CN1152877C - 哌嗪衍生物 - Google Patents
哌嗪衍生物 Download PDFInfo
- Publication number
- CN1152877C CN1152877C CNB998161322A CN99816132A CN1152877C CN 1152877 C CN1152877 C CN 1152877C CN B998161322 A CNB998161322 A CN B998161322A CN 99816132 A CN99816132 A CN 99816132A CN 1152877 C CN1152877 C CN 1152877C
- Authority
- CN
- China
- Prior art keywords
- alkyl
- trifluoromethyl
- nmr
- mass
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000004885 piperazines Chemical class 0.000 title abstract description 10
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 197
- 238000000034 method Methods 0.000 claims abstract description 96
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 102000003141 Tachykinin Human genes 0.000 claims abstract description 9
- 108060008037 tachykinin Proteins 0.000 claims abstract description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 339
- -1 nitro, amino Chemical group 0.000 claims description 281
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 263
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 241
- 150000001875 compounds Chemical class 0.000 claims description 167
- 239000000203 mixture Substances 0.000 claims description 160
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 146
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 39
- 235000010290 biphenyl Nutrition 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- JQNRMIFYOZIDRN-UHFFFAOYSA-N 2-(methoxymethyl)-5-methylmorpholine Chemical compound COCC1CNC(C)CO1 JQNRMIFYOZIDRN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 3
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 241001465754 Metazoa Species 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1028
- 239000002585 base Substances 0.000 description 278
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
- 239000000243 solution Substances 0.000 description 232
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 198
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- 125000000217 alkyl group Chemical group 0.000 description 165
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 126
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 238000006722 reduction reaction Methods 0.000 description 83
- 230000009467 reduction Effects 0.000 description 82
- 238000009834 vaporization Methods 0.000 description 82
- 230000008016 vaporization Effects 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 238000003756 stirring Methods 0.000 description 65
- 229940073608 benzyl chloride Drugs 0.000 description 63
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 62
- 238000002156 mixing Methods 0.000 description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 54
- 238000000746 purification Methods 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 50
- 239000012074 organic phase Substances 0.000 description 48
- AUYNWRLEXAPZAJ-UHFFFAOYSA-N piperazine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CNCCN1 AUYNWRLEXAPZAJ-UHFFFAOYSA-N 0.000 description 48
- 239000012266 salt solution Substances 0.000 description 46
- 238000010898 silica gel chromatography Methods 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- 125000003545 alkoxy group Chemical group 0.000 description 42
- 238000005406 washing Methods 0.000 description 42
- 125000005843 halogen group Chemical group 0.000 description 41
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 39
- 238000000605 extraction Methods 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 31
- 239000012046 mixed solvent Substances 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 30
- 239000000843 powder Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 27
- 239000011734 sodium Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 238000001816 cooling Methods 0.000 description 23
- 238000007738 vacuum evaporation Methods 0.000 description 23
- 239000007864 aqueous solution Substances 0.000 description 22
- 239000004305 biphenyl Substances 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 21
- 239000012299 nitrogen atmosphere Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 19
- 238000003810 ethyl acetate extraction Methods 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 125000003282 alkyl amino group Chemical group 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 18
- 230000008020 evaporation Effects 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 229940017219 methyl propionate Drugs 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 230000007246 mechanism Effects 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 235000015320 potassium carbonate Nutrition 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 206010047700 Vomiting Diseases 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 235000008504 concentrate Nutrition 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- 230000006837 decompression Effects 0.000 description 11
- 239000006210 lotion Substances 0.000 description 11
- 230000008673 vomiting Effects 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 230000008485 antagonism Effects 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000001556 precipitation Methods 0.000 description 10
- LXJOYRVJPWDJBZ-UHFFFAOYSA-N (2-acetamido-3-hydroxyphenyl)arsonic acid Chemical compound OC=1C(=C(C=CC1)[As](O)(O)=O)NC(C)=O LXJOYRVJPWDJBZ-UHFFFAOYSA-N 0.000 description 9
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 125000001118 alkylidene group Chemical group 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000006188 syrup Substances 0.000 description 9
- 235000020357 syrup Nutrition 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 6
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 235000007715 potassium iodide Nutrition 0.000 description 5
