards(NCCLS)推荐的M27-A指南的微量稀释测定法进行抗真菌敏感性测定,以确定所述化合物的MICs。使用含有L-谷氨酰胺并用165mM吗啉丙磺酸缓冲液(pH7.0)缓冲的RPMI 1640培养基(无碳酸氢钠)作为实验培养基。通过血细胞计数方法制备106CFU/ml的接种物悬浮液,经稀释获得约0.5×103至2.5×103CFU/ml的接种物。于35℃孵育微量培养板,当在生长对照中生长良好时读取数据。MICs定义为未观察到可见生长的最低浓度。
试验结果:
MIC(μg/ml)
实验化合物实验微生物 | 实施例12的目标化合物 |
白假丝酶母FP-633 | 0.0625 |
从实验结果,可认识到本发明的目标多肽化合物[Ⅰ]具有抗微生物活性(尤其是抗真菌活性)。
本发明的药用组合物可以以药用制剂的形式使用,例如以固体、半固体或液体的形式使用,该组合物含有目标多肽化合物[Ⅰ]或其药学上可接受的盐,其作为活性成分与适合用于直肠、肺部(鼻腔或口腔吸入)、眼部、外用(局部)、口服给予、胃肠外(包括皮下、静脉内和肌内)给予、吹入(包括来自计量剂量吸入器的气溶胶)、雾化器或干粉吸入器的有机或无机载体或赋形剂混合使用。
可将活性成分例如与通常无毒、药学上可接受的载体一起混合配制成固体形式(如颗粒、片剂、糖锭剂、丸剂、锭剂、胶囊或栓剂、霜剂、软膏剂、气溶胶、供吸入的粉剂)、液体形式(如供注射的溶液、乳液或悬浮液、口服液、滴眼剂)或其它适合使用的形式。而且,如果需要,可包括以上制剂的辅助物质,例如稳定剂、增稠剂、润湿剂、乳化剂和着色剂,香料或缓冲剂,或任何其它通常可用作添加剂的物质。
该药用组合物中包括足以对疾病的过程或症状产生所需的抗微生物效果的量的目标多肽化合物[Ⅰ]或其药学上可接受的盐。
对于应用于人的组合物来说,它优选通过静脉内、肌内、肺部、口服给予或吹入使用。虽然目标多肽化合物[Ⅰ]的治疗有效量的剂量取决于每个接受治疗的病人的年龄和病情并随之变化,但通常按下列情况给药以治疗或预防感染性疾病:在静脉内给药的情况下,目标多肽化合物[Ⅰ]的日剂量为每人每公斤体重0.01-20mg,在肌内给药的情况下,目标多肽化合物[Ⅰ]的日剂量为每人每公斤体重0.1-20mg,在口服给药的情况下,目标多肽化合物[Ⅰ]的日剂量为每人每公斤体重0.5-50mg。
特别是在卡氏肺囊虫感染的治疗或预防的情况下,下列情况是需要注意的。
对于吸入给药,本发明化合物可以方便地以从作为配制成的加压粉末的气溶胶形式方便地传递,所述粉末组合物可借助于吹出粉末吸入装置吸入。优选的吸入传递系统为计量剂量吸入气溶胶,其可以配制为化合物在合适的抛射剂如氟烃或烃中的悬浮液或溶液形式。
由于直接治疗肺部和支气管的需要,气溶胶给药是优选的给药方法。吹入也是所需的方法,尤其是当感染可能扩散到耳朵和其它体腔内时。
或者,可使用静脉内滴注给予来进行胃肠外给药。
为更详细说明本发明的目的,给出下列制备和实施例。
制备1
用碳酸钾(109g)处理4-羟基苯甲酸甲酯(100g)和1,6-二溴己烷(481g)的N,N-二甲基甲酰胺(500ml)的溶液,然后于60℃加热2小时。冷却后,用乙酸乙酯(3L)稀释该混合物并用水(7×1L)洗涤。经硫酸镁干燥有机层,过滤、浓缩得到粗品油状物。加入己烷(约100ml)过滤移出生成的沉淀并弃去,将滤液载于硅胶柱(2kg)上。用己烷洗脱,接着用9∶1己烷-乙酸乙酯和8∶1己烷-乙酸乙酯洗脱,得到为白色固体的4-(6-溴代-正己氧基)苯甲酸甲酯(186g)。
NMR(CDCl3,δ):1.46-1.55(4H,m),1.78-1.97(4H,m),3.38-3.46(2H,m),3.88(3H,s),4.01(2H,t,J=6.3Hz),6.90(2H,d,J=8.9Hz),7.98(2H,d,J=8.9Hz)
质谱(m/z):315,317(M+)
以类似于制备1的方式获得下列化合物。
制备2
4-(7-溴代-正庚氧基)苯甲酸甲酯
NMR(DMSO-d6,δ):1.2-1.6(6H,m),1.6-2.0(4H,m),3.53(2H,t,J=6.7Hz),3.81(3H,s),4.04(2H,t,J=6.4Hz),7.03(2H,d,J=8.9Hz),7.90(2H,d,J=8.9Hz)
质谱(m/z):329(M+1),331(M+3)
制备3
用在甲醇(340ml)中的28%甲醇钠处理4-(6-溴代-正己氧基)苯甲酸甲酯(186g)的甲醇(1L)溶液并回流该溶液2小时。冷却后,用1M盐酸将搅拌的溶液调至pH2。然后用乙酸乙酯提取。用水洗涤有机层,经硫酸镁干燥,过滤并蒸发得到粗品油状物。经硅胶柱(2kg,9∶1己烷-乙酸乙酯洗脱)纯化该油,得到为油状物的4-(6-甲氧基-正己氧基)苯甲酸甲酯(127g)。
NMR(CDCl3,δ):1.37-1.68(6H,m),1.74-1.88(2H,m),3.33(3H,s),3.39(2H,t,J=6.3Hz),3.88(3H,s),4.01(2H,t,J=6.4Hz),6.90(2H,d,J=8.9Hz),7.97(2H,d,J=8.9Hz)
以类似于制备3的方式获得下列化合物。
制备4
4-(7-甲氧基-正庚氧基)苯甲酸甲酯
NMR(DMSO-d6,δ):1.2-1.6(8H,m),1.6-1.9(2H,m),3.21(3H,s),3.29(2H,t,J=6.4Hz),3.81(3H,s),4.04(2H,t,J=6.5Hz),7.03(2H,d,J=8.9Hz),7.90(2H,d,J=8.9Hz)
质谱(m/z):281(M+1)
制备5
用肼一水合物(66ml)处理4-(6-甲氧基-正己氧基)苯甲酸甲酯(17.05g)在1∶1四氢呋喃-甲醇(300ml)中的溶液并回流15小时,然后冷却至室温。将该反应混合物倾入水中,过滤收集生成的沉淀,用水充分洗涤,然后于50℃高真空下干燥,得到为白色固体的4-(6-甲氧基-正己氧基)苯甲酰肼(benzohydrazide)(15.63g)。
NMR(DMSO-d6,δ):1.29-1.58(6H,m),1.65-1.78(2H,m),3.21(3H,s),3.30(2H,t,J=6.4Hz),4.00(2H,t,J=6.4Hz),4.40(2H,s),6.96(2H,d,J=8.8Hz),7.78(2H,d,J=8.8Hz),9.59(1H,s)
质谱(m/z):267(M+1)
以类似于制备5的方式获得下列化合物。
制备6
4-(7-甲氧基-正庚氧基)苯甲酰肼
NMR(DMSO-d6,δ):1.2-1.6(8H,m),1.6-1.9(2H,m),3.21(3H,s),3.30(2H,t,J=6.4Hz),4.00(2H,t,J=6.4Hz),4.40(2H,s),6.96(2H,d,J=8.7Hz),7.78(2H,d,J=8.9Hz),9.59(1H,s)
质谱(m/z):281(M+1)
制备7
于0-5℃,用4-甲氧基羰基苯甲酰氯(83.75g)分次处理4-(6-甲氧基-正己氧基)苯甲酰肼(106.82g)和吡啶(162ml)在四氢呋喃(1L)中的混合物30分钟。于0-5℃再过1小时,于室温下过2小时后,tlc指示反应完成,将该反应混合物倾入水(7L)中。过滤收集生成的沉淀,用水充分洗涤,然后于50℃高真空下干燥,得到为白色固体的N-[4-(6-甲氧基-正己氧基)-苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼(171.9g)。
NMR(DMSO-d6,δ):1.40-1.80(8H,m),3.22(3H,s),3.31(2H,t,J=6.4Hz),3.90(3H,s),4.05(2H,t,J=6.3Hz),7.04(2H,d,J=8.8Hz),7.90(2H,d,J=8.8Hz),8.03(2H,d,J=8.6Hz),8.10(2H,d,J=8.6Hz),10.41(1H,s),10.64(1H,s)
以类似于制备7的方式获得下列化合物。
制备8
N-[4-(7-甲氧基-正庚氧基)-苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼
NMR(DMSO-d6,δ):1.2-1.6(8H,m),1.6-1.9(2H,m),3.21(3H,s),3.30(2H,t,J=6.4Hz),3.90(3H,s),4.05(2H,t,J=6.4Hz),7.04(2H,d,J=8.8Hz),7.90(2H,d,J=8.8Hz),8.03(2H,d,J=8.6Hz),8.10(2H,d,J=8.6Hz),10.42(1H,s),10.63(1H,s)
质谱(m/z):443(M+1)
制备9
将N-[4-(6-甲氧基-正己氧基)苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼(193.4g)和五硫化二磷(113.34g)在四氢呋喃(2.5L)中的混合物加热至回流1小时。然后冷却至室温并倾入水(7L)中。过滤收集生成的沉淀,用水充分洗涤,然后部分干燥。将该固体加入1∶1的乙腈-水(200ml)中,搅拌后过滤。重复该步骤另外2次,用乙腈(500ml×5)充分洗涤生成的黄色粉末,然后于50℃高真空下干燥,得到为黄色粉末的4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸甲酯(179.6g)。
NMR(CDCl3,δ):1.40-1.87(8H,m),3.34(3H,s),3.40(2H,t,J=6.2Hz),3.96(3H,s),4.03(2H,t,J=6.5Hz),6.99(2H,d,J=8.8Hz),7.95(2H,d,J=8.8Hz),8.07(2H,d,J=8.5Hz),8.16(2H,d,J=8.5Hz)
以类似于制备9的方式获得下列化合物。
制备10
4-[5-[4-(7-甲氧基-正庚氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸甲酯
NMR(CDCl3,δ):1.3-2.0(10H,m),3.34(3H,s),3.38(2H,t,J=6.4Hz),3.96(3H,s),4.03(2H,t,J=6.5Hz),6.99(2H,d,J=8.8Hz),7.95(2H,d,J=8.8Hz),8.07(2H,d,J=8.4Hz),8.43(2H,d,J=8.4Hz)
质谱(m/z):441(M+1)
制备11
将4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸甲酯(179.6g)、氢氧化钠(25.3g)、水(250ml)、甲醇(1L)和四氢呋喃(750ml)的混合物于回流下加热1小时,然后冷却至室温并倾入水(7L)中。用6N盐酸将搅拌的混合物的pH调至2.0,过滤收集沉淀,用水充分洗涤,接着用乙腈洗涤,然后在高真空下于50℃干燥,得到为黄色粉末的4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸(167g)。
NMR(DMSO-d6,δ):1.27-1.85(8H,m),3.22(3H,s),3.32(2H,t,J=6.4Hz),4.06(2H,t,J=6.3Hz),7.12(2H,d,J=8.8Hz),7.97(2H,d,J=8.7Hz),8.12(4H,s),13.28(1H,br,s)
以类似于制备11的方式获得下列化合物。
制备12
4-[5-[4-(7-甲氧基-正庚氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸
IR(KBr):2939.0,2867.6,2642.0,1712.5,1604.5,1440.6,1402.0,1253.5cm-1
质谱(m/z):427(M+1)
制备13
于室温下,将4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸(50g)、1-羟基苯并三唑(18g)和1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺、盐酸(34.86g)在二氯甲烷(1L)中的混合物搅拌16小时,然后减压蒸发并于高真空下干燥1小时。将水(1L)加入该残留物中,过滤收集生成的沉淀,用水(1L×5)、乙腈(1L×5)、异丙醚(250ml×2)洗涤,然后在高真空下干燥。得到为黄色粉末的4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(56.92g)。
IR(KBr):1778cm-1
NMR(CDCl3,δ):1.44-1.89(8H,m),3.35(3H,s),3.40(2H,t,J=6.2Hz),4.05(2H,t,J=6.4Hz),7.01(2H,d,J=8.8Hz),7.43-7.63(3H,m),7.98(2H,d,J=8.8Hz),8.13(1H,d,J=8.2Hz),8.24(2H,d,J=8.5Hz),8.41(2H,d,J=8.5Hz)
以类似于制备13的方式获得下列化合物[制备14和15]。
制备14
4-[5-[4-(7-甲氧基-正庚氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):3446.2,2937.1,2865.7,1778.0,1602.6,1253.5cm-1
NMR(CDCl3,δ):1.3-2.0(10H,m),3.34(3H,s),3.39(2H,t,J=6.4Hz),4.03(2H,t,J=6.5Hz),7.01(2H,d,J=8.8Hz),7.4-7.7(3H,m),7.98(2H,d,J=8.8Hz),8.13(1H,d,J=8.2Hz),8.24(2H,d,J=8.7Hz),8.41(2H,d,J=8.7Hz)
质谱(m/z):544(M+1)
制备15
4-[5-(4-戊氧基苯基)异噁唑-3-基]苯甲酸苯并三唑-1-基酯
制备16
向在N,N-二甲基甲酰胺(300ml)中的3-羟基苯甲酸甲酯(25g)和碳酸钾(25g)中加入1-溴代戊烷(25ml),于80℃搅拌该混合物7小时。将该反应混合物加入水和乙酸乙酯的混合物中。取出有机层并经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液,得到3-戊氧基苯甲酸甲酯(35g)。
IR(KBr):2954,2870,1724,1587cm-1
NMR(CDCl3,δ):0.94(3H,t,J=7.0Hz),1.43(4H,m),1.80(2H,m),3.91(3H,s),3.99(2H,t,J=6.6Hz),7.09(1H,ddd,J=7.8,1.7和1.7Hz),7.32(1H,t,J=7.8Hz),7.55(1H,dd,J=1.7和1.1Hz),7.61(1H,ddd,J=7.8,1.7和1.1Hz)
质谱(m/z):223(M+1)
制备17
向在甲醇(200ml)中的3-戊氧基苯甲酸甲酯(35g)中加入1N-氢氧化钠水溶液(200ml),于室温下搅拌该混合物2天。将羟基氯化物(hydroxy chloride)(20ml)加入该反应混合物中。过滤沉淀物并用水、乙腈和二异丙基醚洗涤,得到3-戊氧基苯甲酸(30mg)。
IR(KBr):2954,2848,2570,1691,1600,1591cm-1
NMR(DMSO-d6,δ):0.90(3H,t,J=7.0Hz),1.40(4H,m),1.73(2H,m),4.00(2H,t,J=6.6Hz),7.17(1H,ddd,J=7.7,2.6和1.2Hz),7.39(1H,t,J=7.7Hz),7.42(1H,dd,J=1.5和1.2Hz),7.52(1H,ddd,J=7.7,1.5和1.2Hz)
质谱(m/z):209(M+1)
制备18
向1-羟基苯并三唑(24g)和3-戊氧基苯甲酸(29.5g)的二氯甲烷(500ml)溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(WSCD·HCl)(41g),于环境温度下搅拌该混合物5小时。将该反应混合物加入水中。取出有机层并经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液,得到3-戊氧基苯甲酸苯并三唑-1-基酯(42g)。
IR(KBr):2956,2935,2869,1788,1600cm-1
NMR(CDCl3,δ):0.95(3H,t,J=7.0Hz),1.45(4H,m),1.84(2H,m),4.05(2H,t,J=6.5Hz),7.30(1H,d,J=9.4Hz),7.43-7.56(4H,m),7.74(1H,t,J=2.0Hz),8.10(1H,d,J=8.5Hz),8.53(1H,d,J=8.5Hz)
质谱(m/z):326(M+1)
制备19
向在N,N-二甲基甲酰胺(100ml)中的4-正丁氧基苯甲酸苯并三唑-1-基酯(15g)的溶液中加入氨基硫脲(5.27g),于室温下搅拌该混合物12小时。用二异丙基醚研磨该反应混合物。过滤收集沉淀,得到1-(4-正丁氧基苯甲酰基)氨基硫脲(11.51g)。
NMR(DMSO-d6,δ):0.93(3H,t,J=7.0Hz),1.2-1.5(2H,m),1.6-1.8(2H,m),4.02(2H,t,J=6.5Hz),6.98(2H,d,J=8.8Hz),7.56(1H,s),7.83(1H,s),7.84(2H,d,J=8.8Hz),9.26(1H,s),10.21(1H,s)
以类似于制备19的方式获得下列化合物。
制备20
1-(3-戊氧基苯甲酰基)氨基硫脲
NMR(DMSO-d6,δ):0.90(3H,t,J=6.8Hz),1.39(4H,m),1.73(2H,m),4.01(2H,t,J=6.4Hz),7.10(1H,d,J=8.0Hz),7.30-8.00(5H,m),9.33(1H,s),10.34(1H,s),8.53(1H,d,J=8.5Hz)
质谱(m/z):282(M+1)
制备21
于40℃,用30分钟向1-(4-n-丁氧基苯甲酰基)氨基硫脲(20g)在甲苯(213.3ml)中的淤浆中滴加甲磺酸(6.92ml)。回流下搅拌该混合物12小时。冷却至10℃,滤出磺酸盐并干燥。将该盐溶于水中,用1N氢氧化钠将该溶液调至pH9并用乙酸乙酯提取。分离有机层,用盐水洗涤,经硫酸镁干燥并减压蒸发,得到2-氨基-5-(4-n-丁氧基苯基)-1,3,4-噻二唑(4.314g)。
NMR(CDCl3,δ):0.94(3H,t,J=7.0Hz),1.2-1.6(2H,m),1.6-1.9(2H,m),4.01(2H,t,J=6.5Hz),7.00(2H,d,J=8.8Hz),7.28(2H,s),7.66(2H,d,J=8.8Hz)
以类似于制备21的方式获得下列化合物。
制备22
2-氨基-5-(3-戊氧基苯基)-1,3,4-噻二唑
IR(KBr):3291.9,3114.5,2952.5,1610.3cm-1
NMR(DMSO-d6,δ):0.90(3H,t,J=7.0Hz),1.39(4H,m),1.73(2H,m),4.01(2H,t,J=6.5Hz),7.00(1H,d,J=8.5Hz),7.25-7.42(5H,m)
质谱(m/z):264(M+1)
制备23
向2-氨基-5-(4-n-丁氧基苯基)-1,3,4,-噻二唑(1.5g)的乙醇(30ml)的悬浮液中加入4-溴代乙酰基苯甲酸乙酯(1.86g),于回流下搅拌该混合物1.5小时。用乙酸乙酯研磨该反应混合物。过滤沉淀并干燥。向该粉末在二甲苯(15ml)中的悬浮液中加入三氟乙酸(3ml)。回流下搅拌该混合物3小时。用二异丙基醚研磨该反应混合物。过滤沉淀并干燥,得到4-[2-(4-正丁氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸乙酯三氟乙酸盐(2.15g)。
IR(KBr):1714.4,1602.6,1278.6,1255.4,1178.3cm-1
以类似于制备23的方式获得下列化合物。
制备24
4-[2-(3-戊氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸乙酯-三氟乙酸盐
IR(KBr):2869.6,1704.8,1573.6,1278.6cm-1
质谱(m/z):436(M+1)
制备25
向4-[2-(4-正丁氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐(2.05g)在甲醇(41ml)和四氢呋喃(20.5ml)的混合物中的溶液中加入2N氢氧化钠水溶液(19.1ml)并回流17小时。用1N HCl将该反应混合物调至pH 1-2,过滤收集生成的沉淀,得到4-[2-(4-丁氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸(1.544g)。
以类似于制备25的方式获得下列化合物。
制备26
4-[2-(3-戊氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸
IR(KBr):2935.1,2867.6,1685.5,1608.3,1484.9,1288.2cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.39(4H,m),1.75(2H,m),4.07(2H,t,J=6.5Hz),7.19(1H,m),7.42-7.49(3H,m),8.00(4H,s),8.89(1H,s)
质谱(m/z):408(M+1)
制备27
搅拌下,将原料化合物(1g)的四氢呋喃(10ml)溶液和pH为6.86的标准缓冲液(由Nacalai Tesque,Inc.制备)(10ml)滴加到在冰浴中的苄氧基碳酰氯(0.15ml)中。然后搅拌该溶液2小时。用稀氯化氢酸化该反应混合物并减压蒸发。使残留物溶于水中,经离子交换树脂(DOWEX-50WX4(商标:由Dow Chemical制备)),用水洗脱。合并含有目标化合物的部分,经在ODS(YMC-凝胶ODS-AM-S-50(商标:由YamamuraChemical Lab.制备))上柱层析,用5%乙腈水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(27)(0.78g)。
IR(KBr):3462,3336,1668,1539,1265cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.05(3H,d,J=5.8Hz),1.78-5.53(35H,m),6.71-8.84(16H,m)
质谱(m/z):1068.90(M-Na+)
制备28
于室温下,向在N,N-二-甲基甲酰胺(230ml)中的原料化合物(54.4g)和乙基二异丙胺(35ml)溶液中加入9-芴基甲基氯代甲酸酯(15.8g)。在相同的温度下搅拌该溶液5小时。将乙酸乙酯(1.5L)加入该反应混合物中,搅拌该混合物30分钟。过滤收集粉末,得到粗品物质(94.3g)。该粗品物质经在DOWEX和ODS上柱层析纯化,得到目标化合物(28)(52.6g)。
NMR(DMSO-d6,δ):0.96(3H,d,J=6.8Hz),1.03(3H,d,J=5.6Hz),1.60-2.00(3H,m),2.05-2.49(4H,m),3.18(1H,t,J=11.1Hz),3.60-4.48(17H,m),4.68-5.36(10H,m),5.35(1H,d,J=5.9Hz),6.73(1H,d,J=8.2Hz),6.82(1H,dd,J=8.2和1.6Hz),6.84(1H,m),6.97(1H,m),7.04(1H,d,J=1.6Hz),7.27-7.46(6H,m),7.74-7.78(3H,m),7.89(2H,d,J=7.2Hz),8.06(2H,t,J=7.2Hz),8.77(1H,s)
制备29
向在N,N-二甲基甲酰胺(20ml)中的1-羟基苯并三唑(216mg)和4-[2-(4-丁氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸(420mg)溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(245mg),于室温下搅拌该混合物2小时。然后向该反应混合物中加入原料化合物(1g)和二异丙基乙胺(0.279ml),于室温下搅拌该混合物5小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀并减压干燥。将该粉末加入水中,经在DOWEX-50WX4离子交换柱层析,用水洗脱。合并含有目标化合物的部分,经ODS(YMC-凝胶ODS-AM-S-50)上柱层析,用25-30%乙腈水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(29)(891mg)。
NMR(DMSO-d6,δ):0.94(3H,t,J=7.2Hz),0.96(3H,d,J=7.1Hz),1.11(3H,d,J=5.5Hz),1.3-1.6(2H,m),1.6-2.1(5H,m),2.1-2.7(4H,m),3.25(1H,m),3.6-4.5(16H,m),4.7-5.3(10H,m),5.53(1H,d,J=5.8Hz),6.73(1H,d,J=8.2Hz),6.82(1H,d,J=8.2Hz),6.86(1H,s),7.05(1H,s),7.14(2H,d,J=8.9Hz),7.2-7.5(3H,m),7.90(2H,d,J=8.9Hz),7.9-8.0(4H,m),8.10(1H,d,J=7.7Hz),8.30(1H,d,J=6.8Hz),8.70(1H,d,J=6.8Hz),8.86(1H,s)
质谱(m/z):1356(M+Na+)
以类似于制备29的方式获得下列化合物。
制备30
IR(KBr):3359,1673.9,1648.8,1257.4cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.1Hz),0.96(3H,d,J=6.7Hz),1.09(3H,d,J=5.9Hz),1.3-1.5(4H,m),1.6-2.7(9H,m),3.19(1H,m),3.6-4.6(15H,m),4.7-5.3(11H,m),5.53(1H,d,J=5.9Hz),6.73(1H,d,J=8.3Hz),6.83(1H,d,J=8.3Hz),6.88(1H,s),7.06(1H,s),7.14(2H,d,J=8.9Hz),7.2-7.4(3H,m),7.90(2H,d,J=8.9Hz),7.97(4H,m),8.08(1H,d,J=6Hz),8.31(1H,d,J=5Hz),8.76(1H,d,J=5Hz),8.85(1H,s),8.86(1H,s)
质谱(m/z):1325(M+Na+)
C57H70N11O22S2Na·8H2O的元素分析计算值:
C45.87,H5.81,N10.32
实测值:C46.04,H5.77,N10.28
制备31
于室温下,将4-(4’-羟基苯基)苯甲酸(25.6g)的10%盐酸-甲醇溶液搅拌3天。然后真空蒸发溶剂,残留物用甲苯-乙酸乙酯(20∶1)研磨得到4-(4’-羟基苯基)苯甲酸甲酯(26.5g)。
NMR(CDCl3,δ):3.94(3H,s),6.93(2H,d,J=8.4Hz),7.27(1H,s),7.53(2H,d,J=8.6Hz),7.60(2H,d,J=8.4Hz),8.08(2H,d,J=8.4Hz)
质谱(m/z):229(M++1)
制备32
于室温下,将4-(4’-羟基苯基)苯甲酸(4.98g)、甲基碘(5ml)和碳酸钠(7.19g)的N,N-二甲基甲酰胺(50ml)溶液搅拌17小时。然后使该反应混合物在乙酸乙酯和水之间分配。用乙酸乙酯萃取该水层。用水和盐水洗涤合并的有机层。经硫酸镁干燥后,真空蒸发该溶液。用正己烷研磨其残留物得到4-(4’-甲氧基苯基)苯甲酸甲酯(5.45g)。
IR(KBr):1718cm-1
NMR(CDCl3,δ):3.86(3H,s),3.93(3H,s),7.00(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.61(2H,d,J=8.6Hz),8.07(2H,d,J=8.6Hz)
质谱(m/z):243(M++1)
制备33
将4-[5-[4’-[4”-[3-(哌嗪-1-基)-丙氧基]苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯(1.13g)、1N氢氧化钠水溶液(3.5ml)、甲醇(5ml)和四氢呋喃(5ml)的混合物回流17小时。使该混合物冷却至室温并真空蒸发。向该残留物中加入1N盐酸水溶液。过滤获得粉末,得到4-[5-[4’-[4”-[3-(哌嗪-1-基)-丙氧基]苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸盐酸盐(1.01g)。
IR(KBr):3431,2943,2877,2694,2640,2571,2543,1699cm-1
NMR(DMSO-d6,δ):1.56(2H,m),1.78(4H,m),2.19(2H,m),3.17(6H,m),4.14(2H,t,J=7.0Hz),7.09(2H,d,J=8.8Hz),7.77(2H,d,J=8.8Hz),7.92(2H,d,J=8.6Hz),8.17(2H,d,J=8.6Hz),8.20(2H,d,J=8.5Hz),8.27(2H,d,J=8.5Hz)
质谱(m/z):484(M++1)游离
制备34
用碳酸钾(10.95g)和1-溴代癸烷(19.31g)处理吡唑-4-羧酸甲酯(10g)的N,N-二甲基甲酰胺(100ml)溶液,于室温下搅拌该混合物16小时。加入乙酸乙酯,用水(6×)洗涤该溶液,经硫酸镁干燥,该蒸发的残留物经硅胶层析纯化(5∶1己烷-乙酸乙酯洗脱),得到为白色固体的1-癸基吡唑-4-羧酸甲酯(19.4g)。
NMR(CDCl3,δ):0.84-0.90(3H,m),1.25(14H,br s),1.83-1.90(2H,m),3.82(3H,s),4.15(2H,t,J=7Hz),7.87(1H,s),7.90(1H,s)
质谱(m/z):267(M+)
制备35
用碳酸钾(1.21g)处理4-(4’-羟基苯基)苯甲酸甲酯(2g)的N,N-二甲基甲酰胺(20ml)溶液,于室温下搅拌3-苯氧基丙基溴(2.079)15小时,于85℃搅拌4小时。冷却后,用水猝灭该反应物,过滤收集沉淀,用水充分洗涤,干燥得到4-[4’-(3-苯氧基丙氧基)苯基]-苯甲酸甲酯(2.6g)。
NMR(DMSO-d6,δ):2.14-2.26(2H,m),3.87(3H,s),4.12-4.29(4H,m),6.89-6.98(3H,m),7.08(2H,d,J=8.8Hz),7.25-7.33(2H,m),7.70(2H,d,J=8.8Hz),7.78(2H,d,J=8.5Hz),8.00(2H,d,J=8.4Hz)
质谱(m/z):363(M+)
制备36
用碳酸钾(6.06g)和烯丙基溴(2.46ml)处理4-(4’-羟基苯基)苯甲酸甲酯(5g)的N,N-二甲基甲酰胺(50ml)溶液,然后于60℃加热3小时。冷却后,将该反应混合物倾入冰水(约200ml)中,过滤收集产生的沉淀,用水,接着用异丙基醚洗涤,然后干燥得到为固体的4-[4’-(烯丙基氧基)苯基]-苯甲酸甲酯(5.55g)。
mp:148-149℃
NMR(CDCl3,δ):3.93(3H,s),4.29-4.61(2H,m),5.28-5.49(2H,m),5.99-6.18(1H,m),7.00(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.61(2H,d,J=8.5Hz),8.07(2H,d,J=8.5Hz)
质谱(m/z):269(M+)
制备37
将4-(4’-羟基苯基)苯甲酸(4g)和1N氢氧化钠(41ml)的二甲亚砜(40ml)溶液于85℃加热30分钟,然后用4-苯氧基丁基溴(6.42g)处理并继续加热8小时。冷却后,将该反应物倾入水中并调至pH2,收集产生的沉淀,用水洗涤,干燥后得到4-[4’-(4-苯氧基丁氧基)苯基]苯甲酸(6.7g)。
IR(KBr):1683.6,1594.8,1535.1cm-1
NMR(DMSO-d6,δ):1.89(4H,br s),3.34(1H,br s),4.04-4.10(4H,m),6.91-6.95(3H,m),7.05(2H,d,J=7.9Hz),7.24-7.30(2H,m),7.66-7.76(4H,m),7.98(2H,d,J=7.8Hz)
制备38
于室温下,将4-[4’-(4-苯氧基丁氧基)苯基]苯甲酸(5g)、1-羟基苯并三唑(2.24g)和1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(3.97g)在N,N-二甲基甲酰胺(70ml)中的混合物搅拌18小时,然后用肼基甲酸叔丁酯(2.19g)处理,于室温下将该混合物再搅拌4小时。加入水并收集沉淀,用水洗涤,干燥后得到为固体的N-(叔丁氧基羰基)-N’-[4-[4’-(4-苯氧基丁氧基)苯基]苯甲酰基]肼(6g)。
IR(KBr):1650.8,1492.6,1290.1,1249.6cm-1
NMR(DMSO-d6,δ):1.44(9H,br s),1.90(4H,br s),4.04-4.10(4H,m),6.88-6.96(3H,m),7.05(2H,d,J=8.7Hz),7.24-7.32(2H,m),7.69(2H,d,J=8.8Hz),7.75(2H,d,J=8.5Hz),7.92(2H,d,J=8.2Hz),8.91(1H,s),10.21(1H,s)
制备39
于室温下,将N-(叔丁氧基羰基)-N’-[4-[4’-(4-苯氧基丁氧基)苯基]苯甲酰基]肼(6g)的三氟乙酸(40ml)溶液搅拌2小时,然后减压蒸发,溶于水中,然后用饱和碳酸氢钠溶液调至pH8。收集沉淀,用水洗涤,干燥后得到4-[4’-(4-苯氧基丁氧基)苯基]苯甲酰基肼(5g)。
IR(KBr):3282.3,1604.5cm-1
NMR(DMSO-d6,δ):1.89(4H,br s),4.04-4.09(4H,m),4.55(2H,br),6.83-6.96(3H,m),7.04(2H,d,J=8.6Hz),7.24-7.28(2H,m),7.64-7.72(4H,m),7.88(2H,d,J=8.3Hz),9.79(1H,s)
质谱(m/z):377(M+)
制备40
用4-[4’-(8-甲氧基-正辛氧基)苯基]苯甲酸苯并三唑-1-基酯(1.054g)处理4-甲氧基羰基苯甲酰基肼(432mg)的四氢呋喃(15ml)-吡啶(5ml)溶液,于室温下搅拌该混合物72小时,然后将水(约100ml)加入该反应混合物中,收集沉淀,用水洗涤,干燥后得到N-[4-[4’-(8-甲氧基-正辛氧基)苯基]苯甲酰基]-N’-(4-甲氧基羰基-苯甲酰基)肼(1.10g)。
IR(KBr):3220.5,2933.2,2856.1,1724.0,1679.7,1654.6cm-1
NMR(DMSO-d6,δ):1.20-1.60(10H,m),1.60-1.80(2H,m),3.21(3H,s),3.21-3.33(2H,m),3.90(3H,s),4.02(2H,t,J=6.9Hz),7.05(2H,d,J=8.7Hz),7.70(2H,d,J=8.6Hz),7.79(2H,d,J=8.3Hz),7.99(2H,d,J=8.3Hz),8.04(2H,d,J=8.5Hz),8.11(2H,d,J=8.5Hz),10.60(1H,s),10.70(1H,s)
质谱(m/z):533(M+)
制备41
将N-(4-甲氧基苯甲酰基)-N’-(4-甲氧基羰基苯甲酰基)肼(10g)和五硫化二磷(6.77g)在四氢呋喃(100ml)中的悬浮液回流3小时。冷却该反应混合物并倾入水(300ml)中,搅拌30分钟并用二氯甲烷(1500ml)和甲醇(300ml)提取。用水和盐水洗涤有机层,经硫酸镁干燥有机层,减压蒸发。用乙腈研磨残留物。过滤收集固体,减压干燥得到4-[5-(4-甲氧基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯(8.15g)。
IR(KBr):2952.5,2840.6,1714.4,1606.4,1278.6,1251.6cm-1
NMR(CDCl3,δ):3.89(3H,s),3.96(3H,s),7.01(2H,d,J=8.9Hz),7.97(2H,d,J=8.9Hz),8.07(2H,d,J=8.7Hz),8.16(2H,d,J=8.7Hz)
质谱(m/z):327(M++1)
制备42
于-78℃,向三溴化硼(2.0M在二氯甲烷中,103ml)溶液中滴加4-[5-(4-甲氧基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯(6.75g)和二氯甲烷(100ml)。使该反应混合物温热至室温,搅拌该混合物过夜。将该反应混合物倾入冰水(1000ml)中。过滤收集沉淀,用水洗涤,于60℃减压干燥得到4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯和4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸(6.56g),该粗物质可用于下一步反应。
制备43
向4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯和4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸(600mg)的混合物、碳酸钾(531mg)和N,N-二甲基甲酰胺(3ml)的悬浮液中加入4-苯氧基丁基溴(880mg),于100℃(浴温)搅拌该混合物2小时。冷却后,将该混合物加至0.1N盐酸(100ml)中。过滤收集产生的沉淀,用水洗涤。向该物质中加入四氢呋喃(20ml)、乙醇(20ml)和10%氢氧化钠水溶液(1.39ml)。使该混合物回流2小时。冷却后,用水(100ml)稀释该反应混合物,用1N盐酸调至pH1.8,然后用二氯甲烷(1000ml)、四氢呋喃(200ml)和甲醇(200ml)的混合物提取。用盐水洗涤有机层,经硫酸镁干燥。减压蒸发溶剂。用乙腈研磨残留物。过滤收集固体,干燥得到4-[5-[4-(4-苯氧基丁氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸(685mg)。
IR(KBr):3371.0,2674.8,2547.5,1685.5,1604.5,1249.6cm-1
制备44
向4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯和4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸(2.0g)的混合物、碳酸钾(14.6g)和N,N-二甲基甲酰胺(15ml)的悬浮液中加入1,5-二溴代戊烷(10ml),于100℃(浴温)搅拌该混合物1.5小时。用0.1N盐酸中和得到的混合物并用二氯甲烷提取。用盐水洗涤有机层,经硫酸镁干燥。减压蒸发溶剂。用正己烷研磨残留物。过滤收集固体并干燥。向该化合物中加入苯酚(1.43g)、碳酸钾(2.10g)和N,N-二甲基甲酰胺(30ml),于100℃(浴温)搅拌该混合物20小时。冷却后,将该反应混合物倾入饱和碳酸氢钠水溶液中。过滤收集产生的沉淀,用水洗涤。向该化合物中加入四氢呋喃(20ml)、乙醇(20ml)和10%氢氧化钠水溶液(2.6ml)。使该混合物回流1.5小时。用水稀释该反应混合物,用1N盐酸(10ml)酸化。过滤收集产生的沉淀,用水洗涤,减压干燥得到4-[5-[4-(5-苯氧基正戊氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸(2.47g),该粗物质可用于下一步反应。
质谱(m/z):461(M++1)
制备45
向4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸甲酯和4-[5-(4-羟基苯基)-1,3,4-噻二唑-2-基]苯甲酸(3.12g)的混合物、碳酸钾(22.07g)和N,N-二甲基甲酰胺(15ml)的悬浮液中加入1,5-二-溴代戊烷(15ml),于100℃(浴温)搅拌该混合物5小时。用0.1N盐酸中和得到的混合物并用二氯甲烷提取。用盐水洗涤有机层,经硫酸镁干燥。减压蒸发溶剂。用正己烷研磨残留物。过滤收集固体并干燥得到粗粉(3.71g)。向该粗粉(2.11g)中加入甲醇(10ml)和甲醇钠(28%的甲醇液)(10ml),并回流2小时。然后向该反应混合物中加入甲醇钠(28%的甲醇液)(5ml),使回流1.5小时。冷却后,将该反应混合物加入水和四氢呋喃中,搅拌过夜,用4N盐酸调至pH2。过滤收集产生的沉淀,用乙腈洗涤,减压干燥得到4-[5-[4-(5-甲氧基正戊氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸(1.34g)。
IR(KBr):2940.9,2865.7,2663.2,2549.4,1685.5,1604.5,1432.9,1413.6,1292.1,1253.5cm-1。
NMR(DMSO-d6,δ):1.3-1.7(4H,m),1.7-2.0(2H,m),3.23(3H,s),3.36(2H,m),4.07(2H,t,J=6.4Hz),7.13(2H,d,J=8.8Hz),7.97(2H,d,J=8.8Hz),8.12(4H,s)
质谱(m/z):399(M++1)
制备46
向哌啶(2.98g)和6-氯代烟酸甲酯(5.00g)的N,N-二甲基甲酰胺(75ml)的溶液中加入碳酸钾(12.08g)。于100℃搅拌该混合物3小时。冷却至室温后,向该反应混合物中加入水(100ml),然后于室温下搅拌该混合物15分钟。收集产生的沉淀,用水洗涤,干燥得到6-(1-哌啶基)烟酸甲酯(5.55g),为白色固体。
IR(KBr):2941,2850,1701,1608,1552,1508,1435,1415cm-1。
NMR(CDCl3,δ):1.5-1.8(6H,m),3.6-3.7(4H,m),3.86(3H,s),6.57(1H,d,J=9.1Hz),7.98(1H,dd,J=9.1和2.4Hz),8.78(1H,d,J=2.0Hz)
质谱(m/z):221(M++1)
制备47
向6-(1-哌啶基)烟酸甲酯(5.00g)在乙醇(25ml)和四氢呋喃(10ml)混合溶剂的溶液中加入肼一水合物(11.0ml)。将该溶液回流6小时,在此期间再将肼一水合物(11.0ml)加入该混合物中。冷却至室温后,将反应混合物加入水(100ml)中,然后于室温下搅拌20分钟。过滤收集产生的沉淀,用水洗涤,干燥得到6-(1-哌啶基)烟酰基肼(3.44g),为白色固体。
IR(KBr):3300,2931,2846,1649,1608,1554,1502,1417,1348,1242cm-1。
NMR(CDCl3,δ):1.5-1.8(6H,m),3.4-3.8(6H,m),6.61(1H,d,J=8.9Hz),7.51(1H,br s),7.85(1H,dd,J=9.0和2.5Hz),8.54(1H,d,J=2.0Hz)
质谱(m/z):221(M++1)
制备48
向N-[6-(1-哌啶基)烟酰基]-N’-(4-甲氧基羰基苯甲酰基)肼(2.00g)的吡啶(40ml)溶液中加入五硫化二磷(1.74g)。将该混合物回流4小时。冷却至室温后,将该反应混合物倾入冷水(150ml)中,用1N氢氧化钠水溶液将该混合物调至pH11,于室温下搅拌该混合物30分钟。收集产生的沉淀,用水洗涤,干燥得到4-[5-[6-(1-哌啶基)吡啶-3-基]-1,3,4-噻二唑-2-基]苯甲酸甲酯(1.59g),为黄色固体。
IR(KBr):2933,2848,1720,1604,1433,1279,1109cm-1。
NMR(CDCl3,δ):1.6-1.8(6H,m),3.6-3.8(4H,m),3.96(3H,s),6.73(1H,d,J=9.1Hz),8.06(2H,d,J=8.7Hz),8.14(1H,dd,J=9.2和2.9Hz),8.16(2H,d,J=8.6Hz),8.70(1H,d,J=2.2Hz)
质谱(m/z):381(M++1)
制备49
向4-[5-[2-(1-哌啶基)吡啶-5-基]-1,3,4-噻二唑-2-基]苯甲酸甲酯(1.50g)在四氢呋喃(75ml)和乙醇(15ml)的混合溶剂中的回流悬浮液中滴加10%氢氧化钠水溶液(3.15ml)。使该混合物回流1.5小时,冷却至室温。向该反应混合物中加入水(100ml),用1N盐酸(15ml)将pH调至1。于室温下搅拌该混合物30分钟。过滤收集产生的沉淀,用水洗涤,干燥得到4-[5-[6-(1-哌啶基)吡啶-3-基]-1,3,4-噻二唑-2-基]苯甲酸盐酸盐(1.36g),为黄色固体。
IR(KBr):3479,2935,2854,1695,1605,1431,1281,1250cm-1。
NMR(DMSO-d6,δ):1.5-1.7(6H,m),3.6-3.7(4H,m),6.99(1H,d,J=9.1Hz),8.08(1H,dd,J=9.1和2.5Hz),8.11(4H,s),8.71(1H,d,J=2.4Hz)
质谱(m/z):367(M++1)(游离)
制备50
向4-[5-[6-(1-哌啶基)吡啶-3-基]-1,3,4-噻二唑-2-基]苯甲酸盐酸盐(1.20g)的二氯甲烷(60ml)中的悬浮液中加入三乙胺(0.57ml)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(1.43g)。于室温下搅拌该混合物6小时。向该反应混合物中加入水,分离有机层,用碳酸氢钠水溶液和饱和氯化钠溶液洗涤,经硫酸镁干燥有机层并真空蒸发。将二异丙基醚加入该残留物中,过滤沉淀物,用相同的溶剂洗涤,干燥得到4-[5-[6-(1-哌啶基)吡啶-3-基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(1.18g),为黄色固体。
IR(KBr):2931,2854,1778,1600,1547,1512,1431,1358,1242,993cm-1。
NMR(CDCl3,δ):1.6-1.8(6H,m),3.6-3.8(4H,m),6.75(1H,d,J=9.1Hz),7.4-7.7(3H,m),8.13(1H,d,J=8.2Hz),8.16(1H,dd,J=9.1和2.5Hz),8.24(2H,d,J=8.6Hz),8.40(2H,d,J=8.6Hz),8.72(1H,d,J=2.3Hz)
质谱(m/z):484(M++1)
制备51
将4-(4’-羟基苯基)苯甲酸甲酯(2.02g)、正丁基溴(3ml)和碳酸钠(3.6g)的N,N-二甲基甲酰胺的溶液于80℃搅拌17小时。使该反应混合物冷却至室温并在乙酸乙酯和水之间分配。用乙酸乙酯提取水层。用水和盐水洗涤合并的有机层。经硫酸镁干燥后,真空蒸发该溶液。用正己烷研磨该残留物得到4-(4’-丁氧基苯基)苯甲酸甲酯(2.45g)。
IR(KBr):2956,2935,2873,1722cm-1。
NMR(DMSO-d6,δ):0.94(3H,d,J=7.3Hz),1.45(2H,qt,J=7.3和6.9Hz),1.70(2H,tt,J=6.9和6.9Hz),4.03(2H,t,J=6.9Hz),7.04(2H,d,J=8.8Hz),7.68(2H,d,J=8.8Hz),7.78(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz)
质谱(m/z):285(M++1)
以类似于制备51的方式获得下列化合物[制备52-54]。
制备52
4-(4’-正戊氧基苯基)苯甲酸甲酯
IR(KBr):2958,2935,2866,1722cm-1。
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.39(4H,m),1.74(2H,m),3.87(3H,s),4.02(2H,t,J=6.4Hz),7.04(2H,t,J=8.8Hz),7.69(2H,d,J=8.8Hz),7.78(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz)质谱(m/z):299(M++1)
制备53
4-(4’-正己氧基苯基)苯甲酸甲酯
IR(KBr):2954,2933,2866,1724cm-1。
NMR(DMSO-d6,δ):0.87(3H,m),1.20-1.87(8H,m),3.87(3H,s),4.02(2H,m),7.04(2H,d,J=8.7Hz),7.68(2H,d,J=8.7Hz),7.78(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz)
质谱(m/z):313(M++1)
制备54
4-(4’-正庚氧基苯基)苯甲酸甲酯
IR(KBr):2956,2931,2856,1724cm-1。
NMR(DMSO-d6,δ):0.86(3H,m),1.20-1.80(10H,m),3.87(3H,s),4.05(2H,m),7.04(2H,d,J=8.7Hz),7.69(2H,d,J=8.7Hz),7.78(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz)
质谱(m/z):327(M++1)
制备55
将4-[4’-(3-溴代丙氧基)苯基]苯甲酸甲酯(1.5g)、碳酸钾(1.2g)和顺-2,6-二甲基吗啉(990.6mg)的N,N-二甲基甲酰胺的溶液于室温下搅拌15小时,然后用乙酸乙酯稀释并用水(5×)洗涤,经硫酸镁干燥,蒸发,然后经硅胶层析纯化(20∶1二氯甲烷-乙醇洗脱),得到4-[4’-[3-(2,6-二甲基吗啉代)丙氧基]苯基]苯甲酸甲酯(755mg)。
NMR(CDCl3,δ):1.18(6H,d,J=6.3Hz),1.70-1.90(2H,m),2.00-2.14(2H,m),2.50-2.65(2H,m),2.82(2H,d,J=11Hz),3.74(2H,br s),3.93(3H,s),4.08(2H,t,J=6.2Hz),6.98(2H,d,J=8.7Hz),7.56(2H,d,J=8.7Hz),7.61(2H,d,J=8.3Hz),8.08(2H,d,J=8.3Hz)
质谱(m/z):384(M+)
以类似于制备55的方式获得下列化合物。
制备56
4-[4’-[3-(哌嗪-1-基)丙氧基]苯基]-苯甲酸甲酯
IR(KBr):2933,2852,2771,1718cm-1。
NMR(CDCl3,δ):1.47(2H,m),1.64(4H,m),2.04(2H,tt,J=6.3和6.3Hz),2.51(6H,m),3.93(3H,s),4.07(2H,t,J=6.3Hz),6.98(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.61(2H,d,J=8.6Hz),8.07(2H,d,J=8.6Hz)
质谱(m/z):354(M++1)
制备57
将N-[4-(4’-烯丙氧基苯基)苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼(1.5g)和磷酰氯(15ml)的混合物加热至回流6小时,然后冷却至室温并倾入冰水中,搅拌约2小时后过滤。用水充分洗涤产生的固体,于50℃真空干燥,得到为固体的4-[5-[4’-[4”-烯丙氧基苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯。
IR(KBr):1720.2,1650.8,1284.4,1255.4cm-1
NMR(DMSO-d6,δ):3.98(3H,s),4.61(2H,d,J=5.3Hz),5.30-5.50(2H,m),6.03-6.17(1H,m),7.04(2H,d,J=8.8Hz),7.61(2H,d,J=8.8Hz),7.74(2H,d,J=8.5Hz),8.20(2H,d,J=8.5Hz),8.23(4H,s)
质谱(m/z):413(M+)
以类似于制备57的方式获得下列化合物[制备58-68]。
制备58
4-[5-[4’-(4”-甲氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):1716cm-1
NMR(CDCl3,δ):3.88(3H,s),3.98(3H,s),7.02(2H,d,J=8.8Hz),7.61(2H,d,J=8.8Hz)
质谱(m/z):387(M++1)
制备59
4-[5-[4’-(4”-丁氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):2956,2933,2871,1720cm-1
NMR(CDCl3,δ):1.00(3H,t,J=7.3Hz),1.54(2H,qt,J=7.3和7.0Hz),1.82(2H,tt,J=7.0和7.0Hz),3.98(3H,s),4.03(2H,t,J=7.0Hz),7.00(2H,d,J=8.7Hz),7.60(2H,d,J=8.7Hz),7.73(2H,d,J=8.4Hz),8.22(6H,m)
质谱(m/z):429(M++1)
制备60
4-[5-[4’-(4”-正戊氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):2956,2931,2870,1720cm-1
NMR(CDCl3,δ):0.995(3H,t,J=7.0Hz),1.43(4H,m),1.83(2H,tt,J=7.0Hz),3.98(3H,s),4.02(2H,t,J=7.0Hz),7.00(2H,d,J=8.7Hz),7.60(2H,d,J=8.7Hz),7.73(2H,d,J=8.4Hz),8.23(2H,m)
质谱(m/z):443(M++1)
制备61
4-[5-[4’-(4”-正己氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):2954,2933,2870,1722cm-1
NMR(CDCl3,δ):0.92(3H,t,J=6.7Hz),1.39(6H,m),1.82(2H,tt,J=6.9Hz),3.98(3H,s),4.02(2H,t,J=6.5Hz),7.00(2H,d,J=8.6Hz),7.60(2H,d,J=8.6Hz),7.73(2H,d,J=8.3Hz),8.22(6H,m)
质谱(m/z):457(M++1)
制备62
4-[5-[4’-(4”-正庚氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):2954,2931,2856,1722cm-1
NMR(CDCl3,δ):0.90(3H,br),1.20-2.00(10H,br),3.98(3H,s),4.02(2H,bs),7.00(2H,d,J=7.6Hz),7.59(2H,d,J=7.6Hz),7.73(2H,d,J=6.8Hz),8.20(6H,m)
质谱(m/z):471(M++1)
制备63
4-[5-[4’-[4”-[3-(哌嗪-1-基)丙氧基]苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):2931,2852,2804,2769,1720cm-1
NMR(CDCl3,δ):1.51(2H,m),1.74(4H,m),2.14(2H,m),2.64(6H,m),3.98(3H,s),4.10(2H,t,J=6.2Hz),7.00(2H,d,J=8.8Hz),7.60(2H,d,J=8.7Hz),7.73(2H,d,J=8.20Hz),8.20(2H,d,J=8.5Hz),8.23(4H,s)
质谱(m/z):498(M++1)
制备64
4-[5-(1-正癸基吡唑-4-基)-1,3,4-噁二唑-2-基]苯甲酸甲酯
NMR(CDCl3,δ):0.84-0.91(3H,m),1.26-1.32(14H,m),1.80-2.00(2H,m),3.97(3H,s),4.21(2H,t,J=7.1Hz),7.26(1H,s),8.09(1H,s),8.26(4H,s)
质谱(m/z):411(M+)
制备65
4-[5-[4’-[4”-(3-苯氧基丙氧基)-苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):1718.3,1600.6,1490.7,1280.5,1245.8cm-1
NMR(CDCl3,δ):2.26-2.35(2H,m),3.98(3H,s),4.16-4.27(4H,m),6.91-7.05(5H,m),7.26-7.33(2H,m),7.60(2H,d,J=8.7Hz),7.73(2H,d,J=8.4Hz),8.20(2H,d,J=8.4Hz),8.23(4H,s)
质谱(m/z):507(M+)
制备66
4-[5-[4’-[4”-(4-苯氧基丁氧基)-苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):1720.2,1602.6cm-1