- 229960004839 potassium iodide Drugs 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 4
- MXIUWSYTQJLIKE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoyl chloride Chemical class FC(F)(F)C1=CC=CC=C1C(Cl)=O MXIUWSYTQJLIKE-UHFFFAOYSA-N 0.000 description 4
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 4
- QGLVWTFUWVTDEQ-UHFFFAOYSA-N 2-chloro-3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1Cl QGLVWTFUWVTDEQ-UHFFFAOYSA-N 0.000 description 4
- 102000057234 Acyl transferases Human genes 0.000 description 4
- 108700016155 Acyl transferases Proteins 0.000 description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 206010010741 Conjunctivitis Diseases 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- 239000005977 Ethylene Substances 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 4
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
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- 125000005936 piperidyl group Chemical group 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
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- 239000002904 solvent Substances 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 3
- 101800000399 Neurokinin A Proteins 0.000 description 3
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- 125000005037 alkyl phenyl group Chemical group 0.000 description 3
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及通式I的哌嗪衍生物,其中每个符号如说明书中定义的,以及它的药用接受的盐、制备它们的方法、含该化合物的药用组合物,以及该化合物在治疗或预防人类或动物由速激肽介导的疾病上的应用。
Description
技术领域
本发明涉及新的哌嗪衍生物和它们的盐。
更特别的是,本发明涉及新的哌嗪衍生物和它们的盐,它们具有药理活性,如速激肽(Tachykinin)拮抗机制,特别是P物质拮抗机制、神经激肽A拮抗机制、神经激肽B拮抗机制,等等,制备它们的方法、含有它们的药用组合物以及它们作为药品的应用。
因此,本发明的一个目标是提供新的和有用的哌嗪衍生物以及它们的盐,它们具有药理活性,如速激肽拮抗机制,特别是P物质拮抗机制、神经激肽A拮抗机制、神经激肽B拮抗机制,等等。
本发明的另一个目标是提供所述哌嗪衍生物和它们的盐的制备方法。
本发明的第三个目标是提供含所述哌嗪衍生物以及药用可接受的它们的盐作为活性成份的药用组合物。
本发明的第四个目标是提供所述哌嗪衍生物或药用可接受的它们的盐的应用,如作为速激肽拮抗剂、特别是P物质拮抗剂、神经激肽A拮抗剂或神经激肽B拮抗剂,用于治疗或预防由速激肽介导的在人类或动物中发生的疾病,如呼吸疾病,如气喘、支气管炎、鼻炎、咳嗽、有痰,等等;眼疾病,如结膜炎、春节结膜炎,等等;皮炎病,如接触性皮炎、变应性湿疹、寻麻疹,以及其它湿疹性皮炎,等等;炎症疾病,如风湿性关节炎、骨关节炎,等等;痛或疼痛(例如,偏头痛、头痛、牙疼、癌症疼痛、骨痛,等等)。
技术背景
已知具有药物活性的一些哌嗪衍生物,如速激肽拮抗机制,如WO97/22597 A1和WO 98/57954 A1描述的。
本发明的公开
本发明的目的化合物可由下述通式(I)表示
其中
Y是键或低级亚烷基,
R1是被1至3个相同或不同取代基取代的芳基,取代基选自卤素、低级烷基、低级烷氧基、单(或二、或三)卤代(低级)烷基、硝基、氨基、低级烷基氨基、二(低级)烷基氨基、低级烷基硫基、低级烷基磺酰基、环(低级)烷基磺酰基、氨基磺酰基、低级烷基氨基磺酰基、二(低级)烷基氨基磺酰基、吡咯烷基磺酰基、吗啉磺酰基、吡咯基磺酰基、吡啶基磺酰基、吡咯基和吡啶基;
R2是被1至3个相同或不同取代基取代的芳基,取代基选自低级烷基、单(或二、或三)卤代(低级)烷基、单(或二、或三)卤代(低级)烷基磺酰基氧基、卤素、低级亚烷基二氧基、低级烷氧基、低级烷氧羰基、低级烷氧基(低级)烷氧基(低级)烷氧基、羟基、二苯基(低级)烷基甲硅烷基氧基、三(低级)烷基甲硅烷基氧基、羟基(低级)烷基、氰基、氨基、〔单(或二、或三)卤代(低级)烷基羰基〕氨基、低级烷基氨基、N-(低级烷基)-〔单(或二、或三)卤代(低级)烷基羰基〕氨基、吡咯烷基和吗啉基,其可被低级烷氧基(低级)烷基或低级烷基取代;
R3是氢或低级烷基;和
R4是(3-吡啶基)甲基;
(3-吡啶基)乙基;
3-(3-吡啶基)丙基;
3-(3-吡啶基)丙烯基;
3-(3-吡啶基)丙炔基;
噻唑基(低级)烷基、1,2,4-噻二唑基(低级)烷基或1,2,4-噁二唑基(低级)烷基,每个被卤素、氨基、低级烷基氨基或二(低级)烷基氨基取代;
吡唑基甲基,可被三苯基(低级)烷基或羟基(低级)烷基取代;
吡唑基(低级)烷基,可被低级烷基、低级烷氧基(低级)烷基吗啉基(低级)烷基或低级烷氧基(低级)烷基吗啉基羰基(低级)烷基取代;
吡咯烷基(低级)烷基,可被1或2个相同或不同取代基取代,这些取代基选自羟基、羟基(低级)烷基、低级烷氧基和低级烷氧基(低级)烷基;
哌啶基甲基;
哌啶基(低级)烷基,可被1或2个相同或不同的选自卤素、低级烷基和低级烷氧基(低级)烷基的取代基取代;
{2,6-二〔羟基(低级)烷基〕哌啶}(低级)烷基;
〔2,6-二甲基吗啉代〕(低级)烷基;
〔2,2-二甲基吗啉代〕(低级)烷基;
〔3,3-二甲基吗啉代〕(低级)烷基;
〔顺-3,5-二甲基吗啉代〕(低级)烷基;
〔(3S,5S)-3,5-二甲基吗啉代〕(低级)烷基;
〔(3S,5R)-3,5-二甲基吗啉代〕(低级)烷基;
(2-甲氧基甲基吗啉代)(低级)烷基;
(3-甲氧基甲基吗啉代)(低级)烷基;
(2-甲氧基甲基-5-甲基吗啉代)(低级)烷基;
(2-甲氧基甲基-5,5-二甲基吗啉代)(低级)烷基;
(3,5-二甲氧基甲基吗啉代)(低级)烷基;
(2,2-二甲氧基甲基吗啉代)(低级)烷基;
(2,3-二甲氧基甲基吗啉代)(低级)烷基;
(2,6-二甲氧基甲基吗啉代)(低级)烷基;
(2-甲氧基甲基吗啉代)(低级)烯基;
(3,3-二甲基吗啉代)(低级)炔基;
(2-甲氧基甲基吗啉代)(低级)炔基;
(2-甲氧基甲基-5-甲基吗啉代)(低级)炔基;喹啉基(低级)烷基;
〔1H-吡咯并[3,2-b]吡啶基〕(低级)烷基;
〔4,5,6,7-四氢噻吩并[3,2-c]吡啶基〕(低级)烷基;
〔3,4-二氢-2H-吡啶并[3,2-b]噁嗪基〕(低级)烷基;
〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕(低级)烷基;或
被如下通式的饱和的杂环基团取代的低级烷基,
(其中r,s和t各自是1至2的整数,和q是0至2的整数)
该杂环基可被1个或2个低级烷基取代,
条件是
R4是3-(3-吡啶基)丙基;
3-(3-吡啶基)丙烯基;
可被羟基(低级)烷基取代的吡唑基甲基;
(2-甲氧基甲基吗啉)(低级)烷基;
(3-甲氧基甲基吗啉)(低级)烷基;或
(2-甲氧基甲基吗啉)(低级)炔基时,则
R2不是二(低级)烷基苯基。
要注意的是,由于不对称手性碳原子和双键,目的化合物可包括1个或多个立体异构体,并且所有这些异构体和它们的混合物都包括在本发明的范围内。
另外要注意的是,由于光、酸、碱或等等的作用,目的化合物(I)可能存在异构化或重排,作为所述的异构化或重排的结果得到的化合物也包括在本发明的范围内。
还要注意的是,化合物(I)的溶剂化形式(例如水合物,等等)以及化合物(I)的晶体的任何形式都包括在本发明的范围内。
根据本发明,目的化合物(I)或它们的盐可按下述路线说明的方法制备。
方法1
方法2
其中
Y,R1,R2,R3和R4各自定义如上,
X1是低级亚烷基(alkylene),
Z1是低级亚炔基(alkynylene),
R5是3-吡啶基,和
W1是离去基团。
至于起始化合物(II)和(III),它们中的一些是新的,并且可用后面提到的制备和实施例中描述的方法或其它类似的方式制备。
起始物和目的化合物的合适的盐是常规的非毒性和可药用的盐,并且包括酸加合盐,如有机酸的盐(如乙酸、三氟乙酸、富马酸、马来酸、酒石酸、甲磺酸、苯磺酸、甲酸、对甲苯磺酸等的盐),无机酸盐(例如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等)或与氨基酸形成的盐,氨基酸有精氨酸、天冬氨酸、谷氨酸等,或金属盐,如碱金属盐(如钠盐、钾盐等)和碱土金属盐(如钙盐、镁盐等)、铵盐、有机碱盐(如三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、二环己基二胺盐、N,N’-二苄基亚乙基二胺盐,等等)或类似物。
在本说明书上下文中使用的、希望包括在本发明范围内的各种定义的合适的实施例以及说明详细解释如下。
除非另有说明,术语“低级”意指1至6个碳原子,优选1至4个碳原子。
合适的“低级亚烷基”可包括直链或支链、具有1至6个碳原子,优选1至4个碳原子的低级亚烷基,如亚甲基、亚乙基、三亚甲基、亚丙基、四亚甲基、甲基亚甲基、甲基三亚甲基、己基亚甲基,等等,其中优选低级烷基是亚甲基、亚乙基、三亚甲基或甲基亚甲基。
合适的“低级亚炔基”可包括具有2至6个碳原子的亚炔基,如亚乙炔基、亚丙炔基、亚丁炔基,等等,优选亚丙炔基或亚丁炔基。
合适的“卤素”和在“单(或二、或三)卤代(低级)烷基”、“单(或二、或三)卤代(C1-C4)烷基”等术语中的“卤素”基团可包括氟、氯、溴和碘。
合适的“低级烷基”和在“羟基(低级)烷基”、“吡唑基(低级)烷基”等术语中的“低级烷基”基团可包括直链或支链的具有1至6个碳原子的基团,如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基等等,优选C1-C4烷基,最优选甲基、乙基或丙基。
在“(2-甲氧基甲基吗啉代)(低级)烯基”术语中,合适的“低级烯基”基团可包括乙烯基、1-(或2-)丙烯基、1-(或2-、或3-)丁烯基、1-(或2-、或3-、或4-)戊烯基、1-(或2-、或3-、或4-、或5-)己烯基、甲基乙烯基、乙基乙烯基、1-(或2-、或3-)甲基-1-(或2-)丙烯基、1-(或2-、或3-)乙基-1-(或2-)丙烯基、1-(或2-、或3-、或4-)甲基-1-(或2-、或3-)丁烯基,等等,优选实例可是C2-C4烯基。
合适的“芳基”可包括苯基、萘基,等等,优选的芳基是C6-C10芳基,最优选的芳基是苯基或萘基。
合适的“低级烷氧基”和在“低级烷氧基(低级)烷基吗啉基(低级)烷基”、“低级烷氧基(低级)烷基吗啉基羰基(低级)烷基”等术语中的“低级烷氧基”基团可包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、并丁氧基、叔丁氧基、戊氧基、叔戊氧基、己氧基,等等,优选的基团是C1-C4烷氧基,最优选的基团是甲氧基。
合适的“离去基”可包括低级烷氧基(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,等)、芳氧基(例如苯氧基、萘氧基,等)、酸基团等等。
合适的“酸基团”可以是卤素(例如,氯、溴、碘,等等)、磺酰氧基(例如,甲磺酰氧基、苯磺酰氧基、1,3,5三甲基苯基磺酰氧基、对甲苯磺酰氧基,等等),等等。
目的化合物(I)的优选实例如下:
Y是低级亚烷基(更优选C1-C4亚烷基,最优选亚甲基);
R1是被1或2个相同或不同取代基取代的苯基,取代基选自下列基团:卤素(更优选氟或氯)、低级烷基(更优选C1-C4烷基、最优选甲基)、低级烷氧基(更优选C1-C4烷氧基、最优选甲氧基)、单(或二、或三)卤代(低级)烷基(更优选三卤代(低级)烷基,最优选三氟甲基)、硝基、氨基、低级烷基氨基(更优选C1-C4烷基氨基、最优选甲基氨基)、二(低级)烷基氨基(更优选二(C1-C4)烷基氨基、最优选二甲基氨基)、低级烷硫基(更优选C1-C4烷硫基、最优选甲硫基)、低级烷基磺酰基(更优选C1-C4烷基磺酰基、最优选甲基磺酰基)、环(低级)烷基磺酰基,最优选环戊基磺酰基、氨基磺酰基、低级烷基氨基磺酰基(更优选C1-C4烷基氨基磺酰基、最优选甲基氨基磺酰基)、二(低级)烷基氨基磺酰基(更优选二(C1-C4)烷基氨基磺酰基、最优选二甲基氨基磺酰基)、吡咯烷基磺酰基(更优选吡咯烷并磺酰基)、吗啉基磺酰基(更优选吗啉代磺酰基)、吡咯基磺酰基(更优选1-吡咯基磺酰基)、吡啶基磺酰基(更优选4-吡啶基磺酰基)、吡咯基(更优选1-吡咯基)和吡啶基(更优选4-吡啶基);
R2是被1个或2个相同或不同取代基取代的苯基,取代基选自下述基团:低级烷基(更优选C1-C4烷基、最优选甲基或异丙基)、单(或二、或三)卤代(低级)烷基(更优选单(或二或三)卤代(C1-C4)烷基,最优选三氟甲基)、单(或二或三)卤代低级烷基磺酰氧基(更优选单(或二或三)卤代C1-C4烷基磺酰氧基、最优选三氟甲基磺酰氧基)、卤素(更优选氯或氟)、低级亚烷基二氧代(更优选C1-C4亚烷基二氧代基,最优选亚甲基二氧代基或亚乙基二氧代基)、低级烷氧基(更优选C1-C4烷氧基,更优选甲氧基)、低级烷氧羰基(更优选C1-C4烷氧羰基,最优选甲氧羰基)、低级烷氧(低级)烷氧基(低级)烷氧基(更优选C1-C4烷氧基(C1-C4)烷氧基(C1-C4)烷氧基,最优选(2-甲氧乙氧基)甲氧基)、羟基、二苯基(低级)烷基甲硅烷氧基(更优选二苯基(C1-C4)烷基甲硅烷氧基,最优选二苯基(叔丁基)甲硅烷氧基、三(低级)烷基甲硅烷氧基(更优选三(C1-C4)烷基甲硅烷氧基,最优选二甲基(叔丁基)甲硅烷氧基)、羟基(低级)烷基(更优选羟基(C1-C4)烷基,最优选羟甲基或1-羟基-1-甲乙基)、氰基、氨基、〔单(或二、或三)卤代(低级)烷基羰基〕氨基(更优选〔单(或二、或三)卤代(C1-C4)烷基羰基〕氨基,最优选(三氟甲基羰基)氨基)、低级烷基氨基(更优选C1-C4烷基氨基,最优选甲氨基)、N-(低级烷基)-〔单(或二、或三)卤代(低级)烷基羰基〕氨基(更优选N-(C1-C4烷基)-〔单(或二、或三)卤代(C1-C4)烷基羰基〕氨基,最优选N-甲基-(三氟甲基羰基)氨基)、吡咯烷基(更优选吡咯烷子基)和吗啉基(更优选吗啉代基),其可被低级烷氧基(低级)烷基(更优选(C1-C4)烷基,最优选甲乙基甲基)或低级烷基(更优选C1-C4烷基,最优选甲基)取代;
R3是氢;和
R4是(3-吡啶基)甲基;
(3-吡啶基)乙基(更优选2-(3-吡啶基)乙基);
3-(3-吡啶基)丙基;
3-(3-吡啶基)丙烯基(更优选3-(3-吡啶基)-2-丙烯基);
3-(3-吡啶基)丙炔基(更优选3-(3-吡啶基)-2-丙炔基);
噻唑基(低级)烷基(更优选噻唑基(C1-C4)烷基,最优选4-噻唑基甲基),1,2,4-噻二唑基(低级)烷基(更优选1,2,4-噻二唑基(C1-C4)烷基,最优选1,2,4-噻二唑基-3-基甲基)或1,2,4-噁二唑基(低级)烷基(更优选1,2,4-噁二唑基(C1-C4)烷基,最优选1,2,4-噁二唑基-5-基甲基),每个取代基被下列基团取代:卤素(更优选溴)、氨基、低级烷基氨基(更优选C1-C4烷基氨基,最优选甲氨基)或二(低级)烷基氨基(更优选二(C1-C4)烷基氨基,最优选二甲基氨基);
可被三苯基(低级)烷基(更优选三苯基(C1-C4)烷基,最优选三苯甲基)或羟基(低级)烷基(更优选羟基(C1-C4)烷基,最优选2-羟基乙基)取代的吡唑基甲基(更优选(4-吡唑基)甲基或(5-吡唑基)甲基);
可被低级烷基(更优选C1-C4烷基,最优选甲基)、(低级)烷氧基(低级)烷基吗啉基(低级)烷基(更优选(C1-C4)烷氧基(C1-C4)烷基吗啉基(C1-C4)烷基,最优选2-(2-甲氧基甲基吗啉代基)乙基)或(低级)烷氧基(低级)烷基吗啉基羰基(低级)烷基(更优选(C1-C4)烷氧基(C1-C4)烷基吗啉基羰基(C1-C4)烷基,最优选(2-甲氧基甲基吗啉代基)羰基甲基)取代的吡唑基(低级)烷基(更优选吡唑基(C1-C4)烷基,最优选(4-吡唑基)甲基、(5-吡唑基)甲基或3-(4-吡唑基)丙基;
可被1或2个相同或不同如下取代基取代的吡咯烷基(低级)烷基(更优选吡咯烷基(C1-C4)烷基,最优选2-吡咯烷子基乙基),取代基选自下列基团:羟基、羟基(低级)烷基(更优选羟基(C1-C4)烷基,最优选羟甲基)、低级烷氧基(更优选C1-C4烷氧基,最优选甲氧基)和低级烷氧基(低级)烷基(更优选C1-C4烷氧基(C1-C4)烷基,最优选甲氧甲基);
哌啶基甲基(更优选(4-哌啶基)甲基);
可被1或2个相同或不同取代基取代的哌啶基(低级)烷基(更优选哌啶基(C1-C4)烷基,最优选2-哌啶子基并乙基),取代基选自下述基团:卤素(更优选氟)、低级烷基(更优选C1-C4烷基,最优选甲基)和低级烷氧基(低级)烷基(更优选C1-C4烷氧基(C1-C4)烷基,最优选甲氧基甲基);
〔2,6-二〔羟基(低级)烷基〕哌啶基〕(低级)烷基(更优选〔2,6-二〔羟基(C1-C4)烷基〕哌啶基〕(C1-C4)烷基,最优选2-〔2,6-二(羟基甲基)哌啶子基〕乙基);
(2,6-二甲基吗啉代基)(低级)烷基(更优选(2,6-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2,6-二甲基吗啉代基)乙基);
(2,2-二甲基吗啉代基)(低级)烷基(更优选(2,2-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2,2-二甲基吗啉代基)乙基);
(3,3-二甲基吗啉代基)(低级)烷基(更优选(3,3-二甲基吗啉代基)(C1-C4)烷基,最优选2-(3,3-二甲基吗啉代基)乙基);
(顺-3,5-二甲基吗啉代基)(低级)烷基(更优选顺-(3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-(顺-3,5-二甲基吗啉代基)乙基);
((3S,5S)-3,5-二甲基吗啉代基)(低级)烷基(更优选((3S,5S)-3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-((3S,5S)-3,5-二甲基吗啉代基)乙基);
((3S,5R)-3,5-二甲基吗啉代基)(低级)烷基(更优选((3S,5R)-3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-((3S,5R)-3,5-二甲基吗啉代基)乙基);
(2-甲氧基甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基吗啉代基)(C1-C4)烷基,最优选3-(2-甲氧基甲基吗啉代基)丙基或2-(2-甲氧基甲基吗啉代基)乙基);
(3-甲氧基甲基吗啉代基)(低级)烷基(更优选(3-甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(3-甲氧基甲基吗啉代基)乙基);
(2-甲氧基甲基-5-甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基-5-甲基吗啉代基)(C1-C4)烷基,最优选2-(2-甲氧基甲基-5-甲基吗啉代基)乙基);
(2-甲氧基甲基-5,5-二甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基-5,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2-甲氧基甲基-5,5-二甲基吗啉代基)乙基);
(3,5-二甲氧基甲基吗啉代基)(低级)烷基(更优选(3,5-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(3,5-二甲氧基甲基吗啉代基)乙基);
(2,2-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,2-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,2-二甲氧基甲基吗啉代基)乙基);
(2,3-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,3-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,3-二甲氧基甲基吗啉代基)乙基);
(2,6-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,6-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,6-二甲氧基甲基吗啉代基)乙基);
(2-甲氧基甲基吗啉代基)(低级)烯基(更优选(2-甲氧基甲基吗啉代基)(C2-C4)烯基,最优选4-(2-甲氧基甲基吗啉代基)-2-丁烯基);
(3,3-二甲基吗啉代基)(低级)炔基(更优选(3,3-二甲基吗啉代基)(C2-C4)炔基,最优选4-(3,3-二甲基吗啉代基)-2-丁炔基);
(2-甲氧基甲基吗啉代基)(低级)炔基(更优选(2-甲氧基甲基吗啉代基)(C2-C4)炔基,最优选4-(2-甲氧基甲基吗啉代基)-2-丁炔基);
(2-甲氧基甲基-5-甲基吗啉代基)(低级)炔基(更优选(2-甲氧基甲基-5-甲基吗啉代基)(C2-C4)炔基,最优选4-(2-甲氧基甲基-5-甲基吗啉代基)-2-丁炔基);
喹啉基(低级)烷基(更优选喹啉基(C1-C4)烷基,最优选(6-喹啉基)甲基);
〔1H-吡咯并[3,2-b]吡啶基(低级)烷基(更优选〔1H-吡咯并[3,2-b]吡啶基(C1-C4)烷基,最优选〔1H-吡咯并[3,2-b]吡啶-3-基〕甲基〕;
〔4,5,6,7-四氢噻吩并[3,2-c]吡啶基(低级)烷基(更优选〔4,5,6,7-四氢噻吩并[3,2-c]吡啶基(C1-C4)烷基,最优选2-〔4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基〕乙基〕;
〔3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪基〕(低级)烷基(更优选〔3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪基〕(C1-C4)烷基,最优选2-〔3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪〕-4-基)乙基);
(5,6,7,8-四氢-1,6-二氮杂萘-6-基)(低级)烷基(更优选(5,6,7,8-四氢-1,6-二氮杂萘-6-基)(C1-C4)烷基,最优选2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基);或
被下述通式的饱和杂环基团取代的低级烷基(更优选C1-C4烷基,最优选乙基):
(其中r,s和t各自是1至2的整数,并且q是0至2的整数)(更优选(1S,4S-2-氮杂-5-氧杂双环[2.2.1]-庚-2-基,其可被1个或2个低级烷基(更优选取代C1-C4烷基,最优选甲基)取代。
目的化合物(I)的更优选的具体实例如下:
Y是低级亚烷基(更优选C1-C4亚烷基,最优选亚甲基);
R1是被1或2个相同或不同取代基取代的苯基,取代基选自下列基团:卤素、低级烷基、低级烷氧基、单(或二、或三)卤代(低级)烷基、硝基、氨基、低级烷基氨基、二(低级)烷基氨基、低级烷硫基、低级烷基磺酰基、环(低级)烷基磺酰基、氨基磺酰基、低级烷基氨基磺酰基、二(低级)烷基氨基磺酰基、吡咯烷基磺酰基、吗啉基磺酰基、吡咯基磺酰基、吡啶基磺酰基、吡咯基和吡啶基〔更优选二卤代苯基,双(三卤代(低级)烷基苯基,(三卤代(低级)烷基)(卤代)苯基,(三卤代(低级)烷基)〔(低级)烷基〕苯基,(三卤代(低级)烷基)〔(低级)烷氧基〕苯基,(三卤代(低级)烷基)(硝基)苯基,(三卤代(低级)烷基)(低级烷基氨基)苯基,(三卤代(低级)烷基)(二(低级)烷基氨基)苯基,(三卤代(低级)烷基)〔(低级)烷基硫基〕苯基,(三卤代(低级)烷基)〔(低级)烷基磺酰基〕苯基,(三卤代(低级)烷基)〔环(低级)烷基磺酰基〕苯基,(三卤代(低级)烷基)〔氨基磺酰基〕苯基,(三卤代(低级)烷基)〔低级烷基氨基磺酰基〕苯基,(三卤代(低级)烷基)〔二(低级)烷基氨基磺酰基〕苯基,(三卤代(低级)烷基)〔吡咯烷基磺酰基〕苯基,(三卤代(低级)烷基)〔吗啉基磺酰基〕苯基,(三卤代(低级)烷基)〔吡啶基磺酰基〕苯基,(三卤代(低级)烷基)〔吡咯基〕苯基,或(三卤代(低级)烷基)〔吡啶基〕苯基,最优选3,5-二氯苯基,3,5-双(三氟甲基)苯基,3-氟-5-三氟甲基苯基,3-氯-5-三氟甲基苯基,3-甲基-5-三氟甲基苯基,3-甲氧基-5-三氟甲基苯基,3-硝基-5-三氟甲基苯基,3-甲氨基-5-三氟甲基苯基,3-二甲氨基-5-三氟甲基苯基,3-甲硫基-5-三氟甲基苯基,3-甲磺酰基-5-三氟甲基苯基,3-环戊基磺酰基-5-三氟甲基苯基,3-氨基磺酰基-5-三氟甲基苯基,3-甲氨基磺酰基-5-三氟甲基苯基,3-二甲氨基磺酰基-5-三氟甲基苯基,3-吡咯烷子基磺酰基-5-三氟甲基苯基,3-吗啉代磺酰基-5-三氟甲基苯基,3-(4-吡啶基)磺酰基-5-三氟甲基苯基,3-(1-吡咯基)-5-三氟甲基苯基,或3-(4-吡啶基)-5-三氟甲基苯基;