NMR(CDCl3,δ):2.02(4H,br s),3.93(3H,s),3.97-4.06(4H,m),6.83-7.04(6H,m),7.26-7.33(1H,m),7.60(2H,d,J=8.7Hz),7.89(2H,d,J=8.7Hz),8.18-8.23(6H,m)
质谱(m/z):521(M+)
制备67
4-[5-[4’-[4”-(8-甲氧基-正辛氧基)苯基]-苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
IR(KBr):1720.2cm-1
NMR(CDCl3,δ):1.20-1.95(12H,m),3.34(3H,s),3.38(2H,t,J=7Hz),3.98(3H,s),4.02(2H,t,J=6.5Hz),7.00(2H,d,J=8.7Hz),7.59(2H,d,J=8.7Hz),7.73(2H,d,J=8.5Hz),8.19(2H,d,J=8.5Hz),8.22(4H,s)
质谱(m/z):515(M+)
制备68
4-[5-[4’-[4”-[3-(2,6-二甲基吗啉代)-丙氧基]苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸甲酯
NMR(CDCl3,δ):1.26(6H,d,J=6.3Hz),2.32-2.60(4H,m),3.15-3.30(2H,m),3.43(2H,d,J=11.1Hz),3.98(3H,s),4.10-4.20(2H,m),4.30-4.50(2H,m),6.98(2H,d,J=8.7Hz),7.61(2H,d,J=8.8Hz),7.73(2H,d,J=8.5Hz),8.20(2H,d,J=8.5Hz),8.23(4H,s)
质谱(m/z):528(M+)
以类似于制备9的方式获得下列化合物。
制备69
4-[5-(1-正癸基吡唑-4-基)-1,3,4-噻二唑-2-基]苯甲酸甲酯
NMR(DMSO-d6,δ):0.84(3H,br s),1.23(14H,br s),1.70-1.90(2H,m),3.90(3H,s),4.15-4.23(2H,m),8.09(1H,s),8.13(4H,s),8.58(1H,s)
质谱(m/z):427(M+)
以类似于制备1的方式获得下列化合物。
制备70
4-[4’-(3-溴代丙氧基)苯基]苯甲酸甲酯
NMR(DMSO-d6,δ):2.22-2.32(2H,m),3.69(2H,t,J=6.6Hz),3.87(3H,s),4.15(2H,t,J=6Hz),7.08(2H,d,J=8.8Hz),7.71(2H,d,J=8.7Hz),7.79(2H,d,J=8.5Hz),8.01(2H,d,J=8.4Hz)
以类似于制备19的方式获得下列化合物。
制备71
1-(4-环己氧基苯甲酰基)-3-氨基硫脲
NMR(DMSO-d6,δ):1.32(6H,m),1.71(2H,m),1.91(2H,m),4.45(1H,m),7.00(2H,d,J=8.8Hz),7.57(2H,s),7.84(2H,d,J=8.7Hz),9.27(1H,s),10.21(1H,s)
质谱(m/z):294(M++1)
以类似于制备21的方式获得下列化合物。
制备72
2-氨基-5-(4-环己氧基苯基)-1,3,4-噻二唑
IR(KBr):3272.6,3114.5,2937.1,2856.1,1604.5,1519.6,1465.6cm-1
NMR(DMSO-d6,δ):1.17-1.48(6H,m),1.73(2H,m),1.92(2H,m),4.40(1H,m),7.00(2H,d,J=8.8Hz),7.27(2H,s),7.64(2H,d,J=8.8Hz)
质谱(m/z):276(M++1)
以类似于制备23的方式获得下列化合物。
制备73
4-[2-(4-环己氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2931.3,2861.8,1714.4,1702.8,1502.3,1280.5,1257.4cm-1
质谱(m/z):448(M++1)
以类似于制备25的方式获得下列化合物。
制备74
4-[2-(4-环己氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸
IR(KBr):2931.3,1679.7,1606.4,1473.3,1421.3,1290.1,1249.6cm-1
NMR(DMSO-d6,δ):1.43(6H,m),1.74(2H,m),1.94(2H,m),4.50(1H,m),7.14(2H,d,J=8.8Hz),7.88(2H,d,J=8.8Hz),8.00(4H,s),8.86(1H,s)
质谱(m/z):420(M++1)
以类似于制备5的方式获得下列化合物[制备75-84]。
制备75
4-(4’-甲氧基苯基)苯甲酰基肼
IR(KBr):3292,3205,1655,1622cm-1
NMR(CDCl3,δ):1.59(2H,br),3.86(3H,s),6.99(2H,d,J=7.9Hz),7.38(1H,br),7.55(2H,d,J=7.9Hz),7.62(2H,d,J=7.3Hz),7.79(2H,d,J=7.3Hz)
质谱(m/z):243(M++1)
制备76
4-(4’-丁氧基苯基)苯甲酰基肼
IR(KBr):3340,3277,3194,2956,2918,2870,1655,1610cm-1
NMR(CDCl3,δ):0.99(3H,t,J=7.3Hz),1.53(4H,m),1.80(2H,tt,J=6.4和6.4Hz),4.02(2H,t,J=6.4Hz),6.98(2H,d,J=8.8Hz),7.38(1H,s),7.54(2H,d,J=8.8Hz),7.62(2H,d,J=8.4Hz),7.79(2H,d,J=8.4Hz)
质谱(m/z):285(M++1)
制备77
4-(4’-正戊氧基苯基)苯甲酰基肼
IR(KBr):3288,3205,3059,2958,2937,2868,1655,1622,1601cm-1
NMR(CDCl3,δ):0.94(3H,t,J=6.8Hz),1.44(4H,m),1.60(2H,br),1.82(2H,m),4.00(2H,t,J=6.8Hz),6.98(2H,t,J=8.5Hz),7.38(1H,br),7.54(2H,d,J=8.5Hz),7.62(2H,d,J=8.1Hz),7.79(2H,d,J=8.1Hz)
质谱(m/z):299(M++1)
制备78
4-(4’-正己氧基苯基)苯甲酰基肼
IR(KBr):3288,3207,3057,2954,2935,2868,1655,1626,1606cm-1
NMR(CDCl3,δ):0.91(3H,m),1.36(6H,m),1.81(2H,m),4.01(2H,m),6.98(2H,d,J=8.0Hz),7.20(1H,br),7.54(2H,d,J=8.0Hz),7.62(2H,d,J=7.9Hz),7.78(2H,d,J=7.9Hz)
质谱(m/z):313(M++1)
制备79
4-(4’-正庚氧基苯基)苯甲酰基肼
IR(KBr):3286,3205,3061,2956,2931,2856,1654,1623,1608cm-1
NMR(CDCl3,δ):0.90(3H,m),1.32(8H,m),1.81(2H,m),4.00(2H,m),6.98(2H,d,J=8.4Hz),7.40(1H,br),7.52(2H,d,J=8.4Hz),7.64(2H,d,J=8.4Hz),7.77(2H,d,J=8.4Hz)
质谱(m/z):327(M++1)
制备80
4-[4’-[3-(哌嗪-1-基)丙氧基]苯基]-苯甲酰基肼
IR(KBr):3275,3105,3041,2956,2933,2870,2852,2814,2767,1643cm-1
NMR(CDCl3,δ):1.47(2H,m),1.63(4H,m),2.03(2H,tt,J=6.3Hz),2.50(6H,m),4.06(2H,t,J=6.3Hz),6.98(2H,d,J=8.8Hz),7.41(1H,s),7.54(2H,d,J=8.8Hz),7.62(2H,d,J=8.5Hz),7.79(2H,d,J=8.5Hz)
质谱(m/z):354(M++1)
制备81
1-正癸基-4-吡唑基羰基肼
NMR(DMSO-d6,δ):0.82-0.95(3H,m),1.22(14H,br s),1.62-1.81(2H,m),4.08(2H,t,J=6.9Hz),4.29(2H,d,J=4Hz),7.82(1H,s),8.12(1H,s),9.28(1H,br s)
质谱(m/z):267(M+)
制备82
4-[4’-(3-苯氧基丙氧基)苯基]苯甲酰基肼
NMR(DMSO-d6,δ):2.16-2.26(2H,m),4.11-4.23(4H,m),4.54(2H,s),6.89-6.98(3H,m),7.06(2H,d,J=8.8Hz),7.25-7.33(2H,m),7.67(2H,d,J=8.7Hz),7.70(2H,d,J=8.4Hz),7.89(2H,d,J=8.4Hz),9.79(1H,s)
质谱(m/z):363(M+)
制备83
4-[4’-烯丙氧基苯基]苯甲酰基肼
NMR(DMSO-d6,δ):4.51(2H,s),4.60-4.65(2H,m),5.25-5.47(2H,m),5.98-6.17(1H,m),7.06(2H,d,J=8.8Hz),7.67(2H,d,J=8.8Hz),7.70(2H,d,J=8.4Hz),7.89(2H,d,J=8.4Hz),9.80(1H,s)
质谱(m/z):269(M+)
制备84
4-[4’-[3-(2,6-二甲基吗啉代)-丙氧基]苯基]苯甲酰基肼
NMR(DMSO-d6,δ):1.04(6H,d,J=6.3Hz),1.58(2H,t,J=10.6Hz),1.86-1.92(2H,m),2.40(2H,t,J=7Hz),2.75(2H,d,J=10.2Hz),3.51-3.58(2H,m),4.05(2H,t,J=6.2Hz),4.50(2H,s),7.02(2H,d,J=8.8Hz),7.64-7.71(4H,m),7.88(2H,d,J=8.4Hz),9.79(1H,s)
质谱(m/z):384(M+)
以类似于制备7的方式获得下列化合物[制备85-96]。
制备85
1-[4-(4’-甲氧基苯基)苯甲酰基]-2-(4-甲氧基羰基-苯甲酰基)肼
IR(KBr):3228,2956,2840,1720,1680,1655cm-1
NMR(DMSO-d6,δ):3.82(3H,s),3.90(3H,s),7.06(2H,d,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.79(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz),8.05(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),10.60(1H,s),10.72(1H,s)
质谱(m/z):405(M++1)
制备86
1-[4-(4’-丁氧基苯基)苯甲酰基]-2-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3242,3088,3028,2956,2933,2872,1724,1682,1655,1605cm-1
NMR(DMSO-d6,δ):0.95(3H,t,J=7.3Hz),1.45(2H,qt,J=7.3和6.4Hz),1.73(2H,tt,J=6.4和6.4Hz),3.91(3H,s),4.03(2H,t,J=6.4Hz),7.05(2H,d,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.90(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz),8.05(2H,d,J=8.4Hz),8.05(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),10.60(1H,s),10.72(1H,s)
质谱(m/z):447(M++1)
制备87
1-[4-(4’-戊氧基苯基)苯甲酰基]-2-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3226,3030,2958,2931,2870,1724,1680,1655,1605cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=6.7Hz),1.40(4H,m),1.74(2H,m),3.90(3H,s),4.03(2H,t,J=6.5Hz),7.05(2H,d,J=8.6Hz),7.70(2H,d,J=8.6Hz),7.78(2H,d,J=8.3Hz),8.00(2H,d,J=8.3Hz),8.07(2H,d,J=8.6Hz),8.09(2H,d,J=8.6Hz),10.60(1H,s),10.72(1H,s)质谱(m/z):461(M++1)制备881-[4-(4’-正己氧基苯基)苯甲酰基]-2-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3242,3219,3091,3028,2956,2933,2866,1724,1680,1655,1605cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.2Hz),1.35(6H,m),1.74(2H,m),3.90(3H,s),4.03(2H,t,J=6.9Hz),7.05(2H,d,J=8.7Hz),7.70(2H,d,J=8.7Hz),7.79(2H,d,J=8.3Hz),8.00(2H,d,J=8.3Hz),8.06(2H,d,J=8.6Hz),8.10(2H,d,J=8.6Hz),10.60(1H,s),10.72(1H,s)质谱(m/z):475(M++1)制备891-[4-(4’-正庚氧基苯基)苯甲酰基]-2-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3219,3091,3029,2956,2931,2856,1722,1679,1652,1604cm-1
NMR(DMSO-d6,δ):0.88(3H,br),1.29(8H,br),1.75(2H,br),3.90(3H,s),4.02(2H,br),7.03(2H,d,J=8.4Hz),7.70(2H,d,J=8.4Hz),7.80(2H,d,J=8.8Hz),8.00(2H,d,J=8.8Hz),8.45(2H,br)
质谱(m/z):489(M++1)
制备90
1-[4-[4’-[3-(哌啶-1-基)丙氧基]苯基]-苯甲酰基]-2-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3061,3026,2933,2852,2805,2771,2391,1724cm-1
NMR(DMSO-d6,δ):1.49(6H,m),1.88(2H,tt,J=6.2和6.2Hz),2.36(6H,m),3.90(3H,s),4.06(2H,t,J=6.2Hz),7.05(2H,d,J=8.7Hz),7.70(2H,d,J=8.7Hz),7.78(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz),8.05(2H,d,J=8.5Hz),8.11(2H,d,J=8.5Hz),10.6(1H,s)
质谱(m/z):516(M++1)
制备91
N-(4-甲氧基羰基苯甲酰基)-N’-(1-正癸基-4-吡唑基羰基)肼
NMR(DMSO-d6,δ):0.82-0.89(3H,m),1.24(14H,br s),1.70-1.90(2H,m),3.90(3H,s),4.14(2H,t,J=7Hz),7.95(1H,s),8.02(2H,d,J=8.5Hz),8.10(2H,d,J=8.5Hz),8.28(1H,s),10.18(1H,s),10.50(1H,s)
质谱(m/z):429(M+)
制备92
N-[4-[4’-(3-苯氧基丙氧基)苯基]苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3210.9,1724.0,1650.8,1602.6,1560.1,1523.5,1502.3,1469.5,1432.9,1284.4,1247.7cm-1
NMR(DMSO-d6,δ):2.18-2.24(2H,m),3.90(3H,s),4.13-4.21(4H,m),6.95-6.99(3H,m),7.09(2H,d,J=7.9Hz),7.25-7.33(2H,m),7.69-7.81(4H,m),7.98-8.09(6H,m),10.61(1H,s),10.73(1H,s)
质谱(m/z):525(M+)
制备93
N-[4-(4’-烯丙氧基苯基)苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3228.3,3023.8,1724.0,1679.7,1654.6,1604.5,1554.3,1513.8,1492.6,1434.8cm-1
NMR(DMSO-d6,δ):3.90(3H,s),4.64(2H,d,J=5.1Hz),5.26-5.47(2H,m),5.98-6.17(1H,m),7.08(2H,d,J=8.7Hz),7.72(2H,d,J=8.7Hz),7.80(2H,d,J=8.4Hz),8.00(2H,d,J=8.5Hz),8.05(2H,d,J=8.6Hz),8.11(2H,d,J=8.6Hz),10.60(1H,s),10.72(1H,s)
质谱(m/z):431(M+)
制备94
N-[4-[4’-(4-苯氧基丁氧基)苯基]苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):3228.3,1724.0,1679.7,1654.6,1602.6cm-1
NMR(DMSO-d6,δ):1.90(4H,br s),3.90(3H,s),4.05-4.11(4H,m),6.88-6.96(3H,m),7.05-7.09(2H,m),7.25-7.28(2H,m),7.69-8.09(10H,m),10.60(1H,s),10.72(1H,s)
制备95
N-[4-[4’-[3-(2,6-二-甲基吗啉代)丙氧基]-苯基]苯甲酰基-N’-(4-甲氧基羰基苯甲酰基)肼
IR(KBr):1720.2,1681.6,1645.0,1604.5cm-1
NMR(DMSO-d6,δ):1.05(6H,d,J=6.3Hz),1.53-1.64(2H,m),1.87-1.93(2H,m),2.41(2H,t,J=7.1Hz),2.76(2H,d,J=10.4Hz),3.52-3.59(2H,m),3.90(3H,s),4.00-4.10(2H,m),7.05(2H,d,J=8.7Hz),7.71(2H,d,J=8.7Hz),7.79(2H,d,J=8.4Hz),8.00(2H,d,J=8.6Hz),8.02-8.13(4H,m),10.60(1H,s),10.72(1H,s)
质谱(m/z):546(M+)
制备96
N-[6-(1-哌啶基)烟酰基]-N’-(4-甲氧基羰基-苯甲酰基)肼
IR(KBr):3240,2933,2852,1724,1686,1643,1603,1547,1497,1437cm-1
NMR(DMSO-d6,δ):1.4-1.7(6H,m),3.6-3.7(4H,m),3.90(3H,s),6.92(1H,d,J=9.0Hz),7.9-8.2(5H,m),8.65(1H,s),10.34(1H,s,),10.62(1H,s)
质谱(m/z):383(M++1)
以类似于制备11的方式获得下列化合物[制备97-108]。
制备97
4-[5-[4’-[4”-(8-甲氧基-正辛氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸
NMR(DMSO-d6,δ):1.20-1.60(10H,m),1.60-1.80(2H,m),3.21(3H,s),3.25-3.50(3H,m),3.90-4.10(2H,m),6.95-7.10(2H,m),7.50-7.80(4H,m),7.80-8.00(2H,m),8.10-8.30(4H,m)
质谱(m/z):501(M+)
制备98
4-[5-[4’-(4”-甲氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):2960,2904,2839,2675,2543,1684,1604cm-1
NMR(DMSO-d6,δ):3.83(3H,s),7.08(2H,d,J=8.5Hz),7.91(2H,d,J=8.5Hz),8.17(2H,d,J=8.5Hz),8.20(2H,d,J=8.5Hz),8.28(2H,d,J=8.5Hz)
质谱(m/z):373(M++1)
制备99
4-[5-[4’-(4”-丁氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):2958,2935,2871,1687cm-1
NMR(DMSO-d6,δ):0.95(3H,t,J=7.3Hz),1.46(2H,qt,J=7.3和7.5Hz),1.73(2H,tt,J=7.5和6.3Hz),4.04(2H,t,J=6.3Hz),7.07(2H,d,J=8.9Hz),7.75(2H,d,J=8.9Hz),7.91(2H,d,J=8.4Hz),8.16(2H,d,J=8.3Hz),8.20(2H,d,J=8.3Hz),8.28(2H,d,J=8.4Hz)
质谱(m/z):415(M++1)
制备100
4-[5-[4’-(4”-戊氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):2958,2933,2865,2673,2546,1685cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.40(4H,m),1.75(2H,tt,J=6.6和6.6Hz),4.04(2H,t,J=6.6Hz),7.07(3H,d,J=8.8Hz),7.74(2H,d,J=8.8Hz),7.91(2H,d,J=8.5Hz),8.15(2H,d,J=8.4Hz),8.20(2H,d,J=8.1Hz),8.27(2H,d,J=8.5Hz)
质谱(m/z):429(M++1)
制备101
4-[5-[4’-(4”-己氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):2954,2933,2864,2675,2546,1686cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.8Hz),1.30(6H,m),1.74(2H,tt,J=7.7和6.4Hz),4.04(2H,t,J=6.4Hz),7.07(2H,d,J=8.8Hz),7.74(2H,d,J=8.8H=z),7.91(2H,d,J=8.0Hz),8.16(2H,d,J=8.6Hz),8.20(2H,d,J=8.0Hz),8.27(2H,d,J=8.6Hz)
质谱(m/z):433(M++1)
制备102
4-[5-[4’-(4”-正庚氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr]:2956,2931,2856,2671,2545,1686cm-1
质谱(m/z):457(M+1)
制备103
4-[5-(1-正癸基吡唑-4-基)-1,3,4-噁二唑-2-基]苯甲酸
NMR(DMSO-d6,δ):0.75-0.95(3H,m),1.23(14H,br s),1.83(2H,br s),3.33(1H,br s,CO2H),4.22(2H,t,J=6.8Hz),8.14(1H,s),8.17(4H,s),8.65(1H,s)
质谱(m/z):397(M+)
制备104
4-[5-[1-正癸基吡唑-4-基]-1,3,4-噻二唑-2-基]苯甲酸
NMR(DMSO-d6,δ):0.80-0.90(3H,m),1.23(14H,brs),1.70-1.90(2H,m),3.34(1H,brs),4.19(2H,t,J=6.9Hz),8.08(1H,s),8.10(4H,s),8.58(1H,s)
制备105
4-[5-[4’-[4”-(3-苯氧基丙氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):1685.5,1602.6,1548.6,1490.7,1469.5,1429.0,1400.1,1290.1,1249.6cm-1
NMR(DMSO-d6,δ):2.18-2.24(2H,m),4.13-4.25(4H,m),6.90-6.99(3H,m),7.11(2H,d,J=8.8Hz),7.26-7.33(2H,m),7.75(2H,d,J=8.7Hz),7.91(2H,d,J=8.5Hz),8.15-8.30(6H,m),13.20-13.60(1H,br)
质谱(m/z):493(M+)
制备106
4-[5-[4’-[4”-烯丙氧基苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):1685.5,1652.7,1604.5,1577.5,1548.6,1488.8,1429.0,1288.2,1253.5,823.5cm-1
NMR(DMSO-d6,δ):4.65(2H,d,J=5Hz),5.27-5.48(2H,m),5.99-6.15(1H,m),7.10(2H,d,J=8.7Hz),7.75(2H,d,J=8.6Hz),7.91(2H,d,J=8.3Hz),8.15-8.30(6H,m),12.38(1H,br s)
质谱(m/z):399(M+)
制备107
4-[5-[4’-[4”-(4-苯氧基丁氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸
IR(KBr):1733.7,1697.1,1650.8,1602.6cm-1
NMR(DMSO-d6,δ):1.91(4H,brs),3.33(1H,brs),4.05-4.12(4H,m),6.88-6.96(2H,m),7.07-7.11(2H,m),7.25-7.28(2H,m),7.66-8.00(5H,m),8.14-8.36(6H,m)
制备108
4-[5-[4’-[4”-[3-(2,6-二甲基吗啉代)丙氧基]-苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸
质谱(m/z):514(M+)
以类似于制备13的方式获得下列化合物[制备109-123]。
制备109
4-[5-[4’-(4”-甲氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1782cm-1
NMR(CDCl3,δ):3.89(3H,s),7.03(2H,d,J=8.7Hz),7.53(3H,m),7.62(2H,d,J=8.7Hz),7.76(2H,d,J=8.4Hz),8.13(1H,d,J=8.2Hz),8.23(2H,d,J=8.4Hz),8.41(2H,d,J=8.4Hz),8.48(2H,d,J=8.7Hz)
质谱(m/z):490(M++1)
制备110
4-[5-[4’-(4”-丁氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2956,2933,2872,1776cm-1
NMR(CDCl3,δ):1.00(3H,t,J=7.3Hz),1.52(2H,qt,J=7.3和6.4Hz),1.79(2H,tt,J=6.4和6.4Hz),4.04(2H,t,J=6.4Hz),7.02(2H,d,J=8.7Hz),7.45-7.57(3H,m),7.61(2H,d,J=8.7Hz),7.76(2H,d,J=8.4Hz),8.14(1H,d,J=8.2Hz),8.22(2H,d,J=8.4Hz),8.40(2H,d,J=8.7Hz),8.47(2H,d,J=8.7Hz)
质谱(m/z):532(M++1)
制备111
4-[5-[4’-(4”-正戊氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2956,2935,2868,1779cm-1
NMR(CDCl3,δ):0.95(3H,t,J=6.9Hz),1.44(4H,m),1.77(2H,m),4.03(2H,t,J=6.5Hz),7.02(2H,d,J=8.7Hz),7.45-7.57(3H,m),7.60(2H,d,J=8.7Hz),7.75(2H,d,J=8.4Hz),8.14(1H,d,J=8.2Hz),8.22(2H,d,J=8.4Hz),8.22(2H,d,J=8.4Hz),8.40(2H,d,J=8.7Hz),8.47(2H,d,J=8.7Hz)
质谱(m/z):546(M++1)
制备112
4-[5-[4’-(4”-正己氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2953,2931,2866,1776cm-1
NMR(CDCl3,δ):0.92(3H,t,J=6.7Hz),1.36-1.49(6H,m),1.82(2H,m),4.03(2H,t,J=6.5Hz),7.02(2H,d,J=8.8Hz),7.45-7.57(3H,m),7.61(2H,d,J=8.8Hz),7.76(2H,d,J=8.4Hz),8.14(2H,d,J=8.2Hz),8.22(2H,d,J=8.4Hz),8.41(2H,d,J=8.8Hz),8.48(2H,d,J=8.8Hz)
质谱(m/z):560(M++1)
制备113
4-[5-[4’-(4”-正庚氧基苯基)苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2954,2929,2856,1776cm-1
NMR(CDCl3,δ):0.91(3H,m),1.34(8H,m),1.75(2H,m),4.03(2H,t,J=6.5Hz),7.02(2H,t,J=8.7Hz),7.45-7.57(3H,m),7.61(2H,d,J=8.7Hz),7.76(2H,d,J=8.3Hz),8.14(1H,d,J=8.2Hz),8.22(2H,d,J=8.3Hz),8.41(2H,d,J=8.5Hz),8.48(2H,d,J=8.5Hz)
质谱(m/z):574(M++1)
制备114
4-[5-(1-正癸基吡唑-4-基)-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1783.8,1623.8,1234.2,989.3cm-1
NMR(CDCl3,δ):0.84-0.91(3H,m),1.26-1.34(14H,m),1.80-2.00(2H,m),4.23(2H,t,J=7.1Hz),7.44-7.63(3H,m),8.11-8.15(3H,m),8.35(2H,d,J=8.7Hz),8.45(2H,d,J=8.7Hz)
质谱(m/z):514(M+)
制备115
4-[5-(1-正癸基吡唑-4-基)-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1776.1,1575.6,1234.2,983.5cm-1
NMR(CDCl3,δ):0.84-0.91(3H,m),1.26-1.34(14H,m),1.94(2H,brs),4.21(2H,t,J=7.1Hz),7.43-7.63(3H,m),7.99(1H,s),8.09(1H,s),8.10-8.15(1H,m),8.22(2H,d,J=8.5Hz),8.40(2H,d,J=8.5Hz)
质谱(m/z):530(M+)
制备116
4-[5-[4’-[4”-(3-苯氧基丙氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1778.0,1602.6,1490.7,1471.4,1238.1cm-1
NMR(CDCl3,δ):2.27-2.34(2H,m),4.16-4.26(4H,m),6.91-7.05(5H,m),7.26-7.33(2H,m),7.44-7.62(5H,m),7.74(2H,d,J=7.9Hz),8.13(1H,d,J=8.5Hz),8.21(2H,d,J=7.9Hz),8.37-8.48(4H,m)
质谱(m/z):610(M+)
制备117
4-[5-[4’-[4”-烯丙氧基苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1776.1,1602.6,1488.9,1232.3cm-1
NMR(CDCl3,δ):4.61(2H,d,J=5.2Hz),5.30-5.50(2H,m),6.00-6.19(1H,m),7.04(2H,d,J=8.7Hz),7.44-7.63(4H,m),7.75(2H,d,J=8.4Hz),8.11-8.30(4H,m),8.38-8.49(4H,m)
质谱(m/z):516(M+)
制备118
4-[5-[4’-[4”-(4-苯氧基丁氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):1776.1cm-1
NMR(CDCl3,δ):2.02(4H,brs),4.06-4.11(4H,m),6.83-7.04(5H,m),7.26-7.33(1H,m),7.48-7.63(6H,m),7.76(2H,d,J=8.4Hz),8.14(1H,d,J=8.2Hz),8.22(2H,d,J=8.3Hz),8.41(2H,d,J=8.7Hz),8.48(2H,d,J=8.7Hz)
质谱(m/z):624(M+)
制备119
4-[5-[4’-[4”-(8-甲氧基-正辛氧基)苯基]苯基]-1,3,4-噁二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2931.3,2856.1,1776.1cm-1
NMR(CDCl3,δ):1.30-1.70(10H,m),1.70-1.90(2H,m),3.34(3H,s),3.38(2H,t,J=6.4Hz),4.02(2H,t,J=6.5Hz),7.02(2H,d,J=8.7Hz),7.45-7.63(5H,m),7.76(2H,d,J=8.5Hz),8.12-8.31(3H,m),8.41(2H,d,J=8.8Hz),8.48(2H,d,J=8.8Hz)
质谱(m/z):618(M+)
制备120
4-[5-[4’-(4-苯氧基丁氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):3058.5,2956.3,2873.4,1778.0,1602.6,1236.1cm-1
NMR(CDCl3,δ):2.0-2.1(4H,m),4.0-4.2(4H,m),6.9-7.0(3H,m),7.03(2H,d,J=8.8Hz),7.3-7.4(2H,m),7.4-7.6(3H,m),7.99(2H,d,J=8.8Hz),8.13(1H,d,J=8.2Hz),8.25(2H,d,J=8.6Hz),8.42(2H,d,J=8.6Hz)
质谱(m/z):564(M++1)
制备121
4-[5-[4’-(5-苯氧基-正戊氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯
IR(KBr):2946.7,2871.5,1785.8,1600.6,1255.4,1234.2cm-1
NMR(CDCl3,δ):1.5-2.1(6H,m),3.9-4.2(4H,m),6.8-7.1(5H,m),7.2-7.4(2H,m),7.4-7.7(3H,m),7.98(2H,d,J=8.8Hz),8.13(1H,d,J=8.2Hz),8.25(2H,d,J=8.6Hz),8.41(2H,d,J=8.6Hz)
质谱(m/z):578(M++1)
制备122
4-[5-[4’-(5-甲氧基-正戊氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯
NMR(CDCl3,δ):1.5-2.1(6H,m),3.54(3H,s),3.43(2H,t,J=6.1Hz),4.06(2H,t,J=6.3Hz),7.02(2H,d,J=8.8Hz),7.4-7.7(3H,m),7.98(2H,d,J=8.8Hz),8.13(1H,d,J=8.2Hz),8.25(2H,d,J=8.5Hz),8.41(2H,d,J=8.5Hz)
质谱(m/z):516(M++1)
制备123
4-环己氧基苯甲酸苯并三唑-1-基酯
IR(KBr):2939,2854.1,1776.1,1602.6,1508.1cm-1
NMR(CDCl3,δ):1.25-1.67(6H,m),1.85(2H,m),2.01(2H,m),4.43(1H,m),7.03(2H,d,J=7.0Hz),7.38-7.54(3H,m),8.08(1H,d,J=8.2Hz),8.19(2H,d,J=7.0Hz)
质谱(m/z):338(M++1)
制备124
向在N,N-二甲基甲酰胺(700ml)中的4-甲氧基苯甲酸苯并三唑-1-基酯(80g)的溶液中加入氨基硫脲(28g),于室温下搅拌该混合物23小时。用二异丙基醚研磨该反应混合物。过滤收集沉淀,得到1-(4-甲氧基苯甲酰基)-3-氨基硫脲(57g)。
制备125
于40℃,用30分钟向在甲苯(300ml)中的1-(4-甲氧基苯甲酰基)-3-氨基硫脲(57g)的淤浆中滴加甲磺酸(25ml)。于回流下搅拌该混合物24小时。冷却至10℃后,过滤该磺酸盐并干燥。将该盐溶于水中,用1N氢氧化钠将该溶液调至pH9并用乙酸乙酯提取。分离有机层,用盐水洗涤,经硫酸镁干燥并减压蒸发,得到2-氨基-5-(4-甲氧基苯基)-1,3,4-噻二唑(31.1g)。
IR(KBr):3251,3114.5,1610.3,1525cm-1
NMR(DMSO-d6,δ):3.80(3H,s),7.00(2H,d,J=8.5Hz),7.28(2H,s),7.69(2H,d,J=8.5Hz)
质谱(m/z):208(M+H+)
制备126
于室温下,将4-溴代苯硫酚(6g)、1,7-二溴代庚烷(16.37g)和碳酸钾(8.77g)在二甲基甲酰胺(30ml)中的混合物搅拌5.5小时。用水研磨该反应混合物并用乙酸乙酯提取。分离有机层,用盐水洗涤,经硫酸镁干燥并减压蒸发,得到1-溴代-4-(7-溴代庚硫基)苯(7.62g)。
IR(KBr):1465.6,1089.6,800.3cm-1
NMR(CDCl6,δ):1.37-1.88(10H,m),2.89(2H,t,J=7.2Hz),3.40(2H,t,J=6.8Hz),7.14-7.21(2H,m),7.36-7.43(2H,m)
制备127
向1-溴代-4-(7-溴代庚硫基)苯(5g)的甲醇(25ml)溶液中加入28%甲醇钠的甲醇溶液(7.9g),于回流下搅拌该混合物2小时。减压蒸发该反应混合物。用稀盐酸水溶液将该残留物调至pH2并用乙酸乙酯提取。分离有机层,用盐水洗涤,经硫酸镁干燥并减压蒸发。残留物经硅胶柱层析纯化,用正己烷/乙酸乙酯(50∶1)洗脱,得到1-溴代-4-(7-甲氧基庚硫基)苯(3.59g)。
IR(KBr):1471.4,1118.5,1093.4cm-1
NMR(CDCl3,δ):1.30-1.67(10H,m),2.88(2H,t,J=7.3Hz),3.33(3H,s),3.36(2H,t,J=6.2Hz),7.13-7.20(2H,m),7.35-7.42(2H,m)
质谱(m/z):317.1
制备128
向4-(4-氯代苯基)-4-羟基哌啶(5.0g)的二氯甲烷(50ml)溶液中加入二碳酸二叔丁酯(5.7g)。于室温下搅拌5小时后,真空蒸发溶剂,将该残留物倾入乙酸乙酯和水的混合物中。用盐水连续洗涤有机层并经硫酸镁干燥。真空蒸发溶剂,残留物经硅胶柱层析纯化,用己烷和乙酸乙酯(3∶1)的混合物洗脱。收集含有所需产物的洗脱部分,真空蒸发得到1-叔丁氧基羰基-4-(4-氯代苯基)-4-羟基哌啶(7.58g)。
IR(薄膜):2976,2926,1668cm-1
NMR(CDCl3,δ):1.47(9H,s),1.6-1.8(3H,m),1.9-2.1(2H,m),3.1-3.3(2H,m),3.9-4.1(2H,m),7.2-7.5(4H,m)
(+)APCIMS:212(M+H)+-101
制备129
在冰冷却下,向在N,N-二甲基甲酰胺(10ml)中的1-叔丁氧基羰基-4-(4-氯代苯基)-4-羟基哌啶(1.0g)溶液中加入氢化钠(0.14g)。然后于室温下搅拌该反应混合物30分钟,于60℃搅拌2小时。于60℃向该反应混合物中加入碘代甲烷(4.0ml)。于60℃搅拌6小时后,将该反应混合物倾入乙酸乙酯和水的混合物中。用盐水连续洗涤有机层并经硫酸镁干燥。真空蒸发溶剂,残留物经硅胶柱层析纯化,用己烷和乙酸乙酯(10∶1)的混合物洗脱。收集含有所需产物的洗脱部分。真空蒸发得到1-叔丁氧基羰基-4-(4-氯代苯基)-4-甲氧基哌啶(0.75g)。
IR(薄膜):2976,2935,1680cm-1
NMR(CDCl3,δ):1.47(9H,s),1.7-2.1(4H,m),2.97(3H,s),3.0-3.3(2H,m),3.9-4.1(2H,m),7.2-7.4(4H,m)
(+)APCIMS:226(M+H)+-101
制备130
于冰浴下,向2-茚满醇(4g)和三乙胺(5.8ml)的二氯甲烷(40ml)溶液中搅拌下滴加甲磺酰氯(2.8ml)。然后搅拌该混合物1.5小时。将该反应混合物加入水和二氯甲烷的混合物中。取出有机层,经硫酸镁干燥。过滤除去硫酸镁,减压浓缩滤液,得到甲磺酸2,3-二氢化茚-2-基酯(6.29g)。
IR(KBr):3029.6,1328.7,1162.9cm-1
NMR(CDCl3,δ):3.02(3H,s),3.19-3.44(4H,m),5.48-5.58(1H,m),7.18-7.28(4H,m)
质谱(m/z):119.2(M-OMs+1)
制备131
向4-(5-氨基-1,3,4-噻二唑-2-基)苯甲酸甲酯三氟乙酸盐(8g)的水溶液中加入1N氢氧化钠,将该混合物调至pH8。过滤收集沉淀,得到4-(5-氨基-1,3,4-噻二唑-2-基)苯甲酸(5.05g)。
制备132
将1-(4-硝基苯基)-1H-吡唑-4-羧酸甲酯(19.44g)、铁粉、氯化铵、甲醇和水的混合物于80℃加热30分钟,于100℃加热3小时。蒸发浓缩该反应混合物,将其加入到二氯甲烷中并过滤。用水提取滤液,经硫酸镁干燥并蒸发浓缩,得到1-(4-氨基苯基)-1H-吡唑-4-羧酸甲酯(9.84g)。
IR(KBr):1701,1521,1248cm-1
NMR(CDCl3,δ):3.86(2H,brs),3.90(3H,s),6.75(2H,d,J=8.8Hz),7.45(2H,d,J=8.8Hz),8.05(1H,s),8.26(1H,s)
质谱(m/z):218(M++1)
制备133
于0℃,用硼氢化钠处理1-(4-甲酰基苯基)-1H-吡唑-4-羧酸甲酯(1.00g)、甲醇(10ml)和四氢呋喃(25ml)的混合物。15分钟后,用乙酸乙酯稀释该混合物并用水洗涤。经硫酸镁干燥有机层,过滤并蒸发浓缩,得到1-(4-羟基甲基苯基)-1H-吡唑-4-羧酸甲酯(1.04g)。
IR(KBr):1724,1558,1521,1443,1392,1255cm-1
NMR(CDCl3,δ):3.88(3H,s),4.76(2H,s),7.48(2H,d,J=8.7Hz),7.69(2H,d,J=8.7Hz),8.10(1H,s),8.41(1H,s)
质谱(m/z):233(M++1)
制备134
于室温下,用3-氯代过苯甲酸处理1-(4-甲酰基苯基)-1H-吡唑-4-羧酸甲酯(5.0g)的二氯甲烷(100ml)溶液5分钟。于50℃加热该溶液4小时,在此期间加入另外的3-氯代过苯甲酸(1.87g)。浓缩后,将甲醇(150ml)和碳酸钾(9.00g)加入该残留物中,于室温下搅拌该混合物14小时。将该反应混合物倾入水中,用1N盐酸调至pH8,过滤收集产生的沉淀,得到1-(4-羟基苯基)-1H-吡唑-4-羧酸甲酯(0.51g)。
IR(KBr):1718,1691,1554,1523,1250cm-1
NMR(CDCl3,δ):3.87(3H,s),6.92(2H,d,J=9.0Hz),7.55(2H,d,J=9.0Hz),8.07(1H,s),8.30(1H,s)
质谱(m/z):219(M++1)
制备135
于室温下,将4-(4-羟基哌啶-1-基)苯甲酸乙酯(5.4g)、氧化银(5.31g)和3-溴代环己烯(3.24ml)的四氢呋喃(52ml)溶液搅拌1天。滤出该反应混合物,通过减压蒸发浓缩滤液。向该残留物中加入乙酸乙酯,过滤收集产生的沉淀并干燥。残留物经硅胶层析(3∶2己烷-乙酸乙酯洗脱)纯化,得到4-[4-(2-环己烯氧基)哌啶-1-基]苯甲酸乙酯(3.84g)。
NMR(CDCl3,δ):1.36(3H,t,J=7.1Hz),1.40-2.15(10H,m),3.00-3.20(2H,m),3.50-3.75(3H,m),3.90-4.05(1H,m),4.32(2H,q,J=7.1Hz),5.60-5.90(2H,m),6.86(2H,d,J=9.1Hz),7.90(2H,d,J=9.1Hz)
APCI质谱:330(M++1)
制备136
向4-[4-(2-环己烯氧基)哌啶-1-基]苯甲酸乙酯(3.82g)的甲醇(80ml)溶液中加入10%披钯炭(1.0g),在大气压下通入氢气5小时。过滤该反应混合物,通过减压蒸发浓缩滤液,得到4-(4-环己氧基哌啶-1-基)苯甲酸乙酯(2.38g)。
NMR(CDCl3,δ):1.10-1.32(4H,m),1.36(3H,t,J=7.1Hz),1.40-2.00(9H,m),2.90-3.15(2H,m),3.20-3.45(1H,m),3.50-3.75(3H,m),4.32(2H,q,J=7.1Hz),6.86(2H,dd,J=2.2和9.1Hz),7.85-8.00(2H,m)
APCI质谱(正性):332.3(M++1)
制备137
于0℃,向4-[2-(4-甲氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐(1.0g)的二氯甲烷(10ml)的悬浮液中加入三溴化硼(1.0M的二氯甲烷溶液)(8.0ml),于室温下搅拌该混合物1周。用冷水研磨该反应混合物。过滤收集沉淀并干燥得到4-[2-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸(893mg)。
IR(KBr):3209,1689.3,1604.5,1484.9cm-1
NMR(DMSO-d6,δ):6.97(2H,d,J=8.5Hz),7.81(2H,d,J=8.5Hz),8.00(4H,s),8.84(1H,s)
质谱(m/z):338(M+H+)
制备138
于室温下,向5-(4-戊氧基苯基)-1,3,4-噻二唑-2-基胺(20g)的吡啶(200ml)的溶液中加入4-甲氧基羰基苯甲酰氯(15g),于室温下搅拌该混合物2小时。用水研磨该反应混合物。过滤收集沉淀并干燥得到N-[5-(4-戊氧基苯基)-1,3,4-噻二唑-2-基]terephthalamic acid甲酯(30.3g)。
IR(KBr):2946,2863,1724,1670,1604,1538,1521,1457,1317,1276,1249,1174,1106cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.2-1.5(4H,m),1.6-1.9(2H,m),3.90(3H,s),4.05(2H,t,J=6.5Hz),7.09(2H,d,J=8.8Hz),7.91(2H,d,J=8.8Hz),8.12(2H,d,J=8.4Hz),8.25(2H,d,J=8.4Hz)
质谱(m/z):426(M+H+)
制备139
向N-叔丁氧基羰基-4-哌啶酮(3.3g)和1-(4-环己基苯基)哌嗪(4.0g)的二氯甲烷(20ml)溶液中加入异丙醇钛(Ⅳ)(8ml),于室温下搅拌该混合物2小时。然后向该反应混合物中分次加入乙醇(20ml)和氰基硼氢化钠(1g),于室温下搅拌该反应混合物2小时。用水研磨该反应混合物。滤除沉淀并用二氯甲烷提取该滤液。取出有机层。经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液并层析(硅胶60(商标,由Merck制备)),用己烷/乙酸乙酯洗脱,得到1-叔丁氧基羰基-4-[4-(4-环己基苯基)-哌嗪-1-基]哌啶(1.35g)。
NMR(CDCl3,δ):1.3-1.6(6H,m),1.45(9H,s),1.6-2.0(8H,m),2.3-2.6(2H,m),2.6-3.0(6H,m),3.0-3.3(4H,m),4.17(2H,d,J=13Hz),6.86(2H,d,J=8.7Hz),7.11(2H,d,J=8.7Hz)
质谱(m/z):428(M+H+)
制备140
向4-[4-[4-(4-环己基苯基)哌嗪-1-基]哌啶-1-基]苄腈(1.95g)的乙酸(10ml)溶液中加入浓盐酸(2ml),于120℃搅拌该混合物10小时。将该反应混合物加入水中,过滤收集产生的沉淀,得到4-[4-[4-(4-环己基苯基)哌嗪-1-基]哌啶-1-基]苯甲酸(959mg)。
IR(KBr):3400,2927,2620,2514,1714,1608,1513,1452,1274,1226,1182,1010cm-1
NMR(DMSO-d6,δ):1.2-1.5(5H,m),1.6-1.9(7H,m),2.2(2H,m),2.4(1H,m),2.84(2H,t,J=8.5Hz),3.20(4H,d,J=8.5Hz),3.4-3.8(5H,m),4.08(2H,d,J=12.5Hz),6.93(2H,d,J=8.8Hz),7.03(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),7.78(2H,d,J=8.8Hz),11.13(1H,s)
质谱(m/z):448(M+H+)
制备141
将1-(4-甲酰基苯基)-1H-吡唑-4-羧酸甲酯(5.0g)、1-苯基哌嗪(4.21g)、乙酸(3.7ml)、氰基硼氢化钠(1.55g)、甲醇(110ml)、四氢呋喃(75ml)和二氯甲烷(20ml)的混合物于0℃搅拌15分钟,于室温下搅拌14小时。将该反应混合物倾入饱和碳酸氢钠水溶液中并用乙酸乙酯提取。经硫酸镁干燥有机层,过滤并蒸发。残留物经硅胶层析纯化(1∶1己烷-乙酸乙酯洗脱),从二异丙基醚和丙酮中重结晶,得到1-[4-(4-苯基哌嗪-1-基-甲基)苯基]-1H-吡唑-4-羧酸甲酯(3.90g)。
IR(KBr):1702,1600,1560,1271cm-1
NMR(DMSO-d6,δ):2.4-2.6(4H,m),3.14(3H,t,J=4.8Hz),3.58(2H,s),3.81(3H,s),6.76(1H,t,J=7.2Hz),6.91(2H,d,J=7.8Hz),7.20(2H,t,J=7.8Hz),7.48(2H,t,J=8.6Hz),7.90(2H,d,J=8.6Hz),8.15(1H,s),9.11(1H,s)
质谱(m/z):377(M++1)
制备142
将三乙胺(1.98ml)加入在四氢呋喃(60ml)中的4-(4-羟基苯基)苯甲酸甲酯(3.00g)和N-phenyltrifluoromethanesulfonide(4.84g)的冰冷却的溶液中,然后于相同的温度下搅拌该溶液1小时,于室温下再搅拌18小时。将水(200ml)加入到该反应混合物中并用二氯甲烷提取该混合物。经硫酸镁干燥有机层,过滤并蒸发得到粗品油。使该油经硅胶柱层析纯化,用下列溶剂顺序洗脱:(1)2.5%乙酸乙酯的己烷液,(2)5%乙酸乙酯的己烷溶液。浓缩含有目标化合物的部分,得到为白色固体的4-(4-三氟甲磺酰基氧基苯基)苯甲酸甲酯(5.30g)。
IR(KBr):1713,1691,1606,1522,1495,1420cm-1
NMR(CDCl3,δ):3.95(3H,s),7.31-7.46(2H,m),7.56-7.75(4H,m),8.08-8.20(2H,m),
质谱(m/z):361(M++1)
制备143
向4-哌嗪-1-基-苯甲酸乙酯二盐酸盐(1g)和碳酸氢钾(1.57g)的乙腈(10ml)悬浮液中加入甲磺酸2,3-二氢化茚-2-基酯(0.69g),回流下搅拌该混合物8小时。用水研磨该反应混合物。过滤收集沉淀并减压干燥。粉末状物经硅胶柱层析纯化,用甲醇/二氯甲烷(50∶1)作为洗脱剂,得到4-(4-(2,3-二氢化茚)-2-基-哌嗪-1-基)苯甲酸乙酯(0.38g)。
IR(KBr):1697.1,1606.4,1349.9,1238.1cm-1
NMR(CDCl3,δ):l.37(3H,t,J=7.1Hz),2.67-2.72(4H,m),2.88-3.40(9H,m),4.33(2H,q,J=7.1Hz),6.85-6.90(2H,m),7.12-7.23(4H,m),7.91-7.96(2H,m)
质谱(m/z):351.3(M+1)
制备144
向2-氨基-4’-溴代苯乙酮盐酸盐(5.0g)、4-庚氧基苯甲酸(4.72g)和1-羟基苯并三唑(2.7g)的二氯甲烷(50ml)溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺(WSCD)(3.65ml),于室温下搅拌该混合物3小时。用二氯甲烷(200ml)稀释该反应混合物,用水、1N盐酸、饱和碳酸氢钠水溶液和盐水洗涤。经硫酸镁干燥有机层。滤除硫酸镁,减压蒸发滤液。将该固体在乙酸乙酯中制成淤浆,过滤收集得到2-(4-庚氧基苯甲酰基氨基)-4’-溴代苯乙酮(6.73g)。
IR(KBr):3318.9,2937.1,2858.0,1699.0,1639.2,1556.3,1508.1,1255.4cm-1
NMR(CDCl3,δ):0.80-1.10(3H,m),1.20-1.60(8H,m),1.75-1.95(2H,m),4.01(2H,t,J=6.5Hz),4.91(2H,d,J=4.2Hz),6.94(2H,d,J=8.8Hz),7.14(1H,brs),7.67(2H,d,J=8.6Hz),7.83(2H,d,J=8.8Hz),7.90(2H,d,J=8.6Hz)
APCI-MS(m/z):432,434
制备145
将2-(4-庚氧基苯基)-5-(4-溴代苯基)三唑(2.06g)的四氢呋喃(60ml)溶液冷却至-60℃,缓慢加入正丁基锂(1.56M的正己烷溶液,4.05ml),以维持反应温度于-60℃。搅拌1小时后,加入干冰(4g)。使该反应混合物经30分钟温热至室温。向该反应混合物中加入水(20ml)和0.5N盐酸(80ml),然后用二氯甲烷(700ml)提取。用盐水洗涤有机层,经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液。将该固体在乙腈中制成淤浆,过滤收集得到4-[5-(4-庚氧基苯基)噻唑-2-基]苯甲酸(1.68g)。
IR(KBr):2929.3,2856.1,2674.8,2549.4,1683.6,1604.5,1432.9,1297.9,1253.5cm-1
NMR(DMSO-d6,δ):0.70-1.00(3H,m),1.10-1.60(8H,m),1.60-1.90(2H,m),4.04(2H,t,J=6.4Hz),7.07(2H,d,J=8.7Hz),7.83(2H,d,J=8.2Hz),7.91(2H,d,J=8.7Hz),8.00(2H,d,J=8.2Hz),8.39(1H,s)
APCI-MS(m/z):396
以类似于制备19的方式获得下列化合物。
制备146
N-[4-[5-(4-戊氧基苯基)-1,3,4-噻二唑-2-基]苯甲酰基]-N’-(4-甲氧基羰基苯甲酰基)肼
NMR(DMSO-d6,δ):0.91(3H,t,J=6.9Hz),1.28-1.52(4H,m),1.68-1.86(2H,m),3.91(3H,s),4.08(2H,t,J=6.5Hz),7.14(2H,d,J=8.8Hz),7.98(2H,d,J=8.8Hz),8.01-8.24(8H,m),10.82(2H,s)
质谱(m/z):545(M++1)
制备147
向1-叔丁氧基羰基-4-(4-氯代苯基)-4-甲氧基哌啶(0.72g)的乙酸乙酯(10ml)溶液中加入4NHCl的乙酸乙酯溶液(5.5ml)。搅拌6.7小时后,将该反应混合物倾入乙酸乙酯和水的混合物中,接着将该溶液碱化至pH12。顺序用水和盐水洗涤有机层并经硫酸镁干燥。真空蒸发溶剂得到4-(4-氯代苯基)-4-甲氧基哌啶(0.39g)。
IR(薄膜):2943,2827,1541cm-1
NMR(CDCl3,δ):1.7-2.1(4H,m),2.17(1H,s),2.9-3.2(7H,m),7.33(4H,s)