R2是被1个或2个相同或不同取代基取代的苯基,取代基选自下述基团:低级烷基、单(或二、或三)卤代(低级)烷基、单(或二或三)卤代低级烷基磺酰氧基、卤素、低级亚烷基二氧代、低级烷氧基、低级烷氧羰基、低级烷氧(低级)烷氧基(低级)烷氧基、羟基、二苯基(低级)烷基甲硅烷氧基、三(低级)烷基甲硅烷氧基、羟基(低级)烷基、氰基、氨基、〔单(或二、或三)卤代(低级)烷基羰基〕氨基、低级烷基氨基、N-(低级烷基)-〔单(或二、或三)卤代(低级)烷基羰基〕氨基、吡咯烷基和吗啉基,其可被低级烷氧基(低级)烷基或低级烷基取代;
〔更优选〔(低级)亚烷基二氧代〕苯基、
(低级烷氧基)苯基、卤代苯基、二卤代苯基、三卤代(低级)烷基苯基、(三卤代(低级)烷基(低级烷基)苯基、(卤代)(低级烷基)苯基、(卤代)(低级烷氧基)苯基、(卤代)(羟基)苯基、(卤代)(二苯基(低级)烷基甲硅烷基氧代)苯基、(三卤代(低级)烷基)(羟基)苯基、(羟基(低级)烷基)(羟基)苯基、(氰基)(羟基)苯基、(二卤代(低级)烷基)(羟基)苯基、(低级烷基)(氨基)苯基、(低级烷基)(低级烷基氨基)苯基、(低级烷基)(单(或二、或三)卤代(低级)烷基磺酰氧代)苯基、(低级烷基)〔(单(或二、或三)卤代(低级)烷基羰基)氨基〕苯基、(低级烷基)〔N-(低级烷基)-〔单(或二、或三)卤代(低级)烷基羰基〕氨基〕苯基、(低级烷基)(二苯基(低级)烷基甲硅烷基氧代)苯基、(低级烷基)(低级烷氧基(低级)烷氧基(低级)烷氧基)苯基、(低级烷基)(三(低级)烷基甲硅烷基氧代)苯基、(低级烷氧羰基)(三(低级)烷基甲硅烷基氧代)苯基、(羟基(低级)烷基)(三(低级)烷基甲硅烷基氧代)苯基、(低级烷基)(羟基)苯基、(低级烷基)(吡咯烷基)苯基、(低级烷基)(吗啉基)苯基、(低级烷基)(低级烷氧基(低级)烷基吗啉基)苯基或(低级烷基)(低级烷基)吗啉基)苯基,最优选1,4-苯并二噁烷-6-基、4-甲氧基苯基、4-氟苯基、4-氯苯基、3,4-二氟苯基、4-(三氟甲基)苯基、3-甲氧基-4-三氟甲基苯基、4-氟-3-甲苯基、4-氟-3-甲氧基苯基、3-氟-4-甲苯基、4-氟-3-羟基苯基、4-氯-3-甲氧基苯基、4-氯-3-(二甲基(叔丁基)甲硅烷基氧代)苯基、4-氯-3-羟基苯基、3-羟基-4-(三氟甲基)苯基、3-羟基-4-(羟甲基)苯基、3-羟基-4-甲苯基、3-羟基-4-(1-羟基-1-甲乙基)苯基、4-氰基-3-羟基苯基、3-氰基-4-(二氟甲基)苯基、3-羟基-4-异丙基苯基、3-氨基-4-甲苯基、4-甲基-3-甲氨基苯基、4-甲基-3-(三氟甲基磺酰基氧代)苯基、4-甲基-3-〔(三氟甲基羰基)氨基〕苯基、4-甲基-3-〔N-甲基-(三氟甲基羰基)氨基〕苯基、3-二苯基(叔丁基)甲硅烷基氧代-4-甲苯基、4-甲基-3-〔(2-甲氧基乙氧基)甲氧基〕苯基、3-二甲基(叔丁基)甲硅烷基氧代-4-甲苯基、3-二甲基(叔丁基)甲硅烷基氧代-4-甲氧基羰基苯基、3-二甲基(叔丁基)甲硅烷基氧代-4-(1-羟基-1-甲乙基)苯基、4-甲基-3-吡咯烷子基苯基或4-甲基-3-吗啉代苯基〕;
R3是氢;和
R4是(2,6-二甲基吗啉代基)(低级)烷基(更优选(2,6-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2,6-二甲基吗啉代基)乙基);
(2,2-二甲基吗啉代基)(低级)烷基(更优选(2,2-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2,2-二甲基吗啉代基)乙基);
(3,3-二甲基吗啉代基)(低级)烷基(更优选(3,3-二甲基吗啉代基)(C1-C4)烷基,最优选2-(3,3-二甲基吗啉代基)乙基);
(cis-3,5-二甲基吗啉代基)(低级)烷基(更优选cis-(3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-(cis-3,5-二甲基吗啉代基)乙基);
((3S,5S)-3,5-二甲基吗啉代基)(低级)烷基(更优选((3S,5S)-3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-((3S,5S)-3,5-二甲基吗啉代基)乙基);
((3S,5R)-3,5-二甲基吗啉代基)(低级)烷基(更优选((3S,5R)-3,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-((3S,5R)-3,5-二甲基吗啉代基)乙基);
(2-甲氧基甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基吗啉代基)(C1-C4)烷基,最优选3-(2-甲氧基甲基吗啉代基)丙基或2-(2-甲氧基甲基吗啉代基)乙基);
(3-甲氧基甲基吗啉代基)(低级)烷基(更优选(3-甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(3-甲氧基甲基吗啉代基)乙基);
(2-甲氧基甲基-5-甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基-5-甲基吗啉代基)(C1-C4)烷基,最优选2-(2-甲氧基甲基-5-甲基吗啉代基)乙基);
(2-甲氧基甲基-5,5-二甲基吗啉代基)(低级)烷基(更优选(2-甲氧基甲基-5,5-二甲基吗啉代基)(C1-C4)烷基,最优选2-(2-甲氧基甲基-5,5-二甲基吗啉代基)乙基);
(3,5-二甲氧基甲基吗啉代基)(低级)烷基(更优选(3,5-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(3,5-二甲氧基甲基吗啉代基)乙基);
(2,2-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,2-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,2-二甲氧基甲基吗啉代基)乙基);
(2,3-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,3-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,3-二甲氧基甲基吗啉代基)乙基);
(2,6-二甲氧基甲基吗啉代基)(低级)烷基(更优选(2,6-二甲氧基甲基吗啉代基)(C1-C4)烷基,最优选2-(2,6-二甲氧基甲基吗啉代基)乙基);
(2-甲氧基甲基吗啉代基)(低级)烯基(更优选(2-甲氧基甲基吗啉代基)(C2-C4)烯基,最优选4-(2-甲氧基甲基吗啉代基)-2-丁烯基);
(3,3-二甲氧基吗啉代基)(低级)炔基(更优选(3,3-二甲基吗啉代基)(C2-C4)炔基,最优选4-(3,3-二甲基吗啉代基)-2-丁炔基);
(2-甲氧基甲基吗啉代基)(低级)炔基(更优选(2-甲氧基甲基吗啉代基)(C2-C4)炔基,最优选4-(2-甲氧基甲基吗啉代基)-2-丁炔基);或
(2-甲氧基甲基-5-甲基吗啉代基)(低级)炔基(更优选(2-甲氧基甲基-5-甲基吗啉代基)(C2-C4)炔基,最优选4-(2-甲氧基甲基-5-甲基吗啉代基)-2-丁炔基)。
用于制备本发明的目的化合物(I)的方法1和2在下面详细解释。
方法1
目的化合物(I)或它们的盐可用化合物(II)或它们的在亚氨基上的反应衍生物或它们的盐与化合物(III)或它们的盐反应而制备。
化合物(II)的合适的在亚氨基上的反应衍生物可包括Schiff碱类型亚氨基或它们的互变异构的烯胺型异构体,它们是由化合物(II)与如醛、酮等羰基化合物反应形成的;由化合物(II)与甲硅烷基化合物,如双(三甲基甲硅烷基)乙酰胺、单(三甲基甲硅烷基)乙酰胺、双(三甲基甲硅烷基)脲等反应形成的甲硅烷基衍生物;由化合物(II)与三氯化磷或光气等反应形成的衍生物。
反应通常在常规溶剂中进行,如水、醇(例如甲醇、乙醇等等)、丙酮、二氧六环、乙腈、氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺、吡啶或其它对反应没有不利影响的有机溶剂。这些常规溶剂也可以与水混合物的形式使用。
反应也可以在无机碱或有机碱的存在下进行,例如,碱金属碳酸盐(例如碳酸钾,等等)、碱金属碳酸氢盐、三(低级)烷基胺、吡啶、N-(低级)烷基吗啉、N,N-二(低级)烷基乙胺、(例如,N,N-二异丙基乙胺等等)、N,N-二(低级)烷基苄胺,等等。
反应稳定不是关键的,通常反应在冷却至加热的情况下进行。
方法2
目的化合物(Ib)或它们的盐可由化合物(Ia)或它们的盐进行还原反应制备得到。
反应可以后面实施例8中公开的方式或类似的方式进行。
目的化合物(I)和它们的药用可接受的盐具有如下药理活性,如速激肽拮抗机制、特别是P物质拮抗机制、神经激肽A拮抗机制或神经激肽B拮抗机制,因此对于治疗或预防由速激肽介导的在人类或动物中发生的疾病,特别是P物质介导的疾病是有用的,例如呼吸疾病,如气喘、支气管炎(例如慢性支气管炎、急性支气管炎以及扩散的全部细支气管炎)、鼻炎、咳嗽、有痰,等等;
眼疾病,例如结膜炎、春节结膜炎,等等;
皮炎病,如接触性皮炎、变应性湿疹、寻麻疹,以及其它湿疹性皮炎,等等;
炎症疾病,如风湿性关节炎、骨关节炎,等等;
痛或疼痛(例如,偏头痛、头痛、牙疼、癌症疼痛、骨痛,等等)。
此外预料本发明的目的化合物(I)和它们的药用可接受的盐对于治疗或预防下述疾病是有用的:眼疾病如青光眼、眼色素层炎,等等;
胃肠疾病如溃疡、溃疡性结肠炎、过敏性肠综合症、食物过敏等等;
炎症疾病如肾炎等等;
循环疾病如高血压、心绞痛、心脏衰竭、血栓、雷诺病,等等;
癫痫;间隙麻痹;频尿;膀胱炎;膀胱逼肌反射亢进;尿失禁;帕金森病;dimentia;艾滋病相关的dimentia;早老性痴呆病;唐氏综合症;亨廷顿舞蹈病;类癌瘤综合症;免疫增强或压抑有关的疾病;螺旋菌幽门的或其它螺旋的脲酶-阳性的革兰阴性的细菌引起的疾病;晒斑;血管生成或由血管生成引起的疾病;等等。
还预料本发明的目的化合物(I)和它们的药用可接受的盐对于治疗或预防下述疾病是有用的:慢性栓塞性肺病,特别是慢性肺气肿;虹膜炎;玻璃体视网膜病;牛皮癣;炎症的肠疾病;特别是节段性回肠炎;肝炎;冻伤表皮疼痛,烧伤,带状疱疹或糖尿病患者的神经病;伴随牵涉性痛的血脂过高;手术后的神经瘤,特别是乳房切除术;阴道前庭;与血液透析有关的痒病;扁平苔藓;咽喉炎;支气管扩张;粉尘病;白日咳;肺结核;膀胱纤维变性;呕吐(例如恶心,干呕,呕吐,急性呕吐,延迟性呕吐,期待性呕吐,手术前恶心和呕吐(PONV),药物引起的急性和/或延迟性呕吐,例如癌症化疗药物,等);记忆疾病,特别是焦虑病,与紧张有关的疾病,感情障碍,心理发展障碍和精神分裂症;髓鞘脱夫疾病,如多重硬化和肌萎缩侧面硬化;吗啡停药的衰减;水肿,如由热损伤引起的水肿;小细胞癌,特别是小细胞肺癌(SCLC);高过敏病,如野葛;纤维和胶原疾病,如硬皮病和嗜酸性片形细胞;反射交感性营养不良,如肩/手综合症;嗜好疾病,如酒精中毒;与紧张有关的躯体疾病;风湿疾病如纤维织炎;侵略行为,随意地-起服用安定药;躁狂症或轻躁狂,随意地一起服用安定药;与月经前期综合症(PMS)有关的症状(现在PMS也指晚期黄体方面综合症(LLS);受心理影响的障碍;心理免疫疾病;活动过度或没有活动过度证明(attetion)缺乏疾病(ADD);等等。
此外,本发明的目的化合物(I)和它的药用可接受的盐是中枢神经系统(CNS)穿透物。
对于治疗目的,本发明的化合物(I)和它们的药用可接受的盐可以药物制剂的形式使用,这类制剂含1种作为活性成份的所述化合物,可与药用可接受的载体混合的方式,这类载体如有机或无机固体或液体赋型剂,这类赋型剂适合于口服,非肠道给药,外部的包括表面的,内服的(enternal),静脉的,肌内,吸入,经鼻,关节内,脊柱内,经气管或经眼给药。药用制剂可以是固体,半固体或溶液,如胶囊,片剂,小丸,糖衣丸,粉末,颗粒剂,栓剂,软骨,乳膏,洗剂,吸入剂,注射剂,泥敷剂,胶,胶带,眼滴剂,溶液,糖浆,气雾剂,悬浮液,乳剂,等等。如果需要,这些制剂中可包括辅助物质、稳定剂、润湿剂或乳化剂、缓冲剂以及其它常用的添加剂。
虽然化合物(I)的剂量取决于病人的年龄和病情而变化,化合物(I)的平均单-剂量大约是0.1mg,1mg,10mg,50mg,100mg,250mg,500mg和1000mg,对于治疗速激肽介导的疾病,如气喘等是有效的。通常,每人每天可服用的量在0.1mg和大约1000mg之间。
为了显示目的化合物(I)以及它们的药用可接受的盐的可用性,本发明的-些代表性化合物的药理实验数据在下面说明。
A.
用h-NK1受体结合实验评价NK1拮抗剂向中枢神经系统转移的有效性
[1]实验方法
(1)服用实验化合物并从脑中萃取化合物
雄性SD大鼠静脉内注射含实验化合物(1mg/kg)的溶液,5分钟后,动物用乙醚麻醉,用20ml生理盐水通过主动脉上升(asscendens)流血和灌流。迅速断头,称重,在4倍体积的冰冷蒸馏水中用Polytoron(KINEMATICA)打成匀浆。为了萃取实验化合物,将500μl匀浆,100μl甲醇,500μl 0.1N NaOH和4ml乙酸乙酯混合,室温振荡10分钟。3000rpm离心10分钟回收有机相(2.5ml),干燥,溶解在二甲基亚砜中。
(2)h-NK1受体结合实验
(a)粗CHO细胞膜的制备
在4℃和缓冲液(0.25M蔗糖,25mM Tris-HCl(pH7.4),10mM MgCl2,1mM EDTA,5μg/ml p-APMSF)中,收集永久表达的h-NK1受体CHO细胞并用Dounce匀浆器匀浆化。该组织匀浆离心(500×g,10分钟),片状物再悬浮于相同缓冲液中,匀浆化,离心(100,000×g,1小时)。因此,分离出的粗细胞膜再悬浮在缓冲液(25mM Tris-HCl(pH 7.4),10mM MgCl2,1mM EDTA,5μg/ml p-APMSF)中,储存在-80℃,直到使用。
(b)125I-BH-P物质结合到制备的膜
细胞膜(6μg/ml)用123I-BH-P物质(0.1nM)在0.25ml介质20μg/ml抑糜蛋白酶素,40μg/ml地衣杆菌素,4μg/ml白胃素,5μg/ml p-APMSF,200μg/ml BSA)中有或没有萃取的化合物下,在22℃孵育90分钟。孵育时间结束,内容物迅速用SKATRON细胞收集仪通过Blue Mat11740过滤器(使用前用0.1%聚乙烯亚胺预处理3小时)过滤。然后,滤液用洗涤缓冲液(50mM Tris-HCl(pH 7.4),5mM MnCl2)洗涤,用自动γ计数仪(Packard RIASTAR 5420A)计数辐射活性。所有显示的数据是特有的结合,定义为用3μM未标记的P物质可以替换。
[2]实验结果
下述所有实验化合物显示在1mg/kg的剂量下,125I-BH-P物质结合到h-NK1受体上的抑制率高于80%。
实验化合物:实施例4-(1)、4-(2)、7和8的目的化合物。
B.
狗的呕吐实验
[I]实验方法
每个家养成熟的雌性狗(8-15公斤)静脉注射含实验化合物的溶液,5分钟后,皮下给阿朴吗啡(0.1mg/0.5ml/kg)引起呕吐反应(呕吐和干呕),再观察60分钟。记录观察到的每只动物呕吐和干呕的时间和次数,实验期间每只动物至少检验10天。
[II]实验结果
下述实验化合物在狗的呕吐实验中用0.32mg/kg的剂量时显示100%的抑制率。
实验化合物:实施例4-(1)的目的化合物。
下面给的制备和实施例用于说明本发明的目的。
制备1
室温下3-羟基-4-甲基苯甲酸(2.16g)和N,N-二异丙基乙胺(9.2mL)的1,2-二氯乙烷(40mL)溶液中加入(2-甲氧基乙氧基)甲基氯化物(4.87mL),混合物回流下搅拌24小时。蒸发除去溶剂后,残留物在用稀释的盐酸水相和乙酸乙酯相之间分配,分离有机相并用食盐水洗涤,硫酸镁干燥,减压除去溶剂。粗品油状物用硅胶柱层析纯化,用己烷/乙酸乙酯(3∶1)混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苯甲酸(2-甲氧基乙氧基)甲酯(4.82g),为油状物。
IR(净):1725,1595cm-1
NMR(CDCl3,δ):2.29(3H,s),3.37(3H,s),3.39(3H,s),3.54-3.90(8H,m),5.35(2H,s),5.60(2H,s),7.21(1H,d,J=8.0Hz),7.65(1H,dd,J=1.6和8.0Hz),7.74(1H,d,J=1.4Hz)MASS(API-ES):351(M+Na)+
制备2
在5℃以下和氮气氛中于12分钟内将氢化铝锂(0.35g)以多个小部分的形式加入到3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苯甲酸(2-甲氧基乙氧基)甲酯(3.5g)的四氢呋喃(20mL)的冰冷溶液中。混合物在相同温度下搅拌30分钟后,混合物中加入2N氢氧化钠(0.5mL),混合物搅拌30分钟后,过滤除去不溶物质并用四氢呋喃洗涤,合并滤液和洗液,减压蒸发。残留物溶解在乙酸乙酯中,溶液中加入二氧化锰(IV)(3.5g),回流下搅拌2小时,反应混合物通过Celite过滤,不溶物质用乙酸乙酯洗涤。合并滤液和洗液,减压蒸发。得到的残留物用硅胶柱层析纯化,用己烷/乙酸乙酯(10∶1)混合溶剂洗脱。收集含目的化合物的组分,减压蒸发得到3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苯甲醛(1.7g),为油状物。
IR(净):1687,1407cm-1
NMR(CDCl3,δ):2.31(3H,s),3.38(3H,s),3.55-3.60(2H,m),3.82-3.87(2H,m),5.37(2H,s),7.30(1H,d,J=7.7Hz),7.44(1H,dd,J=1.4和7.7Hz),7.58(1H,d,J=1.4Hz),9.92(1H,s)
MASS(API-ES):279(M+Na+MeOH)+,247(M+Na)+
制备3
在5℃往搅拌的3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苯甲醛(1.7g)和1,4-二乙酰基-2,5-哌嗪二酮(1.6g)混合物的N,N-二甲基甲酰胺(17mL)和叔丁醇(17mL)的混合溶液中加入叔丁醇钾(900mg),混合物在室温下搅拌24小时,然后倾到水中(300mL)。水溶液混合物用稀盐酸水溶液调pH 4-5,然后用乙酸乙酯萃取。萃取液用食盐水洗涤,硫酸钠干燥,减压蒸发。得到的残留物用硅胶柱层析纯化,用甲苯和乙酸乙酯的混合溶剂(3∶1)洗脱,收集含目的化合物的组分,减压蒸发得到1-乙酰基-3-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲苯基〕亚甲基-2,5-哌嗪二酮(2.05g),为粉末。
IR(KBr):3208,1700,1627,1598,1455,1375cm-1
NMR(CDCl3,δ):2.26(3H,s), 2.65(3H,s),3.27(3H,s),3.58-3.62(2H,m),3.81-3.86(2H,m),4.49(2H,s),5.32(2H,s),6.94(1H,dd,J=1.5和7.8Hz),7.15(1H,d,J=7.8Hz),7.23(1H,d,J=1.5Hz),7.27(1H,s),8.34(1H,br s)
MASS(API-ES):417(M+MeOH+Na)+
制备4
室温和大气压下1-乙酰基-3-〔〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲苯基〕亚甲基〕-2,5-哌嗪二酮(2.0g)的四氢呋喃溶液(20ml)中以10%钯碳(50%湿,0.2g)氢化3小时。过滤除去催化剂,滤液减压浓缩。得到的残留物溶解在四氢呋喃(30mL)中,然后加入一水合肼(1.5mL)。室温搅拌1小时,混合物减压浓缩,残留物用异丙醇研磨,过滤收集得到的固体3-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲苄基〕-2,5-哌嗪二酮(1.75g)。
IR(KBr):3183,3060,1675,1454cm-1
NMR(CDCl3,δ):2.21(3H,s),2.95-4.00(8H,m),3.36(3H,s),4.20-4.27(1H,m),5.1 9 ( 1H,d,J=7.0Hz),5.38(1H,d,J=7.0Hz),6.50(1H,br s),6.72(1H,br s),6.75(1H,dd,J=1.4和7.9Hz),6.97(1H,d,J=1.4Hz),7.08(1H,d,J=7.9Hz)
MASS(APCI):323(M+H)+,247,235
制备5
5℃以下和氮气氛中3-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基〕苄基-2,5-哌嗪二酮(1.7g)的四氢呋喃(17mL)冰冷溶液中加入四氢铝锂(0.62mg)混合物回流搅拌3.5小时。混合物冷至5℃以下,2 N氢氧化钠加至混合物中。相同温度下混合物搅拌30分钟,过滤除去不溶物质,并用四氢呋喃洗涤。合并滤液和洗液,减压蒸发。残留物溶解于乙酸乙酯中,硫酸钠干燥,减压蒸发得到2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲苄基〕哌嗪(1.27g),为黄色油状物。
5℃以下苄氧羰酰氯(0.75g)的二氯甲烷(1mL)溶液于5分钟内滴加至上述过程得到的2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲苄基〕哌嗪(1.27g)和三乙胺(2.2mL)的二氯甲烷(10mL)溶液中,混合物在相同温度下搅拌30分钟后,5℃以下于10分钟内3,5-双(三氟甲基)苯甲酰氯(0.93mL)的二氯甲烷(1.0mL)溶液滴加至混合物中。相同温度下搅拌30分钟,反应混合物用食盐水洗涤,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用甲苯和乙酸乙酯(5∶1)混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到1-〔3,5-双(三氟甲基)苯甲酰〕-4-(苄氧羰基)-2-〔3-〔〔2-甲氧基乙氧基〕甲氧基〕-4-甲苄基〕哌嗪(1.61g)为油状物。
IR(净):2879,1700,1645cm-1
NMR(CDCl3,δ):2.19(3H,s),3.35(3H,s),2.40-5.40(17H,m),6.40-8.10(10H,m),7.82(1H,br s)
MASS(APCI):669(M+H)+
制备6
1-〔3,5-双(三氟甲基)苯甲酰〕-4-(苄氧羰基)-2-〔3-〔2-甲氧基乙氧基〕甲氧基-4-甲苄基〕哌嗪(1.6g)的甲醇(20mL)溶液在室温和大气压下用10%钯碳(50%湿,0.2g)氢化4小时,过滤除去催化剂,滤液减压浓缩。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(40∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到1-〔3,5-双(三氟甲基)苯甲酰〕-2-〔3-〔2-甲氧基乙氧基〕甲氧基-4-甲苄基〕哌嗪(0.89g)为油状物。
IR(净):1732,1714,1705,1647,1431cm-1
NMR(CDCl3,δ):2.20(3H,s),2.50-5.20(16H,m),3.00(3H,s),6.40-7.40(5H,m),7.80(1H,s)
MASS(API-ES):557(M+Na)+,535(M+H)+
制备7
室温下往(3R)-3-甲氧基甲基〕吗啉盐酸盐(4.71g)和三乙胺(4.11mL)的甲醇(110mL)混合溶液中加入5.8M的环氧乙烷(22mL)的甲苯溶液。反应混合物在相同的温度下搅拌2天,减压蒸发。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(20∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到2-〔(3R)-3-甲氧基甲基吗啉代〕乙醇(4.67 g)为油状物。
IR(净):3433,2860,1454, 1119,1055cm-l
NMR(CDCl3,δ):2.38-3.05(5H,m),3.33(3H,s),