以类似于制备147的方式获得下列化合物。
制备148
1-[4-(5-甲氧基戊氧基)联苯-4-基]哌嗪二盐酸盐
IR(KBr):2940.9,2508.9,1498.4,1249.6cm-1
NMR(CDCl3,δ):1.51-1.83(6H,m),3.34(3H,s),3.40(2H,t,J=6.2Hz),3.93(2H,t,J=6.4Hz),4.00-4.40(8H,m),6.84-6.89(2H,m),7.36-7.40(2H,m),7.58-7.62(2H,m),7.87-7.92(2H,m),9.90-10.15(1H,m)
质谱(m/z):355(M+1)
制备149
向4-羟基苯乙酮(10g)和氢溴酸吡啶鎓过溴化物(23.5g)的乙酸(80ml)溶液中加入溴化氢(30%的乙酸溶液)(40ml),于室温下搅拌该混合物过夜。将该反应混合物加入冰水中并用乙酸乙酯提取。取出有机层并经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液,得到2-溴代-1-(4-羟基苯基)乙酮(1.72g)。
NMR(CDCl3,δ):4.40(2H,s),5.78(1H,s),6.92(2H,d,J=8.8Hz),7.94(2H,d,J=8.8Hz)
质谱(m/z):217(M+H+)
以类似于制备149的方式获得下列化合物。
制备150
2-溴代-1-(4-戊氧基苯基)乙酮
NMR(CDCl3,δ):0.94(3H,t,J=6.8Hz),1.3-1.5(4H,m),1.82(2H,q,J=6.8Hz),4.03(2H,t,J=6.8Hz)4.40(2H,s),6.94(2H,d,J=9.0Hz),7.96(2H,d,J=9.0Hz)
质谱(m/z):287(M+H+)
制备151
用碳酸钾(5.72g)、碘化钠(4.14g)和1,5-二溴代戊烷处理1-(4-氨基苯基)-1H-吡唑-4-羧酸甲酯(3.0g)的N,N-二甲基甲酰胺(30ml)溶液,将该混合物于室温下搅拌20小时,于80℃搅拌6小时。在此期间再加入N,N-二甲基甲酰胺(20ml)、1,5-二溴代戊烷(1.14g)和碳酸钾(0.95g)。将该反应混合物冷却至室温并倾入水中。过滤收集沉淀,减压干燥。残留物经硅胶层析纯化(二氯甲烷洗脱),得到1-(4-哌啶基苯基)-1H-吡唑-4-羧酸甲酯(1.34g)。
IR(KBr):1720,1521,1248cm-1
NMR(CDCl3,δ):1.5-1.8(6H,m),3.21(4H,t,J=5.3Hz),3.86(3H,s),6.98(2H,d,J=9.1Hz),7.53(2H,d,J=9.1Hz),8.06(1H,s),8.29(1H,s)
质谱(m/z):286(M++1)
以类似于制备151的方式获得下列化合物。
制备152
1-(4-吡咯烷基苯基)-1H-吡唑-4-羧酸甲酯
IR(KBr):1720,1541,1525,1246cm-1
NMR(CDCl3,δ):2.0-2.1(4H,m),3.2-3.4(4H,m),3.86(3H,s),6.59(2H,dd,J=6.9和2.1Hz),7.49(2H,dd,J=6.9和2.1Hz),8.05(1H,s),8.25(1H,s)
质谱(m/z):294(M++23)
制备153
向环己烷-1-4-二羧酸一甲酯(1.57g)的亚硫酰氯(3.14ml)的悬浮液中加入N,N-二甲基甲酰胺(2滴),将该混合物于回流下搅拌1小时。减压蒸发浓缩该反应混合物,得到4-氯代羰基环己烷羧酸甲酯(1.78g)。
NMR(CDCl3,δ):1.38-1.64(4H,m),2.09-2.32(5H,m),2.64-2.77(1H,m),3.68(3H,s)
制备154
于10℃将亚硫酰氯(8.47ml)滴加到甲醇(54ml)中。向该溶液中加入反式-1,4-环己烷二羧酸(4g),于室温下搅拌该混合物24小时。减压蒸发该反应混合物,得到环己烷-1,4-二羧酸二甲酯(4.68g)。
IR(KBr):1729.8,1195.6cm-1
NMR(CDCl3,δ):1.34-2.15(8H,m),2.23-2.34(2H,m),3.67(6H,s)
质谱(m/z):201(M+1)
以类似于制备154的方式获得下列化合物[制备155-157]。
制备155
2,5-二甲基-对苯二酸二甲酯
IR(KBr):1722.1,1261.2,1101.2cm-1
NMR(CDCl3,δ):2.57(6H,s),3.91(6H,s),7.76(2H,s)
质谱(m/z):223(M+1)
制备156
2,4-己烯二酸二甲酯
IR(KBr):1702.8,1612.2,1249.6cm-1
NMR(CDCl3,δ):3.71(6H,s),6.49(2H,dd,J=3.1和11.5Hz),7.40(2H,dd,J=3.1和11.5Hz)
质谱(m/z):171(M+1)
制备157
萘-1,4-二羧酸二甲酯
NMR(CDCl3,δ):4.03(6H,s),7.65(2H,q,J=3.3Hz),8.09(2H,s),8.83(2H,q,J=3.3Hz)
质谱(m/z):245(M+1)
以类似于制备153的方式获得下列化合物[制备158-162]。
制备158
5-氯代羰基噻吩-2-羧酸甲酯
IR(KBr):1724.0,1666.2,1251.6cm-1
NMR(CDCl3,δ):3.86(3H,s),7.73-7.87(2H,m)
制备159
4-氯代羰基-2,5-二甲基苯甲酸甲酯
IR(KBr):1756.8,1718.3,1220.7cm-1
NMR(CDCl3,δ):2.54(3H,s),2.60(3H,s),3.93(3H,s),7.78(1H,s),8.03(1H,s)
制备160
5-氯代羰基-2,4-戊烯酸甲酯
IR(KBr):1745.3,1714.4,1243.9cm-1
NMR(CDCl3,δ):3.70(3H,s),6.29-6.64(2H,m),7.24-7.64(2H,m)
制备161
4-氯代羰基萘-1-羧酸甲酯
IR(KBr):1762.6,1724.0,1257.4cm-1
NMR(CDCl3,δ):3.98(3H,s),7.68-7.77(2H,m),8.14(2H,s),8.66-8.82(2H,m)
制备162
6-氯代羰基萘-2-羧酸甲酯
IR(KBr):1743.3,1714.4,1290.1cm-1
NMR(CDCl3,δ):3.94(3H,s),8.04-8.08(2H,m),8.21-8.27(2H,m),8.68-8.71(2H,m)
制备163
向4-哌啶-1-基-苄腈(3g)和氨基硫脲(1.8g)的甲苯(30ml)溶液中加入三氟乙酸(20ml),于60℃搅拌该混合物6小时。将该反应混合物置于水中,用1N氢氧化钠将该溶液调至pH9,过滤收集沉淀物,得到5-(4-哌啶-1-基-苯基)-[1,3,4]噻二唑-2-基-胺(3.58g)。
IR(KBr):2933,2838,1604,1502,1463,1386,1349,1245,1126,1043,821cm-1
NMR(DMSO-d6,δ):1.57(6H,m),3.24(4H,m),6.96(2H,d,J=8.8Hz),7.19(2H,s),7.54(2H,d,J=8.8Hz)
质谱(m/z):261(M+H+)
以类似于制备163的方式获得下列化合物[制备164-169]。
制备164
5-(4-吗啉基苯基)-[1,3,4]噻二唑-2-基-胺
IR(KBr):3274,3106,1604,1508,1465,1378,1324,1267,1238,1122cm-1
NMR(DMSO-d6,δ):3.19(4H,t,J=4.8Hz),3.74(4H,t,J=4.8Hz),7.00(2H,d,J=8.8Hz),7.22(2H,s),7.59(2H,d,J=8.8Hz)
质谱(m/z):263(M+H+)
制备165
5-[4-(顺式-2,6-二甲基吗啉-4-基)苯基]-[1,3,4]噻二唑-2-基-胺
IR(KBr):3272,3106,1608,1525,1469,1376,1346,1245,1176,1145,1081cm-1
NMR(DMSO-d6,δ):1.16(6H,d,J=6.2Hz),2.31(2H,t,J=11.5Hz),3.6-3.8(4H,m),7.00(2H,d,J=8.8Hz),7.21(2H,s),7.58(2H,d,=8.8Hz)
质谱(m/z):291(M+H+)
制备166
5-(4-硫代吗啉代苯基)-[1,3,4]噻二唑-2-基-胺
IR(KBr):3340,3270,3129,1604,1506,1467,1384,1295,1230,1195cm-1
NMR(DMSO-d6,δ):2.64(4H,t,J=5.0Hz),3.66(4H,t,J=5.0Hz),6.97(2H,d,J=8.8Hz),7.21(2H,s),7.57(2H,d,J=8.8Hz)
质谱(m/z):279(M+H+)
制备167
5-[4-(4-乙基哌嗪基苯基)]-[1,3,4]噻二唑-2-基-胺
IR(KBr):3278,3120,2967,2829,1685,1608,1517,1467,1388,1240,1203,1130cm-1
NMR(DMSO-d6,δ):1.04(3H,t,J=7.2Hz),2.41(2H,q,J=7.2Hz),2.51(4H,m),3.23(4H,m),6.99(2H,d,J=8.8Hz),7.21(2H,s),7.57(2H,d,J=8.8Hz)
质谱(m/z):290(M+H+)
制备168
5-[4-(4-环己基哌嗪基苯基)]-[1,3,4]噻二唑-2-基-胺
IR(KBr):3016,2950,2865,1743,1672,1606,1513,1456,1430,1402,1201,1133cm-1
NMR(DMSO-d6,δ):1.0-1.6(5H,m),1.63(1H,d,J=10Hz),1.85(2H,d,J=10Hz),2.09(2H,d,J=10Hz),2.8-3.3(5H,m),3.55(2H,m),3.99(2H,d,J=10Hz),7.09(2H,d,J=8.8Hz),7.65(2H,d,J=8.8Hz)
质谱(m/z):344(M+H+)
制备169
4-(5-氨基-[1,3,4]噻二唑-2-基)苯甲酸甲酯三氟乙酸盐
IR(KBr):3004,2746,1726,1675,1645,1608,1436,1284,1211,1186,1137,1112cm-1
NMR(DMSO-d6,δ):3.88(3H,s),7.19(2H,s),7.90(2H,d,J=8.5Hz),8.04(2H,d,J=8.5Hz)
质谱(m/z):236(M+H+)
制备170
向4-甲氧基羰基苯基硼酸(2.01g)和1-溴代-4-乙氧基甲基苯(2.00g)在乙二醇二甲醚(20ml)和2M碳酸钠水溶液(6ml)的混合溶剂中的混合物中加入四(三苯膦)钯(0)(0.54g)。于80℃加热该混合物5小时。冷却至室温后,将水(150ml)加入该反应混合物中,过滤收集产生的沉淀,用水充分洗涤并干燥得到粗品固体。该固体经硅胶柱(60g)层析纯化,用下列溶剂顺序洗脱:(1)正己烷∶乙酸乙酯=50∶1,(2)正己烷∶乙酸乙酯=10∶1。浓缩含有目标化合物的部分,干燥得到为白色固体的4-(4’-乙氧基甲基苯基)苯甲酸甲酯(1.85g)。
NMR(CDCl3,δ):1.27(3H,t,J=7.0Hz),3.58(3H,q,J=7.0Hz),3.94(3H,m),4.56(2H,s),7.44(2H,d,J=8.7Hz),7.54-7.61(4H,m),8.04-8.15(2H,m)
以类似于制备170的方式获得下列化合物。
制备171
4-[4’-(2-甲氧基乙氧基甲基)苯基]苯甲酸甲酯
NMR(CDCl3,δ):3.41(3H,m),3.55-3.70(4H,m),3.94(3H,s),4.63(2H,s),7.45(2H,d,J=8.3Hz),7.56-7.74(4H,m),8.07-8.20(2H,m)
质谱(m/z):301(M++1)
制备172
在氮气流下,向4-溴代苄基溴(3.00g)和2-甲氧基乙醇(1.04ml)的四氢呋喃(30ml)的冰冷却溶液中加入氢化钠(60%)(0.58g)。于该温度下搅拌该混合物15分钟,再于室温下搅拌4小时。在冰冷却下向该混合物中加入水(1ml)。用乙酸乙酯稀释该反应混合物,用水和饱和氯化钠溶液顺序洗涤。经硫酸镁干燥有机层,过滤并蒸发得到为淡黄色油状物的1-溴代-4-(2-甲氧基乙氧基甲基)苯(3.l0g)。
NMR(DMSO-d6,δ):3.25(3H,m),3.43-3.60(2H,m),4.46(2H,s),7.28(2H,d,J=8.5Hz),7.49-7.60(4H,m)
以类似于制备172的方式获得下列化合物[制备173-175]。
制备173
4-(4-丙氧基哌啶-1-基)苯甲酸乙酯
NMR(DMSO-d6,δ):0.87(3H,t,J=7.4Hz),1.28(3H,t,J=7.1Hz),1.36-1.60(4H,m),1.80-1.98(2H,m),3.00-3.20(2H,m),3.39(2H,t,J=6.5Hz),3.41-3.76(3H,m),4.23(2H,q,J=7.1Hz),6.97(2H,d,J=9.1Hz),7.76(2H,d,J=9.0Hz)
质谱(m/z):292(M++1)
制备174
4-(4-苄氧基哌啶-1-基)苯甲酸乙酯
NMR(DMSO-d6,δ):1.28(3H,t,J=7.1Hz),1.45-1.66(2H,m),1.85-2.02(2H,m),3.00-3.21(2H,m),3.55-3.78(3H,m),4.23(2H,q,J=7.1Hz),4.55(2H,s),6.98(2H,d,J=9.1Hz),7.23-7.43(5H,m),7.76(2H,d,J=9.0Hz)
质谱(m/z):340(M++1)
制备175
1-(4-庚氧基甲基苯基)-1H-吡唑-4-羧酸甲酯
IR(KBr):1703,1558,1265cm-1
NMR(DMSO-d6,δ):0.85(3H,m),1.1-1.6(10H,m),3.44(2H,t,J=6.4Hz),3.81(3H,s),4.49(2H,s),7.45(2H,d,J=8.5Hz),7.91(2H,d,J=8.5Hz),8.15(1H,s),9.11(1H,s)
质谱(m/z):331(M++1)
制备176
于0-10℃、氮气下,向4-(4-羟基苯基)苯甲酸甲酯(3.00g)和环己醇(1.58g)的四氢呋喃(60ml)溶液中滴加偶氮二羧酸二乙酯(2.48ml),于室温下搅拌该混合物4小时。浓缩后,向该残留物中加入乙酸乙酯(50ml)和正己烷(10ml),过滤收集产生的沉淀并弃去。向滤液中加入硅胶(12g),蒸发该混合物。残留物经硅胶(80g)柱层析纯化,用5%乙酸乙酯在正己烷中的混合溶剂洗脱,得到为白色固体的4-(4-环己氧基苯基)苯甲酸甲酯(1.79g)。
IR(KBr):1720,1603,1525,1495,1437cm-1
NMR(CDCl3,δ):1.22-1.66(6H,m),1.72-1.90(2H,m),1.95-2.10(2H,m),3.93(3H,s),4.22-4.37(1H,m),6.89-7.03(2H,m),7.47-7.76(4H,m),8.00-8.13(2H,m)
质谱(m/z):311(M++1)
以类似于制备176的方式获得下列化合物。
制备177
4-环己氧基苯甲酸甲酯
NMR(CDCl3,δ):1.20-2.10(10H,m),3.88(3H,s),4.20-4.40(1H,m),6.85-6.95(2H,m),7.90-8.00(2H,m)
APCI质谱(正性):235.2(M++1)
制备178
于氮气流下,向4-(哌嗪-1-基)苯甲酸乙酯(2.00g)和4-甲基环己酮(1.05ml)在甲醇(40ml)和乙酸(1.47ml)的混合溶剂的冰冷却的溶液中加入氰基硼氢化钠(0.59g)。于该温度下搅拌该混合物1小时,于室温下搅拌17小时。用饱和碳酸氢钠水溶液猝灭该反应混合物,过滤收集产生的沉淀,用水充分洗涤并干燥得到顺式和反式产物的混合物。经硅胶柱层析分离该混合物,用二氯甲烷-甲醇(从0%至2%的梯度液)的混合溶剂洗脱该混合物,得到为浅绿色固体的4-[4-(顺式-4-甲基环己基)哌嗪-1-基]苯甲酸乙酯(0.80g)和浅绿色固体的4-[4-(反式-4-甲基环己基)哌嗪-1-基]苯甲酸乙酯(0.64g)。经X-射线结晶分析,证实为反式-产物。
4-[4-(顺式-4-甲基环己基)哌嗪-1-基]苯甲酸乙酯
IR(KBr):1697,1608,1520,1446cm-1
NMR(DMSO-d6,δ):0.89(3H,d,J=6.8Hz),1.28(3H,t,J=7.1Hz),1.23-1.52(6H,m),1.52-1.76(3H,m),2.07-2.25(1H,m),2.47-2.63(4H,m),3.20-3.40(4H,m),4.23(2H,q,J=7.1Hz),6.96(2H,d,J=9.1Hz),7.28(2H,d,J=8.9Hz)
质谱(m/z):331(M++1)
4-[4-(反式-4-甲基环己基)哌嗪-1-基]苯甲酸乙酯
IR(KBr):1709,1608,1518,1444cm-1
NMR(DMSO-d6,δ):0.85(3H,d,J=6.8Hz),0.80-1.02(2H,m),1.28(3H,t,J=7.1Hz),1.09-1.56(3H,m),1.56-1.88(4H,m),2.08-2.34(1H,m),2.50-2.67(4H,m),3.18-3.34(4H,m),4.23(2H,q,J=7.1Hz),6.95(2H,d,J=9.1Hz),7.77(2H,d,J=8.9Hz)
质谱(m/z):331(M++1)
以类似于制备178的方式获得下列化合物。
制备179
4-[4-(4,4-二甲基环己基)哌嗪-1-基]苯甲酸乙酯
NMR(CDCl3,δ):0.91(6H,s),1.07-1.55(6H,m),1.36(3H,t,J=7.1Hz),1.64-1.82(2H,m),2.10-2.30(1H,m),2.72(4H,t,J=5.1Hz),3.33(4H,t,J=5.1Hz),4.32(2H,q,J=7.1Hz),6.86(2H,d,J=9.1Hz),7.87-7.99(2H,m)
质谱(m/z):345(M++1)
制备180
于氮气流下,向碳酸铯(1.90g)、乙酸钯(Ⅱ)(46.7mg)和2,2’-双(二苯基膦酰基)-1,1’-联萘(194mg)的甲苯(3.3ml)的混合物中连续加入顺式-2,6-二甲基吗啉(0.58g)的甲苯(5ml)溶液和4-(4-三氟甲磺酰基氧基苯基)-苯甲酸甲酯(1.50g)。于室温下搅拌该混合物30分钟并再回流6小时。冷却至室温后,将水加入该反应混合物中,用二氯甲烷提取该混合物。用饱和氯化钠水溶液洗涤有机层,经硫酸镁干燥,过滤并真空浓缩。用乙腈研磨该残留物,过滤收集得到为淡黄色固体的4-[4-(顺式-2,6-二甲基吗啉代-苯基)]苯甲酸甲酯(525mg)。
IR(KBr):1720,1603,1497,1446cm-1
NMR(CDCl3,δ):1.28(6H,d,J=6.3Hz),2.46(1H,d,J=10.6Hz),2.49(1H,d,J=10.6Hz),3.46-3.62(2H,m),3.72-3.94(2H,m),3.93(3H,s),6.98(2H,d,J=8.9Hz),7.51-7.70(4H,m),8.02-8.14(2H,m)
质谱(m/z):326(M++1)
以类似于制备180的方式获得下列化合物。
制备181
4-[4-(4-环己基哌嗪-1-基)苯基]苯甲酸甲酯
IR(KBr):2929,2852,2829,1714,1603,1529,1498,1439cm-1
NMR(CDCl3,δ):1.00-1.41(5H,m),1.51-2.05(5H,m),2.24-2.43(1H,m),2.69-2.84(4H,m),3.22-3.36(4H,m),3.93(3H,s),7.00(2H,d,J=8.9Hz),7.48-7.68(4H,m),8.00-8.12(2H,m)
质谱(m/z):379(M++1)
制备182
向2-氨基-5-(4-甲氧基苯基)-1,3,4-噻二唑(7.2g)的乙醇(50ml)悬浮液中加入4-溴代乙酰基苯甲酸乙酯(11.3g),回流下搅拌该混合物2.5小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀物并干燥。向该粉末的二甲苯(50ml)悬浮液中加入三氟乙酸(5ml),于回流下搅拌该混合物3.5小时。用二异丙基醚研磨该反应混合物。过滤收集沉淀物并干燥,得到4-[2-(4-甲氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸乙酯三氟乙酸盐(13.7g)。
IR(KBr):2360.4,1746.3,1604.5,1483.0cm-1
质谱(m/z):380((M-TFA)+H+)
以类似于制备182的方式获得下列化合物[制备183-190]。
制备183
4-[2-(4-哌啶-1-基-苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2940,2584,2474,1702,1608,1523,1471,1409,1367,1280cm-1
质谱(m/z):433((M-TFA)+H+)
制备184
4-[2-(4-吗啉-4-基-苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2669,1706,1606,1473,1274,1236,1176,1118,1020,929cm-1
质谱(m/z):435((M-TFA)+H+)
制备185
4-[2-(顺式-2,6-二甲基吗啉-4-基-苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基1苯甲酸乙酯三氟乙酸盐
IR(KBr):2979,1710,1606,1473,1371,1278,1241,1176,1106cm-1
质谱(m/z):463((M-TFA)+H+)
制备186
4-[2-(4-硫代吗啉-4-基-苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2979,1708,1604,1504,1471,1274,1193,1105cm-1
质谱(m/z):451((M-TFA)+H+)
制备187
4-[2-[4-(4-乙基哌嗪-1-基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2983,2931,2674,2605,1702,1606,1471,1405,1282,1241,1201cm-1
NMR(DMSO-d6,δ):1.23-1.38(6H,m),3.30-3.23(6H,m),3.61(2H,d,J=8.2Hz),4.12(2H,d,J=8.2Hz),4.33(2H,q,J=7.2Hz),7.20(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),8.02(4H,s),8.86(1H,s)
质谱(m/z):462((M-TFA)+H+)
制备188
4-[2-[4-(4-环己基哌嗪-1-基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯三氟乙酸盐
IR(KBr):2935,2586,1708,1604,1571,1488,1409,1367,1278,1199,1106cm-1
质谱(m/z):516((M-TFA)+H+)
制备189
4-[6-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-2-基]苯甲酸甲酯三氟乙酸盐
IR(KBr):3214,3027,1720,1629,1610,1513,1434,1284,1187,1112cm-1
NMR(DMSO-d6,δ):3.91(3H,s),7.72(2H,d,J=8.5Hz),7.91(2H,d,J=8.5Hz),8.12(4H,s),8.61(1H,s)
质谱(m/z):352((M-TFA)+H+)
制备190
4-[6-(4-戊氧基苯基)咪唑并[2,1-b][1,3,4]噻二唑-2-基]苯甲酸甲酯三氟乙酸盐
IR(KBr):2952,2869,1720,1612,1494,1471,1436,1405,1280,1251,1182,1110cm-1
质谱(m/z):422((M-TFA)+H+)
制备191
用28%甲醇钠的甲醇溶液(14ml)处理4-[4-(4-溴代丁氧基)苯基]苯甲酸甲酯(1.40g)的甲醇(14ml)溶液并回流该溶液5小时。冷却至室温后,将该反应混合物倾入冷的1N盐酸(110ml)中,过滤收集产生的沉淀,用水充分洗涤并干燥得到白色固体。向该固体在甲醇(20ml)中的混合物中加入浓硫酸(0.5ml)并回流4小时。冷却至室温后,将该反应混合物倾入冷水中,过滤收集产生的沉淀,用水充分洗涤并干燥得到为白色固体的4-[4-(4-甲氧基丁氧基)苯基]苯甲酸甲酯(1.16g)。
IR(KBr):2949,2873,1720,1603,1529,1498,1439cm-1
NMR(DMSO-d6,δ):1.54-1.85(4H,m),3.24(3H,s),3.38(2H,t,J=6.2Hz),3.87(3H,s),4.04(2H,t,J=6.1Hz),7.05(2H,t,J=8.8Hz),7.69(2H,d,J=8.7Hz),7.78(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz)
质谱(m/z):315(M++1)
以类似于制备191的方式获得下列化合物[制备192-194]。
制备192
4-[4’-(3-甲氧基丙氧基)苯基]苯甲酸甲酯。
IR(KBr):2953,2875,1724,1603,1529,1495,1435cm-1
NMR(DMSO-d6,δ):1.96(2H,m),3.26(3H,s),3.49(2H,t,J=6.3Hz),3.87(3H,s),4.08(2H,t,J=6.4Hz),6.98-7.14(2H,m),7.64-7.86(4H,m),7.96-8.10(2H,m)
质谱(m/z):301(M++1)
制备193
1-溴代-4-乙氧基甲基苯
NMR(DMSO-d6,δ):1.15(3H,t,J=7.0Hz),3.47(2H,q,J=7.0Hz),4.42(2H,s),7.28(2H,d,J=8.5Hz),7.46-7.61(2H,m)
制备194
4-[4-(3-乙氧基丙氧基)苯基]苯甲酸甲酯
NMR(DMSO-d6,δ):1.11(3H,t,J=7.0Hz),1.96(2H,m),3.43(2H,q,J=7.0Hz),3.52(2H,t,J=6.3Hz),3.87(3H,s),4.08(2H,t,J=6.3Hz),7.06(2H,d,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.78(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz)
质谱(m/z):315(M++1)
制备195
向4-[2-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯(500mg)和碳酸钾(2g)的N,N-二甲基甲酰胺(25ml)中的悬浮液中加入1,4-二溴代丁烷(1ml)。于室温下搅拌该混合物22小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀并干燥。向该粉末在N,N-二甲基甲酰胺(25ml)中的悬浮液中加入哌啶(2ml),于室温下搅拌该混合物2l小时。用水研磨该反应混合物。过滤收集沉淀,用水、乙腈和二异丙基醚洗涤并干燥得到4-[2-[4-(4-哌啶-1-基-丁氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯(479mg)。
IR(KBr):2933.2,1708.6,1608.3,1471.4,1274.7,1176.4,1101.2cm-1
质谱(m/z):505(M+H+)
以类似于制备195的方式获得下列化合物[制备196-201]。
制备196
4-[2-[4-(5-哌啶-1-基-戊氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2935,1708,1608,1471,1274,1176,1101cm-1
质谱(m/z):519(M+H+)
制备197
4-[2-[4-(6-哌啶-1-基-己氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2933,1710,1608,1471,1274,1176,1103cm-1
质谱(m/z):533(M+H+)
制备198
4-[2-[4-(5-吗啉-4-基-戊氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2940,1708,1608,1471,1276,1176,1116cm-1
质谱(m/z):521(M+H+)
制备199
4-[2-[4-[5-(顺式-2,6-二甲基吗啉-4-基)-戊氧基]苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2937,1708,1608,1471,1409,1369,1307,1278,1176cm-1
质谱(m/z):549(M+H+)
制备200
4-[2-[4-[6-(顺式-2,6-二甲基吗啉-4-基)-己氧基]苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2937,1710,1606,1544,1471,1403,1305,1270,1257,1176cm-1
质谱(m/z):563(M+H+)
制备201
4-[2-[4-(5-硫代吗啉-4-基-戊氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯
IR(KBr):2939,1706,1608,1471,1274,1176,1108cm-1
质谱(m/z):537(M+H+)
制备202
向4-[2-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯(1g)和碳酸钾(4g)的N,N-二甲基甲酰胺(50ml)中的悬浮液中加入1,5-二溴代戊烷(2ml),于室温下搅拌该混合物6小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀,用水和甲醇洗涤。向该粉末在甲醇(10ml)中的悬浮液中加入甲醇钠(28%在甲醇中)(20ml),于80℃搅拌该混合物19小时。用水研磨该反应混合物。过滤收集沉淀,用水、甲醇和二异丙基醚洗涤并干燥得到4-[2-[4-(5-甲氧基戊氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸甲酯(479mg)。
质谱(m/z):452(M+H+)
以类似于制备202的方式获得下列化合物[制备203-205]。
制备203
4-[2-[4-(6-甲氧基己氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸甲酯
IR(KBr):2935,2861,1712,1608,1591,1533,1471,1417,1305,1259,1178,1116cm-1
质谱(m/z):466(M+H+)
制备204
4-[2-[4-(7-甲氧基庚氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸甲酯
IR(KBr):2933,2858,1714,1608,1591,1533,1469,1419,1305,1259,1178,1112cm-1
质谱(m/z):480(M+H+)
制备205
4-[2-[4-(8-甲氧基辛氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸甲酯
IR(K3r):2931,2856,1712,1610,1591,1533,1471,1419,1305,1259,1178,1112cm-1
质谱(m/z):494(M+H+)
制备206
于90℃将哌嗪-1-羧酸叔丁酯(0.64g)、4-溴代-4’-(5-甲氧基戊氧基)联苯(1g)、三(二亚苄基丙酮)(氯仿)二钯(0)(59mg)、(S)-(-)-2,2’-双(二苯膦基)-1,1’-联萘(0.12g)和叔丁醇钠(0.55g)的甲苯(10ml)中的混合物搅拌54小时。将该反应混合物加入水和乙酸乙酯的混合物中。取出有机层并经硫酸镁干燥。滤除硫酸镁,减压蒸发滤液,得到4-[4’-(5-甲氧基戊氧基)联苯-4-基]哌嗪-1-羧酸叔丁酯(1.19g)。
IR(KBr):1691.3,1504.2,1232.3cm-1
NMR(CDCl3,δ):1.49(9H,s),1.49-1.90(6H,m),3.14-3.19(4H,m),3.34(3H,s),3.41(2H,t,J=6.2Hz),3.57-3.62(4H,m),3.99(2H,t,J=6.4Hz),6.91-6.99(4H,m),7.44-7.49(4H,m)
质谱(m/z):455(M+1)
以类似于制备206的方式获得下列化合物。
制备207
4-[4-[4-(7-甲氧基庚硫基)苯基]哌嗪-1-基]苯甲酸
IR(KBr):1681.6,1585.2,1423.2,1230.4cm-1
NMR(DMSO-d6,δ):1.20-1.55(10H,m),2.80(2H,t,J=6.7Hz),3.20(3H,s),3.24-3.43(10H,m),6.82-6.86(2H,m),6.94-6.98(2H,m),7.23-7.27(2H,m),7.69-7.73(2H,m)
质谱(m/z):443.2(M+1)
制备208
使1-叔丁氧基羰基-4-[4-(4-环己基苯基)哌嗪-1-基]哌啶(3.3g)和三氟乙酸(10ml)混合,于室温下搅拌该混合物1小时。将该溶液置于水中,用1N氢氧化钠将pH调至8,用乙酸乙酯提取。分离有机层,用盐水洗涤,经硫酸镁干燥并减压蒸发得到1-(4-环己基苯基)-4-哌啶基哌嗪(3.83g)。
制备209
向4-[2-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸(4.0g)的乙醇(50ml)悬浮液中加入硫酸(1.0ml),于80℃搅拌该混合物9小时。用水研磨该反应混合物,过滤收集沉淀,用水、乙腈和二异丙基醚洗涤,干燥得到4-[2-(4-羟基苯基)咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸乙酯(2.09g) 。
IR(KBr):3215,1679.7,1608.3,1473.3,1288.2cm-1
NMR(DMSO-d6,δ):1.34(3H,t,J=7.1Hz),4.32(2H,q,J=7.1Hz),6.96(2H,d,J=8.5Hz),7.89(2H,d,J=8.5Hz),8.02(4H,s),8.84(1H,s),10.40(1H,s)
质谱(m/z):366(M+H+)
以类似于制备209的方法获得下列化合物。
制备210
4-环己基苯甲酸甲酯
NMR(CDCl3,δ):1.10-1.55(5H,m),1.65-1.95(5H,m),2.45-2.65(1H,m),3.89(3H,s),7.26(2H,d,J=8.2Hz),7.95(2H,d,J=8.2Hz)
APCI质谱:219(M++1)
以类似于制备18的方法获得下列化合物[制备211-253]。
制备211
NMR(CDCl3,δ):1.10-1.45(6H,m),1.45-2.10(8H,m),3.0-3.80(6H,m),6.97(2H,d,J=9.0Hz),7.40-7.65(3H,m),7.90(2H,d,J=8.9Hz),8.13(2H,d,J=8.2Hz),8.18(2H,d,J=8.7Hz),8.39(2H,d,J=8.6Hz)
APCI MASS:581(M+)
制备212
IR(KBr):3008,2935,1792,1770,1600cm-1
NMR(CDCl3,δ):3.97(3H,s),7.07(2H,d,J=8.5Hz),7.43-7.56(3H,m),8.10(1H,d,J=8.5Hz),8.23(2H,d,J=8.5Hz)
MASS(m/z):270(M+H+)
制备213
IR(KBr):1776,1234,1095cm-1
NMR(CDCl3,δ):0.89(3H,m),1.1-2.0(10H,m),3.52(2H,t,J=6.6Hz),4.57(2H,s),7.4-7.6(4H,m),7.75(2H,d,J=8.5Hz),8.14(2H,d,J=8.1Hz),8.22(1H,s),8.26(2H,d,J=8.7Hz),8.43(2H,d,J=8.7Hz),8.59(1H,s)
MASS(m/z):594(M++1)制备214
NMR(CDCl3,δ):1.20-1.60(5H,m),1.70-2.05(5H,m),2.50-2.75(1H,m),7.25-8.50(12H,m)
ESI MASS (正性):502.3(M++Na)
制备215
NMR(CDCl3,δ):1.10-2.20(10H,m),4.30-4.50(1H,m),7.04(2H,d,J=9.1Hz),7.40-8.50(10H,m)
APCI MASS(正性):518.3(M++Na)
制备216
NMR(CDCl3+CD3OD,δ):1.70-2.15(4H,m),2.70-2.90(1H,m),2.90-3.20(2H,m),4.00-4.15(2H,m),7.08(2H,d,J=9.1Hz),7.10-7.40(5H,m),7.40-7.70(3H,m),7.90-8.55(7H,m)
APCI MASS:543(M++1)
制备217
NMR(CDCl3+CD3OD,δ):1.70-2.10(4H,m),2.60-3.15(3H,m),3.90-4.15(2H,m),6.90-7.15(2H,m),7.15-7.40(6H,m),7.40-8.45(9H,m)
制备218
NMR(CDCl3,δ):1.20-2.15(10H,m),4.25-4.50(1H,m),7.05(2H,d,J=6.9Hz),7.35-7.65(3H,m),8.00-8.50(7H,m)
APCI MASS(正性):502.2(M++Na)
制备219
NMR(CDCl3,δ):1.15-2.00(10H,m),2.45-2.75(1H,m),7.30-8.50(12H,m)
APCI MASS(正性):466.2(M++1)
制备220
IR(KBr):2978,2937,2873,1772,1599,1498,1439cm-1
NMR(CDCl3,δ):1.27(3H,t,J=7.0Hz),3.65(2H,q,J=7.0Hz),3.84(2H,t,J=4.8Hz),4.20(2H,t,J=4.8Hz),7.05(2H,d,J=8.8Hz),7.40-7.66(5H,m),7.60(2H,d,J=8.8Hz),7.72(2H,d,J=8.4Hz),8.07-8.17(1H,m),8.28(2H,d,J=8.6Hz),8.43(2H,d,J=8.7Hz)
MASS(m/z):564(M++1)
制备221
IR(KBr):1778.0,1600.6,1230.4,1182.2cm-1
NMR(CDCl3,δ):1.10-1.74(10H,m),2.82(2H,t,J=7.2Hz),3.33(3H,s),3.33-3.65(10H,m),6.88-7.02(4H,m),7.32-7.58(5H,m),8.07-8.18(3H,m)
制备222
IR(KBr):1810.8,1600.6,1257.4,1178.3cm-1
NMR(DMSO-d6,δ):1.30-2.40(18H,m),3.21(3H,s),3.28-3.35(2H,m),4.05(2H,t,J=6.6Hz),7.05-7.10(2H,m),7.40-8.18(6H,m)
MASS(m/z):536(M+1)
制备223
IR(KBr):1776.1,1677.8,1251.6,1197.6cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=6.9Hz),1.23-1.55(4H,m),1.60-1.90(2H,m),4.00-4.10(2H,m),7.03-7.09(2H,m),7.39-8.17(12H,m)
MASS(m/z):552
制备224
IR(KBr):1795.4,1606.4,1442.5,1259.3,1220.7cm-1
NMR(DMSO-d6,δ):1.44-1.95(8H,m),2.71(3H,s),2.75(3H,s),3.35(3H,s),3.40(2H,t,J=6.4Hz),4.05(2H,t,J=6.4Hz),7.02(2H,d,J=8.8Hz),7.43-7.64(3H,m),7.84(1H,s),7.96-8.15(3H,m),8.34(1H,s)
MASS(m/z):558(M+1)
制备225
IR(KBr):1697.1,1604.5,1251.6cm-1
NMR(CDCl3,δ):1.40-2.00(8H,m),3.35(3H,s),3.40(2H,t,J=6.4Hz),4.04(2H,t,J=6.4Hz),6.97-7.02(2H,m),7.20-8.07(9H,m),8.50-8.54(1H,m)
MASS(m/z):506(M+1)
制备226
IR(KBr):1778.0,1602.6,1238.1cm-1
NMR(CDCl3,δ):1.07(3H,t,J=7.4Hz),1.77-1.94(2H,m),4.00(2H,t,J=6.6Hz),7.00-7.05(2H,m),7.46-9.56(16H,m)
MASS(m/z):568(M+1)
制备227
IR(KBr):1778.0,1604.5,1257.4,1172.5cm-1
NMR(CDCl3,δ):1.40-1.90(8H,m),3.35(3H,s),3.41(2H,t,J=6.3Hz),4.05(2H,t,J=6.3Hz),7.00-7.04(2H,m),7.44-9.04(12H,m)
MASS(m/z):580(M+1)
制备228
IR(KBr):2956,2933,2872,1776,1601,1500,1438cm-1
NMR(CDCl3,δ):1.00(3H,t,J=7.3Hz),1.40-1.96(4H,m),4.04(2H,t,J=6.5Hz),7.02(2H,d,J=8.7Hz),7.36-7.66(5H,m),7.73(2H,d,J=8.4Hz),8.00-8.21(3H,m),8.28(2H,d,J=8.6Hz),8.44(2H,d,J=8.7Hz)
MASS(m/z):548(M++1)
制备229
IR(KBr):2870,1778,1649,1601,1529,1500,1471,1439cm-1
NMR(CDCl3,δ):1.70-2.00(4H,m),3.37(3H,s),3.47(2H,t,J=6.1Hz),4.06(2H,t,J=6.1Hz),7.01(2H,d,J=8.7Hz),7.42-7.68(3H,m),7.60(2H,d,J=8.8Hz),7.72(2H,d,J=8.5Hz),8.06-8.20(1H,m),8.28(2H,d,J=8.7Hz),8.43(2H,d,J=8.6Hz)
MASS(m/z):578(M++1)
制备230
NMR(CDCl3,δ):1.29(3H,t,J=7.0Hz),3.60(2H,q,J=7.0Hz),4.58(2H,s),7.40-7.64(5H,m),7.65(2H,d,J=8.2Hz),7.76(2H,d,J=8.4Hz),8.09-8.20(3H,m),8.29(2H,d,J=8.7Hz),8.44(2H,d,J=8.7Hz)
MASS(m/z):534(M++1)
制备231
IR(KBr):2978,2937,2873,1772,1599,1498,1439cm-1
NMR(CDCl3,δ):3.42(3H,m),3.55-3.74(4H,m),4.65(2H,s),7.43-7.63(5H,m),7.65(2H,d,J=8.2Hz),7.76(2H,d,J=8.5Hz),8.08-8.17(3H,m),8.28(2H,d,J=8.7Hz),8.43(2H,d,J=8.6Hz)
MASS(m/z):564(M++1)
制备232
NMR(CDCl3,δ):3.41(3H,s),3.54-3.68(2H,m),3.68-3.80(2H,m),3.90(2H,t,J=4.9Hz),4.22(2H,t,J=4.9Hz),7.04(2H,d,J=8.8Hz),7.44-7.68(3H,m),7.55(2H,d,J=9.1Hz),7.72(2H,d,J=8.5Hz),8.05-8.20(3H,m),8.27(2H,d,J=8.6Hz),8.43(2H,d,J=8.7Hz)
MASS(m/z):594(M++1)
制备233
IR(KBr):2976,2868,1778,1601,1527,1500,1471,1439cm-1
NMR(CDCl3,δ):1.22(3H,t,J=7.0Hz),2.10(2H,m),3.52(2H,q,J=7.0Hz),3.63(2H,t,J=6.2Hz),4.14(2H,t,J=6.5Hz),7.03(2H,d,J=8.8Hz),7.42-7.66(5H,m),7.72(2H,d,J=8.5Hz),8.04-8.20(1H,m),8.10(2H,d,J=8.4Hz),8.28(2H,d,J=8.6Hz),8.43(2H,d,J=8.6Hz)
制备234
IR(KBr):2926,2877,1768,1601,1527,1500,1439,1417cm-1
NMR(CDCl3,δ):2.09(2H,m),3.38(3H,s),3.59(2H,t,J=6.1Hz),4.13(2H,t,J=6.3Hz),7.03(2H,d,J=8.8Hz),7.44-7.66(5H,m),7.72(2H,d,J=8.5Hz),8.08-8.18(3H,m),8.28(2H,d,J=8.7Hz),8.44(2H,d,J=8.7Hz)
MASS(m/z):564(M++1)
制备235
IR(KBr):1776,1655,1601,1529,1498,1439cm-1
NMR(CDCl3,δ):3.49(3H,s),3.80(2H,m),4.20(2H,m),7.05(2H,d,J=8.8Hz),7.40-7.64(4H,m),7.72(2H,d,J=8.4Hz),7.98-8.18(4H,m),8.28(2H,d,J=g.6Hz),8.44(2H,d,J=8.7Hz)
MASS(m/z):550(M++1)
制备236
IR(KBr):1776,1603,1527,1497,1439cm-1
NMR(CDCl3,δ):1.19-2.14(10H,m),4.23-4.40(1H,m),7.02(2H,d,J=8.8Hz),7.41-7.67(5H,m),7.72(2H,d,J=8.5Hz),8.02-8.21(3H,m),8.28(2H,d,J=8.7Hz),8.43(2H,d,J=8.7Hz)
MASS(m/z):574(M++1)
制备237
IR(KBr):2929.3,2856.1,1774.2,1602.6,1253.5cm-1
NMR(CDCl3,δ):0.80-1.10(3H,m),1.10-1.60(8H,m),1.60-2.00(2H,m),4.03(2H,t,J=6.5Hz),6.98(2H,d,J=8.8Hz),7.40-7.70(3H,m),7.81(2H,d,J=8.5Hz),7.93(2H,d,J=8.8Hz),8.12(2H,d,J=8.1Hz),8.17(1H,s),8.31(2H,d,J=8.5Hz)
APCI MASS(m/z):513
制备238
IR(KBr):1776,1603,1524,1441,1414cm-1
NMR(CDCl3,δ):1.03-1.43(5H,m),1.54-2.14(5H,m),2.24-2.50(1H,m),2.65-2.86(4H,m),3.23-3.47(4H,m),6.98(2H,d,J=8.7Hz),7.41-7.68(3H,m),7.92(2H,d,J=8.5Hz),8.13(1H,d,J=8.2Hz),8.24(2H,d,J=8.2Hz),8.40(2H,d,J=8.2Hz)
MASS(m/z):566(M++1)
制备239
IR(KBr):1772,1574,1234cm-1
NMR(CDCl3,δ):2.6-2.75(4H,m),3.2-3.3(4H,m),3.65(2H,s),6.8-7.0(3H,m),7.1-7.3(2H,m),7.4-7.6(4H,m),7.74(2H,d,J=8.5Hz),8.14(2H,d,J=8.1Hz),8.21(1H,s),8.26(2H,d,J=8.6Hz),8.43(2H,d,J=8.6Hz),8.59(1H,s)
MASS(m/z):640(M++1)
制备240
IR(KBr):1780,1520,1236,982cm-1
NMR(CDCl3,δ):1.5-1.8(6H,m),3.42(4H,t,J=5.6Hz),7.02(2H,d,J=9.1Hz),7.4-7.7(5H,m),8.14(2H,d,J=10.5Hz),8.25(2H,d,J=8.6Hz),8.42(2H,d,J=8.6Hz),8.47(1H,s)
MASS(m/z):549(M++1)
制备241
IR(KBr):1776,1571,1252cm-1
NMR(CDCl3,δ):0.8-1.0(3H,m),1.2-1.8(8H,m),4.02(2H,t,J=6.5Hz),7.01(2H,d,J=9.0Hz),7.4-7.7(5H,m),8.1-8.3(4H,m),8.43(2H,d,J=8.6Hz),8.51(1H,s)
制备242
IR(KBr):2927,2854,1599,1531,1498,1444cm-1
MASS(m/z):642(M++1)
制备243
IR(KBr):1782,1597,1533,1502,1444,1421cm-1
NMR(CDCl3,δ):1.30(6H,d,J=6.3Hz),2.40-2.58(2H,m),3.49-3.63(2H,m),3.72-3.94(2H,m),7.01(2H,d,J=8.8Hz),7.42-7.65(5H,m),7.73(2H,d,J=8.5Hz),8.09(2H,d,J=8.6Hz),8.14(1H,d,J=8.4Hz),8.28(2H,d,J=8.6Hz),8.44(2H,d,J=8.6Hz)
MASS(m/z):589(M++1)
制备244
IR(KBr):1778,1603,1441,1414cm-1
NMR(CDCl3,δ):0.92(6H,s),1.10-1.84(8H,m),2.16-2.35(1H,m),2.68-2.87(4H,m),3.30-3.46(4H,m),6.98(2H,d,J=9.0Hz),7.40-7.65(3H,m),7.93(2H,d,J=8.8Hz),8.13(1H,d,J=8.1Hz),8.25(2H,d,J=8.7Hz),8.40(2H,d,J=8.6Hz)
MASS(m/z):594(M++1)
制备245
IR(KBr):1784,1603,1520,1441,1414cm-1
NMR(CDCl3,δ):1.66-2.14(4H,m),3.07-3.28(2H,m),3.56-3.84(3H,m),4.60(2H,s),6.98(2H,d,J=9.0Hz),7.23-7.67(8H,m),7.91(2H,d,J=8.9Hz),8.13(1H,d,J=8.2Hz),8.23(2H,d,J=8.6Hz),8.40(2H,d,J=8.6Hz)
MASS(m/z):589(M++1)
制备246
IR(KBr):1780,1603,1522,1441,1414cm-1
NMR(CDCl3,δ):0.95(3H,d,J=6.9Hz),1.37-2.15(9H,m),2.25-2.44(1H,m),2.68-2.92(4H,m),3.27-3.50(4H,m),6.98(2H,d,J=9.0Hz),7.37-7.67(3H,m),7.93(2H,d,J=8.9Hz),8.08-8.18(1H,m),8.24(2H,d,J=8.6Hz),8.40(2H,d,J=8.6Hz)
制备247
IR(KBr):1778,1603,1524,1441,1414cm-1
NMR(CDCl3,δ):0.90(3H,d,J=6.4Hz),0.90-1.13(2H,m),1.13-2.05(7H,m),2.20-2.48(1H,m),2.62-2.90(4H,m),3.23-3.53(4H,m),6.97(2H,d,J=9.0Hz),7.38-7.66(3H,m),7.92(2H,d,J=8.8Hz),8.06-8.17(1H,m),8.24(2H,d,J=8.6Hz),8.40(2H,d,J=8.7Hz)
制备248
IR(液体石蜡):1782,1603cm-1
NMR(CDCl3,δ):1.9-2.3(4H,m),3.03(3H,s),3.2-3.5(2H,m),3.6-3.9(2H,m),7.03(2H,d,J=8.9Hz),7.36(4H,s),7.4-7.7(3H,m),7.93(2H,d,J=8.9Hz),8.13(1H,d,J=8.2Hz)
(+)APCI MASS:623(M+H)+
制备249
IR(KBr):2923,2848,2823,1766,1602,1515,1450,1378,1259,1222,1186,1153,1089,1014,971cm-1
NMR(CDCl3,δ):1.2-1.5(5H,m),1.6-1.9(7H,m),2.07(2H,m),2.43(1H,m),2.6-2.9(5H,m),3.02(2H,t,J=8.5Hz),3.26(4H,m),4.07(2H,d,J=13Hz),6.8-7.1(4H,m),7.12(2H,d,J=8.6Hz),7.3-7.6(3H,m),8.0-8.2(3H,m)
MASS(m/z):462(M+H+)
制备250
IR(KBr):1780,1682,1655,1601,1549,1498,1429cm-1
NMR(CDCl3,δ):1.62-1.95(2H,m),2.01(2H,m),2.70-3.18(3H,m),4.64(2H,m),6.80(1H,d,J=9.1Hz),7.18-7.40(5H,m),7.40-7.65(3H,m),8.00-8.25(2H,m),8.25(2H,d,J=8.6Hz),8.41(2H,d,J=8.6Hz),8.76(1H,d,J=2.3Hz)
MASS(m/z):560(M++1)
制备251
IR(KBr):1781.9,1602.6,1228.4cm-1
NMR(CDCl3,δ):1.54-1.87(6H,m),3.35(3H,s),3.38-3.68(10H,m),4.00(2H,t,J=6.4Hz),6.93-7.05(6H,m),7.39-7.53(7H,m),8.08-8.18(3H,m)
制备252
IR(KBr):1776.1,1600.6,1232.3cm-1
NMR(CDCl3,δ):2.73-2.78(4H,m),2.93-3.73(9H,m),6.94-6.98(2H,m),7.14-7.58(7H,m),8.07-8.15(3H,m)
MASS(m/z):440(M+1)
制备253
IR(KBr):1778,1599,1576,1527,1498,1473,1439cm-1
NMR(CDCl3,δ):1.47(3H,t,J=7.0Hz),4.11(2H,q,J=7.0Hz),7.02(2H,d,J=8.9Hz),7.42-7.80(7H,m),8.10-8.56(7H,m)
MASS(m/z):520(M++1)
以类似于制备46的方法获得下列化合物[制备254-270]。
制备254
IR(KBr):1702.2,1702.8cm-1
NMR(DMSO-d6,δ):3.83(3H,s),8.06(2H,d,J=8.7Hz),8.20(2H,d,J=8.7Hz),8.24(1H,s),9.31(1H,s),10.04(1H,s)
MASS(m/z):231(M++1)
制备255
IR(KBr):1722,1562,1514,1346,1279cm-1
NMR(CDCl3,δ):3.90(3H,s),7.92(2H,d,J=9.2Hz),8.16(1H,s),8.38(2H,d,J=9.2Hz),8.86(1H,s)
MASS(m/z):246(M++1)
制备256
IR(KBr):2937,2856,2819,2213,1608,1517,1448,384,1349,1247,1224,1180,1122cm-1