3.40-3.80(8H,m)
MASS(APCI):176(M+H)+
制备8
根据制备7的类似方法得到下述化合物。
(1)2-(顺-2,6-二甲基吗啉代)乙醇
IR(净):3431,3402,1456,1373,1325,1146cm-1
NMR(CDCl3,δ):1.17(6H,d,J=6.3Hz),1.84(2H,dd,J=10.2和11.4Hz),2.52(2H,t,J=5.5Hz),2.71-2.78(2H,m),3.65(2H,t,J=5.6Hz),3.49-3.76(2H,m)
MASS(APCI):160(M+H)+
(2)2-〔(2S,5S)-2-甲氧基甲基-5-甲基吗啉代〕乙醇IR(净):3433,3400,1456,1379,1327,1086,1051cm-1
NMR(CDCl3,δ):1.19(3H,d,J=6.3Hz),1.88(1H,d,J=10.8Hz),1.96(1H,t,J=10.5Hz),2.54(2H,t,J=5.5Hz),2.72-2.83(2H,m),3.38(3H,s),3.36-3.45(2H,m),3.63(2H,t,J=5.2Hz),3.60-3.90(2H,m)
MASS(APCI):190(M+H)+
(3)2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙醇
IR(净):3435,1456,1354,1302cm-1
NMR(CDCl3,δ):2.06(1H,t,J=10.7Hz),2.27(1H,td,J=10.7和3.3Hz),2.53-2.58(2H,m),2.68-2.84(2H,m),3.38(3H,s),3.38-3.44(2H,m),3.61-3.75(4H,m),3.89-3.98(1H,m)
MASS(API-ES):176(M+H)+,198(M+Na)+
制备9
在5℃以下和氮气氛中往2-〔(3R)-3-甲氧基甲基吗啉代〕乙醇(505mg)的甲苯(2.5ml)的冰冷溶液中滴加氯化亚砜(429mg)乙醇(505mg)的甲苯(2.5ml)的冰冷溶液中滴加氯化亚砜(429mg)的甲苯(1.5mL)溶液,混合物在70℃搅拌1.5小时。混合物冷至室温,混合物中加入乙酸乙酯,得到的悬浮液减压蒸发,残留物中加入二异丙醚,混合物在室温搅拌15分钟后,过滤收集得到的沉淀,用二异丙醚洗涤并在40℃减压蒸干得到(3R)-4-(2-氯乙基)-3-(甲氧基甲基)吗啉盐酸盐(620 mg)为浅黄色粉末。
mp:162-163℃
IR(KBr):2945,1140,1109,1084cm-1
NMR(DMSO-d6,δ):3.31(3H,s),3.10-4.10(13H,m)
MASS(APCI):194(M+H)+(游离)
制备10
根据制备9的类似方式得到下述化合物。
(1)顺-2,6-二甲基-4-(2-氯乙基)吗啉盐酸盐
IR(KBr):1513,1458,1394,1336,1143 cm-1NMR(DMSO-d6,δ):1.12(6H,d,J=6.3Hz),2.60-2.80(2H,m),3.44-3.50(4H,m),3.95-4.10(4H,m)MASS(APCI):178(M+H)+(游离)
(2)(2S,5S)-4-(2-氯乙基)-2-甲氧基甲基-5-甲基吗啉盐酸盐
IR(KBr):2613,1456,1390,1124,1082cm-1
NMR(DMSO-d6,δ):1.13(3H,d,J=6.3Hz),2.50-3.00(3H,m),3.27(3H,s),3.34-3.51(7H,m),4.03-4.10(4H,m)
MASS(APCI):208(M+H)+(游离)
(3)(2S)-4-(2-氯乙基)-2-(甲氧基甲基)吗啉盐酸盐
NMR(DMSO-d6,δ):3.00(2H,m),3.27(3H,s),3.47(4H,m),3.75-4.12(7H,m),11.91(1H,m)
MASS(APCI):194(M+H)+(游离)
制备11
0℃下将三乙酰氧基硼氢化钠(36.7g)分次加至(2S)-2-氨基-1-丙醇(10.0g)和苯甲醛(13.53mL)在二氯甲烷(140mL)和乙酸(8.38mL)中的混合溶液中,混合物室温搅拌过夜。混合物依次用2N氢氧化钠和食盐水洗涤,用硫酸钠干燥。溶液减压蒸发,得到的残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(30∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到(2S)-2-苄氨基-1-丙醇(15.96g)。
IR(KBr):2843,1496,1454,1377,1340,1065cm-1
NMR(CDCl3,δ):1.10(3H,d,J=6.4Hz),2.77-2.93(1H,m),3.28(1H,dd,J=10.6和6.9Hz),3.61(1H,dd,J=10.6和4.0Hz),3.75,3.87(2H,ABq,J=13Hz),7.21-7.34(5H,m)
MASS(API-ES):166(M+H)+
制备12
室温下将(S)-(+)-甲基缩水甘油醚(8.25mL)滴加到(2S)-2-苄氨基-1-丙醇(7.6g)的甲醇(7.6ml)溶液中,40-50℃搅拌24小时后,溶液减压浓缩。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(30∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到(2S)-2-(N-苄基-N-〔(2S)-2-羟基-3-甲氧基丙基〕氨基)-1-丙醇(10.4g),为油状物。
IR(净):3400,2929,1452,1414,1373,1329cm-1
NMR(CDCl3,δ):0.96(3H,d,J=6.7Hz),2.50-2.60(1H,m),2.57(1H,dd,J=13.4和6.2Hz),2.67(1H,dd,J=13.4和6.5Hz),2.95-3.10(1H,m),3.21-3.52(4H,m),3.30(3H,s),3.49(1H,d,J=13.6Hz),3.71-3.75(1H,m),3.8 3(1H,d,J=13.6Hz),7.21-7.37(5H,m)
MASS(APCI):254(M+H)+
制备13
室温下将三苯基膦(10.09g)加到(2S)-2-(N-苄基-N-〔(2S)-2-羟基-3-甲氧基丙基〕氨基)-1-丙醇(8.86g)的四氯化碳(4.06mL)溶液中,室温搅拌2天后,溶液减压浓缩。残留物用二异丙醚(200mL)研磨三次,可溶性部分倾析法分离,减压蒸发。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(40∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到(2S)-1-(N-苄基-N-(1S)-2-氯-1-甲乙基〕氨基)-3-甲氧基-2-丙醇(4.90g),为油状物。
IR(净):3463,14 52,1362cm-1
NMR(CDCl3,δ):1.43(3H,d,J=6.6Hz),2.53-2.82(4H,m),3.30-3.39(2H,m),3.36(3H,s),3.59(1H,d,J=13.6Hz),3.83(1H,d,J=13.6Hz),3.79-3.87(1H,m),4.01-4.09(1H,m),7.21-7.33(5H,m)
MASS(APCI):272(M+H)+
制备14
0℃下将(2S)-1-(N-苄基-N-〔(1S)-2-氯-1-甲乙基〕氨基)-3-甲氧基-2-丙醇(1.90g)的N,N-二甲基甲酰胺(10mL)溶液加至氢化钠(0.45g,在矿物油中60%)的N,N-二甲基甲酰胺(10mL)冰冷悬浮溶液中,相同温度下搅拌1小时,混合物倾至冰水中,用乙酸乙酯萃取,萃取液用食盐水洗涤,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(10∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发得到(2S,5S)-4-苄基-2-甲氧基甲基-5-甲基吗啉(0.86g),为油状物。
IR(净):2875,1452,1362,1325,1130,1082cm-1
NMR(CDCl3,δ):1.15(3H,d,J=6.3Hz),1.73-1.93(2H,m),2.68-2.77(2H,m),3.35(3H,s),3.4 9(2H,s),3.31-3.49(2H,m),3.68-3.81(2H,m),7.25-7.32(5H,m)
MASS(APCI):236(M+H)+
制备15
室温和大气压下将(2S,5S)-4-苄基-2-甲氧基甲基-5-甲基吗啉(0.86g)在浓盐酸(0.31mL)和甲醇(8.6mL)中的混合溶液用10%钯碳(50%湿,0.2g)氢化3小时。用Celite过滤掉催化剂,得到的滤液减压浓缩得到(2S,5S)-2-甲氧基甲基-5-甲基吗啉盐酸盐(0.71g)为油状物。
IR(净):3433,3402,2939,1597,1456,1392,1331,1107cm-1
NMR(DMSO-d6,δ):1.12(3H,d,J=6.3Hz),2.49-2.75(2H,m),3.13-3.19(2H,m),3.27(3H,s),3.38(2H,d,J=4.8Hz),3.80-4.00(2H,m)
MASS(APCI):146(M+H)+(游离)
制备16
氯化钴(II)六水合物(36.5mg)和酰基转移酶(酰基转移酶Amano,365mg)加至N-乙酰基-3-甲氧基-4-甲基-DL-苯丙氨酸(7.28g)溶解在水(36.5mL)和1N氢氧化钠溶液(29mL)的混合溶液中,混合物在37℃下搅拌15.5小时,并用1N氢氧化钠溶液控制反应混合物的pH为7.5,过滤除去不溶物,用6N盐酸调滤液的pH为3,用乙酸乙酯萃取,用水洗涤,硫酸钠干燥,真空中蒸发得到粗N-乙酰基-3-甲氧基-4-甲基-D-苯丙氨酸(3.17g)。粗产品再进行酰基转移酶反应(氯化钴(II)六水合物15.2mg,酰基转移酶152mg,37℃,pH 7.5,20小时)得到纯N-乙酰基-3-甲氧基-4-甲基-D-苯丙氨酸(2.70g),为粘稠油状物。
[α]D 26.8:-36.16°(C=0.424,MeOH)
IR(净):3350,1740,1725cm-1
NMR(CDCl3,δ):1.99(3H,s),2.17(3H,s),3.00-3.30(2H,m),3.78(3H,s),4.75-4.90(1H,m),6.00-7.10(3H,m),6.36(2H,br s)
MASS(APCI):252(M+H)+
制备17
N-乙酰基-3-甲氧基-4-甲基苯基-D-丙氨酸(2.55g)在6N盐酸(25.5mL)和甲苯(18mL)的混合溶液中搅拌回流4小时,冷至室温后,分离水层,有机层用水(10mL)洗涤2次,水层和洗液合并,减压蒸发,过滤收集得到的结晶,并用冰水洗涤得到3-甲氧基-4-甲基-D-苯丙氨酸盐酸盐(1.35g)为无色结晶。减压蒸发滤液得到粗3-甲氧基-4-甲基-D-苯丙氨酸盐酸盐(0.6g)。
mp:207-211℃
[α]D 27.2:+20.2°(C=0.5,H2O)
IR(KBr):1735,1610,1508cm-1
NMR(D2O,δ):2.18(3H,s),3.17(1H,dd,J=7.6和14.6Hz),3.32(1H,dd,J=6.0和14.6Hz),3.85(3H,s),4.27(1H,dd,J=6.0和7.0Hz),6.85(1H,d,J=7.3Hz),6.91(1H,s),7.2 1(1H,d,J=8.0Hz)
MASS(APCI):210(M+H)+(游离)
制备18