NMR(CDCl3,δ):1.66(6H,m),3.32(4H,t,J=5.0Hz),6.83(2H,d,J=9.1Hz),7.46(2H,d,J=9.1Hz)
MASS(m/z):187(M+H+)
制备257
NMR(CDCl3,δ):3.28(4H,t,J=4.9Hz),3.85(2H,d,J=4.9Hz),6.87(2H,d,J=9.0Hz),7.52(2H,d,J=9.0Hz)
MASS(m/z):189(M+H+)
制备258
NMR(CDCl3,δ):1.27(6H,d,J=6.2Hz),2.52(2H,t,J=11.5Hz),3.57(2H,dd,J=2.2和J=12.7Hz),3.6-3.9(2H,m),6.85(2H,d,J=9.0Hz),7.50(2H,d,J=9.0Hz)
MASS(m/z):217(M+H+)
制备259
NMR(CDCl3,δ):2.69(2H,t,J=5.1Hz),3.77(2H,t,J=5.1Hz),6.81(2H,d,J=9.0Hz),7.49(2H,d,J=9.0Hz)
MASS(m/z):205(M+H+)
制备260
NMR(CDCl3,δ):1.13(3H,t,J=7.2Hz),2.47(2H,q,J=7.2Hz),2.58(4H,t,J=5.1Hz),3.35(4H,t,J=5.1Hz),7.22(2H,d,J=8.8Hz),7.49(2H,d,J=8.8Hz)
MASS(m/z):216(M+H+)
制备261
NMR(CDCl3,δ):1.36(3H,t,J=7.1Hz),1.55-1.75(2H,m),1.80-2.10(4H,m),3.00-3.15(2H,m),3.60-4.00(3H,m),4.31(2H,q,J=7.1Hz),6.82(2H,d,J=9.1Hz),7.90(2H,d,J=9.1Hz)
APCI MASS(正性):250.3(M++1)
制备262
NMR(CDCl3,δ):1.37(3H,t,J=7.1Hz),1.60-2.10(4H,m),2.55-2.80(1H,m),2.95(2H,dt,J=3.1Hz,J=12.3Hz),3.90-4.05(2H,m),4.32(2H,q,J=7.1Hz),6.90(2H,d,J=9.1Hz),7.10-7.35(4H,m),7.93(2H,d,J=9.1Hz
APCI MASS:310.3(M++1)
制备263
NMR(DMSO-d6,δ):1.29(3H,t,J=7.1Hz),3.21-3.34(4H,m),3.40-3.53(4H,m),4.24(2H,q,J=7.1Hz),6.81(1H,t,J=7.2Hz),7.00(2H,d,J=7.9Hz),7.05(2H,d,J=9.0Hz),7.25(2H,t,J=7.9Hz),7.81(2H,d,J=8.9Hz)
MASS(m/z):311(M++1)
制备264
NMR(DMSO-d6,δ):1.28(3H,t,J=7.1Hz),1.26-1.54(2H,m),1.64-1.90(2H,m),2.90-3.16(2H,m),3.58-3.84(3H,m),4.23(2H,q,J=7.1Hz),4.75(1H,brs),6.95(2H,d,J=9.1Hz),7.76(2H,d,J=9.0Hz)
MASS(m/z):250(M++1)
制备265
IR(KBr):2939,2843,1703,1601,1552,1497,1439,1414cm-1
NMR(DMSO-d6,δ):1.59(2H,m),1.87(2H,m),2.78-3.15(3H,m),3.79(3H,s),4.62(2H,m),6.92(1H,d,J=9.1Hz),7.21(5H,m),7.94(1H,dd,J=9.1和2.3Hz),8.65(1H,d,J=2.3Hz)
MASS(m/z):297(M++1)
制备266
IR(KBr):1707,1610,1516,1444cm-1
NMR(DMSO-d6,δ):1.04-1.30(5H,m),1.28(3H,t,J=7.1Hz),1.47-1.86(5H,m),2.16-2.34(1H,m),2.52-2.64(4H,m),3.19-3.34(4H,m),4.23(2H,q,J=7.1Hz),6.95(2H,d,J=9.0Hz),7.77(2H,d,J=8.9Hz)
MASS(m/z):317(M++1)
制备267
IR(液体石蜡):1699,1606cm-1
NMR(CDCl3,δ):1.37(3H,t,J=7.1Hz),1.9-2.2(4H,m),3.01(3H,s),3.2-3.4(2H,m),3.6-3.8(2H,m),4.33(2H,q,J=7.1Hz)
(+)APCI MASS:374(M+H)+
制备268
IR(KBr):2927,2850,2212,1602,1517,1442,1394,1253,1178,1143,927,823cm-1
NMR(CDCl3,δ):1.2(5H,m),1.65(1H,m),1.85(4H,m),2.30(1H,m),2.70(4H,t,J=5.1Hz),3.32(4H,t,J=5.1Hz),6.85(2H,d,J=9.0Hz),7.48(2H,d,J=9.0Hz)
MASS(m/z):270(M+H+)
制备269
制备270
IR(KBr):1708.6,1288.2,1230.4cm-1
NMR(CDCl3,δ):1.38(3H,t,J=7.1Hz),1.50-1.87(6H,m),3.34(3H,s),3.37-3.53(10H,m),4.00(2H,t,J=6.4Hz),4.34(2H,q,J=7.1Hz),6.90-7.04(6H,m),7.45-7.51(4H,m),7.94-7.98(2H,m)
MASS(m/z):503(M+1)
以类似于制备16的方法获得下列化合物[制备271-279]。
制备271
IR(KBr):1724,1558,1521,1257cm-1
NMR(CDCl3,δ):0.91(3H,t,J=6.9Hz),1.3-1.9(8H,m),3.87(3H,s),3.99(2H,t,J=6.5Hz),6.98(2H,d,J=9.0Hz),7.58(2H,d,J=9.0Hz),8.30(1H,s),8.53(1H,s)
MASS(m/z):303(M++1)
制备272
NMR(CDCl3,δ):1.44(3H,t,J=7.0Hz),4.08(2H,qt,J=7.0Hz),6.98(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.62(2H,d,J=8.6Hz),8.07(2H,d,J=8.6Hz)
MASS(m/z):257(M++1)
制备273
IR(KBr):2947,2875,1722,1603,1527,1495,1435cm-1
NMR(CDCl3,δ):1.88-2.18(4H,m),3.51(2H,m),3.93(3H,s),4.05(2H,m),6.98(2H,d,J=8.6Hz),7.50-7.70(4H,m),8.08(2H,d,J=8.2Hz)
MASS(m/z):363(M++1),365(M++3)
制备274
NMR(CDCl3,δ):3.40(3H,s),3.60(2H,m),3.73(2H,m),3.89(2H,m),3.93(3H,s),4.20(2H,m),7.01(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.62(2H,d,J=8.6Hz),8.08(2H,d,J=8.6Hz)
MASS(m/z):331(M++1)
制备275
NMR(CDCl3,δ):1.26(3H,t,J=7.0Hz),3.62(2H,q,J=7.0Hz),3.76-3.87(2H,m),3.93(3H,s),4.12-4.24(2H,m),6.96-7.08(2H,m),7.52-7.70(4H,m),8.02-8.14(2H,m)
MASS(m/z):310(M++1)
制备276
IR(KBr):2949,2877,1722,1695,1603,1529,1497,1435cm-1
NMR(CDCl3,δ):3.47(3H,s),3.78(2H,m),3.93(3H,s),4.18(2H,m),6.95-7.08(2H,m),7.48-7.68(4H,m),8.00-8.12(2H,m)
MASS(m/z):287(M++1)
制备277
IR(KBr):2954,2873,1718,1610,1544,1494,1471,1280,1249,1110cm-1
MASS(m/z):408((M-TFA)+H+)
制备278
IR(KBr):2935,2867,1720,1610,1544,1494,1471,1436,1405,1332,1280,1249,1176,1110cm-1
MASS(m/z):436(M+H+)
制备279
IR(KBr):2950,2867,1708,1608,1525,1471,1409,1305,1259,1274,1176,1103cm-1
MASS(m/z):450(M+H+)
以类似于制备47的方法获得下列化合物[制备280-309]。
制备280
IR(KBr):1653,1626,1574,1524cm-1
NMR(DMSO-d6,δ):0.85(3H,m),1.1-1.6(10H,m),3.44(2H,t,J=6.4Hz),4.42(2H,brs),4.48(2H,s),7.44(2H,d,J=8.6Hz),7.82(2H,d,J=8.6Hz),8.12(1H,s),8.88(1H,s),9.48(1H,brs)
MASS(m/z):331(M++1)
制备281
IR(KBr):1657,1603,1570,1516,1313cm-1
NMR(DMSO-d6,δ):2.4-2.6(4H,m),3.0-3.2(4H,m),3.57(2H,s),4.41(2H,d,J=4.3Hz),6.76(1H,t,J=7.8Hz),6.92(2H,d,J=7.8Hz),7.20(2H,t,J=7.8Hz),7.47(2H,t,J=8.5Hz),7.81(2H,d,J=8.5Hz),8.12(1H,s),8.88(1H,s),9.48(1H,t,J=4.3Hz)
MASS(m/z):377(M++1)
制备282
IR(KBr):1632,1562,1516cm-1
NMR(DMSO-d6,δ):1.5-1.8(6H,m),3.0-3.3(4H,m),4.38(2H,d,J=3.9Hz),7.03(2H,d,J=9.1Hz),8.04(1H,s),8.70(1H,s),9.41(1H,brs)
MASS(m/z):286(M++1)
制备283
IR(KBr):1649,1623,1522cm-1
NMR(DMSO-d6,δ):0.8-1.0(3H,m),1.2-1.8(8H,m),4.00(2H,t,J=4.0Hz),4.39(2H,d,J=4.0Hz),7.05(2H,d,J=9.0Hz),7.72(2H,d,J=9.0Hz),8.07(1H,s),8.76(1H,s),9.44(1H,t,J=4.0Hz)
MASS(m/z):303(M++1)
制备284
IR(KBr):1618,1560,1525cm-1
NMR(DMSO-d6,δ):1.9-2.1(4H,m),3.1-3.3(4H,m),4.38(2H,brs),6.62(2H,d,J=9.0Hz),7.58(2H,d,J=9.0Hz),8.02(1H,s),8.64(1H,s),9.40(1H,brs)
MASS(m/z):294(M++23)
制备285
NMR(CDCl3,δ):1.10-1.40(5H,m),1.40-2.10(10H,m),2.90-3.15(2H,m),3.25-3.50(1H,m),3.50-3.75(3H,m),4.05(2H,d,J=3.9Hz),6.88(2H,d,J=9.0Hz),7.63(2H,dd,J=9.0和2.0Hz)
APCI MASS(正性):318.3(M++1)
制备286
NMR(CDCl3,δ):1.70-2.10(4H,m),2.60-2.85(1H,m),2.85-3.05(2H,m),3.05-3.50(2H,m),3.85-4.10(2H,m),6.85-7.00(2H,m),7.10-7.40(5H,m),7.68(2H,d,J=8.8Hz)
APCI MASS:296(M++1)
制备287
NMR(CDCl3,δ):1.20-2.10(10H,m),4.10(2H,brs),4.20-4.40(1H,m),6.91(2H,d,J=8.9Hz),7.49(1H,brs),7.78(2H,d,J=8.9Hz)
ESI MASS:257.3(M++Na)
制备288
NMR(CDCl3,δ):1.10-1.55(5H,m),1.60-2.00(5H,m),2.40-2.65(1H,m),7.25(2H,d,J=8.2Hz),7.67(2H,d,J=8.2Hz)
APCI MASS:219(M++1)
制备289
IR(KBr):2958,2929,2850,2821,1651,1628,1603,1529,1487,1443cm-1
NMR(DMSO-d6,δ):1.00-1.36(5H,m),1.50-1.92(5H,m),2.16-2.38(1H,m),2.57-2.64(4H,m),3.10-3.28(4H,m),4.48(2H,s),7.01(2H,d,J=8.9Hz),7.59(2H,d,J=8.8Hz),7.67(2H,d,J=8.5Hz),7.86(2H,d,J=8.4Hz),9.76(1H,s)
MASS(m/z):379(M++1)
制备290
NMR(DMSO-d6,δ):3.13-3.54(8H,m),4.38(2H,s),6.81(1H,t,J=7.2Hz),7.00(2H,d,J=6.9Hz),7.01(2H,d,J=8.8Hz),7.24(2H,t,J=7.9Hz),7.74(2H,d,J=8.8Hz),9.51(1H,s)
MASS(m/z):297(M++1)
制备291
NMR(DMSO-d6,δ):0.87(3H,t,J=7.4Hz),1.37-1.60(4H,m),1.80-1.98(2H,m),2.90-3.10(2H,m),3.38(2H,t,J=6.6Hz),3.38-3.70(3H,m),4.34和4.35(2H,s),6.92(2H,d,J=9.0Hz),7.68(2H,d,J=8.9Hz),9.45(1H,brs)
MASS(m/z):278(M++1)
制备292
IR(KBr):1666,1605,1545,1495,1448cm-1
NMR(DMSO-d6,δ):1.17(6H,d,J=6.1Hz),2.20-2.38(2H,m),3.59-3.78(4H,m),4.49(2H,s),7.03(2H,d,J=8.9Hz),7.61(2H,d,J=8.8Hz),7.69(2H,d,J=8.5Hz),7.87(2H,d,J=8.4Hz),9.77(1H,s)
MASS(m/z):326(M++1)
制备293
NMR(DMSO-d6,δ):0.88(6H,s),1.05-1.52(6H,m),1.52-1.73(2H,m),2.08-2.26(1H,m),2.52-2.72(4H,m),3.10-3.31(4H,m),4.36(2H,s),6.91(2H,d,J=8.9Hz),7.69(2H,d,J=8.8Hz),9.46(1H,s)
MASS(m/z):331(M++1)
制备294
IR(KBr):1637,1606,1554,1508,1456cm-1
NMR(DMSO-d6,δ):1.46-1.70(2H,m),1.87-2.06(2H,m),2.92-3.12(2H,m),3.52-3.73(3H,m),4.35(2H,s),4.54(2H,s),6.94(2H,d,J=8.9Hz),7.20-7.42(5H,m),7.69(2H,d,J=8.8Hz),9.45(1H,s)
MASS(m/z):326(M++1)
制备295
NMR(DMSO-d6,δ):1.16-2.04(10H,m),4.29-4.51(1H,m),4.51(2H,s),7.03(2H,d,J=8.8Hz),7.64(2H,d,J=8.8Hz),7.69(2H,d,J=8.4Hz),7.88(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):311(M++1)
制备296
IR(KBr):2912,2870,2846,1608,1597,1533,1493,1423cm-1
NMR(CDCl3,δ):1.74(2H,m),1.97(2H,m),2.70-3.12(3H,m),3.31(2H,brs),4.58(2H,m),6.69(1H,d,J=9.0Hz),7.05-7.55(6H,m),7.88(1H,dd,J=9.0和2.3Hz),8.56(1H,d,J=2.3Hz)
MASS(m/z):297(M++1)
制备297
NMR(DMSO-d6,δ):1.35(3H,t,J=7.0Hz),4.07(2H,q,J=7.0Hz),4.50(2H,s),7.02(2H,d,J=8.8Hz),7.66(2H,d,J=8.7Hz),7.70(2H,d,J=8.4Hz),7.89(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):257(M++1)
制备298
IR(KBr):2956,2916,2870,1612,1535,1514,1493cm-1
NMR(DMSO-d6,δ):1.55-1.87(4H,m),3.24(3H,s),3.38(2H,t,J=6.2Hz),4.03(2H,t,J=6.1Hz),4.57(2H,brs),7.03(2H,d,J=8.7Hz),7.58-7.78(4H,m),7.89(2H,d,J=8.3Hz),9.79(1H,s)
MASS(m/z):315(M++1)
制备299
IR(KBr):1626,1606,1566,1524,1498,1454cm-1
NMR(DMSO-d6,δ):1.00-1.35(5H,m),1.35-1.90(5H,m),2.16-2.36(1H,m),2.54-2.69(4H,m),3.12-3和28(4H,m),4.35(2H,s),6.91(2H,d,J=8.9Hz),7.69(2H,d,J=8.8Hz),9.46(1H,s)
MASS(m/z):303(M++1)
制备300
IR(KBr):1659,1626,1606,1531,1498,1446cm-1
NMR(DMSO-d6,δ):0.89(3H,d,J=6.8Hz),1.32-1.80(9H,m),2.10-2.26(1H,m),2.50-2.65(4H,m),3.15-3.30(4H,m),4.36(2H,s),6.92(2H,d,J=9.0Hz),7.69(2H,d,J=8.8Hz),9.46(1H,s)
MASS(m/z):317(M++1)
制备301
IR(KBr):1660,1606,1549,1506,1446cm-1
NMR(DMSO-d6,δ):0.86(3H,d,J=6.4Hz),0.84-1.05(2H,m),1.05-1.54(3H,m),1.60-1.90(4H,m),2.12-2.33(1H,m),2.54-2.65(4H,m),3.11-3.27(4H,m),4.36(2H,s),6.91(2H,d,J=8.9Hz),7.69(2H,d,J=8.8Hz),9.46(1H,s)
MASS(m/z):317(M++1)
制备302
NMR(DMSO-d6,δ):1.17(3H,t,J=7.0Hz),3.51(2H,q,J=7.0Hz),4.50(2H,m),4.52(2H,s),7.42(2H,d,J=8.2Hz),7.66-7.80(4H,m),7.92(2H,d,J=8.9Hz),9.83(1H,s)
MASS(m/z):271(M++1)
制备303
NMR(DMSO-d6,δ):3.27(3H,m),3.45-3.68(4H,m),4.54(4H,s),7.43(2H,d,J=8.2Hz),7.66-7.81(4H,m),7.92(2H,d,J=8.4Hz),9.83(1H,s)
MASS(m/z):301(M++1)
制备304
NMR(DMSO-d6,δ):3.25(3H,s),3.44-3.55(2H,m),3.55-3.65(2H,m),3.73-3.86(2H,m),4.08-4.20(2H,m),4.52(2H,s),7.05(2H,d,J=8.8Hz),7.67(2H,d,J=8.7Hz),7.70(2H,d,J=8.4Hz),7.89(2H,d,J=8.5Hz),9.80(1H,s)
MASS(m/z):331(M++1)
制备305
NMR(DMSO-d6,δ):1.11(3H,t,J=7.0Hz),1.96(2H,m),3.43(2H,q,J=7.0Hz),3.52(2H,t,J=6.4Hz),4.07(2H,t,J=6.4Hz),4.50(2H,s),7.03(2H,d,J=8.8Hz),7.66(2H,d,J=8.7Hz),7.70(2H,d,J=8.5Hz),7.89(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):315(M++1)
制备306
NMR(DMSO-d6,δ):1.14(3H,t,J=7.0Hz),3.51(2H,q,J=7.0Hz),3.66-3.80(2H,m),4.07-4.20(2H,m),4.51(2H,s),7.05(2H,d,J=8.8Hz),7.67(2H,d,J=8.8Hz),7.70(2H,d,J=8.4Hz),7.89(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):301(M++1)
制备307
IR(KBr):2933,2873,1608,1531,1491cm-1
NMR(DMSO-d6,δ):1.97(2H,m),3.26(3H,s),3.49(2H,t,J=6.3Hz),4.07(2H,t,J=6.4Hz),4.50(2H,brs),7.03(2H,d,J=8.8Hz),7.66(2H,d,J=8.7Hz),7.70(2H,d,J=8.5Hz),7.88(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):301(M++1)
制备308
IR(KBr):2927,2881,1630,1606,1533,1489cm-1
NMR(DMSO-d6,δ):3.32(3H,s),3.67(2H,m),4.14(3H,s),4.52(2H,s),7.05(2H,d,J=8.8Hz),7.67(2H,d,J=8.8Hz),7.70(2H,d,J=8.6Hz),7.89(2H,d,J=8.4Hz),9.79(1H,s)
MASS(m/z):287(M++1)
制备309
IR(液体石蜡):3292,1603cm-1
NMR(DMSO-d6,δ):1.8-2.2(4H,m),2.92(3H,s),3.0-3.2(2H,m),3.6-3.8(2H,m),4.36(2H,s),6.98(2H,d,J=8.8Hz),7.44(4H,s),7.71(2H,d,J=8.8Hz),9.46(1H,s)
(+)APCI MASS:360(M+H)+
以类似于制备7的方法获得下列化合物[制备310-345]。
制备310
IR(KBr):1724,1282cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.9Hz),1.1-1.6(10H,m),3.45(2H,t,J=6.4Hz),3.90(3H,s),4.50(2H,s),7.48(2H,d,J=8.6Hz),7.86(2H,d,J=8.6Hz),8.04(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),8.26(1H,s),9.02(1H,s),10.37(1H,s),10.70(1H,s)
MASS(m/z):493(M++1)
制备311
IR(KBr):1718,1614,1279cm-1
NMR(DMSO-d6,δ):2.4-2.6(4H,m),3.0-3.2(4H,m),3.59(2H,s),3.90(3H,s),6.77(1H,t,J=7.7Hz),6.92(2H,d,J=7.7Hz),7.20(2H,t,J=7.7Hz),7.50(2H,t,J=8.5Hz),7.86(2H,d,J=8.5Hz),8.04(2H,t,J=8.6Hz),8.11(2H,d,J=8.6Hz),8.26(1H,s),9.02(1H,s),10.37(1H,s),10.70(1H,s)
MASS(m/z):539(M++1)
制备312
NMR(DMSO-d6,δ):1.10-2.00(14H,m),2.95-3.15(2H,m),3.40-3.75(4H,m),3.90(3H,s),7.00(2H,d,J=8.9Hz),7.80(2H,d,J=8.8Hz),8.03(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.25(1H,s),10.58(1H,s)APCI MASS(正性):480.3(M++1)
制备313
IR(KBr):1724,1635,1570,1520,1279cm-1
NMR(DMSO-d6,δ):1.5-1.7(6H,m),3.1-3.3(4H,m),3.90(3H,s),7.05(2H,d,J=9.1Hz),7.66(2H,d,J=9.1Hz),8.04(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),8.85(1H,s),10.30(1H,s),10.68(1H,s)
MASS(m/z):448(M++1)
制备314
IR(KBr):1716,1603,1552,1521,1470,1284,1257cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.8Hz),1.2-1.8(8H,m),3.90(3H,s),4.02(2H,t,J=6.4Hz),7.08(2H,d,J=9.0Hz),7.77(2H,d,J=9.0Hz),8.04(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),8.91(1H,s),10.33(1H,s),10.69(1H,s)
MASS(m/z):465(M++1)
制备315
NMR(DMSO-d6,δ):1.60-1.95(4H,m),2.65-3.00(3H,m),3.90(3H,s),4.04(2H,m),7.05(2H,d,J=8.9Hz),7.10-7.40(5H,m),7.83(2H,d,J=8.9Hz),8.00-8.15(4H,m),10.27(1H,s),10.59(1H,s)
APCI MASS:458(M+)
制备316
IR(KBr):1720,1645,1560,1525,1281cm-1
NMR(DMSO-d6,δ):1.9-2.1(4H,m),3.2-3.4(4H,m),3.90(3H,s),6.64(2H,d,J=9.0Hz),7.63(2H,d,J=9.0Hz),8.04(2H,d,J=8.7Hz),8.11(2H,d,J=8.7Hz),8.15(1H,s),8.78(1H,s),10.28(1H,s),10.67(1H,s)
MASS(m/z):456(M++23)
制备317
NMR(DMSO-d6,δ):1.10-2.10(10H,m),3.90(3H,s),4.35-4.55(1H,m),7.04(2H,d,J=8.8Hz),7.88(2H,d,J=8.8Hz),8.00-8.15(4H,m),10.41(1H,s),10.64(1H,s)
APCI MASS(m/z):397(M++1)
制备318
NMR(DMSO-d6,δ):1.15-1.60(5H,m),1.60-1.90(5H,m),2.50-2.70(1H,m),3.90(3H,s),7.37(2H,d,J=8.3Hz),7.85(2H,d,J=8.2Hz),8.00-8.15(4H,m),10.48(1H,s),10.68(1H,s)
APCI MASS:381(M++1)
制备319
IR(KBr):2927,2852,1722,1684,1645,1603,1495,1446cm-1
NMR(DMSO-d6,δ):1.00-1.36(5H,m),1.51-1.91(5H,m),2.20-2.38(1H,m),2.56-2.72(4H,m),3.12-3.28(4H,m),3.90(3H,s),7.03(2H,d,J=8.9Hz),7.64(2H,d,J=8.7Hz),7.77(2H,d,J=8.5Hz),7.97(2H,d,J=8.4Hz),8.00-8.16(4H,m),10.57(1H,s),10.71(1H,s)
MASS(m/z):541(M++1)
制备320
NMR(DMSO-d6,δ):3.21-3.54(8H,m),3.90(3H,s),6.82(1H,t,J=7.2Hz),7.01(2H,d,J=7.9Hz),7.08(2H,d,J=8.9Hz),7.25(2H,t,J=7.9Hz),7.85(2H,d,J=8.8Hz),8.04(2H,d,J=8.6Hz),8.09(2H,d,J=8.6Hz),10.31(1H,s),10.60(1H,s)
MASS(m/z):459(M++1)
制备321
NMR(DMSO-d6,δ):0.88(3H,t,J=7.4Hz),1.41-1.63(4H,m),1.84-2.01(2H,m),2.96-3.16(2H,m),3.40(2H,t,J=6.6Hz),3.40-3.76(3H,m),3.90(3H,s),7.00(2H,d,J=8.9Hz),7.80(2H,d,J=8.8Hz),8.00-8.16(4H,m),10.25(1H,s),10.58(1H,s)
MASS(m/z):440(M++1)
制备322
NMR(DMSO-d6,δ):1.18(6H,d,J=6.1Hz),2.18-2.43(2H,m),3.51-3.83(4H,m),3.90(3H,s),7.06(2H,d,J=8.9Hz),7.66(2H,d,J=8.7Hz),7.78(2H,d,J=8.4Hz),7.98(2H,d,J=8.4Hz),7.98-8.16(4H,m),10.58(1H,s),10.71(1H,s)
MASS(m/z):488(M++1)
制备323
NMR(DMSO-d6,δ):0.89(6H,s),1.05-1.72(8H,m),2.09-2.30(1H,m),2.54-2.73(4H,m),3.14-3.37(4H,m),3.90(3H,s),6.99(2H,d,J=8.9Hz),7.81(2H,d,J=8.8Hz),8.03(2H,d,J=8.6Hz),8.09(2H,d,J=8.7Hz),10.26(1H,s),10.58(1H,s)
MASS(m/z):493(M++1)
制备324
IR(KBr):1714,1687,1653,1605,1560,1522,1460,1439cm-1
NMR(DMSO-d6,δ):1.45-1.70(2H,m),1.87-2.10(2H,m),2.98-3.20(2H,m),3.56-3.78(3H,m),3.90(3H,s),4.56(2H,s),7.01(2H,d,J=9.0Hz),7.21-7.46(5H,m),7.80(2H,d,J=8.8Hz),8.04(2H,d,J=8.7Hz),8.09(2H,d,J=8.7Hz),10.26(1H,s),10.58(1H,s)
MASS(m/z):488(M++1)
制备325
NMR(DMSO-d6,δ):1.18-2.05(10H,m),3.90(3H,s),4.34-4.50(1H,m),7.05(2H,d,J=8.8Hz),7.69(2H,d,J=8.7Hz),7.78(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz),8.06(2H,d,J=8.6Hz),8.11(2H,d,J=8.6Hz),10.60(1H,s),10.72(1H,s)
MASS(m/z):473(M++1)
制备326
IR(KBr):2945,2852,1720,1693,1645,1601,1524,1485cm-1
NMR(DMSO-d6,δ):1.61(2H,m),1.87(2H,m),2.78-3.14(3H,m),3.90(3H,s),4.61(2H,m),6.96(1H,d,J=9.2Hz),7.27(5H,m),7.98-8.10(1H,m),8.03(2H,d,J=8.7Hz),8.10(2H,d,J=8.6Hz),8.70(1H,d,J=2.3Hz),10.34(1H,s),10.62(1H,s)
MASS(m/z):459(M++1)
制备327
NMR(DMSO-d6,δ):1.36(3H,t,J=7.0Hz),3.90(3H,s),4.09(2H,q,J=6.9Hz),7.04(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.79(2H,d,J=8.4Hz),8.00(2H,d,J=8.5Hz),8.06(2H,d,J=8.8Hz),8.10(2H,d,J=8.7Hz),10.60(1H,s),10.72(1H,s)
MASS(m/z):419(M++1)
制备328
IR(KBr):2951,2872,1724,1680,1651,1605,1554,1497,1439cm-1
NMR(DMSO-d6,δ):1.57-1.89(4H,m),3.25(3H,s),3.39(2H,t,J=6.2Hz),3.91(3H,s),4.05(2H,t,J=6.1Hz),7.05(2H,d,J=8.8Hz),7.71(2H,d,J=8.7Hz),7.79(2H,d,J=8.4Hz),8.00(2H,d,J=8.5Hz),8.06(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.61(1H,s),10.73(1H,s)
MASS(m/z):477(M++1)
制备329
IR(KBr):1720,1678,1643,1608,1564,1525,1502cm-1
NMR(DMSO-d6,δ):0.96-1.36(5H,m),1.49-1.91(5H,m),2.16-2.35(1H,m),2.52-2.75(4H,m),3.10-3.35(4H,m),3.90(3H,s),6.99(2H,d,J=8.9Hz),7.81(2H,d,J=8.8Hz),8.04(2H,d,J=8.6Hz),8.09(2H,d,J=8.7Hz),10.27(1H,s),10.59(1H,s)
MASS(m/z):465(M++1)
制备330
IR(KBr):1722,1676,1641,1608,1500,1446cm-1
NMR(DMSO-d6,δ):0.90(3H,d,J=6.8Hz),1.30-1.85(9H,m),2.11-2.30(1H,m),2.63-2.69(4H,m),3.18-3.38(4H,m),3.90(3H,s),6.99(2H,d,J=9.0Hz),7.81(2H,d,J=8.8Hz),8.04(2H,d,J=9.1Hz),8.09(2H,d,J=8.7Hz),10.27(1H,s),10.58(1H,s)
MASS(m/z):479(M++1)
制备331
IR(KBr):1722,1678,1643,1608,1500,1446cm-1
NMR(DMSO-d6,δ):0.86(3H,d,J=6.4Hz),0.88-1.08(2H,m),1.08-1.51(3H,m),1.60-1.90(4H,m),2.14-2.35(1H,m),2.54-2.66(4H,m),3.13-3.36(4H,m),3.90(3H,s),6.98(2H,d,J=8.9Hz),7.81(2H,d,J=8.8Hz),8.03(2H,d,J=8.7Hz),8.09(2H,d,J=8.6Hz),10.26(1H,s),10.58(1H,s)
MASS(m/z):479(M++1)
制备332
NMR(DMSO-d6,δ):1.18(3H,t,J=7.0Hz),3.52(2H,q,J=7.0Hz),3.90(3H,m),4.52(2H,s),7.45(2H,d,J=8.2Hz),7.75(2H,d,J=8.2Hz),7.84(2H,d,J=8.4Hz),8.03(2H,d,J=8.4Hz),8.00-8.17(4H,m),10.64(1H,s),10.74(1H,s)
MASS(m/z):433(M++1)
制备333
NMR(DMSO-d6,δ):3.28(3H,m),3.47-3.66(4H,m),3.91(3H,s),4.56(2H,s),7.46(2H,d,J=8.3Hz),7.76(2H,d,J=8.2Hz),7.85(2H,d,J=8.4Hz),7.98-8.16(6H,m),10.65(1H,s),10.74(1H,s)
MASS(m/z):463(M++1)
制备334
NMR(DMSO-d6,δ):3.26(3H,s),3.39-3.55(2H,m),3.53-3.66(2H,m),3.77(2H,t,J=4.5Hz),3.90(3H,s),4.16(2H,t,J=4.5Hz),7.08(2H,d,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.80(2H,d,J=8.4Hz),8.00(2H,d,J=8.5Hz),8.06(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.61(1H,s),10.73(1H,s)
MASS(m/z):493(M++1)
制备335
NMR(DMSO-d6,δ):1.12(3H,t,J=7.0Hz),1.88-2.12(2H,m),3.44(2H,q,J=7.0Hz),3.53(2H,t,J=6.4Hz),3.91(3H,s),4.09(2H,t,J=6.4Hz),7.06(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.79(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz),8.06(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.61(1H,s),10.72(1H,s)
MASS(m/z):477(M++1)
制备336
NMR(DMSO-d6,δ):1.14(3H,t,J=7.0Hz),3.52(2H,q,J=7.0Hz),3.68-3.78(2H,m),3.90(3H,s),4.14-4.22(2H,m),7.08(2H,d,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.80(2H,d,J=8.4Hz),8.00(2H,d,J=8.4Hz),8.06(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.61(1H,s),10.73(1H,s)
MASS(m/z):463(M++1)
制备337
IR(KBr):1724,1680,1655,1605,1495,1437cm-1
NMR(DMSO-d6,δ):1.98(2H,m),3.26(3H,s),3.49(2H,t,J=6.3Hz),3.90(3H,s),4.09(2H,t,J=6.4Hz),7.06(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.79(2H,d,J=8.5Hz),8.00(2H,d,J=8.5Hz),8.06(2H,d,J=8.7Hz),8.10(2H,d,J=8.7Hz),10.60(1H,s),10.72(1H,s)
MASS(m/z):463(M++1)
制备338
IR(KBr):1724,1682,1645,1605,1495,1439,1404cm-1
NMR(DMSO-d6,δ):3.33(3H,s),3.69(2H,m),3.90(3H,s),4.16(2H,m),7.07(2H,d,J=8.9Hz),7.72(2H,d,J=8.7Hz),7.72(2H,d,J=8.7Hz),7.80(2H,d,J=8.6Hz),9.79(1H,s)
MASS(m/z):287(M++1)
制备339
IR(液体石蜡):3259,1724,1672,1626,1605cm-1
NMR(DMSO-d6,δ):1.9-2.2(4H,m),2.93(3H,s),3.0-3.4(2H,m),3.7-3.8(2H,m),3.90(3H,s),7.06(2H,d,J=8.9Hz),7.45(4H,s),7.82(2H,d,J=8.9Hz),8.0-8.2(4H,m),10.27(1H,s),10.59(1H,s)
(+)APCI MASS:522(M+H)+
制备340
IR(KBr):3247.5,1727.9,1687.4,1255.4cm-1
NMR(DMSO-d6,δ):1.23-1.99(16H,m),2.15-2.45(2H,m),3.21(3H,s),3.27-3.35(2H,m),3.60(3H,s),4.02(2H,t,J=6.4Hz),7.00(2H,d,J=8.6Hz),7.83(2H,d,J=8.6Hz),9.74(1H,s),10.12(1H,s)
MASS(m/z):435(M+1)
制备341
IR(KBr):3236.0,1724.0,1677.8,1255.4cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.30-1.50(4H,m),1.70-1.80(2H,m),3.87(3H,s),4.03(2H,t,J=6.4Hz),7.03-7.07(2H,m),7.68-8.00(8H,m),10.50-11.00(2H,m)
MASS(m/z):467(M+1)
制备342
IR(KBr):3201.3,1714.4,1594.8,1253.5cm-1
NMR(DMSO-d6,δ):1.30-1.80(8H,m),2.42(3H,s),3.21(3H,s),3.28-3.34(2H,m),3.34(3H,s),3.85(3H,s),4.04(2H,t,J=6.4Hz),7.04(2H,d,J=8.8Hz),7.36(1H,s),7.73(1H,s),7.95(2H,d,J=9Hz),10.22(1H,s),10.39(1H,s)
MASS(m/z):457(M+1)
制备343
IR(KBr):3199.3,1716.3,1608.3,1253.5cm-1
NMR(DMSO-d6,δ):1.37-1.80(8H,m),3.21(3H,s),3.28-3.33(2H,m),3.71(3H,s),4.03(2H,t,J=6.4Hz),6.39-6.59(2H,m),7.00-7.04(2H,m),7.24-7.47(2H,m),7.83-7.88(2H,m),10.35(2H,d,J=6.9Hz)
MASS(m/z):405(M+1)
制备344
IR(KBr):3193.5,1718.3,1606.4,1249.6cm-1
NMR(DMSO-d6,δ):1.00(3H,t,J=7.4Hz),1.75-1.85(2H,m),3.97-4.03(5H,m),7.06-8.78(12H,m),10.64(1H,s),10.72(1H,s)
MASS(m/z):483(M+1)
制备345
IR(KBr):3220.5,1720.2,1685.5,1290.1,1251.6cm-1
NMR(DMSO-d6,δ):1.30-1.80(8H,m),3.22(3H,s),3.28-3.34(2H,m),3.94(3H,s),4.05(2H,t,J=6.3Hz),7.04-7.08(2H,m),7.91-8.71(8H,m),10.47(1H,bs),10.70(1H,bs)
MASS(m/z):479(M+1)
以类似于制备41的方法获得下列化合物[制备346-355]。
制备346
IR(KBr):1726,1284cm-1
NMR(CDCl3,δ):0.89(3H,t,J=6.8Hz),1.2-1.8(10H,m),3.51(2H,t,J=6.6Hz),3.97(3H,s),4.56(2H,s),7.48(2H,d,J=8.6Hz),7.74(2H,d,J=8.6Hz),8.07(2H,d,J=8.6Hz),8.17(2H,d,J=8.6Hz),8.18(1H,s),8.55(1H,s)
MASS(m/z):491(M++1)
制备347
NMR(CDCl3+CD3OD,δ):1.15-1.40(6H,m),1.40-2.30(12H,m),2.80-3.55(4H,m),3.65-3.80(4H,m),3.97(3H,s),4.00-4.25(1H,m),7.20(2H,d,J=8.6Hz),7.93(2H,d,J=8.6Hz),8.06(2H,d,J=8.6Hz),8.16(2H,d,J=8.6Hz)
ESI MASS(正性):478(M++1)
制备348
NMR(CDCl3+CD3OD,δ):1.20-1.60(5H,m),1.65-2.05(5H,m),2.50-2.70(1H,m),3.97(3H,s),7.36(2H,d,J=8.2Hz),7.92(2H,d,J=8.3Hz),8.05-8.20(4H,m)
APCI MASS(正性):379.2(M++1)
制备349
NMR(CDCl3,δ):1.20-2.15(10H,m),3.97(3H,s),4.30-4.50(1H,m),7.01(2H,d,J=8.9Hz),7.92(2H,d,J=8.9Hz),8.00-8.30(4H,m)
APCI MASS(正性):395.2(M++1)
制备350
IR(KBr):1722,1651,1574,1522,1279cm-1
NMR(CDCl3,δ):0.92(3H,t,J=6.7Hz),1.2-1.9(8H,m),3.97(3H,s),4.01(2H,t,J=6.5Hz),7.01(2H,d,J=9.0Hz),7.64(2H,d,J=9.0Hz),8.07(2H,d,J=8.6Hz),8.15(1H,s),8.17(2H,d,J=8.6Hz),8.46(1H,s)
MASS(m/z):465(M++1)
制备351
IR(KBr):1727.9,1249.6,1180.2cm-1
NMR(DMSO-d6,δ):1.30-2.30(18H,m),3.21(3H,s),3.28-3.35(2H,m,3.62(3H,s),4.04(2H,t,J=6.4Hz),7.07(2H,d,J=8.7Hz),7.85(2H,d,J=8.7Hz)
MASS(m/z):433(M+1)
制备352
IR(KBr):1724.0,1604.5,1261.2,1182.2cm-1
NMR(DMSO-d6,δ):1.23-1.80(8H,m),2.48(3H,s),3.22(3H,s),3.22-3.33(2H,m),3.33(3H,s),3.87(3H,s),4.07(2H,t,J=6.4Hz),7.13(2H,d,J=8.9Hz),7.76-8.00(4H,m)
MASS(m/z):455(M+1)
制备353
IR(KBr):1718.3,1629.6,1257.4,1226.5cm-1
NMR(DMSO-d6,δ):1.25-1.75(8H,m),3.21(3H,s),3.28-3.34(2H,m),3.72(3H,s),4.06(2H,t,J=6.4Hz),6.33-6.41(2H,m),7.09-7.13(2H,m),7.27-7.60(2H,m),7.90-7.95(2H,m)
MASS(m/z):403(M+1)
制备354
IR(KBr):1716.3,1297.9,1255.4cm-1
NMR(DMSO-d6,δ):1.20-1.80(8H,m),3.22(3H,s),3.28-3.33(2H,m),3.95(3H,s),4.08(2H,t,J=6.4Hz),7.12-7.17(2H,m),7.97-8.73(8H,m)
MASS(m/z):477(M+1)
制备355
IR(KBr):2935.1,2854.1,1257.4,827.3cm-1
NMR(CDCl3,δ):0.80-1.10(3H,m),1.20-1.60(8H,m),1.70-2.00(2H,m),4.01(2H,t,J=6.5Hz),6.96(2H,d,J=8.8Hz),7.44(2H,d,J=8.7Hz),7.54(2H,d,J=8.7Hz),7.89(2H,d,J=8.8Hz),7.95(1H,s)
APCI MASS(m/z):430,432
以类似于制备48的方法获得下列化合物[制备356-382]。
制备356
IR(KBr):1714,1514,1277cm-1
NMR(CDCl3,δ):2.66(4H,brs),3.23(4H,brs),3.64(2H,s),3.90(3H,s),6.92(3H,m),7.26(2H,m),7.52(2H,d,J=8.0Hz),7.73(2H,d,J=8.0Hz),8.0-8.3(5H,m),8.56(1H,s)
MASS(m/z):537(M++1)
制备357
IR(KBr):1718,1520,1275,1242cm-1
NMR(CDCl3,δ):1.5-1.8(6H,m),3.24(4H,t,J=5.3Hz),3.97(3H,s),7.02(2H,d,J=9.1Hz),7.59(2H,d,J=9.1Hz),8.07(2H,d,J=8.7Hz),8.14(1H,s),8.17(2H,d,J=8.7Hz),8.44(1H,s)
MASS(m/z):446(M++1)
制备358
NMR(DMSO-d6,δ):1.50-1.95(4H,m),2.60-3.05(3H,m),3.90(3H,s),3.95-4.10(2H,m),6.90-7.35(7H,m),7.65-8.15(6H,m)
APCI MASS(m/z):456(M+)
制备359
NMR(CDCl3,δ):2.0-2.2(4H,m),3.2-3.4(4H,m),3.97(3H,s),6.62(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),8.07(2H,d,J=8.4Hz),8.13(1H,s),8.17(2H,d,J=8.4Hz),8.40(1H,s)
MASS(m/z):432(M++1)
制备360
NMR(CDCl3,δ):0.95(3H,t,J=6.6Hz),1.33-1.94(6H,m),3.99(3H,s),4.05(2H,t,J=6.5Hz),7.02(2H,d,J=8.8Hz),7.98(2H,d,J=8.7Hz),8.05-8.33(8H,m)
MASS(m/z):543(M++1)
制备361
IR(KBr):1722,1603,1500,1439,1417cm-1
NMR(CDCl3,δ):3.30-3.69(8H,m),3.93(3H,s),6.88-7.17(3H,m),7.03(2H,d,J=9.0Hz),7.34(2H,t,J=7.7Hz),7.94(2H,d,J=8.8Hz),8.08(2H,d,J=8.6Hz),8.16(2H,d,J=8.6Hz)
MASS(m/z):457(M++1)
制备362
NMR(CDCl3,δ):0.95(3H,t,J=7.4Hz),1.40-2.16(6H,m),3.03-3.30(2H,m),3.45(2H,t,J=6.7Hz),3.44-3.95(3H,m),3.96(3H,s),6.85-7.12(2H,m),7.80-7.97(2H,m),8.07(2H,d,J=8.6Hz),8.15(2H,d,J=8.6Hz)
MASS(m/z):438(M++1)
制备363
IR(KBr):1722,1605,1520,1439,1414cm-1
NMR(CDCl3,δ):0.92(6H,s),1.12-1.90(8H,m),2.18-2.24(1H,m),2.68-2.86(4H,m),3.27-3.46(4H,m),3.96(3H,s),6.97(2H,d,J=9.0Hz),7.90(2H,d,J=8.9Hz),8.07(2H,d,J=8.6Hz),8.15(2H,d,J=8.6Hz)
MASS(m/z):491(M++1)
制备364
IR(KBr):1716,1606,1520,1441,1417cm-1
NMR(CDCl3,δ):1.70-2.26(4H,m),3.10-3.31(2H,m),3.60-3.84(3H,m),3.96(3H,s),4.60(2H,s),6.90-7.20(2H,m),7.26-7.46(5H,m),7.91(2H,d,J=8.8Hz),8.09(2H,d,J=8.7Hz),8.15(2H,d,J=8.7Hz)
MASS(m/z):486(M++1)
制备365
IR(KBr):2941,2845,1713,1601,1549,1504,1431,1404cm-1
NMR(CDCl3,δ):1.79(2H,m),2.01(2H,m),2.84(1H,m),3.08(2H,m),3.96(3H,s),4.64(2H,m),6.80(1H,d,J=9.1Hz),7.18-7.40(5H,m),8.03-8.23(5H,m),8.73(1H,d,J=2.3Hz)
MASS(m/z):457(M++1)
制备366
IR(KBr):2949,2870,1722,1605,1504,1437cm-1
NMR(CDCl3,δ):1.66-2.00(4H,m),3.27(3H,s),3.47(2H,t,J=6.0Hz),3.97(3H,s),4.05(2H,t, J=6.1Hz),7.00(2H,d,J=8.6Hz),7.59(2H,d,J=8.6Hz),7.70(2H,d,J=8.2Hz),8.00-8.14(4H,m),8.17(2H,d,J=8.5Hz)
MASS(m/z):475(M++1)
制备367
IR(KBr):1720,1605,1522,1439,1416cm-1
NMR(CDCl3,δ):1.00-1.41(5H,m),1.56-2.14(5H,m),2.24-2.41(1H,m),2.66-2.82(4H,m),3.27-3.43(4H,m),3.96(3H,s),6.96(2H,d,J=9.0Hz),7.89(2H,d,J=8.9Hz),8.06(2H,d,J=8.6Hz),8.14(2H,d,J=8.6Hz)
MASS(m/z):463(M++1)
制备368
IR(KBr):1718,1605,1520,1439,1414cm-1
NMR(CDCl3,δ):0.95(3H,d,J=6.9Hz),1.38-1.90(9H,m),2.24-2.47(1H,m),2.66-2.92(4H,m),3.28-3.53(4H,m),3.96(3H,s),6.97(2H,d,J=9.0Hz),7.90(2H,d,J=8.9Hz),8.07(2H,d,J=8.7Hz),8.15(2H,d,J=8.7Hz)
MASS(m/z):477(M++1)
制备369
IR(KBr):1724,1605,1520,1437,1412cm-1
NMR(CDCl3,δ):0.89(3H,d,J=6.4Hz),0.89-1.13(2H,m),1.13-2.07(7H,m),2.24-2.50(1H,m),2.68-2.93(4H,m),3.30-3.52(4H,m),3.96(3H,s),6.97(2H,d,J=8.9Hz),7.90(2H,d,J=8.9Hz),8.07(2H,d,J=8.6Hz),8.15(2H,d,J=8.6Hz)
MASS(m/z):477(M++1)
制备370
IR(KBr):2976,1716,1601,1531,1500,1479,1437cm-1
NMR(CDCl3,δ):1.46(3H,t,J=7.0Hz),3.97(3H,s),4.10(2H,q,J=7.0Hz),7.00(2H,d,J=8.7Hz),7.59(2H,d,J=8.7Hz),7.70(2H,d,J=8.4Hz),8.07(2H,d,J=8.3Hz),8.10-8.30(4H,m)
MASS(m/z):417(M++1)
制备371
IR(KBr):2926,2852,1722,1599,1529,1498,1437cm-1
NMR(CDCl3,δ):1.00-1.41(5H,m),1.51-2.05(5H,m),2.24-2.43(1H,m),2.69-2.84(4H,m),3.22-3.36(4H,m),3.97(3H,s),7.02(2H,d,J=8.8Hz),7.59(2H,d,J=8.7Hz),7.70(2H,d,J=8.4Hz),8.06(2H,d,J=8.5Hz),8.09-8.15(4H,m)
MASS(m/z):539(M++1)
制备372
IR(KBr):1718,1601,1429cm-1