室温下于10分钟内将氯化亚砜(0.7mL)滴加至3-甲氧基-4-甲基-D-苯丙氨酸盐酸盐(1.75g)的甲醇(8mL)的溶液中,反应液在40-50℃搅拌2小时,然后混合物中再加入氯化亚砜(0.7mL),混合物再搅拌1小时,减压蒸发,得到的固体用二异丙醚研磨,过滤收集得到无色结晶的3-甲氧基-4-甲基-D-苯丙氨酸甲酯盐酸盐(1.70g)
mp:196-197℃
[ α]D 30:-4.60°(C=0.5,MeOH)
IR(液体石蜡):3400,1741,1583,1465,1446,1249cm-1
NMR(D2O,δ):2.19(3H,s),3.21(1H,dd,J=7.4和14.5Hz),3.32(1H,dd,J=6.0和14.5Hz),3.85(6H,s),4.43(1H,dd,J=6.0和7.4Hz),6.82(1H,dd,J=1.4和7.6Hz),6.87(1H,d,J=1.4Hz),7.22(1H,d,J=7.6Hz)
MASS(APCI):22 4(M+H)+(游离),207,164
制备19
小部分分次将以冰冷却的碳酸钾(1.70g)加至3-甲氧基-4-甲基-D-苯丙氨酸甲酯盐酸盐(1.60g)的二氯甲烷(7mL)和水(9mL)的混合溶液中,在5℃以下于15分钟内将氯乙酰氯(0.66mL)加至混合物中,然后混合物再搅拌30分钟。分离有机相,用食盐水洗涤,硫酸镁干燥,减压蒸发得到油状的(2R)-2-〔N-(氯乙酰基)-氨基〕-3-(3-甲氧基-4-甲基苯基)丙酸甲酯。
IR(净):3305,1737,1643,1583cm-1
制备20
20℃下将苄胺(1.65g)和碳酸钾(1.28g)依次加至(2R)-2-〔N-(氯乙酰基)-氨基〕-3-(3-甲氧基-4-甲基苯基)丙酸甲酯(1.85g)的N,N-二甲基甲酰胺(15mL)溶液中,35℃下搅拌1.5小时,混合物倾至冰水(20mL)和二氯甲烷(20mL)的混合溶液中,搅拌下混合物用稀盐酸水溶液调pH至9以后。分离有机相,用食盐水(20mL)洗涤,硫酸镁干燥,减压蒸发得到(2R)-2-〔N-(苄基氨基乙酰基)-氨基〕-3-(3-甲氧基-4-甲基苯基)丙酸甲酯。用上述方法得到的(2R)-2-〔N-(苄基氨基乙酰基)-氨基〕-3-(3-甲氧基-4-甲基苯基)丙酸甲酯和乙酸(0.18mL)的异丙醇(10mL)溶液回流搅拌12小时。
混合物冷至室温后,将异丙醚加至混合物中,过滤收集得到的沉淀,用异丙醚洗涤得到(3R)-1-苄基-3-(3-甲氧基-4-甲基苄基)哌嗪-2,5-二酮(1.45g)无色结晶
mp:205-209℃
[α]D 30:+11.12°(C=0.4,DMF)
IR(KBr):3237,1677,1656,1465,1446,1442cm-1NMR(DMSO-d6,δ):2.08(3H,s),2.76(1H,d,J=17.2Hz),2.87(1H,dd,J=4.8和13.4Hz),3.11(1H,dd,J=4.8和13.4Hz),3.46(1H,d,J=17.2Hz),3.69(3H,s),4.25(1H,d,J=14.6Hz),420-4.30(1H,m),4.52(1H,d,J=14.6Hz),6.54(1H,dd,J=1.4和7.4Hz),6.69(1H,d,J=1.4Hz),6.87(1H,d,J=7.4Hz),7.04-7.11(2H,m),7.24-7.30(3H,m),8.33(1H,d,J=2.2Hz)
MASS(APCI):339(M+H)+
制备21
5℃以下和氮气氛中,氢化铝锂(0.378g)加至(3R)-1-苄基-3-(3-甲氧基-4-甲基苯基)-2,5-哌嗪二酮(1.35g)的四氢呋喃(22mL)冰冷悬浮溶液中,混合物回流搅拌3小时,混合物冷至5℃以下后,2N氢氧化钠加至混合物中,混合物搅拌30分钟后,过滤除去不溶物,用四氢呋喃洗涤,合并滤液和洗液,减压蒸发得到(3R)-1-苄基-3-(3-甲氧基-4-甲基苯基)哌嗪为油状物。在5℃以下3,5-双(三氟甲基)苯甲酰氯(0.8mL)的二氯甲烷(1mL)溶液于5分钟内滴加至用上述方法得到的(3R)-1-苄基-3-(3-甲氧基-4-甲基苯基)哌嗪和三乙胺(0.84mL)的二氯甲烷(10mL)冰冷溶液中,在相同温度下搅拌30分钟后,反应混合物用食盐水洗涤,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(4∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-甲基苄基)哌嗪(1.92g)为油状物。
IR(净):2950,2850,1640,1590,1515cm-1
NMR(CDCl3,δ):2.16(3H,s),2.00-5.20(14H,m),6.25-6.32(1H,m),6.70-6.90(2H,m),7.20-7.44(7H,m),7.80(1H,br s)
MASS(APCI):551(M+H)+,573(M+Na)+
制备22
20分钟内将三溴化硼的二氯甲烷(1M溶液,3.7mL)溶液滴加至(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-甲基苄基)哌嗪(0.68g)的二氯甲烷(5mL)冰冷溶液中,相同温度下搅拌2小时后,随后在室温下再搅拌12小时,混合物倾至饱和的碳酸氢钠水溶液中,分离有机相,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(4∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)哌嗪(0.56 g)为红色泡沫状物。
IR(净):1630,1430cm-1
NMR(CDCl3,δ):2.00-5.20(14H,m),5.61(1H,br s),6.20-6.25(1H,m),6.60-7.70(2H,m),7.20-7.60(7H,m),7.80-7.85(1H,m)
MASS(API-ES):519(M-H2O+H)+,537(M+H)+,559(M+Na)+
制备23
5℃以下和氮气氛中,氢化钠(在矿物油中60%,18mg)分小部分加至(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)哌嗪(0.20g)的N,N-二甲基甲酰胺(2mL)的冰冷溶液中,混合物搅拌5分钟,(2-甲氧基乙氧基)甲基氯化物(0.064mL)加至混合物中,反应液室温搅拌2.5小时,再加入水。反应液用乙酸乙酯萃取,萃取液用硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(7∶3)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)哌嗪(0.21g)为油状物。
IR(净):2950,1645,1435cm-1
NMR(CDCl3,δ):2.19(3H,s),3.34(3H,s),2.00-5.20(17H,m),6.60-7.40(10H,m),7.70-7.80(1H,m)
MASS(API-ES):625(M+H)+,647(M+Na)+
制备24
(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)哌嗪(0.38g)的甲醇混合物在室温和大气压下用20%氢氧化钯-碳(0.06g)氢化8小时,通过Celite过滤除去催化剂,滤液减压浓缩。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇(30∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)哌嗪(0.32g)为油状物。
IR(KBr):3000-2700,1629,1513,1444cm-1
NMR(CDCl3,δ):2.20(3H,s),2.50-5.30(16H,m),3.36(3H,s),6.40-7.50(5H,m),7.80(1H,s)
MASS(API-ES):535(M+H)+,557(M+Na)+
实施例1
室温下1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}哌嗪(440mg)的N,N-二甲基甲酰胺(2.2ml)溶液中加入(3R)-4-(2-氯乙基)-3-(甲氧基甲基)吗啉盐酸盐(289mg),碳酸钾(434mg)和碘化钾(149mg)。混合物在73℃下搅拌2小时,冷至室温后,混合物倾至冰水中,混合物的水溶液用饱和的碳酸氢钠水溶液碱化,得到的混合物用乙酸乙酯萃取,萃取液用食盐水洗涤,硫酸钠干燥,减压蒸发。得到的残留物用硅胶柱层析纯化,以二氯甲烷和甲醇(40∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}-4-{2-〔(3R)-3-甲氧基甲基吗啉代基〕乙基}哌嗪(450 mg),为浅黄色油状物。
IR(净):2879,1639,1437,1281,1136,1009cm-1
NMR(CDCl3,δ):2.20(3H,s),1.95-5.40(34H,m),6.40-8.10(6H,m)
MASS(APCI):692(M+H)+
实施例2
根据类似于实施例1的方法得到下述化合物。
(1)1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲基吗啉代基)乙基〕-2-{3-〔(2-甲氧基乙氧基)-甲氧基〕-4-甲基苄基}哌嗪。
IR(净):1680,1643,1508,1435cm-1
NMR(CDCl3,δ):1.17(6H,d,J=6.3Hz),1.78(2H,t,J=10.8Hz),2.20(3H,br s),2.20-5.30(23H,m),3.36(3H,s),6.42-8.02(6H,m)
MASS(APCI):676(M+H)+
(2)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}-4-{2-〔(2S,5S)-2-甲氧基甲基-5-甲基吗啉代基〕乙基}哌嗪。
IR(净):2933,2881,1643,1439,1281,1086,1012cm-1
NMR(CDCl3,δ):1.18(3H,d,J=6.2Hz),1.78-1.96(2H,m),2.20(3H,br s),2.20-5.30(25H,m),3.37(3H,s),3.36(3H,s),6.66-7.80(6H,m)
MASS(API-ES):706.3(M+H)+,728.3(M+Na)+
实施例3
室温下将1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}-4-{2-〔(3R)-3-甲氧基甲基吗啉代基〕乙基}哌嗪(430mg)溶解在甲醇(10ml)中,该溶液中加入甲磺酸(0.215ml)。该温度下搅拌18小时后,反应混合物减压浓缩至原体积的1/3,然后倾至冰水中。混合物水溶液用15%氢氧化钠水溶液碱化,得到的混合物用乙酸乙酯萃取,萃取液用食盐水洗涤,硫酸钠干燥,减压蒸发。残留物用硅胶柱层析纯化,以二氯甲烷和甲醇(30∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发,残留物用4N氯化氢的乙酸乙酯溶液处理,得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-{2-〔(3R)-3-(甲氧基甲基)吗啉代基〕乙基}哌嗪二盐酸盐(280mg),为白色粉末。
mp:167-172℃
[α]D 28:-8.50°(C=0.20,MeOH)
IR(KBr):3400,1645,1429,1282,1184,1138cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.60-5.10(25H,m),6.18-7.10(3H,m),7.3 6-8.22(3H,m),9.25(1H,br)
MASS(APCI):604(M+H)+(游离)