NMR(CDCl3,δ):1.29(6H,d,J=6.3Hz),2.36-2.56(2H,m),3.44-3.63(2H,m),3.74-3.93(2H,m),3.96(3H,s),6.99(2H,d,J=8.9Hz),7.58(2H,d,J=8.8Hz),7.69(2H,d,J=8.5Hz),8.05(2H,d,J=8.4Hz),8.09(2H,d,J=8.6Hz),8.16(2H,d,J=8.6Hz)
MASS(m/z):486(M++1)
制备373
IR(KBr):1707,1603,1529,1498,1433,1414cm-1
NMR(CDCl3,δ):1.23-2.12(10H,m),3.97(3H,s),4.18-4.38(1H,m),7.00(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.69(2H,d,J=8.4Hz),8.10(2H,d,J=8.5Hz),8.06-8.25(4H,m)
MASS(m/z):471(M++1)
制备374
IR(KBr):2956,2933,2872,1722,1605,1502,1435cm-1
NMR(CDCl3,δ):1.00(3H,t,J=7.2Hz),1.52(2H,m),1.79(2H,m),3.97(3H,s),4.03(2H,m),7.00(2H,m),7.45-7.78(4H,m),7.96-8.29(6H,m)
MASS(m/z):445(M++1)
制备375
IR(KBr):1716,1435cm-1
NMR(CDCl3,δ):1.28(3H,t,J=7.0Hz),3.60(2H,q,J=7.0Hz),3.97(3H,m),4.58(2H,s),7.47(2H,d,J=8.3Hz),7.56-7.78(4H,m),8.04-8.29(6H,m)
MASS(m/z):431(M++1)
制备376
IR(KBr):1720,1651,1606,1560,1504,1435cm-1
NMR(CDCl3,δ):3.42(3H,m),3.55-3.71(4H,m),3.97(3H,s),4.64(2H,s),7.47(2H,d,J=8.2Hz),7.64(2H,d,J=8.2Hz),7.68-7.80(2H,m),8.04-8.26(6H,m)
MASS(m/z):461(M++1)
制备377
IR(KBr):2926,2877,1720,1605,1504,1437cm-1
NMR(CDCl3,δ):3.41(3H,s),3.54-3.64(2H,m),3.69-3.78(2H,m),3.86-3.96(2H,m),3.97(3H,s),4.14-4.28(2H,m),6.95-7.18(2H,m),7.51-5.64(2H,m),5.64-6.77(2H,m),8.00-8.26(6H,m)
MASS(m/z):491(M++1)
制备378
NMR(CDCl3,δ):1.22(3H,t,J=7.0Hz),2.09(2H,m),3.52(2H,q,J=7.0Hz),3.63(2H,t,J=6.2Hz),3.97(3H,s),4.13(2H,t,J=6.2Hz),7.02(2H,d,J=8.8Hz),7.59(2H,d,J=8.8Hz),7.70(2H,d,J=8.5Hz),8.07(2H,d,J=8.4Hz),8.08-8.26(4H,m)
MASS(m/z):475(M++1)
制备379
NMR(CDCl3,δ):1.27(3H,t,J=7.0Hz),3.63(2H,q,J=7.0Hz),3.74-3.90(2H,m),3.97(3H,s),4.14-4.28(2H,m),7.04(2H,d,J=8.7Hz),7.59(2H,d,J=8.7Hz),7.69(2H,d,J=8.3Hz),8.06(2H,d,J=8.2Hz),8.10(2H,d,J=8.5Hz),8.16(2H,d,J=8.5Hz)
MASS(m/z):461(M++1)
制备380
IR(KBr):1722,1605,1531,1500,1435cm-1
NMR(CDCl3,δ):2.09(2H,m),3.38(3H,s),3.59(2H,t,J=6.1Hz),3.97(3H,s),4.13(2H,t,J=6.3Hz),7.02(2H,d,J=8.8Hz),7.50-7.64(2H,m),7.70(2H,d,J=8.5Hz),8.07(2H,d,J=8.4Hz),8.08-8.25(4H,m)
MASS(m/z):461(M++1)
制备381
IR(KBr):1720,1643,1603,1531,1500,1435cm-1
NMR(CDCl3,δ):3.48(3H,s),3.80(2H,m),3.97(3H,s),4.18(2H,m),7.04(2H,d,J=8.8Hz),7.51-7.77(4H,m),8.03-8.23(6H,m)
MASS(m/z):447(M++1)
制备382
IR(液体石蜡):1714,1601cm-1
NMR(CDCl3,δ):1.7-2.0(4H,m),2.75(3H,s),3.0-3.2(2H,m),3.4-3.6(2H,m),3.69(3H,s),6.77(2H,d,J=8.8Hz),7.08(4H,s),7.60(2H,d,J=8.8Hz),7.7-8.0(4H,m)
(+)APCI MASS:520(M+H)+
以类似于制备33的方法获得下列化合物[制备383-388]。
制备383
IR(KBr):1699,1684cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.6Hz),1.2-1.7(10H,m),3.46(2H,t,J=6.6Hz),4.51(2H,s),7.50(2H,d,J=8.6Hz),7.95(2H,d,J=8.6Hz),8.13(4H,s),8.42(1H,s),9.36(1H,s)
MASS(m/z):477(M++1)
制备384
IR(KBr):1583,1543,1516,1396cm-1
NMR(DMSO-d6,δ):2.4-2.6(4H,m),3.1-3.3(4H,m),3.60(2H,s),6.77(1H,t,J=7.4Hz),6.93(2H,d,J=7.4Hz),7.20(2H,t,J=7.4Hz),7.9-8.1(6H,m),8.39(1H,s),9.32(1H,s)
MASS(m/z):523(M++1)
制备385
IR(KBr):1716,1520,1277,1109cm-1
MASS(m/z):432(M++1)
制备386
IR(KBr):1684,1518,1252cm-1
制备387
NMR(DMSO-d6,δ):1.60-2.10(4H,m),2.70-3.10(3H,m),4.08(2H,m),7.10-7.40(7H,m),7.95(2H,d,J=8.5Hz),8.18(4H,AB-q,J=8.3Hz,J=16.1Hz)
APCI MASS:426(M++1)
制备388
IR(KBr):1687,1610,1568,1527cm-1
MASS(m/z):418(M++1)
以类似于制备57的方法获得下列化合物[制备389-393]。
制备389
NMR(CDCl3-CD3OD,δ):2.10-2.25(2H,m),2.65-3.15(3H,m),3.45-3.70(2H,m),3.99(3H,s),7.30-7.40(5H,m),7.90-8.40(8H,m)
APCI MASS:440(M+)
制备390
NMR(DMSO-d6,δ):1.10-2.10(10H,m),3.91(3H,s),4.40-4.60(1H,m),7.17(2H,d,J=8.9Hz),8.00-8.30(6H,m)
APCI MASS(正性):379.2(M++1)
制备391
NMR(DMSO-d6,δ):1.20-1.60(5H,m),1.60-1.95(5H,m),2.50-2.75(1H,m),3.92(3H,s),7.50(2H,d,J=8.3Hz),8.07(2H,d,J=8.3Hz),8.18(2H,d,J=8.7Hz),8.28(2H,d,J=8.7Hz)
APCI MASS (正性):363.3(M++1)
制备392
IR(KBr):1724.0,1253.5,1199.5cm-1
NMR(CDCl3,δ):0.95(3H,t,J=7.0Hz),1.35-1.60(4H,m),1.70-1.95(2H,m),3.88-4.05(5H,m),6.98-7.03(2H,m),7.57-8.17(8H,m)
MASS(m/z):449(M+1)
制备393
IR(KBr):1718.3,1602.6,1249.6cm-1
NMR(CDCl3,δ):1.01(3H,t,J=7.4Hz),1.50-1.80(2H,m),3.97-4.05(5H,m),7.06-7.10(2H,m),7.70-9.35(12H,m)
MASS(m/z):465(M+1)
以类似于制备49的方法获得下列化合物[制备394-457]。
制备394
NMR(DMSO-d6,δ):1.10-1.95(12H,m),3.55-3.80(4H,m),7.08(2H,d,J=8.9Hz),7.83(2H,d,J=8.8Hz),8.07(4H,s)
APCI MASS:464(M+)
制备395
NMR(DMSO-d6,δ):1.10-1.60(5H,m),1.60-1.95(5H,m),2.50-2.70(1H,m),7.45(2H,d,J=8.3Hz),7.96(2H,d,J=8.3Hz),8.14(4H,s)
制备396
NMR(DMSO-d6,δ):1.20-2.10(10H,m),4.35-4.60(1H,m),7.13(2H,d,J=8.9Hz),7.95(2H,d,J=8.9Hz),8.12(4H,s)
APCI MASS(负性):379.2(M+-1)
制备397
NMR(DMSO-d6,δ):1.50-2.00(4H,m),2.65-3.10(3H,m),3.95-4.15(2H,m),6.90-7.35(7H,m),7.70-8.30(6H,m)
APCI MASS:442(M+)
制备398
NMR(DMSO-d6,δ):1.20-2.10(10H,m),4.40-4.60(1H,m),7.17(2H,d,J=8.9Hz),7.95-8.30(6H,m),13.0-13.5(1H,m)
APCI MASS(正性):365.2(M++1)
制备399
NMR(CDCl3,δ):1.15-1.60(5H,m),1.65-2.05(5H,m),2.50-2.70(1H,m),7.41(2H,d,J=8.3Hz),8.05(2H,d,J=8.4Hz),8.23(4H,s)
APCI MASS(正性):349.2(M++1)
制备400
IR(KBr):2935,2858,1705,1649,1601,1531,1500,1441,1400cm-1
MASS(m/z):523(M+-1)
制备401
MASS(m/z):527(M+-1)
制备402
NMR(DMSO-d6,δ):3.30-3.64(8H,m),6.75-7.33(7H,m),7.70-8.29(6H,m)
MASS(m/z):443(M+-2HCl+1)
制备403
NMR(DMSO-d6,δ):0.88(3H,t,J=7.4Hz),1.35-1.63(4H,m),1.82-2.03(2H,m),2.99-3.20(2H,m),3.40(2H,t,J=6.6Hz),3.40-3.80(3H,m),7.09(2H,d,J=9.0Hz),7.84(2H,d,J=8.9Hz),8.11(4H,s),13.22(1H,brs)
MASS(m/z):424(M+-HCl+1)
制备404
IR(KBr):1686,1601,1531,1500,1421cm-1
NMR(DMSO-d6,δ):1.18(6H,d,J=6.1Hz),2.24-2.45(2H,m),3.63-3.82(4H,m),7.08(2H,d,J=8.6Hz),7.68(2H,d,J=8.8Hz),7.90(2H,d,J=8.5Hz),8.08(2H,d,J=8.3Hz),8.13(2H,d,J=8.7Hz),8.16(2H,d,J=8.7Hz)
MASS(m/z):472(M++1)
制备405
IR(KBr):1705,1606,1524,1441,1412cm-1
MASS(m/z):477(M++1)
制备406
IR(KBr):1686,1603,1568,1520,1416cm-1
NMR(DMSO-d6,δ):1.49-1.71(2H,m),1.90-2.10(2H,m),3.06-3.24(2H,m),3.58-3.80(3H,m),4.56(2H,s),7.10(2H,d,J=9.0Hz),7.23-7.46(5H,m),7.85(2H,d,J=8.9Hz),8.10(4H,m)
MASS(m/z):472(M++1)
制备407
IR(KBr):1682,1606,1572,1524,1498,1427cm-1
NMR(DMSO-d6,δ):1.25-2.05(10H,m),4.35-4.50(1H,m),7.07(2H,d,J=8.8Hz),7.64-7.94(4H,m),7.99-8.26(6H,m)
MASS(m/z):457(M++1)
制备408
IR(KBr):2933,2846,1686,1599,1552,1500,1429cm-1
NMR(DMSO-d6,δ):1.56-2.00(4H,m),2.74-3.18(3H,m),4.62(2H,m),7.00-7.40(6H,m),7.99-8.26(5H,m),8.74(1H,s),13.20(1H,brs)
MASS(m/z):443(M++1)
制备409
IR(KBr):1686,1603,1574,1527,1500,1427cm-1
NMR(DMSO-d6,δ):1.36(3H,t,J=7.0Hz),4.10(2H,q,J=7.1Hz),7.00-7.13(2H,m),7.65-8.25(10H,m)
MASS(m/z):403(M++1)
制备410
IR(KBr):1693,1603,1572,1527,1500,1471,1425cm-1
NMR(DMSO-d6,δ):1.60-1.84(4H,m),3.25(3H,s),3.30-3.50(2H,m),4.00-4.16(2H,m),7.07(2H,d,J=8.8Hz),7.73(2H,d,J=8.6Hz),7.87(2H,d,J=8.5Hz),8.04-8.20(6H,m)
MASS(m/z):461(M++1)
制备411
IR(KBr):1705,1606,1524,1441,1412cm-1
NMR(DMSO-d6,δ):1.00-2.20(10H,m),3.00-3.35(9H,m),7.18(2H,d,J=9.1Hz),7.92(2H,d,J=8.7Hz),8.11(4H,s)
MASS(m/z):447(M+-1)
制备412
IR(KBr):1703,1605,1524,1441,1412cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.8Hz),1.43-2.00(9H,m),3.16-3.48(9H,m),7.17(2H,d,J=8.4Hz),7.92(2H,d,J=8.3Hz),8.12(4H,s)
制备413
IR(KBr):1705,1605,1524,1443,1414cm-1
NMR(DMSO-d6,δ):0.88(3H,d,J=6.4Hz),0.86-1.60(5H,m),1.74-1.92(2H,m),2.00-2.20(2H,m),2.97-3.35(9H,m),7.18(2H,d,J=8.9Hz),7.92(2H,d,J=8.8Hz),8.12(4H,s)
制备414
IR(KBr):2956,2935,2872,1686,1605,1500,1427cm-1
NMR(DMSO-d6,δ):0.95(3H,t,J=7.2Hz),1.44(2H,m),1.74(2H,m),4.05(2H,m),7.02-7.14(2H,m),7.66-8.30(10H,m)
MASS(m/z):431(M++1)
制备415
IR(KBr):1686,1606,1425cm-1
NMR(DMSO-d6,δ):1.18(3H,t,J=7.0Hz),3.52(2H,q,J=6.9Hz),4.53(2H,s),7.46(2H,d,J=8.5Hz),7.77(2H,d,J=8.3Hz),7.92(2H,d,J=8.4Hz),8.10-8.24(6H,m)
MASS(m/z):417(M++1)
制备416
IR(KBr):1682,1605,1566,1425cm-1
NMR(DMSO-d6,δ):3.28(3H,m),3.46-3.64(4H,m),4.56(2H,s),7.47(2H,d,J=8.2Hz),7.78(2H,d,J=8.2Hz),7.92(2H,d,J=8.4Hz),8.07-8.25(6H,m)
MASS(m/z):447(M++1)
制备417
IR(KBr):1684,1603,1500,1423cm-1
NMR(DMSO-d6,δ):3.26(3H,s),3.35-3.54(2H,m),3.54-3.68(2H,m),3.77(2H,t,J=4.5Hz),4.17(2H,t,J=4.5Hz),7.09(2H,d,J=8.8Hz),7.74(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),8.10(2H,d,J=8.4Hz),8.09-8.20(4H,m)
MASS(m/z):477(M++1)
制备418
NMR(DMSO-d6,δ):1.12(3H,t,J=7.0Hz),1.97(2H,m),3.39(2H,q,J=7.0Hz),3.53(2H,t,J=6.3Hz),4.09(2H,t,J=6.3Hz),7.07(2H,d,J=8.8Hz),7.73(2H,d,J=8.7Hz),7.87(2H,d,J=8.5Hz),8.10(2H,d,J=8.4Hz),8.10-8.25(4H,m)
制备419
IR(KBr):1686,1603,1529,1498,1470,1427cm-1
NMR(DMSO-d6,δ):1.15(3H,t,J=7.0Hz),3.52(2H,q,J=7.0Hz),3.68-3.80(2H,m),4.13-4.24(2H,m),7.08(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.86(2H,d,J=8.5Hz),8.09(2H,d,J=8.4Hz),8.10-8.21(4H,m)
MASS(m/z):447(M++1)
制备420
IR(KBr):1686,1603,1529,1498,1470,1427cm-1
NMR(DMSO-d6,δ):1.98(2H,m),3.27(3H,s),3.50(2H,t,J=6.2Hz),4.09(2H,m),7.07(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),8.10(2H,d,J=8.5Hz),8.10-8.21(4H,m)
MASS(m/z):447(M++1)
制备421
IR(KBr):1684,1603,1525,1500,1421cm-1
NMR(DMSO-d6,δ):3.32(3H,s),3.69(2H,m),4.17(2H,m),7.09(2H,d,J=8.9Hz),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.6Hz),8.03-8.20(6H,m)
MASS(m/z):433(M++1)
制备422
IR(液体石蜡):1684,1601cm-1
NMR(DMSO-d6,δ):1.8-2.2(4H,m),2.94(3H,s),3.1-3.3(2H,m),3.7-3.9(2H,m),7.14(2H,d,J=8.9Hz),7.45(4H,s),7.86(2H,d,J=8.9Hz),8.0-8.2(4H,m)
(+)APCI MASS:506(M+H)+
制备423
IR(KBr):1664.3,1602.6,1230.4cm-1
制备424
IR(KBr):1685.5,1608.3,1238.1cm-1
NMR(DMSO-d6,δ):2.79-4.42(13H,m),6.92-7.14(2H,m),7.21-7.30(4H,m),7.81-7.96(2H,m),11.60(1H,bs),12.55(1H,bs)
MASS(m/z):323(M+1)
制备425
IR(KBr):1726.0,1251.6,1180.2cm-1
NMR(DMSO-d6,δ):1.30-2.40(18H,m),3.21(3H,s),3.28-3.35(2H,m),4.04(2H,t,J=6.4Hz),7.07(2H,d,J=8.8Hz),7.86(2H,d,J=8.8Hz),12.14(1H,s)
MASS(m/z):419(M+1)
制备426
IR(KBr):1683.6,1251.6,825.4cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=6.9Hz),1.24-1.55(4H,m),1.60-1.90(2H,m),4.00-4.10(2H,m),7.02-7.08(2H,m),7.63-8.36(8H,m)
MASS(m/z):435(M+1)
制备427
IR(KBr):1693.2,1305.6,1259.3,1178.3cm-1
NMR(DMSO-d6,δ):1.38-1.80(8H,m),2.56(3H,s),3.22(3H,s),3.28-3.34(5H,m),4.06(2H,t,J=6.4Hz),7.12(2H,d,J=8.9Hz),7.72(1H,s),7.86(1H,s),7.97(2H,d,J=8.8Hz),13.12(1H,bs)
MASS(m/z):441(M+1)
制备428
IR(KBr):1675.8,1606.4,1259.3cm-1
NMR(DMSO-d6,δ):1.40-2.00(8H,m),3.35(3H,s),3.40(2H,t,J=6.3Hz),4.03(2H,t,J=6.3Hz),6.13-6.20(2H,m),6.96-7.94(6H,m)MASS(m/z):389(M+1)
制备429
IR(KBr):1699.0,1604.5,1249.6,1193.7cm-1
NMR(DMSO-d6,δ):1.00(3H,t,J=7.4Hz),1.67-1.85(2H,m),3.99(2H,t,J=6.5Hz),7.04-7.09(2H,m),7.65-9.32(12H,m)
MASS(m/z):451(M+1)
制备430
IR(KBr):1685.5,1253.5,1174.4cm-1
NMR(DMSO-d6,δ):1.20-1.80(8H,m),3.22(3H,s),3.29-3.35(2H,m),4.00-4.15(2H,m),7.12-7.17(2H,m),7.97-8.68(8H,m)
MASS(m/z):463(M+1)
制备431
IR(KBr):2950.6,1708.6,1608.3,1473.3,1419.4,1367.3,1259.3,1211.1,1174.4cm-1
MASS(m/z):477(M+H+)
制备432
IR(KBr):2946,1710,1608,1469,1413,1369,1307,1263,1218,1176cm-1
MASS(m/z):491(M+H+)
制备433
IR(KBr):2944,1706,1606,1469,1417,1375,1259,1176cm-1
MASS(m/z):505(M+H+)
制备434
IR(KBr):3396,2948,2871,1608,1542,1471,1382,1263,1180,1110cm-1
MASS(m/z):493(M+H+)
制备435
IR(KBr):2942,1687,1608,1471,1309,1261,1176cm-1
MASS(m/z):521(M+H+)
制备436
IR(KBr):2937,1706,1683,1606,1469,1417,1307,1255,1174,1110cm-1
MASS(m/z):535(M+H+)
制备437
IR(KBr):2946,2570,1706,1608,1469,1415,1371,1309,1259,1216,1174,1108cm-1
MASS(m/z):509(M+H+)
制备438
IR(KBr):2940,2867,2665,2547,1681,1606,1469,1421,1311,1290,1255,1176,1116cm-1
MASS(m/z):438(M+H+)
制备439
IR(KBr):2939,2861,1681,1606,1469,1421,1311,1253,1174,1114,1016,833cm-1
MASS(m/z):452(M+H+)
制备440
IR(KBr):2935,2858,1681,1606,1571,1467,1419,1311,1253,1174,1112cm-1
MASS(m/z):466(M+H+)
制备441
IR(KBr):2931,2854,2663,1679,1606,1467,1421,1311,1290,1253,1174,1116cm-1
MASS(m/z):480(M+H+)
制备442
IR(KBr):2935,2850,2819,1608,1589,1537,1473,1417,1240cm-1MASS(m/z):405(M+H+)
制备443
IR(KBr):3361,2969,2848,1606,1585,1535,1475,1402,1238,1180,1114,927cm-1
制备444
IR(KBr):2975,2873,2829,2665,1681,1606,1469,1423,1315,1288,1240,1176cm-1
MASS(m/z):435(M+H+)
制备445
IR(KBr):2969,2530,1672,1604,1467,1423,1288,1267,1228,1191cm-1
MASS(m/z):423(M+H+)
制备446
IR(KBr):2937,1702,1606,1473,1405,1369,1268,1241,1176cm-1
MASS(m/z):434(M+H+)
制备447
MASS(m/z):488(M+H+)
制备448
IR(KBR):2956,2869,2665,2543,1681,1608,1544,1492,1469,1423,1332,1292,1245,1172cm-1
MASS(m/z):394(M+H+)
制备449
IR(KBr):2954,2865,2665,2545,1681,1608,1544,1492,1423,1332,1292,1247,1172cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=6.8Hz),1.3-1.5(4H,m),1.6-1.8(2H,m),4.00(2H,t,J=6.8Hz),6.99(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz),8.11(4H,s),8.69(1H,s)
MASS(m/z):408(M+H+)
制备450
IR(KBr):2933,2865,2667,2545,1681,1608,1544,1492,1469,1423,1332cm-1
MASS(m/z):422(M+H+)
制备451
IR(KBr):2933,2863,1677,1606,1469,1421,1313,1292,1255,1174cm-1
MASS(m/z):422(M+H+)
制备452
IR(KBr):2935,2871,2667,2545,1683,1608,1542,1525,1461,1421,1319,1294,1257,1176cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),1.2-1.5(4H,m),1.6-1.9(2H,m),4.05(2H,t,J=6.5Hz),7.09(2H,d,J=8.8Hz),7.91(2H,d,J=8.8Hz),8.09(2H,d,J=8.5Hz),8.22(2H,d,J=8.5Hz),13.3(1H,s)
MASS(m/z):412(M+H+)
制备453
IR(KBr):1726.0,1687.4,1259.3,1176.4cm-1
NMR(DMSO-d6,δ):1.23-1.44(4H,m),1.85-1.96(4H,m),2.10-2.40(2H,m),3.58(3H,s),12.08(1H,s)
质谱(m/z):187(M+1)
制备454
IR(KBr):1724.0,1702.8,1309.4,1265.1cm-1
NMR(DMSO-d6,δ):2.49(6H,s),3.84(3H,s),7.70-7.72(2H,m),13.14(1H,bs)
制备455
IR(KBr):1727.9,1675.8,1232.3cm-1
NMR(DMSO-d6,δ):3.70(3H,s),6.24-6.51(2H,m),7.24-7.46(2H,m),12.66(1H,bs)
质谱(m/z):157(M+1)
制备456
IR(KBr):1726.0,1685.5,1286.3,1251.6cm-1
NMR(DMSO-d6,δ):3.98(3H,s),7.68-7.77(2H,m),8.11(2H,s),8.64-8.82(2H,m),13.58(1H,bs)
质谱(m/z):231(M+1)
制备457
IR(KBr):1724.0,1697.1,1290.1cm-1
NMR(DMSO-d6,δ):3.95(3H,s),8.04-8.08(2H,m),8.20-8.27(2H,m),8.68-8.71(2H,m)
质谱(m/z):231(M+1)
制备458
向1-羟基苯并三唑(244mg)和4-[5-(4-戊氧基苯基)异噁唑-3-基]苯甲酸(528mg)的二氯甲烷(10ml)溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(WSCD·HCl)(430mg),于室温下搅拌该混合物4.5小时。将该反应混合物加入水中。取出有机层并经硫酸镁干燥。滤除硫酸镁,减压浓缩滤液得到4-[5-(4-戊氧基苯基)异噁唑-3-基]苯甲酸苯并三唑-1-基酯(640mg)。
IR(KBr):1776.1,1253.5,1234.2,1002.8cm-1
NMR(CDCl3,δ):0.95(3H,t,J=7.0Hz),1.2-1.6(4H,m),1.6-1.9(2H,m),4.03(2H,t,J=6.5Hz),6.81(1H,s),7.01(2H,d,J=8.3Hz),7.3-7.6(3H,m),7.79(2H,d,J=8.3Hz),8.11(2H,d,J=8.0Hz),8.12(1H,d,J=8.2Hz),8.39(2H,d,J=8.0Hz)
制备459
搅拌及并冰冷却下,向原料化合物(459)(5.0g)和三乙甲硅烷(6.67ml)的二氯甲烷(125ml)悬浮液中滴加三氟乙酸(32.2ml)。于室温下搅拌该混合物2小时。将该反应混合物缓慢倾入pH6.86的标准缓冲液(1.2L)中,搅拌及冰冷却下,用1N氢氧化钠将pH调至8.5-10。真空蒸发该混合物以除去有机溶剂,经非离子吸附树脂Diaion SP-205(商标,由Mitsubishi Chemical Industries制备)(400ml)层析,依次用水(2L)、10%甲醇水溶液(2L)、20%甲醇水溶液(2L)、30%甲醇水溶液(2L)、50%甲醇水溶液(2L)、60%甲醇水溶液(2L)和90%甲醇水溶液(2L)洗脱。收集含有所需化合物的部分并真空蒸发。冻干生成的残留物得到目标化合物(459)(3.13g)。
NMR(DMSO-d6,δ) :0.85(3H,t,J=7.0Hz),0.96(3H,d,J=6.7Hz),1.02(3H,d,J=6.1Hz),1.24(26H,m),1.35-1.50(2H,m),1.55-2.50(11H,m),2.80-3.30(2H,m),3.60-5.40(20H,m),6.60-6.80(3H,m),6.85-7.75(5H,m),8.00-8.15(2H,m),8.71(1H,宽S)
APCI质谱(m/z):1141.1(M+-Na)
制备460
于5-10℃,将在四氢呋喃(1L)和pH6.86的标准缓冲液(1L)的混合物中的原料化合物(460)(100g)溶液滴加到苄氧基碳酰氯(16.8ml)中,用饱和碳酸氢钠水溶液调至pH7.0-8.0。在相同条件下搅拌该溶液3小时,用1N盐酸调节pH至6.0。真空蒸发该混合物以除去有机溶剂。残留物经过离子交换树脂DOWEX 50WX4 Na+型(由DowChemical制备)(1L)并用水(3L)洗涤。洗脱液经反相硅胶(ODS SP-120,由Daiso Co.,Ltd.制备)(2.5L)层析,依次用水(12L)、10%甲醇水溶液(12L)和20%甲醇水溶液(12L)洗脱。收集含有目标化合物的部分,真空蒸发浓缩并冻干得到目标化合物(460)(76g,收率65%)。NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.05(3H,d,J=5.7Hz),1.60-2.50(7H,m),3.10-5.20(29H,m),6.73(1H,d,J=8.2Hz),6.75-6.90(2H,m),6.90-7.10(2H,m),7.20-7.40(7H,m),7.63(1H,d,J=7.8Hz),8.00-8.15(2H,m)
ESI质谱(负性):1069.3(M+-Na)
制备461
于冰冷却下,向原料化合物(461)(30g)和氰基硼氢化钠(3.45g)的二氯甲烷(300ml)溶液中边搅拌边滴加三氟乙酸(150ml)。在相同条件下搅拌该混合物3小时。将该反应混合物缓慢倾入到pH6.86的标准缓冲液(1.2L)中,在冰-氯化钠浴上搅拌,用1N氢氧化钠调节pH至8.5-10。分离水层,在冰箱中冷却过夜。真空蒸发水液以除去有机溶剂,残留物经反相硅胶(ODS SP-120,由Daiso Co.,Ltd.制备)(700ml)层析,依次用水(5L)和5%甲醇水溶液(6L)洗脱。收集含有目标化合物的部分,经真空蒸发浓缩并冻干得到目标化合物(461)(17.3g)。
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.07(3H,d,J=5.7Hz),1.40-2.45(7H,m),2.85-3.30(2H,m),3.60-4.50(13H,m),4.60-5.35(10H,m),6.65-7.10(5H,m),7.20-7.75(8H,m),7.92(1H,宽d,J=8.4Hz),8.84(1H,s)
ESI质谱(负性):1053.3(M+-Na)
实施例1
于4℃,向原料化合物(1)(0.6g)和氰基硼氢化钠(0.076g)的二氯甲烷(6ml)悬浮液中逐渐加入三氟乙酸(3ml)。于4℃搅拌该混合物1小时。减压蒸发该反应混合物。将残留物加入水中,用1N氢氧化钠水溶液将pH调至8.5。该溶液经ODS(YMC-凝胶ODS-AM S-50)柱层析,用30%乙腈水溶液洗脱,合并含有目标化合物的部分并减压蒸发以除去乙腈。冻干残留物得到目标化合物(1)(0.417g)。
IR(KBr):3350,1668.1,1629.6,1241.9cm-1
NMR(DMSO-d6,δ):0.87(3H,t,J=6.7Hz),0.96(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.2-1.55(8H,m),1.55-2.1(5H,m),2.1-2.5(4H,m),3.01(1H,m),3.19(1H,m),3.46(1H,m),3.6-3.87(3H,m),3.87-4.55(13H,m),4.6-5.5(8H,m),6.52(1H,d,J=8.1Hz),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.85(1H,s),7.0-7.15(3H,m),7.19(1H,s),7.27-7.55(3H,m),7.55-7.78(3H,m),7.8-8.0(2H,m),8.76(1H,s),8.85(1H,s)
质谱(m/z):1248(M+Na+)
C53H72N9NaO21S·7H2O的元素分析计算值:
C 47.07, H 6.41, N 9.32实测值:C 46.82, H 6.54, N 9.25以类似于实施例1的方式获得下列化合物[实施例2和3]。实施例2
IR(KBr):3349.7,1666.2,1631.5,1267.0cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.11(3H,d,J=5.9Hz),1.7-2.0(2H,m),2.0-2.6(4H,m),2.6-2.8(1H,m),3.1-3.3(1H,m),3.3-3.5(1H,m),3.5-4.5(16H,m),4.6-4.9(2H,m),5.1-5.5(5H,m),6.72(1H,d,J=8.2Hz),6.81(1H,dd,J=8.2和1.9Hz),6.9-7.5(4H,m),7.05(1H,d,J=1.9Hz),7.4-7.9(3H,m),8.84(1H,s)
质谱(m/z):965(M+Na+)
C35H51N8O19SNa·5.5H2O的元素分析计算值:
C 40.35,H 6.00,N 10.75
实测值:C 40.33,H 5.92,N 10.63
实施例3
IR(KBr):3350,1648.8,1276.6cm-1
质谱(m/z):1266(M-Na+)
实施例4
在低于5℃下,向原料化合物(4)(46.1g)和NaBH3CN(7.7g)的二氯甲烷(600ml)悬浮液中滴加三氟乙酸(240ml)15分钟。于相同温度下搅拌该混合物3小时。将该反应混合物的下层(三氟乙酸层)倾入大体积的冰冷却碳酸氢钠水溶液(pH=8.5)中。将上层(二氯甲烷层)也倾入大体积的冰冷却碳酸氢钠水溶液中。将水层合并在一起并经ODS柱层析纯化,得到目标化合物(4)。
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.04-1.12(3H,m),1.48-2.00(3H,m),2.07-2.50(4H,m),2.90-3.34(2H,m),3.60-4.48(18H,m),4.60-5.40(9H,m),6.72(1H,d,J=8.2Hz),6.81(1H,dd,J=8.2和1.6Hz),6.84(1H,m),6.98(1H,m),7.04(1H,d,J=1.6Hz),7.28-7.50(6H,m),7.58(2H,m),7.73(2H,d,J=7.4Hz),7.84(1H,m),7.88(2H,d,J=7.6Hz),8.84(1H,s)
质谱(m/z):1141(M+)
实施例5
于室温下,向原料化合物(5)(38.7g)的二甲基甲酰胺(250ml)的溶液中加入哌啶(17ml)。于相同温度下搅拌该溶液2.5小时。将乙酸乙酯(2.5L)加入该反应混合物中,并搅拌该混合物30分钟。过滤收集该粉末得到目标化合物(5)(34.6g)。
实施例6
于10℃,向原料化合物(6)(0.3g)和三乙基甲硅烷(0.44ml)的二氯甲烷(7ml)的溶液中滴加三氟乙酸(2ml)。于室温下搅拌该混合物4小时。于10℃将该反应混合物加入1N氢氧化钠(31ml)中。水层经ODS(YMC-凝胶ODS-AM S-50(商标,由Yamamura Chemical Lab.制备))柱层析,用水洗脱。合并含有目标化合物的部分并真空蒸发。冻干残留物得到目标化合物(6)(0.13g)。
IR(KBr):3361.3,1668.1,1631.5,1268.9cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.06(3H,d,J=5.5Hz),1.60-2.50(9H,m),2.90-2.97(1H, m),3.16-3.50(2H,m),3.69-4.50(13H,m),4.74-5.31(10H,m),6.72-7.65(14H,m),7.93-7.97(1H,m),8.71(1H,s)
实施例7
向原料化合物(7)(110mg)的水(5ml)溶液中加入10%披钯炭(11mg),并在大气压下通入氢气7小时。将该反应混合物通过硅藻土过滤,冻干得到目标化合物(7)(70mg)。
IR(KBr):3394,3327,1676,1633,1439cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.8Hz),1.08(3H,d,J=6.0Hz),1.88-5.83(35H,m),6.68-8.71(10H,m)
质谱(m/z):903.17(M-Na+)
实施例8
向原料化合物(8)(350mg)的N,N-二甲基甲酰胺(6ml)的溶液中加入4-[4-(4-环己基苯基)-哌嗪-1-基]苯甲酸苯并三唑-1-基酯(230mg),于室温下搅拌该混合物2小时。用乙酸乙酯研磨该反应混合物。过滤收集产生的沉淀,并减压干燥。将该粉末溶于水中,经离子交换树脂(DOWEX-50WX4(商标:由Dow Chemical制备))柱层析,用水洗脱。合并含有目标化合物的部分,经ODS(YMC-凝胶·ODS-AM·S-50(商标:由Yamamura Chemical Lab.制备))柱层析,用30%乙腈水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(8)(160mg)。
IR(KBr):1666.2,1633.4,1608.3,1511.9,1230.4cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.09(3H,d,J=5.4Hz),1.2-1.5(6H,m),1.6-2.1(7H,m),2.1-2.6(5H,m),3.02(1H,m),3.1-3.5(10H,m),3.6-4.5(14H,m),4.6-5.3(9H,m),6.73(1H,d,J=8.2Hz),6.77(1H,d,J=8.2Hz),6.80(1H,s),6.91(2H,d,J=8.7Hz),6.9-7.1(5H,m),7.26(1H,s),7.3-7.5(2H,m),7.66(1H,brs),7.78(2H,d,J=8.6Hz),8.04(1H,d,J=7.3Hz),8.31(1H,d,J=7.3Hz),8.84(1H,s)
质谱(m/z):1311(M+Na+)
C58H77N10O20S·6H2O的元素分析计算值:
C 49.85,H 6.42,N 10.02
实测值:C 50.06,H 6.36,N 10.07
以类似于实施例8的方式获得下列化合物[实施例9-11]。
实施例9
IR(KBr):3350,1648.8,1276.6cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.8Hz),1.11(3H,d,J=5.2Hz),1.5-1.7(6H,m),1.7-2.6(7H,m),2.94(1H, m),3.1-3.5(6H,m),3.6-4.6(14H,m),4.7-5.3(9H,m),6.73(1H,d,J=8.2Hz),6.82(1H,d,J=8.2Hz),6.84(1H,s),7.04(1H,s),7.06(2H,d,J=8.7Hz),7.18(1H,s),7.3-7.5(2H,m),7.66(1H,brs),7.83(2H,d,J=8.7Hz),8.0-8.2(5H,m),8.75(1H,d,J=7.1Hz),8.84(1H,s)
质谱(m/z):1266(M-Na+)
实施例10
IR(KBr):3361.3,1646.9,1517.7,1257.4cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.3Hz),0.96(3H,d,J=6.5Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(4H,m),1.6-2.6(9H,m),2.95(1H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.4(9H,m),6.73(1H,d,J=8.2Hz),6.82(1H,d,J=8.2Hz),6.90(1H,s),7.06(1H,s),7.14(2H,d,J=8.9Hz),7.23(1H,s),7.3-7.5(2H,m),7.68(1H,brs),7.90(2H,d,J=8.9Hz),7.8-8.2(5H,m),8.60(1H,d,J=6.7Hz),8.85(2H,s)
质谱(m/z):1308(M-Na+)
C57H70N11O21S2Na·10H2O的元素分析计算值:
C 45.26,H 6.00,N 10.19
实测值:C 45.05,H 5.83,N 10.19
实施例11
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.12(3H,d,J=6.0Hz),1.2-1.6(8H,m),1.6-2.6(9H,m),2.9-3.1(1H,m),3.1-3.5(7H,m),3.6-4.6(16H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H, s),7.05(1H,s),7.13(2H,d,J=8.8Hz),7.16(1H,m),7.3-7.6(2H,m),7.67(1H,br),7.97(2H,d,J=8.8Hz),7.9-8.2(5H,m),8.7-9.0(2H,m)
质谱(m/z):1327.07(M-Na+)
C58H75N10NaO22S2·5H2O的元素分析计算值:
C 48.33,H 5.94,N 9.72
实测值:C 48.27,H 6.05,N 9.69
实施例12
于室温下,向原料化合物(12)(60.0g)和二乙基异丙基胺(16.6ml)的二乙基甲酰胺(340ml)的溶液中加入4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(37.4g)。于相同温度下搅拌该溶液17小时。将乙酸乙酯(3.4L)加入该反应混合物中,搅拌该混合物30分钟。过滤收集粉末并用乙酸乙酯(3.5L)洗涤,得到粗品N-酰化的原料混合物(12)(93.0g)。该物质可不经进一步纯化而使用。于0℃,用30分钟向粗品N-酰化的原料混合物(12)(93.0g)和NaBH3CN(9.0g)的二氯甲烷(900ml)悬浮液中加入三氟乙酸(450ml)。于相同温度下搅拌该溶液2小时。将该反应混合物缓慢倾入冰冷却的氢氧化钠水溶液(8<pH<11,温度<7℃)中。用水提取分离的有机层两次。合并的水溶液经SP20(7L)柱层析,用水洗涤,用60%CH3CN水液洗脱。浓缩洗脱液以除去CH3CN,经反相(ODS)快速色谱法层析,用17%CH3CN/水洗脱,接着冻干合适的部分得到28.3g目标化合物(12)。
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.9Hz),1.30-1.60(6H,m),1.65-2.60(9H,m),2.80-3.50(5H,m),3.22(3H,s),3.60-4.60(14H,m),4.07(2H,t,J=6.7Hz),4.60-5.30(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.13(2H,d,J=8.9Hz),7.16(1H,s),7.42-7.46(2H,m),7.66(1H,br),7.97(2H,d,J=8.8Hz),8.07-8.13(5H,m),8.77(1H,d,J=6.8Hz),8.84(1H,s)
质谱(m/z):1313.25(M-Na+)
C57H73N10O22S2Na·7H2O的元素分析计算值:
C 46.78,H 5.99,N 9.57
实测值:C 46.56,H 5.94,N 9.45
实施例13
用4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(343mg)处理原料化合物(13)(400mg)的N,N-二甲基甲酰胺(4ml)的溶液,然后于室温下搅拌15小时。将乙酸乙酯加入该反应混合物中,过滤收集产生的沉淀,用乙酸乙酯充分洗涤并干燥。使该粉末溶于饱和碳酸氢钠溶液中,过滤,然后经ODS柱层析(YMC-凝胶ODS-AM S-50)纯化,用19-21%乙腈水溶液洗脱,合并含有产物的部分,蒸发除去乙腈。冻干得到非晶体白色粉末的目标化合物(13)(306.4mg)。
IR(KBr):1675.8,1650.8,1631.5,1540.8,1513.8,1452.1,1257.4cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.09(3H,d,J=5.4Hz),1.30-1.60(6H,m),1.65-2.60(10H,m),2.80-4.60(17H,m),3.22(3H,s),3.32(2H,t,J=6.3Hz),4.07(2H,t,J=6.5Hz),4.68-5.80(8H,m),6.68(1H,d,J=8Hz),6.76(1H,d,J=8Hz),6.86(1H,s),6.98(1H,s),7.13(2H,d,J=8.8Hz),7.16(1H,s),7.30-7.50(3H,m),7.97(2H,d,J=8.8Hz),8.03-8.13(4H,m),8.76-8.79(2H,m)
质谱(m/z):1343.13(M+Na+)
C57H73N10O21S2Na·8H2O的元素分析计算值:
C 46.72,H 6.12,N 9.56
实测值:C 46.66,H 5.97,N 9.53
以类似于实施例13的方式获得下列化合物。
实施例14
IR(KBr):1675.8,1650.8,1631.5,1540.8,1513.8,1450.2cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.9Hz),1.12-1.80(8H,m),1.80-2.60(10H,m),2.90-3.05(1H,m),3.21(3H,s),3.27(2H,t,J=6.3Hz),3.30-3.50(2H,m),3.68-4.60(14H,m),4.07(2H,t,J=6Hz),4.70-5.45(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.87(1H,s),6.97(1H,s),7.13(2H,d,J=8.9Hz),7.15(1H,s),7.42-7.71(3H,m),7.97(2H,d,J=8.7Hz),8.03-8.12(4H,m),8.73-8.81(3H,m)
质谱(m/z):1311.32(M-Na+)
C58H75N10O21S2Na·7H2O的元素分析计算值:
C 47.67,H 6.14,N 9.58
实测值:C 47.49,H 6.09,N 9.47
实施例15
用4-[5-[4-(6-甲氧基-正己氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(428mg)处理原料化合物(15)(508mg)的N,N-二甲基甲酰胺(10ml)的溶液,于室温下搅拌该混合物18小时。将乙酸乙酯加入该反应混合物中,过滤收集产生的沉淀,用乙酸乙酯充分洗涤并干燥。使该粉末溶于饱和碳酸氢钠溶液(100m1)中,用水(100m1)处理。然后经ODS柱层析(YMC-凝胶ODS-AM S-50)纯化,用16-17%乙腈水溶液洗脱,合并含有目标化合物的部分,蒸发除去乙腈。冻干得到非晶体白色粉末的目标化合物(15)(400mg)。
IR(KBr):1668.1,1650.8,1631.5,1538.9,1513.8,1450.2,1259.3cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.9Hz),1.30-1.60(6H,m),1.65-2.60(9H,m),2.80-3.50(5H,m),3.22(3H,s),3.60-4.60(14H,m),4.07(2H,t,J=6.7Hz),4.60-5.30(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.13(2H,d,J=8.9Hz),7.16(1H,s),7.42-7.46(2H,m),7.66(1H,br),7.97(2H,d,J=8.8Hz),8.07-8.13(5H,m),8.77(1H,d,J=6.8Hz),8.84(1H,s)
质谱(m/z):1313.25(M-Na+)
C57H73N10O22S2Na·7H2O的元素分析计算值:
C 46.78,H 5.99,N 9.57
实测值:C 46.56,H 5.94,N 9.45
实施例16
向原料化合物(16)(200mg)和4-[5-(4-哌啶-1-基-苯基)-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯的N,N-二甲基甲酰胺(31ml)的溶液中加入二甲基氨基吡啶(0.034g),于室温下搅拌该混合物6.5小时。用乙酸乙酯研磨该反应混合物,过滤收集产生的沉淀,减压干燥。将该固体溶于水中,经离子交换树脂(DOWEX-50WX4(商标:由Dow Chemical制备))柱层析,用水洗脱。合并含有目标化合物的部分,经ODS(YMC-凝胶ODS-AM S-50(商标:由Yamamura Chemical Lab.制备))柱层析,用50%甲醇水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去甲醇。残留物经冻干得到目标化合物(16)(190mg)。
IR(KBr):3367,1651,1539,1443cm-1
NMR(DMSO-d6,δ):0.95-5.30(49H,m),6.63-8.72(19H,m)
质谱(m/z):1250.22(M-Na+)
C55H68N11NaO19S2·12H2O的元素分析计算值:
C 44.05,H 6.25,N 10.27
实测值:C 43.94,H 5.76,N 10.14
实施例17
向1-羟基苯并三唑(64mg)和4-[2-(4-丁氧基苯基)咪唑并[2,1-b][1,3,4]-噻二唑-6-基]苯甲酸(125mg)的N,N-二甲基甲酰胺(4ml)的溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(73mg),于室温下搅拌该混合物4小时。然后向该反应混合物中加入原料化合物(17)(200mg),于室温下搅拌该混合物4小时。用乙酸乙酯研磨该反应混合物。过滤收集产生的沉淀,减压干燥。将该粉末加入饱和碳酸氢钠水溶液中并经ODS(YMC-凝胶ODS-AM S-50)柱层析,用30%乙腈水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(17)(123mg)。
NMR(DMSO-d6,δ):0.91(3H,t,J=7.3Hz),0.96(3H,d,J=7.2Hz),1.11(3H,d,J=5.5Hz),1.3-1.6(2H,m),1.6-2.6(9H,m),2.95(1H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.5(9H,m),6.73(1H,d,J=8.2Hz),6.82(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.14(2H,d,J=8.9Hz),7.24(1H,s),7.3-7.5(2H,m),7.68(1H,brs),7.90(2H,d,J=8.9Hz),7.8-8.1(5H,m),8.56(1H,d,J=6.7Hz),8.85(2H,s)
质谱(m/z):1341(M+Na+)
实施例18
向原料化合物(18)(1.70g)和三乙基甲硅烷(1.58g)的二氯甲烷(15ml)悬浮液中滴加三氟乙酸(15ml),于氮气下搅拌该混合物30分钟。减压蒸发该反应混合物。使残留物溶于pH6.86的磷酸盐缓冲液中,用1N氢氧化钠水溶液将其调至pH9.5。该溶液经ODS(YMC-凝胶ODS-AM S-50)柱层析,用30%乙腈水溶液(v/v)洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(18)(136mg)。
IR(KBr):3350,2933,1668,1635,1540,1471,1249,1045cm-1
NMR(DMSO-d6,δ):0.88(3H,t,J=6.7Hz),0.96(3H,d,J=6.7Hz),1.08(3H,d,J=5.8Hz),1.2-1.6(8H,m),1.6-2.4(10H,m),2.8-4.1(16H,m),4.1-5.3(11H,m),6.6-7.2(9H,m),7.3-7.7(3H,m),7.9-8.3(4H,m),8.7-8.9(1H,d,J=6.0Hz),9.04(1H,s)
质谱(m/z):1244.5(M+Na+)
C54H72N9O20NaS·6H2O的元素分析计算值:
C 48.75,H 6.36,N 9.48
实测值:C 48.53,H 6.24,N 9.40
以类似于实施例18的方式获得下列化合物[实施例19和20]。
实施例19
NMR(DMSO-d6,δ):0.95(3H,t,J=7.3Hz),0.96(3H,d,J=7.1Hz),1.10(3H,d,J=5.8Hz),1.3-1.6(2H,m),1.6-2.6(10H,m),2.95(1H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.4(8H,m),6.71(1H,d,J=8.1Hz),6.78(1H,d,J=8.1Hz),6.87(1H,s),6.97(1H,s),7.14(2H,d,J=8.9Hz),7.24(1H,s),7.44(1H,d,J=7.9Hz),7.5-7.8(2H,m),7.89(2H,d,J=8.9Hz),7.9-8.0(6H,m),8.12(1H,d,J=7.7Hz),8.60(1H,d,J=7.2Hz),8.72(1H,s),8.85(1H,s)
质谱(m/z):1278(M-Na+)
实施例20
NMR(DMSO-d6,δ):0.91(3H,t,J=7.3Hz),0.96(3H,d,J=7.1Hz),1.09(3H,d,J=5.8Hz),1.3-1.6(4H,m),1.6-2.6(10H,m),2.95(1H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.4(8H,m),6.71(1H,d,J=8.1Hz),6.78(1H,d,J=8.1Hz),6.87(1H,s),6.97(1H,s),7.14(2H,d,J=8.9Hz),7.24(1H, s),7.44(1H,d,J=7.9Hz),7.5-7.8(2H,m),7.89(2H,d,J=8.9Hz),7.9-8.0(6H,m),8.12(1H,d,J=7.7Hz),8.60(1H,d,J=7.2Hz),8.72(1H,s),8.85(1H,s)
质谱(m/z):1338(M+Na+)
以类似于实施例1的方式获得下列化合物[实施例21-29]。
实施例21
IR(KBr):3353,1666.2,1631.5,1510,1236cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.8Hz),0.95(3H,d,J=6.7Hz),1.09(3H,d,J=5.8Hz),1.2-1.5(10H,m),1.55-2.6(9H,m),2.95(1H,m),3.0-3.5(10H,m),3.6-4.5(15H,m),4.6-5.4(10H,m),6.6-7.1(10H,m),7.27(1H,s),7.35-7.5(2H,m),7.65(1H,brs),7.78(2H,d,J=8.8Hz),8.03(1H,d,J=8.7Hz),8.30(1H,d,J=8.7Hz),8.83(1H,s)
MASS(m/z):1357(M+Na)+
C60H83N10O21SNa·5H2O的元素分析计算值:
C 50.55, H 6.58, N 9.83
实测值:C 50.56, H 6.59, N 9.76实施例22
IR(KBr):3350,1658.5,1633,1278cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.7Hz),0.96(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.2-1.4(8H,m),1.45-2.45(9H,m),2.62(2H,t,J=7.4Hz),2.98(1H,m),3.2(1H,m),3.25-3.5(1H,m),3.6-5.4(23H,m),6.73(1H,d,J=8.2Hz),6.83(1H,dd,J=1.5和8.2Hz),6.88(1H,s),7.05(1H,d,J=1.5Hz),7.31(2H,d,J=8.2Hz),7.1-7.5(4H,m),7.64(2H,d,J=8.2Hz),7.74(2H,d,J=8.4Hz),7.6-7.8(1H, m),7.95(2H,d,J=8.4Hz),8.0-8.2(1H,m),8.61(1H,d,J=6.7Hz),8.84(1H,s)
MASS(m/z):1243(M+Na)+
C55H73N8NaO20S·6H2O的元素分析计算值:
C 49.69, H 6.44, N 8.43
实测值:C 49.99, H 6.53, N 8.40实施例23
(液体石蜡):1668.1,1629.6,1540.8,1515.8cm-1
NMR(DMSO-d6,δ):0.87(3H,t,J=6.7Hz),0.95(3H,d,J=6.7Hz),1.07(3H,d,J=5.9Hz),1.25-1.48(4H,m),1.49-2.05(5H,m),2.05-2.70(8H,m),2.70-3.05(3H,m),3.08-3.45(2H,m),3.55-3.86(2H,m),3.88-4.50(11H,m),4.65-5.36(10H,m),6.67-6.90(3H,m),7.04(1H,d,J=1.0Hz),7.10-7.80(12H,m),8.00(1H,d,J=8.4Hz),8.13(1H,d,J=7.7Hz),8.84(1H,s)
MASS(m/z):1227.5(M+Na)+
C55H73N8NaO20S·5H2O的元素分析计算值:
C 50.38, H 6.38, N 8.54
实测值:C 50.07, H 6.60, N 8.58实施例24
IR(KBr):3350,2929,1664,1635,1515,1440,1278,1245,1085,1047cm-1
NMR(DMSO-d6,δ):0.86(3H,m),0.96(3H,d,J=7.7Hz),1.11(3H,d,J=5.7Hz),1.30(6H,m),1.5-2.4(9H,m),2.6-2.8(2H,t,J=7.2Hz),2.9-3.1(1H,m),3.1-3.3(1H,m),3.4-3.6(1H,m),3.7-4.6(14H,m),4.6-5.3(9H,m),6.7-7.0(3H, m),7.04(1H,s),7.21(1H,s),7.30(2H,d,J=8.2Hz),7.4-7.5(1H,m),7.6-7.8(5H,m),7.95(2H,d,J=8.4Hz),8.10(1H,d,J=8.4Hz),8.60(1H,d,J=8.4Hz),8.84(1H,s)
MASS(m/z):1230(M+Na)+
C54H71N8NaO20S·4.5H2O的元素分析计算值:
C 50.34, H 6.26, N 8.70
实测值:C 50.43, H 6.19, N 8.59实施例25
IR(KBr):3350,1666.2,1631.5,1510.0,1236.1cm-1
NMR(DMSO-d6,δ):0.88(3H,t,J=6.6Hz),0.95(3H,d,J=6.7Hz),1.08(3H,d,J=5.7Hz),1.2-1.5(6H,m),1.6-2.1(5H,m),2.1-2.5(4H,m),2.8-3.0(1H,m),3.1-3.3(5H,m),3.3-3.4(4H,m),3.6-5.4(23H,m),6.73(1H,d,J=8.1Hz),6.8-6.9(4H,m),6.94(2H,d,J=9.3Hz),7.01(2H,d,J=8.7Hz),7.04(1H,s),7.2-7.5(3H,m),7.6-7.7(1H,m),7.78(2H,d,J=8.7Hz),8.05(1H,d,J=8Hz),8.30(1H,d,J=6.7Hz),8.85(1H,s)
MASS(m/z):1329(M+Na)+
C58H79N10O21SNa·6H2O的元素分析计算值:
C 49.22, H 6.48, N 9.90
实测值:C 49.46, H 6.44, N 9.96实施例26
IR(KBr):3347.8,1670.1,1652.7,1635.3cm-1
NMR(DMSO-d6,δ):0.85(3H,t,J=6.6Hz),0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.9Hz),1.18-1.40(8H,m),1.50-2.10(5H,m),2.10-2.60(4H,m),2.76(2H,t,J=7.6Hz),2.85-3.50(3H,m),3.60-4.60(14H,m),4.60-5.33(9H,m),6.67-7.00(3H,m),7.05(1H,d,J=0.4Hz),7.20-7.50(4H,m),7.60-7.80(2H,m),7.85-8.00(3H,m),8.10(1H,d,J=8.5Hz),8.45(1H,s),8.68(1H,d,J=8.4Hz),8.48(1H,s)
MASS(m/z):1217.4(M+Na-1)
C53H71N8O21SNa·4H2O的元素分析计算值:
C 49.61, H 6.20, N 8.73
实测值:C 49.62, H 6.38, N 8.68实施例27
IR(KBr):3361.3,1668.1,1635.3cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.8Hz),0.95(3H,d,J=6.7Hz),1.10(3H,d,J=5.9Hz),1.20-1.48(6H,m),1.55-2.13(5H,m),2.13-2.60(4H,m),2.76(2H,t,J=7.6Hz),2.89-3.08(1H,m),3.10-3.50(3H,m),3.60-3.85(2H,m),3.85-4.65(12H,m),4.65-5.50(8H,m),6.62-7.05(3H,m),7.06(1H,d,J=0.4Hz),7.15-7.55(4H,m),7.55-7.80(2H,m),7.80-8.03(3H,m),8.03-8.20(1H,m),8.45(1H,s),8.60-9.05(2H,m)
MASS(m/z):1203.4(M+Na-1)
C52H69N8NaO20S·6H2O的元素分析计算值:C 48.44, H 6.33, N8.69
实测值:C 48.55, H 6.39, N 8.70实施例28
IR(KBr):3359.4,1664.3,1631.5,1510.0,1230.4,1045.2cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.5Hz),1.08(3H,d,J=5.6Hz),1.2-1.6(10H, m),1.6-2.1(5H,m),2.1-2.5(4H, m),2.95(1H,m),3.0-3.2(5H,m),3.20(3H,s),3.29(3H,t,J=6.4Hz),3.2-3.5(5H,m),3.6-4.5(16H,m),4.6-5.4(9H,m),6.73(1H,d,J=8.2Hz),6.8-7.1(10H,m),7.2-7.5(2H,m),7.70(1H,brs),7.78(2H,d,J=8.6Hz),8.10(1H,brs),8.32(1H,d,J=7.2Hz),8.90(1H,brs)
MASS(m/z):1387(M+Na)+
C61H84N10O22SNa·8H2O的元素分析计算值:
C 48.53, H 6.74, N 9.28
实测值:C 48.38, H 7.18, N 9.18实施例29
IR(KBr):3355.5,1666.2,1631.5,1608.3,1236.1,1045.2cm-1
NMR(DMSO-d6,δ):0.93(3H,d,J=6.6Hz),1.07(3H,d,J=5.7Hz),1.2-1.6(8H,m),1.6-2.1(5H,m),2.1-2.6(4H,m),2.96(1H,m),3.1-3.3(5H,m),3.19(3H,s),3.28(3H,t,J=6.5Hz),3.3-3.5(5H,m),3.7-4.5(16H,m),4.65-5.3(9H,m),6.71(1H,d,J=8.1Hz),6.8-7.1(9H,m),7.26(1H,s),7.3-7.5(2H,m),7.66(1H,brs),7.76(2H,d,J=8.6Hz),8.07(1H,d,J=7.7Hz),8.31(1H,d,J=6.8Hz),8.83(1H,s)
MASS(m/z):1373(M+Na)+
以类似于实施例8的方式得到下列化合物[实施例30-54]。实施例30
1R(KBr):3369,2935,1664,1631,1444,1257,1047cm-1
NMR(DMSO-d6,δ):0.89(3H,d,J=6.9Hz),0.95(3H,d,J=6.8Hz),1.11(3H,d,J=5.8Hz),1.2-1.5(6H,m),1.6-2.4(9H,m),2.9-3.4(2H,m),3.6-4.5(16H,m),4.7-5.4(9H,m),6.73(1H,d,J=8.2Hz),6.8-7.0(2H,m),7.0-7.2(4H,m),7.3-7.7(3H,m),7.97(2H,d,J=8.7Hz),8.1-8.3(5H,m),8.81(1H,d,J=7.0Hz),8.85(1H,s)
MASS(m/z):1329.8(M+Na)+
C56H71N10O21S2Na的元素分析计算值:C 46.93, H 5.98, N 9.77
实测值:C 46.72, H 6.11, N 9.72实施例31
IR(KBr):3353,2935,2873,1658,1635,1440,1257,1047cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.9Hz),0.96(3H,d,J=6.8Hz),1.12(3H,d,J=5.8Hz),1.2-1.5(6H,m),1.6-2.4(9H,m),2.9-3.2(2H,m),3.3-3.4(1H, m),3.8-4.6(16H,m),4.6-5.4(9H,m),6.7-7.0(3H,m),7.0-7.2(4H,m),7.3-7.7(3H,m),7.9-8.3(7H,m),8.7-8.9(2H,m)
MASS(m/z):1313.0(M+Na)+
C56H71N10O22S的元素分析计算值:C 48.07, H 5.98, N 10.01
实测值:C 48.23, H 6.17, N 10.00实施例32
IR(KBr):3350,2927,1668,1627,1288,1047cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.8Hz),0.95(3H,d,J=6.8Hz),1.13(3H,d,J=6.7Hz),1.2-1.5(10H,m),1.6-2.4(8H,m),2.9-3.2(2H,m),3.4-4.6(16H,m),4.6-5.3(9H,m),6.5-7.5(8H,m),7.6-8.2(4H,m),8.31(1H,s),8.43(1H,dd,J=8.7和2.5Hz),8.6-8.8(1H,d,J=6.3Hz),8.85(1H,s),8.99(1H,d,J=2.5Hz)
MASS(m/z):1315.3(M+Na)+
C56H73N10O22NaS·7H2O的元素分析计算值:
C 47.39, H 6.18, N 9.87
实测值:C 47.11, H 6.29, N 9.72实施例33
IR(KBr):3350,2925,1670,1625,1259,1047cm-1
NMR(DMSO-d6,δ):0.7-1.0(6H,m),1.1-1.2(3H,d,J=5.7Hz),1.2-2.5(15H,m),3.0-3.3(2H,m),3.4-3.6(1H,m),3.6-3.8(2H,m),3.9-4.6(16H,m),4.7-5.4(9H,m),6.6-7.3(6H,m),7.3-8.0(5H,m),8.0-8.3(5H,m),8.6-9.0(2H,m)
MASS(m/z):1286.8(M+Na)+
C55H70N9O22NaS·5.5H2O的元素分析计算值:
C 48.46, H 5.99, N 9.25
实测值:C 48.47, H 6.01, N 9.26实施例34
MASS(m/z):1387(M+Na)+实施例35
IR(KBr):3363,1662.3,1631.5,1240cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.8Hz),0.8-1.5(15H,m),1.5-2.6(16H,m),2.8-3.5(11H,m),3.6-4.6(14H,m),4.6-5.3(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.84(1H,s),7.00(2H,d,J=8.8Hz),7.04(1H,s),7.13(1H,s),7.3-7.5(2H,m),7.63(1H,brs),7.79(2H,d,J=8.8Hz),8.05(1H,d,J=7.7Hz),8.29(1H,d,J=6.8Hz),8.83(1H,s)
MASS(m/z):1215(M-SO3+Na)
C58H84N10O20S·7H2O的元素分析计算值:C 49.78, H 7.06, N 10.01
实测值:C 49.93, H 6.92, N 9.98实施例36
IR(KBr):1648,1631cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.8Hz),1.12(3H,d,J=5.7Hz),1.65-2.50(7H,m),2.84-3.13(3H,m),3.74-5.41(23H,m),3.83(3H,s),6.74(1H,d,J=8.2Hz),6.77(1H,d,J=10.6Hz),6.83(1H,m),7.08(3H,m),7.17(1H,m),7.43(2H,m),7.65(1H,m),7.77(2H,d,J=8.7Hz),7.92(2H,d,J=8.5Hz),8.08(1H,m),8.11(2H,d,J=8.4Hz),8.22(2H,d,J=7.6Hz),8.25(2H,d,J=7.6Hz),8.85(2H,m)
MASS(m/z):1273
C57H65N10O22SNa·11H2O的元素分析计算值:
C 45.78, H 5.86, N 9.37
实测值:C 45.75, H 5.95, N 9.27实施例37
IR(KBr):2968,2937,2879,1651,1632cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=5.5Hz),1.01(3H,t,J=7.1Hz),1.12(3H,t,J=5.8Hz),1.75(2H,q,J=7.1Hz),1.60-2.48(7H,m),2.75-3.10(3H,m),3.60-5.35(23H,m),4.01(2H,t,J=7.1Hz),6.73(1H,d,J=8.2Hz),6.78(1H,d,J=9.7Hz),6.87(1H,m),7.07(3H,m),7.16(1H,m),7.43(2H,m),7.64(1H,m),7.74(2H,d,J=8.8Hz),7.91(2H,d,J=8.5Hz),8.00(1H,m),8.10(2H,d,J=8.5Hz),8.21(2H,d,J=7.4Hz),8.25(2H,d,J=8.3Hz),8.83(2H,m)
MASS(m/z):1301
C59H69N10O22SNa·10H2O的元素分析计算值:
C 47.07, H 5.96, N 9.30
实测值:C 46.88, H 5.70, N 9.14实施例38
IR(KBr):2935,2873,1668,1651,1632cm-1
NMR(DMSO-d6,δ):0.92-0.99(6H,m),1.12(3H,d,J=6.1Hz),1.48(2H,qt,J=5.5和5.5Hz),1.74(2H,tt,J=5.5和5.5Hz),1.60-2.40(7H,m),2.80-3.20(3H,m),4.05(2H,t,J=5.5Hz),3.74-5.25(23H,m),6.74(1H,d,J=8.2Hz),6.78(1H,d,J=9.5Hz),6.87(1H,m),7.07(3H,m),7.17(1H,m),7.43(2H,m),7.65(1H,m),7.70(1H,m),7.74(2H,d,J=8.7Hz),7.91(2H,d,J=8.5Hz),8.00(1H,m),8.10(2H,d,J=8.6Hz),8.21(2H,d,J=7.6Hz),8.25(2H,d,J=8.1Hz),8.88(2H,m)
MASS(m/z):1315
C60H71N10O22SNa·9H2O的元素分析计算值:
C 48.00, H 5.97, N 9.33
实测值:C 48.05, H 5.95, N 9.34实施例39
IR(KBr):2943,2870,1668,1651,1632cm-1
NMR(DMSO-d6,δ):0.95(6H,m),1.13(3H,d,J=5.7Hz),1.39(4H,m),1.60-2.50(9H,m),2.80-3.20(3H,m),3.74-5.25(23H,m),4.04(2H, t,J=6.3Hz),6.74(1H,d,J=8.2Hz),6.78(1H,d,J=11.2Hz),6.88(1H,m),7.07(3H,m),7.17(1H,m),7.45(2H,m),7.67(1H,m),7.74(2H,d,J=8.8Hz),7.91(2H,d,J=8.3Hz),8.00(1H,m),8.10(2H,d,J=8.4Hz),8.21(2H,d,J=7.9Hz),8.25(2H,d,J=7.9Hz),8.25(2H,d,J=7.9Hz),8.80(1H,m),8.85(1H,s)
MASS(m/z):1330,1329
C61H73N10O22SNa·10H2O的元素分析计算值:
C 47.78, H 6.11, N 9.18
实测值:C 47.90, H 6.05, N 9.18实施例40
IR(KBr):2933,2871,1666,1650,1632cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.9Hz),0.96(3H,d,J=6.8Hz),1.12(3H,d,J=5.7Hz),1.32-1.43(6H,m),1.60-2.50(9H,m),3.02(3H,m),4.04(2H,t,J=6.4Hz),3.74-5.25(23H,m),6.74(1H,d,J=8.2Hz),6.78(1H,d,J=11.1Hz),6.88(1H,m),7.07(3H,m),7.17(1H,m),7.43(2H,m),7.67(1H,m),7.75(2H,d,J=8.8Hz),7.91(2H,d,J=8.5Hz),8.00(1H,m),8.11(2H,d,J=8.5Hz),8.20(2H,d,J=7.9Hz),8.25(2H,d,J=8.1Hz),8.84(2H,m)
MASS(m/z):1343,1327
C62H75N10O22SNa·7H2O的元素分析计算值:
C 49.86, H 6.01, N 9.38
实测值:C 49.87, H 6.01, N 9.30实施例41
IR(KBr):2931,2858,1651,1632cm-1
NMR(DMSO-d6,δ):0.88(3H,t,J=6.6Hz),0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.2Hz),1.30(8H,m),1.60-2.40(9H,m),2.80-3.20(3H,m),4.03(2H,t,J=6.3Hz),3.74-5.25(23H,m),6.72(1H,d,J=8.2Hz),6.78(1H,d,J=9.7Hz),6.87(1H,m),7.06(3H,m),7.16(1H,m),7.44(2H,m),7.70(1H,m),7.74(2H,d,J=8.8Hz),7.90(2H,d,J=8.5Hz),8.00(1H,m),8.10(2H,d,J=8.6Hz),8.20(2H,d,J=7.8Hz),8.25(2H,d,J=8.2Hz),8.84(2H,m)
MASS(m/z):1361,1357,1341
C63H77N10O22SNa·6H2O的元素分析计算值:
C 50.80, H 6.02, N 9.40
实测值:C 50.79, H 6.28, N 9.48实施例42
IR(KBr):2939,1668,1651,1632cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=5.3Hz),1.13(3H,d,J=6.0Hz),1.35-2.50(15H,m),2.60-3.20(9H,m),3.65-5.40(25H,m),6.73(1H,d,J=8.5Hz),6.78(1H,d,J=11.2Hz),6.88(1H,m),7.09(3H,m),7.17(1H,m),7.44(2H,m),7.70(1H,m),7.76(2H,d,J=7.1Hz),7.91(2H,d,J=6.6Hz),8.08(1H,m),8.11(2H,d,J=7.4Hz),8.22(2H,d,J=6.1Hz),8.25(2H,d,J=6.3Hz),8.84(2H,m)
MASS(m/z):1388,1384,1368
C64H78N11O22SNa·7H2O的元素分析计算值:
C 50.09,H 6.04,N 10.04
实测值:C 50.18,H 6.03,N 9.65实施例43
IR(KBr):1650.8,1629.6cm-1
NMR(DMSO-d6,δ):0.80-0.86(3H,m),0.96(3H,d,J=6.6Hz),1.12(3H,d,J=5.6Hz),1.23(14H,brs),1.74-2.50(9H,m),2.98(1H,d,J=13.4Hz),3.10-3.46(2H,m),3.70-4.60(16H,m),4.64-5.32(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.4Hz),6.89(1H,brs),7.05(1H,d,J=1.7Hz),7.16(1H,brs),7.42-7.47(2H,m),7.66(1H,brs),8.06-8.17(6H,m),8.65(1H,s),8.80(1H,d,J=7.5Hz),8.84(1H,s)
MASS(m/z):1297.03(M-Na)+
C57H77N12O21SNa·7H2O的元素分析计算值:
C 47.30,H 6.34,N 11.61
实测值:C 47.33,H 6.16,N 11.54实施例44
IR(KBr):3361.3,1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.80-0.90(3H,m),0.96(3H,d,J=6.7Hz),1.15(3H,d,J=6Hz),1.23(14H,brs),1.70-2.65(9H,m),2.90-3.10(1H,m),3.20-3.42(2H,m),3.65-4.60(16H,m),4.66-5.40(9H,m),6.73(1H,d,J=8.3Hz),6.83(1H,d,J=8.8Hz),6.89(1H,s),7.05(1H,s),7.18(1H,s),7.42-7.46(2H,m),7.66(1H,brs),8.05(4H,s),8.08(1H,s),8.57(1H,s),8.57-8.84(3H,m)
MASS(m/z):1313.01(M-Na)+
C57H77N12O20S2Na·7H2O的元素分析计算值:
C 46.78,H 6.27,N 11.48
实测值:C 46.89,H 6.34,N 11.41实施例45
IR(KBr):1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=6Hz),1.70-2.60(9H,m),2.80-3.60(3H,m),3.60-4.60(19H,m),4.65-5.40(8H,m),6.73(1H,d,J=8.2Hz),6.81-6.99(6H,m),7.05(1H,s),7.11(2H,d,J=8.8Hz),7.34-7.26(2H,m),7.34-7.73(3H,m),7.76(2H,d,J=8.8Hz),7.91(2H,d,J=8.4Hz),8.11(2H,d,J=8.4Hz),8.19-8.30(4H,m),8.70-9.00(3H,m)
MASS(m/z):1393.13(M-Na)+
C65H73N10O23SNa·9H2O的元素分析计算值:
C 49.43,H 5.81,N 8.87
实测值:C 49.24,H 5.61,N 8.77实施例46
IR(KBr):3361.3,1668.1,1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.12(3H,d,J=5.6Hz),1.70-2.60(7H,m),2.80-5.27(26H,m),4.65(2H,d,J=5.2Hz),5.27-5.48(2H,m),5.99-6.18(1H,m),6.72(1H,d,J=8.1Hz),6.82(1H,d,J=8.1Hz),6.89(1H,s),7.07(1H,s),7.10(2H,d,J=8.8Hz),7.12(1H,s),7.46(2H,brs),7.68(1H,brs),7.75(2H,d,J=8.7Hz),7.91(2H,d,J=8.4Hz),8.11(2H,d,J=8.5Hz),8.19-8.31(4H,m),8.80-8.83(2H,m)
MASS(m/z):1298.97(M-Na)+
C59H67N10O2SNa·9H2O的元素分析计算值:
C 47.71,H 5.77,N 9.43
实测值:C 47.90,H 5.61,N 9.41实施例47
IR(KBr):1650.8,1631.5,1540.8,1513.8cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.7Hz),1.70-2.60(11H,m),2.80-3.60(3H,m),3.60-4.60(18H,m),4.65-5.40(9H,m),6.73(1H,d,J=8.1Hz),6.82(1H,d,J=9.5Hz),6.87-6.97(5H,m),7.06(1H,s),7.09(2H,d,J=8.8Hz),7.25-7.33(2H,m),7.33-7.73(3H,m),7.75(2H,d,J=8.6Hz),7.91(2H,d,J=8.5Hz),8.11(2H,d,J=8.5Hz),8.19-8.27(4H,m),8.70-8.90(3H,m)
MASS(m/z):1407.15(M-Na)+
C66H75N10O23SNa·7H2O的元素分析计算值:
C 50.90,H 5.76,N 8.99
实测值:C 50.80,H 5.90,N 8.90实施例48
IR(KBr):1675.8,1650.8,1540.8,1513.8cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.9Hz),1.13(3H,d,J=5.9Hz),1.20-1.60(12H,m),1.64-2.68(7H,m),2.80-3.60(3H,m),3.21(3H,s),3.60-5.40(27H,m),6.73(1H,d,J=8.4Hz),6.83(1H,d,J=9.3Hz),6.89(1H,s),7.05(1H,s),7.07(2H,d,J=8.7Hz),7.17(1H,s),7.30-7.70(3H,m),7.74(2H,d,J=8.7Hz),7.91(2H,d,J=8.4Hz),8.11(2H,d,J=8.5Hz),8.19-8.27(4H,m),8.74-8.90(3H,m)
MASS(m/z):1401.12(M-Na)+实施例49
IR(KBr):1675.8,1650.8,1540.8cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.4Hz),1.03-1.10(9H,m),1.50-2.50(11H,m),2.70-5.50(34H,m),6.71(1H,d,J=7.3Hz),6.79-6.90(2H,m),7.00-7.10(4H,m),7.30-7.80(3H,m),7.75(2H,d,J=8.6Hz),7.91(2H,d,J=8.4Hz),8.11(2H,d,J=7.4Hz),8.19-8.27(4H,m),8.60-8.90(3H,m)
MASS(m/z):1414.08(M-Na)+
C65H80N11O23SNa·11.6H2O的元素分析计算值:
C 47.39,H 6.31,N 9.35
实测值:C 47.40,H 6.07,N 9.22实施例50
IR(KBr):3353.6,1650.8,1631.5,1538.9,1515.8,1442.5,1114.7cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.7Hz),1.7-2.6(11H,m),2.9-3.1(1H,m),3.1-3.5(2H,m),3.7-4.6(18H,m),4.7-5.3(9H,m),6.74(1H,d,J=8.0Hz),6.83(1H,d,J=8.0Hz),6.87-7.02(4H,m),7.05(1H,s),7.15(2H,d,J=8.7Hz),7.17(1H,m),7.2-7.4(2H,m),7.4-7.6(2H,m),7.67(1H,br),7.98(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.77(1H,d,J=8.5Hz),8.84(1H,s)
MASS(m/z):1346.72(M-Na)+
C60H71N10NaO22S·11H2O的元素分析计算值:
C 45.92,H 5.97,N 8.92
实测值:C 46.13,H 5.75,N 8.92实施例51
IR(KBr):3363.2,1650.8,1538.9,1515.8,1442.5,1247.7cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.9Hz),1.5-2.5(13H,m),2.9-3.1(1H,m),3.1-3.5(2H,m),3.6-5.4(27H,m),6.73(1H,d,J=8.2Hz),6.82(1H,d,J=8.2Hz),6.87-7.00(4H,m),7.05(1H,s),7.14(2H,d,J=8.7Hz),7.16(1H,s),7.27(2H,m),7.42(2H,m),7.66(1H,br),7.97(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.7-8.9(2H,m)
MASS(m/z):1360.75(M-Na)+
C61H73N10NaO22S2·9H2O的元素分析计算值:
C 47.34,H 5.93,N 9.05
实测值:C 47.27,H 5.76,N 8.94实施例52
IR(KBr):3365.2,1650.8,1631.5,1538.9,1515.8,1442.5,1245.8cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.6Hz),1.7-2.7(9H,m),2.9-3.1(1H,m),3.1-3.5(2H,m),3.6-4.6(18H,m),4.6-5.5(9H,m),6.73(1H,d,J=8.3Hz),6.83(1H,d,J=8.3Hz),6.84-7.00(4H,m),7.05(1H,s),7.17(2H,d,J=8.7Hz),7.19(1H,m),7.2-7.6(4H,m),7.67(1H,br),7.98(2H,d,J=8.7Hz),7.8-8.2(5H,m),8.6-9.0(2H,m)
MASS(m/z):1332.97(M-Na)+
C59H69N10NaO22S·8H2O的元素分析计算值:
C 47.20,H 5.71,N 9.33
实测值:C 47.10,H 5.59,N 9.24实施例53
IR(KBr):3353.6,1650.8,1631.5,1538.9,1513.8,1450.2,1442.5,1257.4cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.12(3H,d,J=5.7Hz),1.3-2.6(13H,m),2.9-3.1(1H,m),3.1-3.6(7H,m),3.6-4.6(16H,m),4.6-5.5(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.13(2H,d,J=8.8Hz),7.15(1H,m),7.3-7.8(3H,m),7.97(2H,d,J=8.8Hz),7.8-8.2(5H,m),8.6-9.0(2H,br)
MASS(m/z):1298.85(M-Na)+
C56H71N10NaO22S·10H2O的元素分析计算值:
C 44.74,H 6.10,N 9.32
实测值:C 44.78,H 5.96,N 9.27实施例54
IR(KBr):3365,1647,1541,1516,1437,1248,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.6Hz),1.49-1.74(6H,m),1.74-2.55(7H,m),2.90-3.50(3H,m),3.60-3.85(6H,m),3.85-4.59(13H,m),4.70-5.40(8H,m),6.74(1H,d,J=8.2Hz),6.81(1H,s),6.87(1H,d,J=8.2Hz),6.99(1H,d,J=9.1Hz),7.06(1H,s),7.19(1H,s),7.35-7.50(2H,m),7.68(1H,m),8.05(1H,m),8.06(4H,s),8.08(1H,dd,J=9.1和2.5Hz),8.71(1H,d,J=2.5Hz),8.77(1H,d,J=7.4Hz),8.82(1H,brs)
MASS(m/z):1266.93(M-Na)+
C54H67N12NaO20S2·10H2O的元素分析计算值:
C 44.08,H 5.96,N 11.42
实测值:C 44.28,H 5.81,N 11.48
以类似于实施例17的方式得到下列化合物[实施例55和56]。实施例55
IR(KBr):3359,1651,1539,1522cm-1
NMR(DMSO-d6,δ):0.8-1.0(6H,m),1.11(3H,d,J=5.5Hz),1.3-1.6(4H,m),1.6-2.15(5H,m),2.2-2.5(4H,m),2.97(1H,m),3.20(1H,m),3.74(2H,m),3.8-4.6(14H,m),4.6-5.4(10H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.22(1H,m),7.45(3H,m),7.52(2H,d,J=4.9Hz),7.66(1H,m),7.96(5H,m),8.08(1H,d,J=8.2Hz),8.59(1H,d,J=6.4Hz),8.85(1H,s),8.89(1H,s)
MASS(m/z):1307.69(M-Na)+
C57H70N11O21S2Na·10H2O的元素分析计算值:
C 45.26,H 6.00,N 10.19
实测值:C 45.11,H 5.84,N 10.28实施例56
IR(KBr):3359,1651,1539,1524,1458,1254cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.12(3H,d,J=5.5Hz),1.2-1.6(6H,m),1.6-2.1(7H,m),2.1-2.4(4H,m),2.96(1H,m),3.19(1H,m),3.42(1H,m),3.74(2H,m),3.8-4.6(12H,m),4.73(1H,m),4.8-5.0(3H,m),5.06(1H,d,J=5.8Hz),5.1-5.3(5H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.15(2H,d,J=8.8Hz),7.23(1H,s),7.3-7.5(2H,m),7.66(1H,s),7.88(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,d,J=7.8Hz),8.58(1H,d,J=7.8Hz),8.85(2H,s)
MASS(m/z):1319.74(M-Na)+
C58H70N11O21S2Na·10H2O的元素分析计算值:
C 45.70,H 5.95,N 10.11
实测值:C 45.58,H 5.80,N 10.13
以类似于实施例18的方式得到下列化合物[实施例57-60]。实施例57
IR(KBr):3350,2929,1664,1629,1446,1284,1047.2cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.7Hz),0.96(3H,d,J=6.7Hz),1.07(3H,d,J=5.9Hz),1.2-1.5(10H,m),1.6-2.5(9H,m),2.9-3.5(4H,m),3.7-4.5(16H,m),4.7-4.8(1H,m),4.87(1H,d,J=5.9Hz),5.0-5.4(5H,m),6.7-6.9(4H,m),6.96(1H,s),7.17(1H,s),7.40(1H,d,J=8.4Hz),7.5-7.8(2H,m),8.0-8.2(2H,m),8.61(1H,d,J=7.7Hz),8.68(1H,d,J=8.9Hz)
MASS(m/z):1182.4(M+Na)+
C49H70N9NaO20S·4H2O的元素分析计算值:
C 47.76,H 6.38,N 10.23
实测值:C 47.81,H 6.73,N 10.12实施例58
IR(KBr):3349,2929,1664,1633,1535,1515,1440,1272,1045cm-1
NMR(DMSO-d6,δ):0.86(3H,t,J=6.8Hz),0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.8H),1.2-1.4(8H,m),1.5-2.5(10H,m),2.58(2H,t,J=7.6Hz),2.9-3.1(1H,m),3.2-3.6(3H,m),3.7-4.2(5H,m),4.1-4.6(8H,m),4.7-5.2(7H,m),5.3-5.4(1H,m),6.7-7.8(14H,m),7.95(2H,,dJ=8.3Hz),8.10(1H,d,J=8.4Hz),8.63(1H,d,J=7.7Hz),8.71(1H,s)
MASS(m/z):1227.5(M+Na)+
C55H73N8NaO19S·5H2O的元素分析计算值:
C 51.00,H 6.46,N 8.65
实测值:C 50.90,H 6.54,N 8.81实施例59
IR(液体石蜡):3353.0,1668.1,1629.6,1540.8,1515.8cm-1
NMR(DMSO-d6,δ):0.87(3H,t,J=6.7Hz),0.96(3H,d,J=6.7Hz),1.06(3H,d,J=6.0Hz),1.18-1.48(4H,m),1.48-2.06(5H,m),2.06-2.70(8H,m),2.70-3.08(3H,m),3.09-3.50(2H,m),3.60-4.65(14H,m),4.65-5.50(9H,m),6.65-6.90(3H,m),6.90-7.90(13H,m),8.02(1H,d,J=8.4Hz),8.15(1H,d,J=7.7Hz),8.71(1H,s)
MASS(m/z):1227.5(M+Na)+
C55H73N8NaO19S·5H2O的元素分析计算值:
C 50.99,H 6.46,N 8.65
实测值:C 50.84,H 6.62,N 8.81实施例60
IR(KBr):3353.6,1635.3,1257.4cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.8Hz),0.97(3H,d,J=6.7Hz),1.09(3H,d,J=5.7Hz),1.2-1.5(6H,m),1.65-2.6(10H,m),2.97(1H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.4(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.87(1H,s),6.97(1H,s),7.13(2H,d,J=8.9Hz),7.16(1H,s),7.4-7.8(3H,m),7.97(2H,d,J=8.9Hz),7.9-8.2(5H,m),8.72(1H,s),8.78(1H,d,J=7.1Hz)
MASS(m/z):1267(M-Na)+
下列化合物[实施例61到72]可以用类似于实施例13的方法获得。实施例61
1R(KBr):1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.80-0.87(3H,s),0.97(3H,d,J=6.8Hz),1.10(3H,d,J=5.9Hz),1.23(14H,brs),1.73-2.65(10H,m),2.92-3.50(3H,m),3.60-4.60(16H,m),4.70-5.50(8H,m),6.71(1H,d,J=8.2Hz),6.77-6.81(1H,m),6.86(1H,s),6.97(1H,s),7.07-7.86(4H,m),8.11(1H,s),8.06-8.17(4H,m),8.66(1H,s),8.66-8.88(3H,m)
MASS(m/z):1326.62(M+Na)+
C57H77N12O20SNa·7H2O的元素分析计算值:
C 47.83,H 6.41,N 11.74
实测值:C 47.77,H 6.45,N 11.62实施例62
IR(KBr):1668.1,1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.81-0.90(3H,m),0.97(3H,d,J=6.7Hz),1.10(3H,d,J=6Hz),1.23(14H,brs),1.75-2.70(10H,m),2.95-3.02(1H,m),3.17-3.30(2H,m),3.60-4.60(16H,m),4.70-5.46(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.5Hz),6.87(1H,brs),6.98(1H,s),7.18(1H,brs),7.40-7.80(3H,m),8.05-8.10(4H,m),8.08(1H,s),8.57(1H,s),8.71-8.80(3H,m)
MASS(m/z):1297.14(M-Na)+
C57H77N12O19S2Na·7H2O的元素分析计算值:
C 47.30,H 6.34,N 11.61
实测值:C 47.07,H 6.23,N 11.42实施例63
IR(KBr):1675.8,1650.8cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.11(3H,d,J=6.4Hz),1.70-2.60(10H,m),2.90-3.60(3H,m),3.60-4.60(18H,m),4.68-5.60(8H,m),6.70(1H,d,J=8.3Hz),6.78(1H,d,J=9.7Hz),6.87(1H,s),6.93-6.99(4H,m),7.11(2H,d,J=8.8Hz),7.26-7.34(2H,m),7.09-7.78(4H,m),7.76(2H,d,J=8.7Hz),7.91(2H,d,J=8.5Hz),8.12(2H,d,J=8.6Hz),8.19-8.27(4H,m),8.60-9.00(3H,m)
MASS(m/z):1377.26(M-Na)+
C65H73N10O22SNa·6H2O的元素分析计算值:
C 51.72,H 5.68,N 9.28
实测值:C 51.54,H 5.73,N 9.25实施例64
IR(KBr):1675.8,1650.8,1631.5cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=5.6Hz),1.70-2.60(8H,m),2.80-3.60(3H,m),3.60-5.26(22H,m),4.65(2H,d,J=5.2Hz),5.26-5.48(2H,m),5.99-6.18(1H,m),6.70(1H,d,J=8Hz),6.78(1H,d,J=9.9Hz),6.87(1H,s),6.97(1H,s),7.00-7.20(1H,m),7.10(2H,d,J=8.9Hz),7.30-7.80(3H,m),7.75(2H,d,J=8.9Hz),7.92(2H,d,J=8.5Hz),8.12(2H,d,J=8.6Hz),8.19-8.27(5H,m),8.50-9.00(2H,m)
MASS(m/z):1282.84(M-Na)+
C59H67N10O21SNa·7H2O的元素分析计算值:
C 49.44,H 5.70,N 9.77
实测值:C 49.33,H 5.64,N 9.74实施例65
IR(KBr):1650.8,1631.5,1540.8,1513.8,1245.8cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=5.9Hz),1.80-2.60(11H,m),2.80-3.60(3H,m),3.65-4.60(19H,m),4.63-5.50(8H,m),6.70(1H,d,J=8Hz),6.77(1H,d,J=7.9Hz),6.87-6.97(5H,m),7.02-7.22(1H,m),7.09(2H,d,J=8Hz),7.25-7.33(2H,m),7.40-7.80(3H,m),7.75(2H,d,J=8.9Hz),7.91(2H,d,J=8.5Hz),8.11(2H,d,J=8.4Hz),8.23-8.27(4H,m),8.50-9.00(3H,m)
MASS(m/z):1391.07(M-Na)+
C66H75N10O22SNa·7H2O的元素分析计算值:
C 51.42,H 5.82,N 9.09
实测值:C 51.37,H 5.78,N 9.05实施例66
IR(KBr):3353.6,2939.0,1650.8,1631.5,1538.9,1513.8,1442.5cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.7Hz),1.7-2.6(12H,m),2.9-3.1(1H,m),3.1-3.7(2H,m),3.7-4.7(18H,m),4.7-5.5(8H,m),6.71(1H,d,J=8.0Hz),6.78(1H,d,J=8.0Hz),6.83-7.05(5H,m),7.15(2H,d,J=8.7Hz),7.17(1H,m),7.2-7.35(2H,m),7.35-7.9(3H,m),7.98(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.75(1H,br),8.80(1H,d,J=7.0Hz)
MASS(m/z):1331.28(M-Na)+
C60H71N10NaO21S2·9H2O的元素分析计算值:
C 47.49,H 5.91,N 9.23
实测值:C 47.41,H 5.71,N 9.17实施例67
IR(KBr):3353.6,1666.2,1650.8,1631.5,1538.9,1513.8,1442.5,1247.7cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.4-2.7(14H,m),2.9-3.1(1H,m),3.1-3.5(2H,m),3.6-4.6(18H,m),4.7-5.5(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,d,J=8.1Hz),6.84-7.00(5H,m),7.14(2H,d,J=8.7Hz),7.16(1H,m),7.27(2H,m),7.44(1H,d,J=8.6Hz),7.59(1H,br),7.71(1H,br),7.98(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.75(1H,br),8.79(1H,d,J=7.2Hz)
MASS(m/z):1345.3(M-Na)+
C61H73N10NaO21S2·8H2O的元素分析计算值:
C 48.41,H 5.93,N 9.25
实测值:C 48.30,H 5.91,N 9.17实施例68
IR(KBr):3353.6,2937.1,1650.8,1540.8,1513.8,1452.1,1243.9cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.7-2.7(10H,m),2.9-3.1(1H,m),3.1-3.6(2H,m),3.6-4.7(18H,m),4.7-5.5(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,d,J=8.1Hz),6.84-7.10(5H,m),7.17(2H,d,J=8.7Hz),7.19(1H,m),7.2-7.4(2H,m),7.44(1H,d,J=9.2Hz),7.5-7.9(2H, m),7.98(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.6-9.0(2H,m)
MASS(m/z):1316.8(M-Na)+
C59H69N10NaO21S2·9H2O的元素分析计算值:C 47.13,H 5.83,N9.32
实测值:C 47.40,H 5.67,N 9.30实施例69
IR(KBr):3361.3,2937.1,1650.8,1631.5,1538.9,1513.8,1450.2,1440.6,1257.4cm-1
NMR(DMSO-d6,δ):0.99(3H,m),1.11(3H,m),1.3-2.7(14H,m),2.9-3.1(1H,m),3.1-3.6(7H,m),3.6-4.7(16H,m),4.7-5.6(8H,m),6.69(1H,d,J=8.2Hz),6.77(1H,d,J=8.2Hz),6.86(1H,s),6.98(1H,s),7.13(2H,d,J=8.7Hz),7.15(1H,m),7.3-7.9(3H,m),7.97(2H,d,J=8.7Hz),7.9-8.2(5H,m),8.6-8.9(2H,m)
MASS(m/z):1283.2(M-Na)+
C56H71N10NaO21S2·10H2O的元素分析计算值:
C 45.22,H 6.17,N 9.42
实测值:C 45.30,H 5.90,N 9.38实施例70
IR(KBr):3400,1651,1541,1261cm-1
NMR(DMSO-d6,δ):0.95-5.40(58H,m),6.67-8.77(19H,m)
MASS(m/z):1325.29(M-Na)+
C59H77N10NaO21S2·37/4H2O的元素分析计算值:
C 46.74,H 6.35,N 9.24
实测值:C 46.74,H 6.10,N 9.15实施例71
IR(KBr):3363,1648,1619,1506,1257cm-1
NMR(DMSO-d6,δ):0.97(3H,t,J=3.3Hz),1.02(3H,d,J=7.3Hz),1.11(3H,d,J=5.5Hz),1.68-5.40(38H,m),6.69-8.86(22H,m)
MASS(m/z):1254(M-Na)+
C59H69N10NaO21S·41/5H2O的元素分析计算值:
C 48.64,H 5.91,N 9.61
实测值:C 48.63,H 5.85,N 9.55实施例72
IR(KBr):3300,1651,1506,1437cm-1
NMR(DMSO-d6,δ):0.87-5.30(50H,m),6.66-8.73(20H,m)
MASS(m/z):1236.29(M-Na)+
C56H70N9NaO21S·23/3H2O的元素分析计算值:
C 48.10,H 6.15,N 9.01
实测值:C 48.14,H 6.03,N 8.97
下列化合物[实施例73和74]可以用类似于实施例17的方法获得。实施例73
IR(KBr):3359,1676,1651,1632,1514cm-1
NMR(DMSO-d6,δ):0.87-1.0(6H,m),1.09(3H,d,J=5.4Hz),1.2-1.6(4H,m),1.6-2.1(5H,m),2.1-2.6(5H,m),3.00(1H,m),3.2(1H,m),3.5(1H,m),3.6-4.6(16H,m),4.6-5.6(8H,m),6.70(1H,d,J=8.2Hz),6.77(1H,d,J=8.2Hz),6.87(1H,s),6.97(1H,s),7.20(1H,m),7.3-7.8(6H,m),7.8-8.4(6H,s),8.4-8.8(2H,m),8.89(1H,s)
MASS(m/z):1292.51(M-Na)+
C57H70N11O20S2Na·12H2O的元素分析计算值:
C 44.67,H 6.18,N 10.05
实测值:C 44.89,H 6.05,N 10.02实施例74
IR(KBr):3359,1668,1650,1631cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.4Hz),1.08(3H,d,J=5.4Hz),1.2-1.6(6H,m),1.6-2.0(7H,m),2.1-2.4(4H,m),3.01(1H,m),3.20(1H,m),3.67(1H,m),3.7-4.6(16H,m),4.6-5.6(8H,m),6.68(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.85(1H,s),7.15(2H,d,J=8.9Hz),7.16(1H,s),7.2-7.8(4H,m),7.88(2H,d,J=8.9Hz),7.96(4H,s),8.56(1H,s),8.84(2H,s)
MASS(m/z):1304.08(M-Na)+
C58H70N11O20S2Na·12H2O的元素分析计算值:
C 45.10,H 6.13,N 9.98
实测值:C 45.33,H 5.89,N 9.94
下列化合物[实施例75到85]可以用类似于实施例13的方法获得。实施例75
IR(KBr):1668,1649,1632,1541,1516cm-1
NMR(DMSO-d6,δ):0.86(3H,m),0.97(3H,d,J=6.7Hz),1.0-1.2(3H,m),1.2-1.4(8H,m),1.45-1.65(2H,m),1.7-2.6(8H,m),2.8-3.5(3H,m),3.46(2H,t,J=6.4Hz),3.6-4.6(14H,m),4.51(2H,s),4.7-5.4(8H,m),6.65-6.85(2H,m),6.88(1H,s),6.97(1H,s),7.18(1H,s),7.4-7.8(3H,m),7.50(2H,d,J=8.6Hz),8.02(2H,d,J=8.6Hz),8.0-8.2(5H,m),8.41(1H,s),8.72(1H,s),8.7-8.9(1H,m),9.35(1H,s)
MASS(m/z):1407(M++23)
C61H77N12NaO20S2·7H2O的元素分析计算值:
C 48.47,H 6.07,N 11.12
实测值:C 48.51,H 6.01,N 11.17实施例76
IR(KBr):1632,1518,1441,1250cm-1
NMR(DMSO-d6,δ):0.89(3H,t,J=6.6Hz),0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.3Hz),1.1-1.5(6H,m),1.6-2.5(10H,m),2.9-3.1(1H,m),3.1-3.5(2H,m),3.6-4.6(14H,m),4.03(2H,t,J=6.4Hz),4.7-5.1(4H,m),5.15-5.25(3H,m),5.3-5.45(1H,m),6.7-6.85(2H,m),6.87(1H,s),6.97(1H,s),7.10(2H,d,J=8.9Hz),7.18(1H,s),7.4-7.8(3H,m),7.85(2H,d,J=8.9Hz),8.0-8.2(5H,m),8.06(1H,s),8.72(1H,s),8.75-8.9(1H,m),9.23(1H,s)
MASS(m/z):1333(M+-23)
C59H73N12NaO20S2·8H2O的元素分析计算值:
C 47.20,H 5.97,N 11.19
实测值:C 47.27,H 6.04,N 11.26实施例77
IR(KBr):1633,1608,1531,1444,1419cm-1
NMR(DMSO-d6,δ):0.88-1.25(6H,m),1.49-2.50(11H,m),2.84-5.48(33H,m),6.62-6.98(3H,m),7.00-7.16(2H,m),7.10(2H,d,J=8.5Hz),7.25-7.80(7H,m),7.85(2H,d,J=8.5Hz),7.91-8.14(6H,m),8.65-8.89(2H,m)
MASS(m/z):1371.69(M-Na+)
C62H74N11NaO21S2·8H2O的元素分析计算值:
C 48.34,H 5.89,N 10.00
实测值:C 48.39,H 5.65,N 9.95实施例78
IR(KBr):1649,1605,1541,1516,1448cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.9Hz),1.40-2.45(12H,m),2.78-3.50(7H,m),3.64-5.34(23H,m),6.47(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.00-7.50(10H,m),7.67(1H,brs),7.98-8.20(6H,m),8.74(1H,d,J=2.5Hz),8.65-8.92(2H,m)
MASS(m/z):1343.11(M-Na+)
C60H71N12NaO20S2·7H2O的元素分析计算值:
C 48.25,H 5.74,N 11.25
实测值:C 48.32,H 5.62,N 11.24实施例79
IR(KBr):1637,1539,1512,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=7.1Hz),1.36(3H,t,J=6.9Hz),1.73-2.52(8H,m),2.79-3.34(3H,m),4.10(2H,q,J=7.0Hz),3.66-4.60(14H,m),4.70-5.54(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,dd,J=8.4和1.7Hz),6.87(1H,s),6.98(1H,d,J=1.7Hz),7.06(2H,d,J=8.9Hz),7.19(1H,s),7.45(1H,d,J=8.8Hz),7.60(1H,m),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),7.96-8.24(8H,m),8.73(1H,brs),8.80(1H,d,J=7.3Hz)
MASS(m/z):1287.49(M-Na+)
C58H67N10NaO20S2·7H2O的元素分析计算值:
C 48.46,H 5.68,N 9.74
实测值:C 48.19,H 5.69,N 9.56实施例80
IR(KBr):1649,1635,1510,1443cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.8Hz),1.12(3H,d,J=5.8Hz),1.55-2.51(11H,m),2.76-3.64(3H,m),3.25(3H,s),3.64-4.60(18H,m),4.60-5.54(9H,m),6.73(1H,d,J=8.2Hz),6.83(1H,d,J=8.6Hz),6.89(1H,s),7.02-7.15(3H,m),7.36-7.79(3H,m),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.4Hz),8.00-8.26(8H,m),8.70-8.92(2H,m)
MASS(m/z):1361.12(M-Na+)
C61H73N10NaO22S2·7H2O的元素分析计算值:
C 48.47,H 5.80,N 9.27
实测值:C 48.63,H 5.71,N 9.19实施例81
IR(KBr):1633,1533,1512,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10-1.20(3H,m),1.56-2.50(12H,m),2.88-3.28(3H,m),3.25(3H,s),3.63-4.56(18H,m),4.70-5.50(8H,m),6.69(1H,d,J=8.1Hz),6.77(1H,d,J=8.1Hz),6.87(1H,s),6.98(1H,s),7.07(2H,d,J=8.8Hz),7.28-7.72(3H,m),7.73(2H,d,J=8.7Hz),7.87(2H,d,J=8.4Hz),7.94-8.20(8H,m),8.64-8.92(2H,m)
MASS(m/z):1345.44(M-Na+)
C61H73N10NaO21S2·6H2O的元素分析计算值:
C 49.59,H 5.80,N 9.48
实测值:C 49.52,H 5.68,N 9.39实施例82
IR(KBr):1635,1608,1531,1444,1419cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.8Hz),1.10(3H,d,J=5.7Hz),1.03-1.20(5H,m),1.50-2.55(14H,m),2.55-2.77(4H,m),2.89-3.55(7H,m),3.67-4.63(14H,m),4.68-5.50(8H,m),6.71(1H,d,J=8.2Hz),6.78(1H,d,J=8.2Hz),6.87(1H,s),6.97(1H,s),7.08(2H,d,J=8.7Hz),7.18(1H,s),7.44(1H,d,J=7.5Hz),7.58(1H,m),7.71(1H,m),7.85(2H,d,J=8.8Hz),7.94-8.20(5H,m),8.72(1H,s),8.78(1H,d,J=7.0Hz)
MASS(m/z):1332.99(M-Na+)
C60H77N12NaO19S2·7H2O的元素分析计算值:
C 48.58,H 6.18,N 11.33
实测值:C 48.58,H 6.02,N 11.22实施例83
IR(KBr):1633,1535,1512,1443cm-1
NMR(DMSO-d6,δ):0.95(3H,t,J=7.4Hz),0.97(3H,d,J=7.1Hz),1.11(3H,d,J=5.6Hz),1.35-1.56(2H,m),1.66-2.55(10H,m),2.90-3.38(3H,m),3.68-4.62(16H,m),4.75-5.52(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.88(1H,s),6.99(1H,s),7.07(2H,d,J=8.8Hz),7.10-7.68(3H,m),7.73(2H,d,J=8.7Hz),7.86(2H,d,J=8.4Hz),8.05-8.25(8H,m),8.50-8.92(2H,m)
MASS(m/z):1315.58(M-Na+)
C60H71N10NaO20S2·10H2O的元素分析计算值:
C 47.43,H 6.04,N 9.22
实测值:C 47.60,H 5.66,N 9.24实施例84
IR(KBr):1647,1539,1512,1448cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.16-1.20(3H,m),1.15(3H,t,J=7.0Hz),1.73-2.58(8H,m),2.84-3.35(3H,m),3.49(2H,q,J=7.0Hz),3.66-4.62(18H,m),4.74-5.50(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.3和1.7Hz),6.88(1H,brs),6.98(1H,d,J=1.7Hz),7.09(2H,d,J=8.8Hz),7.19(1H,brs),7.36-7.69(2H,m),7.74(2H,d,J=8.8Hz),7.86(2H,d,J=8.5Hz),8.02-8.24(8H,m),8.63-8.90(2H,m)
MASS(m/z):1331.2(M-Na+)
C60H71N10NaO21S2·8H2O的元素分析计算值:
C 48.06,H 5.85,N 9.34
实测值:C 47.93,H 5.82,N 9.23实施例85
IR(KBr):1633,1537,1513,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.8Hz),1.11(3H,d,J=5.8Hz),1.74-2.52(8H,m),2.90-3.40(3H,m),3.35(3H,s),3.62-4.57(18H,m),4.70-5.49(8H,m),6.70(1H,d,J=8.1Hz),6.78(1H,d,J=8.1Hz),6.87(1H,s),6.97(1H,s),7.09(2H,d,J=8.8Hz),7.10-7.51(3H,m),7.74(2H,d,J=8.7Hz),7.87(2H,d,J=8.7Hz),7.94-8.28(8H,m),8.56-8.92(2H,m)
MASS(m/z):1317.28(M-Na+)
C59H69N10NaO21S2·9H2O的元素分析计算值:
C 47.13,H 5.83,N 9.32
实测值:C 47.24,H 5.55,N 9.35实施例86
向原料化合物(86)(0.15g)和4-[4-[4-(5-甲氧基戊氧基)联苯-4-基]哌嗪-1-基]苯甲酸苯并三唑-1-基-酯(0.12g)的N,N-二甲基甲酰胺(3ml)溶液中加入二氨基吡啶(0.024g),于室温下搅拌该混合物15小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀,减压干燥。将固体溶于稀碳酸氢钠水溶液中,经在ODS(YMC-凝胶ODS-AM S-50(商标:由Yamamura Chmical Lab.制备)上柱层析,用60%甲醇水溶液洗脱。合并含有目标化合物的部分并减压蒸发除去甲醇。冻干生成的残留物得到目标化合物(86)(0.169)。
IR(KBr):1666.2,1629.6,1228.4,1043.3cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.4Hz),1.08(3H,d,J=5.4Hz),1.44-5.17(55H,m),6.69-8.72(22H,m)
MASS(m/z):1405.4(M+Na)
C64H83N10NaO21S·7.5H2O的元素分析计算值:
C 50.62,H 6.50,N 9.32
实测值:C 50.52,H 6.42,N 9.16下列化合物[实施例87到105]可以用类似于实施例86的方法获得。实施例87
IR(KBr):1668.1,1629.6,1230.4cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.07(3H,d,J=5.7Hz),1.24-5.50(59H,m),6.68-8.80(18H,m)
MASS(m/z):1327.5(M-Na)
C60H83N10NaO20S·6.5H2O的元素分析计算值:
C 49.07,H 6.59,N 9.54
实测值:C 49.05,H 6.64,N 9.44实施例88
IR(KBr):1666.2,1631.5,1240.0cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.07(3H,d,J=5.9Hz),1.40-5.40(52H,m),6.69-8.71(19H,m)
MASS(m/z):1249.3(M-Na)
C58H77N10NaO19S·8H2O的元素分析计算值:
C 49.15,H 6.61,N 9.88
实测值:C 48.96,H 6.49,N 9.79实施例89
IR(KBr):1668.1,1631.5,1238.1cm-1
NMR(DMSO-d6,δ):0.82-5.38(69H,m),6.69-8.40(14H,m)
MASS(m/z):1265.6,1243.5(M-Na)
C57H83N10NaO19S·7H2O的元素分析计算值:
C 49.13,H 7.02,N 10.05
实测值:C 49.19,H 7.02,N 10.00实施例90
IR(KBr):1664.3,1629.6,1232.3cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.07(3H,d,J=5.6Hz),1.16-5.20(53H,m),6.70-8.30(18H,m)
MASS(m/z):1265.4(M-Na)
C58H77N10NaO20S·8.5H2O的元素分析计算值:
C 48.29,H 6.57,N 9.71
实测值:C 48.04,H 6.21,N 9.60实施例91
IR(KBr):1666.2,1631.5,1232.3,1045.2cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.07(3H,d,J=5.8Hz),1.30-5.40(53H,m),6.69-8.71(18H,m)
MASS(m/z):1296.3(M+Na)
C58H77N10NaO19S·8H2O的元素分析计算值:
C 49.15,H 6.61,N 9.88
实测值:C 49.14,H 6.53,N 9.90实施例92
IR(KBr):3330.5,1666.2,1631.5,1255.4cm-1
NMR(DMSO-d6,δ):0.94-5.26(68H,m),6.66-8.26(11H,m)
MASS(m/z):1319.35(M-Na)
C57H79N10NaO22S2·4.5H2O的元素分析计算值:
C 48.06,H 6.23,N 9.83
实测值:C 48.10,H 6.26,N 9.72实施例93
IR(KBr):1660.4,1631.5,1442.5,1249.6cm-1
NMR(DMSO-d6,δ):0.88-1.45(11H,m),1.60-3.40(18H,m),3.75-5.30(22H,m),6.72-9.00(20H,m)
MASS(m/z):1334.69(M-Na)
C59H71N10NaO22S2·6H2O的元素分析计算值:
C 48.29,H 5.70,N 9.54
实测值:C 48.40,H 5.62,N 9.44实施例94
IR(KBr):1666.2,1631.5,1515.8,1257.4,1178.3cm-1
NMR(DMSO-d6,δ):0.94-5.25(51H,m),6.67-8.84(16H,m)
MASS(m/z):1341.55(M-Na)
C59H77N10NaO22S2·6H2O的元素分析计算值:
C 48.09,H 6.09,N 9.51
实测值:C 47.98,H 6.01,N 9.49实施例95
IR(KBr):1666.2,1629.6,1257.4,1178.3cm-1
NMR(DMSO-d6,δ):0.94-5.16(55H,m),6.41-8.84(18H,m)
MASS(m/z):1289.3(M-Na)
C55H73N10NaO22S2·7H2O的元素分析计算值:
C 45.89,H 6.09,N 9.73
实测值:C 45.67,H 5.91,N 9.74实施例96
IR(KBr):1666.2,1633,4,1249.6cm-1
NMR(DMSO-d6,δ):0.96-5.20(47H,m),6.72-9.29(24H,m)
MASS(m/z):1351.41(M-Na)
C63H71N10NaO22S·8.5H2O的元素分析计算值:
C 49.51,H 5.80,N 9.16
实测值:C 49.64,H 5.49,N 9.13实施例97
IR(KBr):1666.2,1631.5,1515.8,1257.4,1178.3cm-1
NMR(DMSO-d6,δ):0.94-5.24(55H,m),6.72-8.84(20H,m)
MASS(m/z):1363.41(M-Na)
C61H75N10NaO22S2·7H2O的元素分析计算值:
C 48.41,H 5.93,N 9.25
实测值:C 48.45,H 5.80,N 9.14实施例98
IR(KBr):3355.5,2935.1,2873.4,1633.4,1521.6,1438.6,1255.4cm-1
NMR(DMSO-d6,δ):0.85-1.05(m,6H),1.10(d,3H,J=5.8Hz),1.25-1.60(m,4H),1.60-2.60(m,9H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.60(m,16H),4.60-5.60(m,9H),6.71(d,1H,J=8.2Hz),6.81(d,1H,J=8.2Hz),6.89(s,1H),7.05(s,1H),7.08(d,2H,J=8.9Hz),7.15-7.30(m,1H),7.30-7.55(m,2H),7.55-7.70(m,1H),7.80(d,2H,J=8.3Hz),7.91(d,2H,J=8.9Hz),7.96(d,2H,J=8.3Hz),8.00-8.20(m,1H),8.38(s,1H),8.65(d,1H,J=6.8Hz),8.75-9.00(m,1H)
MASS(m/z):1268.40(M-Na)
C56H70N9NaO21S2·8H2O的元素分析计算值:
C 46.82,H 6.03,N 8.78
实测值:C 47.11,H 5.84,N 8.82实施例99
IR(KBr):3396.0,2933.2,2871.5,1648.8,1631.5,1538.9,1515.8,1456.0,1438.6,1253.5cm-1
NMR(DMSO-d6,δ):0.75-0.90(m,3H),0.96(d,3H,J=6.7Hz),1.11(d,3H,J=5.8Hz),1.10-1,60(m,6H),1.60-2.60(m,9H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.65(m,16H),4.65-5.60(m,9H),6.73(d,1H,J=8.2Hz),6.82(d,1H,J=8.2Hz),6.89(s,1H),7.05(s,1H),7.07(d,2H,J=8.9Hz),7.15-7.30(m,1H),7.30-7.55(m,2H),7.55-7.75(m,1H),7.80(d,2H,J=8.3Hz),7.91(d,2H,J=8.9Hz),7.96(d,2H,J=8.3Hz),8.00-8.20(m,1H),8.38(s,1H),8.65(d,1H,J=6.8Hz),8.75-9.00(m,1H)
MASS(m/z):1282.09(M-Na)
C57H72N9NaO21S2·7H2O的元素分析计算值:
C 47.79,H 6.05,N 8.80
实测值:C 47.89,H 5.96,N 8.77实施例100
IR(KBr):3430.7,2931.3,2858.0,1668.1,1648.0,1631.5,1515.8,1456.0,1438.6,1255.4cm-1
NMR(DMSO-d6,δ):0.75-0.90(m,3H),0.96(d,3H,J=6.7Hz),1.11(d,3H,J=5.6Hz),1.10-1.55(m,8H),1.60-2.60(m,9H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.65(m,16H),4.65-5.40(m,9H),6.74(d,1H,J=8.2Hz),6.83(d,1H,J=8.2Hz),6.89(s,1H),7.05(s,1H),7.08(d,2H,J=8.8Hz),7.20(s,1H),7.30-7.55(m,2H),7.60-7.75(m,1H),7.80(d,2H,J=8.2Hz),7.92(d,2H,J=8.8Hz),7.96(d,2H,J=8.2Hz),8.07(d,1H,J=7.0Hz),8.38(s,1H),8.66(d,1H,J=6.8Hz),8.85(s,1H)
MASS(m/z):1296.16(M-Na)
C58H74N9NaO21S2·6H2O的元素分析计算值:
C 48.77,H 6.07,N 8.82
实测值:C 48.61,H 6.06,N 8.78实施例101
IR(KBr):3425.0,2969.8,2937.1,2881.1,1633.4,1517.7,1438.6,1247.7cm-1
NMR(DMSO-d6,δ):0.80-1.10(m,6H),1.10(d,3H,J=5.7Hz),1.60-2.60(m,10H),2.85-3.10(m,1H),3.10-3.60(m,2H),3.60-4.60(m,16H),4.65-5.50(m,8H),6.71(d,1H,J=8.1Hz),6.79(d,1H,J=8.1Hz),6.88(s,1H),6.98(s,1H),7.06(d,2H,J=8.8Hz),7.20(m,1H),7.30-8.20(m,12H),7.70(d,2H,J=8.8Hz),8.48(s,1H),8.60-8.85(m,2H)
MASS(m/z):1300.35(M-Na)
C60H70N9NaO20S2·7H2O的元素分析计算值:
C 49.68,H 5.84,N 8.69
实测值:C 49.59,H 5.49,N 8.68实施例102
IR(KBr):3349.7,2937.1,2871.5,1633.4,1519.6,1438.6,1255.4cm-1
NMR(DMSO-d6,δ):0.70-1.05(m,6H),1.08(d,3H,J=5.9Hz),1.20-1.55(m,4H),1.60-2.60(m,10H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.60(m,16H),4.60-5.50(m,8H),6.70(d,1H,J=8.1Hz),6.77(d,1H,J=8.1Hz),6.86(s,1H),6.96(s,1H),7.07(d,2H,J=8.9Hz),7.20(m,1H),7.30-7.50(m,1H),7.50-7.80(m,2H),7.79(d,2H,J=8.4Hz),7.90(d,2H,J=8.9Hz),7.96(d,2H,J=8.4Hz),8.00-8.20(m,1H),8.37(s,1H),8.50-8.80(m,2H)
MASS(m/z):1252.57(M-Na)
C56H70N9NaO20S2·7H2O的元素分析计算值:
C 47.96,H 6.04,N 8.99
实测值:C 47.78,H 5.87,N 8.87实施例103
IR(KBr):3432.7,2935.1,2869.6,1633.4,1535.1,1438.6,1251.6cm-1
NMR(DMSO-d6,δ):0.75-0.95(m,3H),0.97(d,3H,J=6.8Hz),1.10(d,3H,J=5.9Hz),1.20-1.55(m,6H),1.60-2.60(m,10H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.60(m,16H),4.65-5.50(m,8H),6.71(d,1H,J=8.2Hz),6.78(d,1H,J=8.2Hz),6.87(s,1H),6.97(s,1H),7.04(d,2H,J=8.7Hz),7.20(m,1H),7.30-7.90(m,3H),7.67(d,2H,J=8.7Hz),8.01(s,4H),8.05-8.20(m,1H),8.26(s,1H),8.60-8.90(m,2H)
MASS(m/z):1266.27(M-Na)
C57H72N9NaO20S2·6H2O的元素分析计算值:
C 48.96,H 6.05,N 9.01
实测值:C 49.07,H 5.97,N 8.94实施例104
1R(KBr):3353.6,2931.3,2861.8,1631.5,1519.6,1438.6,1253.5cm-1
NMR(DMSO-d6,δ):0.70-0.95(m,3H),0.97(d,3H,J=6.8Hz),1.10(d,3H,J=6.0Hz),1.20-1.60(m,6H),1.60-2.60(m,10H),2.80-3.10(m,1H),3.10-3.60(m,2H),3.60-4.65(m,16H),4.70-5.50(m,8H),6.71(d,1H,J=8.1Hz),6.79(d,1H,J=8.1Hz),6.88(s,1H),6.98(s,1H),7.08(d,2H,J=8.9Hz),7.21(m,1H),7.44(d,1H,J=7.4Hz),7.50-7.80(m,2H),7.80(d,2H,J=8.4Hz),7.91(d,2H,J=8.9Hz),7.97(d,2H,J=8.4Hz),8.12(d,1H,J=8.1Hz),8.37(s,1H),8.60-8.80(m,1H),8.72(s,1H)
MASS(m/z):1266.27(M-Na)
C57H72N9NaO20S2·6H2O的元素分析计算值:
C 48.96,H 6.05,N 9.01
实测值:C 48 75,H 5.98,N 8.91实施例105
IR(KBr):1666.2,1629.6,1240.0,1047.2cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.07(3H,d,J=5.8Hz),1.60-5.40(47H,m),6.68-8.80(18H,m)
MASS(m/z):1231.3(M+1)
C55H71N10NaO19S·8H2O的元素分析计算值:
C 48.03,H 6.38,N 10.18
实测值:C 47.84,H 6.46,N 10.12实施例106
用4-[5-[4-[4-[2-(2-甲氧基乙氧基)乙氧基]苯基]苯基1-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(144mg)和二异丙基乙胺(58μl)处理原料化合物(106)(200mg)的N,N-二甲基甲酰胺(4ml)的溶液,于室温下搅拌该混合物19小时。将乙酸乙酯加入该反应混合物中,过滤收集产生的沉淀,用乙酸乙酯和二异丙基醚充分洗涤并干燥。将粉末状物溶于饱和碳酸氢钠水溶液中,过滤并经ODS柱层析(YMC-凝胶ODS-AM S-50)纯化,用17-18%乙腈水溶液洗脱。合并含有产物的部分,蒸发除去乙腈,冻干得到目标化合物(106)(225mg),为无定形淡黄色粉末。
IR(KBr):1659,1633,1533,1510,1444cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.6Hz),1.76-2.47(8H,m),2.83-3.32(3H,m),3.26(3H,s),3.40-4.60(22H,m),4.70-5.54(8H,m),6.69(1H,d,J=8.2Hz),6.77(1H,d,J=8.2Hz),6.87(1H,brs),6.98(1H,s),7.09(2H,d,J=8.8Hz),7.34-7.55(3H,m),7.74(2H,d,J=8.7Hz),7.87(2H,d,J=8.5Hz),8.00-8.20(8H,m),8.66-8.92(2H,m)
MASS(m/z):1361.4(M-Na+)
C61H73N10NaO22S2·10H2O的元素分析计算值:
C 46.80,H 5.99,N 8.95
实测值:C 46.93,H 5.80,N 8.89
下列化合物[实施例107到132]可以用类似于实施例106的方法获得。实施例107
IR(KBr):3367,2925,1668,1631,1538,1511,1450,1265,1230,1085,1047cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.07(3H,d,J=5.9Hz),1.2-1.6(5H,m),1.6-2.1(10H,m),2.1-2.5(8H,m),2.63(4H,m),2.79(2H,m),2.98(2H,m),3.06(4H,m),3.20(1H,m),3.71(2H,m),3.8-4.6(14H,m),4.6-5.6(9H,m),6.70(1H,d,J=8.2Hz),6.78(1H,s),6.83(3H,d,J=8.2Hz),6.94(2H,d,J=8.7Hz),7.04(3H,m),7.2-7.7(3H,m),7.74(2H,d,J=8.7Hz),8.07(1H,m),8.23(1H,m),8.56(1H,m),8.84(1H,s)
MASS(m/z):1348.35(M-Na+)
C63H86N11NaO20S2·11H2O的元素分析计算值:
C 48.18,H 6.93,N 9.81
实测值:C 48.19,H 6.68,N 9.71实施例108
IR(KBr):1676,1651,1622,1514cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.05-1.1(3H,m),1.7-2.65(12H,m),2.8-3.2(7H,m),3.60(2H,s),2.65-4.1(5H,m),4.1-4.6(9H,m),4.7-5.45(8H,m),6.65-7.85(3H,m),7.85-7.05(4H,m),7.15-7.3(3H,m),7.4-7.8(3H,m),7.52(2H,d,J=8.6Hz),7.94(2H,d,J=8.6Hz),8.0-8.2(5H,m),8.41(1H,s),8.72(1H,s),8.75-8.9(1H,m),9.34(1H,s)
MASS(m/z):1407(M+-23)
C64H75N14NaO19S2·9H2O的元素分析计算值:
C 48.24,H 5.88,N 12.30
实测值:C 48.41,H 5.68,N 12.22实施例109
IR(KBr):1649,1632,1541,1514cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.7Hz),1.1-1.35(5H,m),1.35-2.5(17H,m),2.85-3.55(6H,m),3.55-4.1(8H,m),4.1-4.6(9H,m),4.7-5.45(8H,m),6.71(1H,d,J=8.3Hz),6.78(1H,d,J=8.3Hz),6.85-6.9(1H,m),6.9-7.0(1H,m),7.08(2H,d,J=8.9Hz),7.1-7.25(1H,m),7.35-7.75(3H,m),7.84(2H,d,J=8.9Hz),7.9-8.2(5H,m),8.6-8.85(2H,m)
MASS(m/z):1348(M+-23)实施例110
IR(KBr):1651,1632,1539,1514cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.8Hz),1.10(3H,d,J=5.8Hz),1.2-1.6(5H,m),1.6-2.75(14H,m),2.85-3.1(1H,m),3.1-3.55(2H,m),3.65-4.1(5H,m),4.1-4.6(9H,m),4.6-5.45(8H,m),6.71(1H,d,J=9.0Hz),6.78(1H,d,J=9.0Hz),6.85-6.95(1H,m),6.95-7.0(1H,m),7.1-7.25(1H,m),7.4-7.8(3H,m),7.46(2H,d,J=8.3Hz),7.96(2H,d,J=8.3Hz),8.0-8.2(1H,m),8.06(2H,d,J=8.8Hz),8.12(2H,d,J=8.8Hz),8.72(1H,s),8.75-8.85(1H,m)
MASS(m/z):1249(M+-23)
C56H69N10NaO19S2·7H2O的元素分析计算值:
C 46.86,H 6.11,N 9.76
实测值:C 47.02,H 6.01,N 9.77实施例111
IR(KBr):1649,1632,1541,1522cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.10(3H,d,J=6.1Hz),1.1-1.65(6H,m),1.65-2.5(12H,m),2.85-3.6(3H,m),3.6-4.1(5H,m),4.1-4.6(10H,m),4.75-5.45(8H,m),6.71(1H,d,J=8.9Hz),6.78(1H,d,J=8.9Hz),6.85-6.9(1H,m),6.9-7.0(1H,m),7.14(2H,d,J=8.9Hz),7.15-7.25(1H,m),7.4-7.8(3H,m),7.95(2H,d,J=8.9Hz),8.05(2H,d,J=8.9Hz),8.1-8.2(1H,m),8.11(2H,d,J=8.9Hz),8.72(1H,s),8.75-8.85(1H,m)
MASS(m/z):1265(M+-23)
C56H69N10NaO20S2·9H2O的元素分析计算值:
C 46.34,H 6.04,N 9.65
实测值:C 46.24,H 5.95,N 9.58实施例112
IR(KBr):1664,1628cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.5Hz),1.05-1.2(3H,m),1.5-1.75(6H,m),1.75-2.5(8H,m),2.8-3.5(7H,m),3.6-4.1(5H,m),4.1-4.6(9H,m),4.7-5.5(8H,m),6.65-6.85(2H,m),6.87(1H,s),6.97(1H,s),7.07(2H,d,J=9.2Hz),7.1-7.25(1H,m),7.35-7.8(3H,m),7.75(2H,d,J=9.2Hz),8.0-8.2(1H,m),8.06(4H,s),8.32(1H,s),8.6-8.9(2H,m),9.17(1H,s)
MASS(m/z):1316(M+-23)
C58H70N13NaO19S2·10H2O的元素分析计算值:
C 45.82,H 5.97,N 11.98
实测值:C 45.80,H 5.74,N 11.91实施例113
IR(KBr):1633,1518,1250cm-1
NMR(DMSO-d6,δ):0.8-1.05(6H,m),1.12(3H,d,J=5.4Hz),1.2-1.55(6H,m),1.65-2.5(9H,m),2.9-3.5(3H,m),3.6-4.6(16H,m),4.7-5.35(9H,m),6.73(1H,d,J=8.3Hz),6.83(1H,d,J=8.3Hz),6.85-6.95(1H,m),7.0-7.25(2H,m),7.10(2H,d,J=9.1Hz),7.3-7.55(2H,m),7.6-7.75(1H,m),7.85(2H,d,J=9.1Hz),8.0-8.2(5H,m),8.36(1H,s),8.7-8.9(1H,m),8.84(1H,s),9.24(1H,s)
MASS(m/z):1349(M+-23)
C59H73N12NaO21S2·8H2O的元素分析计算值:
C 46.70,H 5.91,N 11.08
实测值:C 46.64,H 5.88,N 10.90实施例114
IR(KBr):1612,1497,1446cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=6.1Hz),1.6-2.5(12H,m),2.6-3.1(4H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.6-5.45(8H,m),6.71(1H,d,J=8.9Hz),6.78(1H,d,J=8.9Hz),6.87(1H,s),6.98(1H,d,J=1.8Hz),7.18(3H,d,J=8.9Hz),7.2-7.35(5H,m),7.4-7.8(3H,m),7.97(2H,d,J=8.9Hz),8.0-8.2(1H,m),8.09(2H,d,J=8.4Hz),8.20(2H,d,J=8.4Hz),8.72(1H,s),8.75-8.9(1H,m)
MASS(m/z):1310(M+-23)
C61H72N11NaO20S·9H2O的元素分析计算值:
C 48.67,H 6.06,N 10.30
实测值:C 48.67,H 5.89,N 10.15实施例115
IR(KBr):1672,1628,1605,1531,1444cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.5Hz),1.10(3H,d,J=5.9Hz),1.6-2.5(12H,m),2.6-3.1(4H,m),3.1-3.5(2H,m),3.6-4.6(16H,m),4.7-5.45(8H,m),6.71(1H,d,J=8.1Hz),6.78(1H,d,J=8.1Hz),6.8-6.9(1H,m),6.9-7.0(1H,m),7.18(3H,d,J=9.2Hz),7.2-7.35(5H,m),7.35-7.8(3H,m),7.87(2H,d,J=9.2Hz),8.0-8.2(5H,m),8.72(1H,s),8.75-8.85(1H,m)
MASS(m/z):1326(M+-23)
C61H72N11NaO19S2·9H2O的元素分析计算值:
C 48.44,H 6.00,N 10.19
实测值:C 48.54,H 5.91,N 10.15实施例116
IR(KBr):1676,1649,1541,1514,1255cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.6Hz),1.2-2.5(18H,m),2.9-3.1(1H,m),2.9-3.6(2H,m),3.65-4.1(5H,m),4.1-4.6(10H,m),4.7-5.45(8H,m),6.72(1H,d,J=9.3Hz),6.78(1H,d,J=9.3Hz),6.85-6.95(1H,m),6.95-7.0(1H,m),7.1-7.25(1H,m),7.18(2H,d,J=8.9Hz),7.4-7.8(3H,m),8.0-8.15(5H,m),8.21(2H,d,J=8.6Hz),8.72(1H,s),8.75-8.95(1H,m)
MASS(m/z):1249(M+-23)
C56H69N10NaO21S·9H2O的元素分析计算值:
C 46.86,H 6.11,N 9.76
实测值:C 47.13,H 5.98,N 9.79实施例117
IR(KBr):1659,1628cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.8Hz),1.09(3H,d,J=6.0Hz),1.2-1.6(5H,m),1.6-2.7(14H,m),2.8-3.6(3H,m),3.6-4.1(5H,m),4.1-4.6(9H,m),4.6-5.4(8H,m),6.7-7.0(4H,m),7.1-7.2(1H,m),7.4-7.8(3H,m),7.49(2H,d,J=7.2Hz),8.05-8.2(5H,m),8.21(2H,d,J=8.4Hz),8.70(1H,s),8.8-8.9(1H,m)
MASS(m/z):1233(M+-23)
C56H69N10NaO20S·8H2O的元素分析计算值:
C 48.00,H 6.11,N 9.99
实测值:C 47.81,H 6.04,N 9.93实施例118
IR(KBr):1664,1635,1605,1531,1510,1444cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.1Hz),1.11(3H,d,J=6.0Hz),1.07-1.37(5H,m),1.50-2.44(14H,m),2.56-3.50(11H,m),3.65-4.60(14H,m),4.73-5.44(8H,m),6.71(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.87(1H,s),6.97(1H,s),7.05(2H,d,J=8.9Hz),7.18(1H,s),7.35-7.77(2H,m),7.44(1H,d,J=9.4Hz),7.66(2H,d,J=8.8Hz),7.85(2H,d,J=8.5Hz),7.95-8.21(7H,m),8.72(1H,s),8.80(1H,d,J=7.5Hz)
MASS(m/z):1409.4(M-Na+)
C66H81N12NaO19S2·7H2O的元素分析计算值:
C 50.83,H 6.14,N 10.78
实测值:C 51.17,H 6.03,N 10.42实施例119
IR(KBr):1659,1633,1531,1508,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.00(3H,t,J=7.4Hz),1.10(3H,d,J=5.6Hz),1.66-2.56(10H,m),2.91-3.36(3H,m),3.65-4.60(14H,m),4.00(2H,d,J=6.4Hz),4.72-5.52(8H,m),6.70(1H,d,J=8.1Hz),6.77(1H,d,J=8.1Hz),6.87(1H,s),6.98(1H,s),7.07(2H,d,J=8.9Hz),7.34-7.82(3H,m),7.73(2H,d,J=8.8Hz),7.86(2H,d,J=8.5Hz),8.04-8.22(8H,m),8.74-8.92(2H,m)
MASS(m/z):1301.2(M-Na)+
C59H69N10NaO20S2·10H2O的元素分析计算值:
C 47.07,H 5.96,N 9.30
实测值:C 46.90,H 5.72,N 9.22实施例120
IR(KBr):1659,1635,1533,1510,1444cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.1Hz),1.11(3H,d,J=5.8Hz),1.18(6H,d,J=6.1Hz),1.74-2.69(10H,m),2.80-3.52(3H,m),3.59-4.59(18H,m),4.72-5.49(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,dd,J=8.1和1.6Hz),6.87(1H,s),6.98(1H,d,J=1.6Hz),7.07(2H,d,J=9.0Hz),7.18(1H,s),7.33-7.72(3H,m),7.68(2H,d,J=8.8Hz),7.85(2H,d,J=8.5Hz),7.96-8.25(7H,m),8.72(1H,s),8.80(1H,d,J=7.5Hz)
MASS(m/z):1356.3(M-Na+)
C62H74N11NaO20S2·9H2O的元素分析计算值:
C 48.28,H 6.01,N 9.99
实测值:C 48.54,H 5.94,N 9.95实施例121
IR(KBr):1659,1635,1606,1529,1518,1444,1419cm-1
NMR(DMSO-d6,δ):0.90(6H,s),0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.8Hz),1.03-2.66(21H,m),2.66-3.54(8H,m),3.65-4.58(14H,m),4.68-5.43(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,dd,J=8.1和1.6Hz),6.87(1H,s),6.98(1H,d,J=1.6Hz),7.11(2H,d,J=8.6Hz),7.18(1H,s),7.44(1H,d,J=9.0Hz),7.48-7.77(2H,m),7.88(2H,d,J=8.7Hz),7.95-8.20(5H,m),8.72(1H,s),8.78(1H,d,J=7.7Hz)
MASS(m/z):1361.4(M+-1)
C62H82N12O19S2·10H2O的元素分析计算值:
C 48.24,H 6.66,N 10.89
实测值:C 48.22,H 6.38,N 10.79实施例122
IR(KBr):1659,1633,1531,1510,1444cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.11(3H,d,J=5.8Hz),1.10-2.68(18H,m),2.90-3.55(3H,m),3.66-4.62(15H,m),4.72-5.52(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,d,J=8.1Hz),6.87(1H,s),6.98(1H,s),7.07(2H,d,J=8.9Hz),7.19(1H,s),7.45(1H,d,J=8.9Hz),7.47-7.77(1H,m),7.71(2H,d,J=8.8Hz),7.86(2H,d,J=8.5Hz),7.93-8.28(8H,m),8.54-8.92(1H,m),8.81(1H,d,J=7.7Hz)
MASS(m/z):1341.3(M-Na+)
C62H73N10NaO20S2·8H2O的元素分析计算值:
C 49.33,H 5.94,N 9.28
实测值:C 49.40,H 5.87,N 9.23实施例123
IR(KBr):1659,1633,1531,1443cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=6.1Hz),1.36(3H,t,J=6.9Hz),1.64-2.50(7H,m),2.65-3.46(3H,m),4.13(2H,q,J=7.0Hz),3.67-4.58(14H,m),4.70-5.34(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.90(1H,s),6.97-7.13(3H,m),7.19(1H,s),7.33(1H,s),7.44(2H,m),7.70(1H,brs),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),8.00-8.22(6H,m),8.80(1H,d,J=6.9Hz),8.84(1H,s)
MASS(m/z):1303.3(M-Na+)
C58H67N10NaO21S2·10H2O的元素分析计算值:
C 46.21,H 5.82,N 9.29
实测值:C 46.47,H 5.65,N 9.29实施例124
IR(KBr):1633,1608,1531,1444,1419cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.12(3H,d,J=5.5Hz),1.05-1.36(5H,m),1.47-2.50(13H,m),2.58-3.46(11H,m),3.64-4.60(14H,m),4.70-5.34(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.08(2H,d,J=8.7Hz),7.01-7.25(2H,m),7.35-7.74(3H,m),7.86(2H,d,J=8.8Hz),7.98-8.26(5H,m),8.53-8.86(1H,m),8.85(1H,s)
MASS(m/z):1349.05(M-Na+)
C60H77N12NaO20S2·6H2O的元素分析计算值:
C 48.64,H 6.05,N 11.34
实测值:C 48.38,H 6.09,N 11.15实施例125
IR(KBr):1658,1633,1606,1531,1444,1419cm-1
NMR(DMSO-d6,δ):0.90(3H,d,J=6.7Hz),0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.9Hz),1.31-2.51(18H,m),2.51-2.70(4H,m),2.88-3.46(7H,m),3.55-4.59(14H,m),4.69-5.56(8H,m),6.70(1H,d,J=8.1Hz),6.77(1H,d,J=8.1Hz),6.86(1H,s),6.97(1H,s),7.08(2H,d,J=8.7Hz),7.09-7.78(3H,m),7.86(2H,d,J=8.7Hz),7.96-8.18(6H,m),8.63-8.92(1H,s),8.78(1H,d,J=6.9Hz)
MASS(m/z):1347.3(M-Na+)
C61H79N12NaO19S2·11H2O的元素分析计算值:
C 46.68,H 6.49,N 10.71
实测值:C 46.67,H 6.19,N 10.64实施例126
IR(KBr):1658,1633,1606,1531,1518,1444,1417cm-1
NMR(DMSO-d6,δ):0.86(3H,d,J=6.4Hz),0.87-1.44(2H,m),0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.9Hz),1.60-2.55(16H,m),2.55-2.73(4H,m),2.96-3.54(7H,m),3.65-4.60(14H,m),4.70-5.28(8H,m),6.71(1H,d,J=8.3Hz),6.79(1H,dd,J=8.3和1.7Hz),6.87(1H,s),6.98(1H,d,J=1.7Hz),7.07(2H,d,J=9.0Hz),7.18(1H,s),7.44(1H,d,J=8.4Hz),7.50-7.78(2H,m),7.85(2H,d,J=8.9Hz),7.95-8.24(5H,m),8.72(1H,s),8.79(1H,d,J=7.1Hz)
MASS(m/z):1347.3(M-Na+)
C61H79N12NaO19S2·11H2O的元素分析计算值:
C 46.68,H 6.49,N 10.71
实测值:C 46.77,H 6.20,N 10.65实施例127
IR(KBr):1633,1533,1516,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.6Hz),1.18(3H,t,J=7.0Hz),1.73-2.52(8H,m),2.86-3.38(3H,m),3.52(2H,q,J=7.0Hz),3.63-4.60(16H,m),4.53(2H,s),4.71-5.53(6H,m),6.68(1H,d,J=8.0Hz),6.76(1H,d,J=7.8Hz),6.87(1H,s),6.98(1H,s),7.28-7.83(3H,m),7.47(2H,d,J=8.5Hz),7.77(2H,d,J=8.2Hz),7.92(2H,d,J=8.5Hz),8.00-8.25(8H,m),8.70-8.85(2H,m)
MASS(m/z):1301.3(M-Na+)
C59H69N10NaO20S2·9H2O的元素分析计算值:
C 47.64,H 5.89,N 9.42
实测值:C 47.92,H 5.84,N 9.39实施例128
IR(KBr):1659,1633,1533,1514,1443,cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10(3H,d,J=5.9Hz),1.75-2.53(8H,m),2.81-3.36(3H,m),3.28(3H,s),3.47-4.64(20H,m),4.56(2H,s),4.74-5.60(6H,m),6.69(1H,d,J=8.3Hz),6.77(1H,d,J=8.3Hz),6.87(1H,s),6.98(1H,s),7.26-7.84(3H,m),7.47(2H,d,J=8.4Hz),7.78(2H,d,J=8.3Hz),7.92(2H,d,J=8.5Hz),8.03-8.28(8H,m),8.74-8.90(2H,m)
MASS(m/z):1331.3(M-Na+)
C60H71N10NaO21S2·9H2O的元素分析计算值:
C 47.49,H 5.91,N 9.23
实测值:C 47.36,H 5.81,N 9.16实施例129
IR(KBr):1668,1651,1632,1539,1512cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.10-1.12(3H,m),1.12(3H,t,J=7.0Hz),1.70-2.50(10H,m),2.80-3.30(3H,m),3.41(2H,q,J=7.0Hz),3.53(2H,t,J=6.4Hz),3.66-4.60(14H,m),4.10(2H,t,J=6.4Hz),4.70-5.52(8H,m),6.71(1H,d,J=8.1Hz),6.79(1H,dd,J=8.1和1.6Hz),6.87(1H,s),6.98(1H,d,J=1.6Hz),7.08(2H,d,J=8.8Hz),7.18(1H,s),7.32-7.68(3H,m),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),8.04-8.24(7H,m),8.56-8.91(1H,m),8.81(1H,d,J=7.0Hz)
MASS(m/z):1345.3(M-Na+)
C61H73N10NaO21S2·10H2O的元素分析计算值:
C 47.28,H 6.05,N 9.04
实测值:C 47.44,H 5.91,N 9.02实施例130
IR(KBr):1649,1537,1512,1443cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.7Hz),1.74-2.22(10H,m),2.80-3.30(3H,m),3.27(3H,s),3.50(2H,t,J=6.3Hz),3.65-4.60(14H,m),4.09(2H,t,J=6.4Hz),4.60-5.58(8H,m),6.70(1H,d,J=8.1Hz),6.77(1H,d,J=8.1Hz),6.87(1H,s),6.99(1H,s),7.07(2H,d,J=8.9Hz),7.10-7.72(3H,m),7.73(2H,d,J=8.8Hz),7.87(2H,d,J=8.5Hz),8.00-8.35(8H,m),8.64-8.96(2H,m)
MASS(m/z):1331.3(M-Na+)
C60H71N10NaO21S2·9H2O的元素分析计算值:
C 47.49,H 5.91,N 9.23
实测值:C 47.39,H 5.75,N 9.16实施例131
IR(KBr):3349.7,1633.4,1537.0,1515.8,1442.5,1419.4cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.8Hz),1.10(3H,d,J=5.3Hz),1.7-2.5(12H,m),2.94(3H,s),2.94-4.6(21H,m),4.7-5.4(8H,m),6.71(1H,d,J=8Hz),6.79(1H,dd,J=8.4和1.7Hz),6.88(1H,brs),6.97(1H,brs),7.15(2H,d,J=9Hz),7.17(1H,brs),7.45(4H,s),7.4-7.8(3H,m),7.87(2H,d,J=8.8Hz),8.02(4H,s),8.02-8.07(1H,m),8.72(1H,s),8.78(1H,d,J=7.6Hz)
MASS(m/z):1390.23(M-Na)
C62H73ClN11O20S2Na·7H2O的元素分析计算值:
C 48.32,H 5.69,N 10.00
实测值:C 48.15,H 5.51,N 9.93实施例132
IR(KBr):1633.4,1535.1,1523.5,1442.5,1419.4,1276.6,1243.9cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.8Hz),1.12(3H,d,J=6Hz),1.7-2.5(10H,m),2.94(3H,s),2.9-5.4(31H,m),6.73(1H,d,J=8.3Hz),6.81-6.85(1H,m),6.89(1H,brs),7.05(1H,brs),7.15(2H,d,J=8.7Hz),7.17(1H,brs),7.45(4H,s),7.3-7.7(3H,m),7.87(2H,d,J=8.7Hz),8.06(4H,s),8.0-8.15(1H,m),8.7-9.0(2H,m)
MASS(m/z):1405.8(M-Na+)
C62H73ClN11O21S2Na·6H2O的元素分析计算值:
C 48.39,H 5.57,N 10.01
实测值:C 48.39,H 5.52,N 9.90实施例133
向4-[2-[4-(4-哌啶-1-基丁氧基)苯基]咪唑并[2,1-b][1,3,4]噻二唑-6-基]苯甲酸(147mg)、1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺盐酸盐(WSCD·HCl)(74mg)和1-羟基苯并三唑(66mg)的N,N-二甲基甲酰胺(4ml)溶液中加入二异丙基乙胺(0.5m1)。于室温下搅拌24小时后,将原料化合物(133)(200mg)加入该溶液中,于室温下搅拌该混合物8小时。
用乙酸乙酯研磨该反应混合物。过滤收集沉淀,减压干燥。将粉末状物溶于水中,经在离子交换树脂(DOWEX-50WX4(商标:由DowChemical制备))上柱层析,用水洗脱。合并含有目标化合物的部分,经在ODS(YMC-凝胶ODS-AM·S-50(商标:由Yamamura ChemicalLab.制备))上柱层析,用20%乙腈水溶液洗脱。合并含有目标化合物的部分,减压蒸发除去乙腈。残留物经冻干得到目标化合物(133)(30mg)。
IR(KBr):3326,2933,1666,1631,1523,1463,1367,1257cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(8H,m),1.6-2.15(5H,m),2.2-2.5(10H,m),2.97(2H,m),3.20(1H,m),3.74(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.66(1H,m),7.88(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,d,J=7.8Hz),8.58(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1377.25(M-Na+)
下列化合物[实施例134到159]可以用类似于实施例133的方法获得。实施例134
IR(KBr):3353,2940,1666,1631,1523,1465,1257cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(10H,m),1.6-2.15(5H,m),2.2-2.5(10H,m),2.97(2H,m),3.20(1H,m),3.74(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.14(2H,d,J=8.2Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,d,J=7.8Hz),8.57(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1391.13(M-Na+)实施例135
IR(KBr):3349,2939,1666,1633,1523,1440,1257cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(12H,m),1.6-2.15(5H,m),2.2-2.5(10H,m),2.97(2H,m),3.20(1H,m),3.74(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.83(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,d,J=7.8Hz),8.60(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1405.31(M-Na+)
C63H81N12NaO21S2·8H2O的元素分析计算值:
C 48.09,H 6.21,N 10.68
实测值:C 48.04,H 6.15,N 10.49实施例136
IR(KBr):3351,2939,1658,1633,1527,1465,1444,1257cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(4H,m),1.6-2.15(5H,m),2.2-2.5(10H,m),2.97(2H,m),3.20(1H,m),3.56(4H,t,J=4.6Hz),3.71(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.85(1H,d,J=8.2Hz),6.93(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,d,J=7.8Hz),8.57(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1392.65(M-Na+)
C61H77N12NaO22S3·10H2O的元素分析计算值:
C 45.86,H 6.12,N 10.52
实测值:C 45.75,H 5.83,N 10.46实施例137
IR(KBr):3347,2935,1666,1631,1523,1463,1255,1078,1047cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.03(6H,d,J=6.3Hz),1.11(3H,d,J=5.7Hz),1.3-1.6(6H,m),1.6-2.15(5H,m),2.2-2.5(6H,m),2.71(2H,d,J=10.2Hz),2.97(2H,m),3.20(1H,m),3.56(2H,m),3.71(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.74(1H,d,J=8.2Hz),6.85(1H,d,J=8.2Hz),6.93(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,d,J=7.8Hz),8.57(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1420.94(M-Na+)
C63H81N12NaO22S2·8H2O的元素分析计算值:
C 47.60,H 6.15,N 10.57
实测值:C 47.84,H 6.06,N 10.50实施例138
IR(KBr):3347,2937,1666,1631,1521,1465,1257,1074,1047cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.03(6H,d,J=6.3Hz),1.08(3H,d,J=5.7Hz),1.3-1.6(6H,m),1.6-2.15(5H,m),2.2-2.5(6H,m),2.45(2H,m),2.71(2H,d,J=10.2Hz),2.97(2H,m),3.20(1H,m),3.56(2H,m),3.71(2H,m),3.8-4.6(13H,m),4.6-5.4(8H,m),6.68(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.86(1H,s),6.97(1H,s),7.14(2H,d,J=8.9Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,m),7.96(4H,s),8.07(1H,m),8.60(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1405.74(M-Na+)
C63H81N12NaO21S2·9H2O的元素分析计算值:
C 47.54,H 6.27,N 10.56
实测值:C 47.68,H 6.21,N 10.50实施例139
MASS(m/z):1435.29(M-Na+)实施例140
IR(KBr):3328,2939,1664,1633,1525,1465,1442,1257,1047cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(6H,m),1.6-2.15(5H,m),2.2-2.5(6H,m),2.5-2.7(2H,m),2.59(4H,s),2.97(2H,m),3.20(1H,m),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.80(1H,d,J=8.2Hz),6.88(1H,s),7.05(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,d,J=7.8Hz),8.57(1H,d,J=7.8Hz),8.85(1H,s),8.95(1H,s)
MASS(m/z):1408.94(M-Na+)
C61H77N12NaO21S3·10H2O的元素分析计算值:
C 45.40,H 6.06,N 10.42
实测值:C 45.49,H 5.59,N 10.26实施例141
IR(KBr):3340,2939,1631,1523,1465,1442,1257,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(4H,m),1.6-2.15(5H,m),2.2-2.5(4H,m),2.97(2H,m),3.20(1H,m),3.23(3H,s),3.34(2H,t,J=6.2Hz),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,m),8.57(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1338.33(M-Na+)
C58H72N11NaO22S2·10H2O的元素分析计算值:
C 45.16,H 6.01,N 9.99
实测值:C 45.39,H 5.80,N 10.02实施例142
IR(KBr):3340,2935,1648,1631,1537,1515,1456,1257,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(4H,m),1.6-2.15(5H,m),2.2-2.5(6H,m),2.97(2H,m),3.20(1H,m),3.23(3H,s),3.34(2H,t,J=6.2Hz),3.74(2H,m),3.8-4.6(13H,m),4.6-5.4(8H,m),6.68(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.86(1H,s),6.97(1H,s),7.14(2H,d,J=8.9Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,m),7.96(4H,s),8.07(1H,m),8.60(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1322.3(M-Na+)
C58H72N11NaO21S2·9H2O的元素分析计算值:
C 46.18,H 6.01,N 10.21
实测值:C 45.96,H 5.86,N 10.12实施例143
IR(KBr):3349,2937,1666,1631,1523,1465,1257,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(6H,m),1.6-2.15(5H,m),2.2-2.5(4H,m),2.97(2H,m),3.20(1H,m),3.23(3H,s),3.34(2H,t,J=6.2Hz),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,m),8.57(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1352.48(M-Na+)
C59H74N11NaO22S2·12H2O的元素分析计算值:
C 44.50,H 6.20,N 9.67
实测值:C 44.74,H 5.71,N 9.70实施例144
IR(KBr):3330,2931,1666,1631,1523,1465,1257,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(8H,m),1.6-2.15(5H,m),2.2-2.5(4H,m),2.97(2H,m),3.20(1H,m),3.23(3H,s),3.34(2H,t,J=6.2Hz),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,m),8.57(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1366.46(M-Na+)
C60H76N11NaO22S2·13H2O的元素分析计算值:
C 44.36,H 6.33,N 9.48
实测值:C 44.40,H 5.88,N 9.30实施例145
IR(KBr):3324,2933,1666,1631,1523,1465,1257,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.3-1.6(10H,m),1.6-2.15(5H,m),2.2-2.5(4H,m),2.97(2H,m),3.20(1H,m),3.23(3H,m),3.34(2H,t,J=6.2Hz),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.76(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.90(2H,d,J=8.8Hz),7.95(4H,s),8.07(1H,m),8.57(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1380.30(M-Na+)
C61H78N11NaO22S2·10H2O的元素分析计算值:
C 46.24,H 6.23,N 9.72
实测值:C 46.29,H 6.02,N 9.71
实施例146
IR(KBr):3351,3330,2935,1664,1633,1606,1529,1465,1446,1267,1238cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.4Hz),1.10(3H,d,J=5.4Hz),1.60(6H,s),1.7-2.1(3H,m),2.1-2.6(4H,m),2.98(2H,m),3.20(1H,m),3.4(4H,m),3.73(2H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.70(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.06(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.74(2H,d,J=8.9Hz),7.94(4H,s),8.07(1H,m),8.56(1H,m),8.79(1H,s),8.95(1H,s)
MASS(m/z):1304.84(M-Na+)
C57H69N12NaO20S2·7H2O的元素分析计算值:
C 47.04,H 5.75,N 11.55
实测值:C 47.32,H 5.75,N 11.67实施例147
IR(KBr):3351,3330,2933,1668,1631,1515,1454,1268,1236cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.4Hz),1.11(3H,d,J=5.4Hz),1.6-2.1(3H,m),2.1-2.6(4H,m),2.98(2H,m),3.20(1H,m),3.4(4H,m),3.76(6H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.70(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.89(1H,s),7.05(1H,s),7.06(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.74(2H,d,J=8.9Hz),7.94(4H,s),8.07(1H,m),8.56(1H,m),8.79(1H,s),8.95(1H,s)
MASS(m/z):1306.85(M-Na+)实施例148
IR(KBr):3355,2975,2935,1666,1631,1610,1523,1465,1241cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.18(6H,d,J=6.2Hz),1.6-2.1(3H,m),2.1-2.6(6H,m),2.98(2H,m),3.20(1H,m),3.4(2H,m),3.73(4H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.70(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.89(1H,s),7.04(1H,s),7.11(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.78(2H,d,J=8.9Hz),7.95(4H,s),8.07(1H,m),8.54(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1334.95(M-Na+)
C58H71N12NaO21S2·10H2O的元素分析计算值:
C 45.25,H 5.96,N 10.92
实测值:C 45.25,H 5.76,N 10.94实施例149
IR(KBr):3355,2971,2933,1668,1648,1631,1610,1535,1515,1463,1241cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.18(6H,d,J=6.2Hz),1.6-2.1(3H,m),2.1-2.6(8H,m),2.98(2H,m),3.20(1H,m),3.4(2H,m),3.73(4H,m),3.8-4.6(11H,m),4.6-5.6(8H,m),6.70(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.89(1H,s),6.96(1H,s),7.12(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.78(2H,d,J=8.9Hz),7.95(4H,s),8.12(1H,m),8.56(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1319.3(M-Na+)
C58H71N12NaO20S2·9H2O的元素分析计算值:
C 46.27,H 5.96,N 11.16
实测值:C 46.03,H 5.85,N 11.02实施例150
IR(KBr):3353,2927,1666,1631,1608,1535,1465,1432,1265,1193,1047cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.7Hz),1.6-2.1(3H,m),2.1-2.6(4H,m),2.66(4H,m),2.98(2H,m),3.20(1H,m),3.73(2H,m),3.79(4H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.72(1H,d,j=8.2Hz),6.81(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.11(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.77(2H,d,J=8.9Hz),7.94(4H,s),8.07(1H,m),8.54(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1322.96(M-Na+)实施例151
IR(KBr):3353,1666,1629,1523,1454,1378,1268,1238cm-1
NMR(DMSO-d6,δ):0.9-1.4(9H,m),1.4-2.1(3H,m),2.1-2.6(10H,m),2.98(2H,m),3.20(1H,m),3.4(4H,m),3.74(2H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.72(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.88(1H,s),7.05(1H,s),7.09(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.78(2H,d,J=8.9Hz),7.94(4H,s),8.07(1H,m),8.54(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1334.63(M-Na+)实施例152
IR(KBr):3353,2927,1675,1650,1538,1513,1456,1396,1340,1238,1047cm-1
NMR(DMSO-d6,δ):0.95(3H,d,J=6.7Hz),1.0-1.4(8H,m),1.58(1H,m),1.78(4H,m),1.8-2.1(3H,m),2.1-2.6(5H,m),2.63(4H,m),2.98(2H,m),3.20(1H,m),3.4(4H,m),3.74(2H,m),3.8-4.6(12H,m),4.6-5.6(9H,m),6.72(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.08(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.77(2H,d,J=8.9Hz),7.94(4H,s),8.10(1H,m),8.58(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1388.3(M-Na+)实施例153
IR(KBr):3353,2931,1668,1650,1631,1537,1513,1456,1396,1270,1238,1197cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.7Hz),1.0-1.4(8H,m),1.58(1H,m),1.75(4H,m),1.7-2.1(3H,m),2.1-2.6(7H,m),2.63(4H,m),2.98(2H,m),3.20(1H,m),3.4(4H,m),3.74(2H,m),3.8-4.6(11H,m),4.6-5.6(8H,m),6.72(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.88(1H,s),7.04(1H,s),7.08(2H,d,J=8.9Hz),7.2-7.7(4H,m),7.77(2H,d,J=8.9Hz),7.94(4H,s),8.11(1H,m),8.58(1H,m),8.80(1H,s),8.95(1H,s)
MASS(m/z):1372.3(M-Na+)实施例154
IR(KBr):3353,2935,1666,1633,1540,1513,1461,1440,1247cm-1
NMR(DMSO-d6,δ):0.9-1.1(6H,m),1.10(3H,d,J=5.7Hz),1.47(2H,m),1.6-2.1(5H,m),2.1-2.6(4H,m),2.98(2H,m),3.20(1H,m),3.71(2H,m),3.8-4.6(14H,m),4.6-5.6(9H,m),6.67(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.88(1H,s),6.99(2H,d,J=8.8Hz),7.05(1H,s),7.2-7.7(4H,m),7.82(2H,d,J=8.8Hz),7.97(4H,s),8.10(1H,m),8.58(1H,m),8.66(1H,s),8.78(1H,s)
MASS(m/z):1294.53 (M-Na+)
C56H68N11NaO21S2·9H2O的元素分析计算值:
C 45.43,H 5.85,N 10.41
实测值:C 45.52,H 5.81,N 10.41实施例155
IR(KBr):3361,2935,1650,1631,1540,1515,1463,1442,1247,1047cm-1
NMR(DMSO-d6,δ):0.9-1.1(6H,m),1.10(3H,d,J=5.7Hz),1.2-1.5(4H,m),1.6-2.1(5H,m),2.1-2.6(4H,m),2.98(2H,m),3.20(1H,m),3.71(2H,m),3.8-4.6(14H,m),4.6-5.6(9H,m),6.69(2H,d,J=8.2Hz),6.80(1H,d,J=8.2Hz),6.87(1H,s),6.99(2H,d,J=8.8Hz),7.05(1H,s),7.2-7.7(4H,m),7.82(2H,d,J=8.8Hz),8.06(4H,s),8.10(1H,m),8.58(1H,m),8.67(1H,s),8.76(1H,s)
MASS(m/z):1308.25(M-Na+)
C57H70N11NaO21S2·8H2O的元素分析计算值:
C 46.37,H 5.87,N 10.44
实测值:C 46.29,H 5.44,N 10.19实施例156
IR(KBr):3359,2933,1666,1631,1540,1513,1463,1440,1295,1247,1047cm-1
NMR(DMSO-d6,δ):0.9-1.1(6H,m),1.10(3H,d,J=5.7Hz),1.2-1.5(6H,m),1.6-2.1(5H,m),2.1-2.6(4H,m),2.98(2H,m),3.20(1H,m),3.71(2H,m),3.8-4.6(14H,m),4.6-5.6(9H,m),6.69(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.87(1H,s),6.98(2H,d,J=8.8Hz),7.04(1H,s),7.2-7.7(4H,m),7.82(2H,d,J=8.8Hz),8.06(4H,s),8.10(1H,m),8.58(1H,m),8.67(1H,s),8.77(1H,s)
MASS(m/z):1322.61(M-Na+)
C58H72N11NaO21S2·11H2O的元素分析计算值:
C 45.10,H 6.13,N 9.98
实测值:C 45.31,H 5.81,N 9.84实施例157
IR(KBr):3351,2933,1631,1523,1465,1440,1255,1178,1047cm-1
NMR(DMSO-d6,δ):0.8-1.0(6H,m),1.10(3H,d,J=5.7Hz),1.2-1.6(6H,m),1.6-2.1(5H,m),2.1-2.5(4H,m),2.98(2H,m),3.20(1H,m),3.73(2H,m),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.79(1H,d,J=8.2Hz),6.88(1H,s),7.05(1H,s),7.14(2H,d,J=8.8Hz),7.23(1H,m),7.3-7.5(2H,m),7.67(1H,m),7.89(2H,d,J=8.8Hz),7.96(4H,s),8.07(1H,m),8.54(1H,m),8.85(1H,s),8.95(1H,s)
MASS(m/z):1322.12(M-Na+)
C58H72N11NaO21S2·8H2O的元素分析计算值:
C 46.74,H 5.95,N 10.34
实测值:C 46.81,H 5.67,N 10.23实施例158
IR(KBr):3359,2935,1652,1631,1538,1523,1429,1382,1299,1253,1047cm-1
NMR(DMSO-d6,δ):0.8-1.0(6H,m),1.10(3H,d,J=5.7Hz),1.3-1.5(4H,m),1.6-2.1(5H,m),2.1-2.5(4H,m),2.98(2H,m),3.20(1H,m),3.75(2H,s),3.8-4.6(14H,m),4.6-5.4(9H,m),6.69(1H,d,J=8.2Hz),6.77(1H,d,J=8.2Hz),6.85(1H,s),7.01(2H,d,J=8.8Hz),7.05(1H,s),7.23(1H,m),7.43(2H,d,J=8.2Hz),7.69(1H,m),7.77(2H,d,J=8.8Hz),7.87(2H,d,J=8.3Hz),8.05(1H,d,J=7.9Hz),8.19(2H,d,J=8.3Hz),8.54(1H,m),8.61(1H,d,J=6.7Hz),8.82(1H,s)
MASS(m/z):1312.10(M-Na+)
C56H70N11NaO22S2·13H2O的元素分析计算值:
C 42.83,H 6.16,N 9.81
实测值:C 42.83,H 5.39,N 9.75实施例159
MASS(m/z):1429.04(M-Na+)实施例160
向1-羟基苯并三唑(26mg)和4-[5-[4-(4-丙氧基哌啶-1-基)苯基]-1,3,4-噻二唑-2-基]苯甲酸盐酸盐(60mg)的N,N-二甲基甲酰胺(2.4ml)溶液中加入1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺(48μl),于室温下搅拌该混合物19小时。然后,向该反应混合物中加入原料化合物(160)(120mg)和N,N’-二异丙基乙胺(34μl),于室温下搅拌该混合物24小时。用乙酸乙酯研磨该反应混合物。过滤收集产生的沉淀,用二异丙基醚洗涤并减压干燥。将该固体加入饱和碳酸氢钠水溶液中,经在ODS(YMC-凝胶ODS-AM S-50)上柱层析,用20%乙腈水溶液洗脱。合并含有目标化合物的部分并减压蒸发除去乙腈。冻干残留物得到目标化合物(160)(48mg),为黄色粉末。
NMR(DMSO-d6,δ):0.88(3H,d,J=7.4Hz),0.96(3H,d,J=6.7Hz),1.10(3H,d,J=5.6Hz),1.38-2.47(16H,m),2.80-5.50(30H,m),6.70(1H,d,J=8.2Hz),6.81(1H,d,J=8.2Hz),6.87(1H,s),7.04(1H,s),7.09(2H,d,J=9.2Hz),7.26-7.76(3H,m),7.84(2H,d,J=8.8Hz),7.97-8.14(6H,m),8.64-8.95(2H,m)
MASS(m/z):1347.44(M-Na+)
下列化合物[实施例161和162]可以用类似于实施例160的方法获得。实施例161
NMR(DMSO-d6,δ):0.96(3H,d,J=6.6Hz),1.10(3H,d,J=5.6Hz),1.68-2.50(7H,m),2.80-5.50(34H,m),6.71(1H,d,J=8.2Hz),6.80(1H,d,J=8.2Hz),6.86(1H,s),6.76-6.94(1H,m),6.94-7.09(3H,m),7.09-7.34(4H,m),7.34-7.78(3H,m),7.90(2H,d,J=8.7Hz),7.96-8.17(6H,m),8.49-8.88(2H,m)
MASS(m/z):1343.23(M-Na+)实施例162
IR(KBr):1655,1527cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.8Hz),1.10(3H,d,J=5.7Hz),1.8-2.6(12H,m),2.8-3.6(7H,m),3.7-4.6(14H,m),4.7-5.5(8H,m),6.6-6.85(4H,m),6.85-6.95(1H,m),6.97(1H,s),7.15-7.25(1H,m),7.4-7.8(3H,m),7.72(2H,d,J=8.9Hz),8.0-8.2(5H,m),8.30(1H,s),8.71(1H,s),8.7-8.9(1H,m),9.11(1H,s)
MASS(m/z):1302(M+-23)
C57H68N13NaO19S2·9H2O的元素分析计算值:
C 45.99,H 5.82,N 12.23
实测值:C 45.92,H 5.73,N 12.09实施例163
于室温及搅拌下,向原料化合物(163)(2.0g)的三氟乙酸(48ml)溶液中加入1N盐酸(8ml)。于相同的温度下搅拌该混合物过夜。减压蒸发该反应混合物以除去三氟乙酸。将标准溶液(pH6.86)(100ml)和乙腈(50ml)加入残留物中,用1N氢氧化钠将该溶液调至pH3。该溶液经反相硅胶,YMC-凝胶ODS-AM 120-S50(商标:由YMC制备)(600ml)层析,依次用20%乙腈水溶液(2L)、30%乙腈水溶液(3L)和40%乙腈水溶液(4L)洗脱。收集含有所需化合物的部分并真空蒸发除去有机溶剂。冻干生成的残留物得到白色粉末。用乙酸乙酯(30ml)洗涤该白色粉末,于室温下真空干燥3小时得到目标化合物(163)(1.02g)。
NMR(DMSO-d6+D2O,δ):0.96(3H,d,J=6.7Hz),1.09(3H,d,J=6.0Hz),1.25-1.60(8H,m),1.60-2.45(10H,m),2.80-3.10(1H,m),3.21(3H,s),3.30(2H,t,J=6.4Hz),3.60-4.50(15H,m),4.65-4.95(2H,m),6.41(1H,d,J=8.3Hz),6.50-7.70(2H,m),7.11(1H,s),7.16(1H,s),7.25-7.60(2H,m),7.85-8.25(8H,m)
ESI-质谱(m/z):1255.08(M++Na+)
C58H76N10O18S·4H2O的元素分析计算值:
C 53.37,H 6.49,N 10.73
实测值:C 53.61,H 6.44,N 10.84
实施例164
在冰冷却及搅拌下,向原料化合物(164)(6.0g)在四氢呋喃(120ml)和NN-二甲基甲酰胺(30ml)的混合物中的溶液中加入三甲基甲硅烷基氯(22.8ml)和三乙胺(37.6ml),于室温下将该混合物静置过夜。将四氢呋喃(50ml)加入该反应混合物中。滤除产生的沉淀。将滤液于2-5℃静置过夜并真空蒸发。使残留物溶于己烷(50ml)和乙酸乙酯(50m1)的混合物(1∶1,v/v)中,真空蒸发该溶液得到残留物。该残留物经硅胶(600m1)层析,依次用己烷和乙酸乙酯的混合物(3∶2,v/v)以及己烷和乙酸乙酯的混合物(1∶1,v/v)洗脱。收集含有所需化合物的部分并真空蒸发。使产生的残留物(5.68g)溶于乙腈(30ml)和甲醇(30ml)的混合物中。于室温及搅拌下,向该溶液中依次加入二异丙基乙胺(1.68ml)和三甲基甲硅烷基重氮甲烷(4.82ml),使该混合物在相同的温度下静置过夜。将乙酸乙酯(150ml)和饱和碳酸氢钠水溶液(100ml)加入该反应混合物中。分离有机层,用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥,真空蒸发得到残留物。使残留物溶于四氢呋喃(30ml)和乙酸(3.68ml)的混合物中。在冰冷却及搅拌下,向该溶液中加入1M叔丁基氟化铵的水溶液,在相同的温度下搅拌该混合物4小时。真空蒸发该反应混合物并使之溶解于20%乙腈水溶液中。该溶液经反相硅胶,YMC-凝胶ODS-AM120-S50(商标:由YMC制备)(700ml)层析,依次用20%乙腈水溶液(3.5L)、30%乙腈水溶液(3.5L)和40%乙腈水溶液(3.5L)洗脱。收集含有所需化合物的部分并真空蒸发除去有机溶剂。冻干生成的残留物得到白色粉末。经液相层析纯化该白色粉末,用38%乙腈在pH6.86的标准缓冲液中的溶液洗脱,得到两种化合物。
第一种化合物经反相硅胶,YMC-凝胶ODS-AM 120-S50(商标:由YMC制备)(700ml)层析,并依次用20%乙腈水溶液(3.5L)和50%乙腈水溶液(3.5L)洗脱。收集含有所需化合物的部分并真空蒸发除去有机溶剂。冻干生成的残留物得到目标化合物(164-Ⅰ)(1.37g)。
另一种目标化合物(164-Ⅱ)经反相硅胶,YMC-凝胶ODS-AM120-S50(商标:由YMC制备)(700ml)层析,依次用20%乙腈水溶液(3.5L)和50%乙腈水溶液(3.5L)洗脱。收集含有所需化合物的部分并真空蒸发除去有机溶剂。冻干生成的残留物得到目标化合物(164-Ⅱ)(275mg)。
目标化合物(164-Ⅰ)
NMR(DMSO-d6+D2O,δ):0.96(3H,d,J=6.7Hz),1.09(3H,d,J=6.1Hz),1.25-2.50(19H,m),2.85-3.00(1H,m),3.74(3H,s),3.31(2H,t,J=6.4Hz),3.75-4.55(17H,m),4.70-5.00(2H,m),6.40-6.70(3H,m),7.14(2H,d,J=8.9Hz),7.98(2H,d,J=8.9Hz),8.05(2H,d,J=8.7Hz),8.12(2H,d,J=8.7Hz)
ESI-质谱(m/z):1269.4(M++Na+)(正性)
1246.4(M+-1)(负性)
C59H78N10O18S·3H2O的元素分析计算值:
C 54.45,H 6.51,N 10.76
实测值:C 54.11,H 6.74,N 11.18
目标化合物(164-Ⅱ)
NMR(DMSO-d6+D2O,δ):0.96(3H,d,J=6.7Hz),1.10(3H,d,J=6.1Hz),1.20-2.45(19H,m),3.72(3H,s),3.73(3H,s),3.80-5.00(15H,m),6.55-6.90(3H,m),7.13(2H,d,J=8.9Hz),7.97(2H,d,J=8.9Hz),8.00-8.20(4H,m)
ESI-质谱(m/z):1283.4(M+Na+)(正性)
根据类似的方法,通过使用叔丁基二甲基甲硅烷代替实施例6中的叔丁基甲硅烷获得下列化合物。
实施例165
以类似于WO97/32975中的实施例2-3的方式获得下列化合物。实施例166
IR(KBr):3394,3327,1676,1633,1439cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.8Hz),1.08(3H,d,J=6.0Hz),1.88-5.83(35H,m),6.68-8.71(10H,m)
质谱(m/z):903.17(M-Na+)
实施例167
向原料化合物(167)(0.1g)和4-[5-[4-(7-甲氧基庚氧基)苯基]-1,3,4-噻二唑-2-基]苯甲酸苯并三唑-1-基酯(66.1mg)的二甲基甲酰胺(1ml)溶液中加入二异丙基乙胺(0.029ml),于室温下搅拌该混合物5小时。用乙酸乙酯研磨该反应混合物。过滤收集沉淀,减压干燥得到目标化合物(167)(159mg)。
IR(KBr):3344,1648.8,1637.3,1513.8,1257.4,1043.3cm-1
NMR(DMSO-d6,δ):0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.6Hz),1.2-1.6(23H,m),1.6-2.6(12H,m),2.9-4.6(25H,m),4.7-5.5(9H,m),6.71(1H,d,J=8.2Hz),6.78(1H,d,J=8.2Hz),6.88(1H,s),6.97(1H,s),7.13(2H,d,J=8.8Hz),7.16(1H,s),7.44(1H,d,J=8.0Hz),7.59(1H,brs),7.70(1H,brs),7.97(2H,d,J=8.8Hz),7.9-8.2(6H,m),8.72(1H,s),8.79(1H,d,J=7.3Hz)
质谱(m/z):1311(M-二异丙基胺-1)
C66H95N11O21S2·5H2O的元素分析计算值:
C 51.72,H 6.90,N 10.05
实测值:C 51.89,H 6.57,N 9.98
以类似于实施例167的方式获得下列化合物。
实施例168
IR(KBr):3344,1664.3,1633.4,1506.1,1436.7,1257.4cm-1
NMR(DMSO-d6,δ):0.91(3H,t,J=7.0Hz),0.97(3H,d,J=6.6Hz),1.10(3H,d,J=5.6Hz),1.0-1.5(19H,m),1.6-2.7(10H,m),3.0-3.3(3H,m),3.7-4.6(15H,m),4.8-5.3(11H,m),5.54(1H,d,J=5.6Hz),6.73(1H,d,J=8.2Hz),6.83(1H,dd,J=8.2和1.5Hz),6.85(1H,s),7.04(1H,d,J=1.5Hz),7.12(2H,d,J=8.8Hz),7.2-7.5(3H,m),7.23(1H,s),7.56(1H,s),7.58(1H,m),7.85(2H,d,J=8.8Hz),7.9-8.1(5H,m),8.26(1H,d,J=8.7Hz),8.85(1H,s),8.87(1H,d,J=7.3Hz)
质谱(m/z):1268(M-二异丙基胺-1)
以类似于WO97/32975中的实施例2-3的方式获得下列化合物。
实施例169
IR(KBr):1664,1627,1234,1086,1043cm-1
NMR(DMSO-d6,δ):0.96(3H,d,J=6.7Hz),1.14(3H,d,J=5.9Hz),1.3-2.55(8H,m),2.6-3.6(3H,m),3.65-4.5(15H,m),4.7-5.4(7H,m),6.65-7.05(4H,m),7.07(1H,s),7.4-8.25(7H,m),8.71(1H,s)
质谱(m/z):903(M-1)。
Claims (10)
1.由下面通式[Ⅰ]表示的多肽化合物或其盐:其中R1为氢,
可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基,
由可具有一个或多个合适的取代基的杂环基取代的芳酰基,
由带有高级烷基的芳基取代的芳酰基,
由带有低级烷基的芳基取代的芳酰基,
由带有低级烷基的芳基取代的芳基(C2-C6)链烷酰基,
由具有一个或多个合适取代基的不饱和稠合杂环基取代的低级链烷酰基,
由具有一个或多个合适取代基的吡啶基取代的低级链烷酰基,
氨基保护基团,
庚基萘酰基,
己基萘酰基,
由具有一个或多个合适取代基的杂环氨基甲酰基取代的芳酰基,
由具有一个或多个合适取代基的环(低级)烷基取代的低级链烷酰基,
由带有具有一个或多个合适的取代基的杂环基的噻吩基取代的低级链烷酰基,或
由具有一个或多个合适取代基的杂环基取代的低级链烷酰基,R2为氢或羟基,R3为羟基、羟基磺酰基氧基或低级烷氧基,和R4为羟基或低级烷氧基。
2.权利要求1的化合物,其中R1为由具有一个或多个合适取代基的杂环基取代的芳酰基。
3.权利要求2的化合物,其中R1为由含有1或2个硫原子和1-3个氮原子且带有苯基的不饱和3-8元杂单环基取代的苯甲酰基,所述苯基具有选自含有1-4个氮原子的饱和3-8元杂单环基,所述杂单环基可以具有带二(低级)烷基的环(低级)烷基、低级烷氧基(低级)烷氧基、低级烷氧基(高级)烷氧基和由含有1或2个氧原子和1-3个氮原子并带有二(低级)烷基的饱和3-8元杂单环基取代的苯基;或由含有1或2个硫原子和1-3个氮原子且带有具有低级烷氧基的苯基的不饱和稠合杂环基取代的苯甲酰基。
4.权利要求3的化合物,其中R1为由具有携带哌啶基的苯基的噻二唑基取代的苯甲酰基,
由具有携带低级烷氧基(低级)烷氧基的苯基的噻二唑基取代的苯甲酰基,
由具有携带低级烷氧基(高级)烷氧基的苯基的噻二唑基取代的苯甲酰基,
由具有苯基的噻二唑基取代的苯甲酰基,所述苯基具有由环己基取代的哌嗪基,
由具有苯基的噻二唑基取代的苯甲酰基,所述苯基由具有携带二(低级)烷基的吗啉代的苯基取代,或
由具有携带低级烷氧基的苯基的咪唑并噻二唑基取代的苯甲酰基。
5.权利要求4的化合物,其中R1为由具有携带哌啶基的苯基的噻二唑基取代的苯甲酰基,或
由具有携带低级烷氧基(高级)烷氧基的苯基的噻二唑基取代的苯甲酰基,R3为羟基磺酰氧基,及R4为羟基。
6.制备权利要求1的式[Ⅰ]多肽化合物或其盐的方法,该方法包括ⅰ)使下式[Ⅰb]化合物或其在氨基上的反应性衍生物或其盐:其中R2、R3和R4如权利要求1所定义,与下式[Ⅲ]化合物或其在羧基上的反应性衍生物或其盐反应:
R1a-OH [Ⅲ]其中R1a为可具有一个或多个合适的取代基的芳基氨基(低级)链烷酰基;
由可具有一个或多个合适的取代基的杂环基取代的芳酰基;
由带有高级烷基的芳基取代的芳酰基;
由带有低级烷基的芳基取代的芳酰基;
由带有低级烷基的芳基取代的芳基(C2-C6)链烷酰基;
由可具有一个或多个合适的取代基的不饱和稠合杂环基取代的低级链烷酰基;
由可具有一个或多个合适的取代基的吡啶基取代的低级链烷酰基;
氨基保护基团,
庚基萘酰基,
己基萘酰基,
由具有一个或多个合适的取代基的杂环氨基甲酰基取代的芳酰基,
由具有一个或多个合适的取代基的环(低级)烷基取代的低级链烷酰基,
由具有可携带一个或多个合适的取代基的杂环基的噻吩基取代的低级链烷酰基,或
7.药用组合物,它含有作为活性成分的权利要求1的化合物或其药学上可接受的盐和与其混合的药学上可接受的载体或赋形剂。
8.权利要求1的化合物或其药学上可接受的盐作为药物的用途。
9.权利要求1的化合物或其药学上可接受的盐用作药物。
10.预防和/或治疗由病原微生物引起的感染性疾病的方法,该方法包括给予人或动物权利要求1的化合物或其药学上可接受的盐。
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KR20080066938A (ko) * | 2005-10-07 | 2008-07-17 | 깃세이 야쿠힌 고교 가부시키가이샤 | 질소 함유 복소환 화합물 및 그것을 함유하는 의약 조성물 |
EP2947080B1 (en) | 2007-08-13 | 2017-10-25 | Monsanto Technology LLC | Compositions and methods for controlling nematodes |
KR20100075892A (ko) | 2007-10-29 | 2010-07-05 | 아스테라스 세이야쿠 가부시키가이샤 | 폴리펩티드 화합물 |
CN101970462B (zh) | 2008-03-14 | 2013-06-19 | 安斯泰来制药株式会社 | 环状化合物及其盐 |
WO2010081851A1 (en) | 2009-01-14 | 2010-07-22 | Genoscience Pharma | Piperidin-4-ylpiperazine compounds for the treatment of hcv infection |
US9353072B2 (en) * | 2012-10-31 | 2016-05-31 | Purdue Research Foundation | Antimicrobial substituted thiazoles and methods of use |
WO2019207413A1 (en) | 2018-04-25 | 2019-10-31 | Universidad De La República (Udelar) | Cyclic hexapeptides compounds with anti-malarial activity |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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FI912873A (fi) | 1990-06-18 | 1991-12-19 | Fujisawa Pharmaceutical Co | Ny polypeptidfoerening och foerfarande foer dess framstaellning. |
US5965525A (en) * | 1992-03-19 | 1999-10-12 | Eli Lilly And Company | Cyclic peptide antifungal agents |
IL109615A (en) * | 1993-05-17 | 2000-12-06 | Fujisawa Pharmaceutical Co | Cyclic polypeptide derivatives processes for the preparation thereof and pharmaceutical compositions containing the same |
MX9702531A (es) * | 1994-10-07 | 1997-06-28 | Fujisawa Pharmaceutical Co | Compuesto nuevo. |
US5629289A (en) * | 1995-07-25 | 1997-05-13 | Eli Lilly And Company | Cyclic peptide antifungal agents |
-
1999
- 1999-02-05 WO PCT/JP1999/000538 patent/WO1999040108A1/en not_active Application Discontinuation
- 1999-02-05 CA CA002320416A patent/CA2320416A1/en not_active Abandoned
- 1999-02-05 JP JP54028799A patent/JP3561917B2/ja not_active Expired - Fee Related
- 1999-02-05 BR BR9907967-4A patent/BR9907967A/pt not_active IP Right Cessation
- 1999-02-05 IL IL13749499A patent/IL137494A0/xx unknown
- 1999-02-05 US US09/446,101 patent/US6232290B1/en not_active Expired - Fee Related
- 1999-02-05 CN CNB998049018A patent/CN1240713C/zh not_active Expired - Fee Related
- 1999-02-05 EP EP99902855A patent/EP1053247A1/en not_active Withdrawn
- 1999-02-05 TR TR2000/03064T patent/TR200003064T2/xx unknown
- 1999-02-05 HU HU0102515A patent/HUP0102515A3/hu unknown
- 1999-02-05 KR KR10-1999-7012552A patent/KR100396737B1/ko not_active IP Right Cessation
- 1999-02-09 AR ARP990100549A patent/AR014554A1/es unknown
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2000
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2003
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101516387B (zh) * | 2006-07-26 | 2014-06-04 | 桑多斯股份公司 | 卡泊芬净制剂 |
CN102421909A (zh) * | 2009-05-14 | 2012-04-18 | 安斯泰来制药株式会社 | 聚酮化合物 |
Also Published As
Publication number | Publication date |
---|---|
EP1053247A1 (en) | 2000-11-22 |
HUP0102515A2 (hu) | 2001-11-28 |
TR200003064T2 (tr) | 2001-02-21 |
AR014554A1 (es) | 2001-02-28 |
NO20003996D0 (no) | 2000-08-08 |
CA2320416A1 (en) | 1999-08-12 |
BR9907967A (pt) | 2000-10-17 |
WO1999040108A1 (en) | 1999-08-12 |
JP2001522377A (ja) | 2001-11-13 |
KR100396737B1 (ko) | 2003-09-13 |
CN1240713C (zh) | 2006-02-08 |
IL137494A0 (en) | 2001-07-24 |
US6232290B1 (en) | 2001-05-15 |
NO20003996L (no) | 2000-10-09 |
JP2004067699A (ja) | 2004-03-04 |
JP3561917B2 (ja) | 2004-09-08 |
HUP0102515A3 (en) | 2001-12-28 |
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