实施例4
根据类似于实施例3的方法得到下述化合物。
(1)1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲基吗啉代基)乙基〕-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐。
mp:188-200℃
[α]D 29:+0.70°(C=0.25,MeOH)
IR(KBr):3402,1643,1516,1429cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.0Hz),2.08(3H,brs),2.00-5.10(19H,m),6.19-8.21(6H,m)
MASS(APCI):588(M+H)+(游离)
(2)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-{2-〔(2S,5S)-2-甲氧基甲基-5-甲基吗啉代基〕乙基}哌嗪二盐酸盐。
mp:214-218℃
[α]D 29:+0.80°(C=0.25,MeOH)
IR(KBr):3433,3398,1645,1516,1429,1371,1281,1182,1140cm-1
NMR(DMSO-d6,δ):1.16(3H,d,J=6.0Hz),2.08(3H,brs),2.50-5.10(21H,m),3.27(3H,s),6.20-8.20(6H,m),9.00-9.20(1H,m)
MASS(APCI):618(M+H)+(游离)
(3)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苯甲酰基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪。
NMR(CDCl3,δ):0.60-5.30(14H,m),5.77(1H,br s),6.20-8.90(10H,m)
MASS(APCI):562(M+H)+
实施例5
根据类似于实施例1的方法,然后根据类似于实施例3的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-{2-〔(2S)-2-(甲氧基甲基)吗啉代基〕乙基}-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐。
mp:207-210℃
[α]D 26:-6.40°(C=0.4,MeOH)
IR(KBr):3300,3000,2700,1644,1428cm-1
NMR(DMSO-d6,δ):2.18(3H,s),2.20-5.20(22H,m),6.10-8.20(6H,m),9.00-9.40(1H,br s),11.00-12.00(2H,m)
MASS(APCI):604(M+H)+(游离)
(2)1-〔3,5-双(三氟甲基)苯甲酰基〕-4-{2-〔(2S)-2-(甲氧基甲基)吗啉代基〕乙基}-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐。
IR(KBr):1645,1516,1458,1425,1369cm-1
NMR(DMSO-d6,δ):2.08(3H,br s),3.28(3H,br s),2.40-5.10(22H,m),6.19-8.22(6H,m)
MASS(APCI):604(M+H)+(游离)
实施例6
1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}哌嗪(0.4g),1-氯-3-(3-吡啶基)-2-丙炔盐酸盐(0.17g),碳酸钾(0.52g)和痕量的碘化钾的N,N-二甲基甲酰胺(7ml)的混合溶液于80℃搅拌4小时。冷却后,蒸发除去溶剂,反应混合物中加入乙酸乙酯和碳酸氢钠水溶液。分离有机相,用硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,以乙酸乙酯洗脱,收集含目的化合物的组分,减压蒸发得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-{3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基}-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪(0.44g),为油状物。
NMR(CDCl3,δ):0.60-5.60(23H,m),6.30-8.90(10H,m)MASS(APCI):650(M+H)+
实施例7
1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪(0.11g)的甲醇(10ml)溶液与4N氯化氢的乙酸乙酯(1ml)溶液反应,然后混合物减压蒸发。残留物用二氯甲烷和乙酸乙酯的混合溶液研磨,过滤收集得到的粉末得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪二盐酸盐(0.07g)。
mp:180-190℃
IR(KBr):1693,1676,1645,1549,1531,1516,1460,1456,1427,1392,1367,1317,1281,1217,1188,1066cm-1
NMR(DMSO-d6,δ):1.60-5.20(14H,m),6.10-9.00(10H,m)
MASS(APCI):562(M+H)+(游离)
实施例8
1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪(0.16g)溶解在甲醇(10ml)和四氢呋喃(10ml)的混合溶剂中的溶液在室温下用10%钯-活性碳(20mg)氢化1.5小时,过滤除去催化剂,滤液减压浓缩。残留物用硅胶柱层析纯化,以乙酸乙酯为洗脱液,收集含目的化合物的组分,减压蒸发,得到的残留物用4N氯化氢的乙酸乙酯溶液处理,得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-(3-吡啶基)-丙基〕哌嗪二盐酸盐(0.17g),为白色固体。
mp:60-70℃
IR(KBr):1707,1693,1676,1645,1628,1558,1550,1541,1516,1466,1456,1427,1387,1365,1329,1319,1281,1182,1136,1039cm-1
NMR(DMSO-d6,δ):1.80-5.20(18H,m),6.00-9.00(10H,m)
MASS(APCI):566(M+H)+(游离)
制备25
冰浴冷却和氮气氛中,3-甲氧基-对甲苯甲酸(45.32g)的四氢呋喃(280ml)溶液加到硼氢化钠(9.29g)的四氢呋喃(45ml)悬浮溶液中,搅拌10分钟后,在3-15℃下往混合物中加入三氟化硼的二乙醚化物(41.5ml),混合物室温搅拌过夜。混合物中加入水(210ml)和二异丙醚(60ml)。分离有机层,水层用二异丙醚(100ml)萃取,合并的有机相依次用1N氢氧化钠溶液和食盐水洗涤,用硫酸钠干燥,真空蒸发得到3-甲氧基-4-甲基苄醇(41.63g),为油状物。
IR(净):3330,1615,1590,1510,1465,1418,1255cm-1
NMR(CDCl3,δ):1.70(1H,br s),2.21(3H,s),3.84(3H,s),4.65(2H,s),6.80-7.16(3H,m)
制备26
3-甲氧基-4-甲基苄醇(41.61g),浓盐酸(125ml)和甲苯(83ml)的混合物在90℃下搅拌1小时,冷却后,混合物中加入冰水(125ml)和二异丙醚(80ml),分离有机相,水层用二异丙醚(160ml)萃取,合并的有机相用饱和的碳酸氢钠溶液和食盐水洗涤,用硫酸钠干燥,真空蒸发得到3-甲氧基-4-甲基苄基氯化物(46.35g),为油状物。
IR(净):1615,1590 ,1510,1470,1415,1255cm-1
NMR(CDCl3,δ):2.21(3H,s),3.85(3H,s),4.57(2H,s),6.82-7.15(3H,m)
制备27
3-甲氧基-4-甲基苄基氯化物(46.35g)和乙酰氨基丙二酸乙酯(71.16g)依次加到乙醇钠(24.34g)的乙醇(230ml)溶液中,混合物回流搅拌2小时,倾至冰水(690ml)中,用6N盐酸调混合物的pH值至7,过滤收集得到的沉淀,用乙醇水溶液(3∶1,100ml)洗涤,干燥得到粗品2-乙酰氨基-2-(3-甲氧基-4-甲基苄基)丙二酸二乙酯(85.03g)。粗品(80.66g)的庚烷(400ml)悬浮液在50℃下搅拌1小时,并冷至室温。过滤收集得到的沉淀,用庚烷洗涤,干燥得到纯品(74.57g)为无色结晶。
mp:123-125℃
IR(KBr):3251,1747,1 643,1518,1267,1213,1190,1051cm-1
NMR(CDCl3,δ):1.30(6H,t,J=7.1Hz),2.03(3H,s),2.16(3H,s),3.61(2H,s),3.76(3H,s),4.28(4H,q,J=7.1Hz),6.44-7.06(4H,m)
制备28
2-乙酰氨基-2-(3-甲氧基-4-甲基苄基)丙二酸二乙酯(10.0g),氢氧化钾(1.88g)的水(25ml)和乙醇(25ml)的混合溶液回流搅拌1小时,混合物中再加入氢氧化钾(1.88g)的水(10ml)溶液,回流搅拌2小时。冷至室温后,反应混合物减压浓缩,得到的水溶液中加入水(50ml)和乙酸乙酯(50ml),分离水层,用6N盐酸调pH至1.5,该溶液用乙酸乙酯萃取,用食盐水洗涤,硫酸钠干燥,减压蒸发得到N-乙酰基-3-甲氧基-4-甲基-DL-苯丙氨酸(7.58g),为粘稠的油状物。
IR(净):3350,1740,1725cm-1
NMR(CDCl3,δ):1.99(3H,s),2.17(3H,s),3.00-3.30(2H,m),3.78(3H,s),4.75-4.90(1H,m),6.00-7.10(3H,m),6.37(2H,br s)
制备29
根据类似制备27的方法得到下述化合物。
(1)2-乙酰氨基-2-(4-氯-3-甲氧基苄基)丙二酸二乙酯
mp:122-123℃
IR(KBr):3247,2977,1749, 1643,1523,1309,1205cm-1
NMR(CDCl3,δ):1.30(6H,t,J=7.1Hz),2.03(3H,s),3.64(2H,s),3.83(3H,s),4.16-4.35(4H,m),6.53(1H,dd,J=2.0和8.0Hz),6.56(1H,d,J=2.0Hz),6.56(1H,s),7.23(1H,d,J=8.0Hz)
MASS(APCI):372(M+H)+,330,282
(2)2-乙酰氨基-2-(4-氟-3-甲氧基苄基)丙二酸二乙酯
mp:128-131℃
IR(KBr):2981,1747,1641,1520,1269,1211cm-1
NMR(CDCl3,δ):1.30(6H,t,J=7.1Hz),2.04(3H,s),3.62(2H,s),3.82(3H,s),4.27(4H,q,J=7.1Hz),6.4 8-7.09(4H,m)
MASS(APCI):356(M+H)+
(3)2-乙酰氨基-2-(3,4-二氟苄基)丙二酸二乙酯
IR(液体石蜡):3259,1749,1645,1518,1317,1277,1205,1051,1016cm-1
NMR(DMSO-d6,δ):1.16(6H,t,J=7.1Hz),1.91(3H,s),3.42(2H,s),4.15(4H,q,J=7.1Hz),6.76-7.45(3H,m),8.19(1H,s)
MASS(APCI):344(M+H)+,302
(4)2-乙酰氨基-2-〔3-甲氧基-4-(三氟甲基)苄基〕丙二酸二乙酯
mp:119-120℃
IR(KBr):3500-3150,2700-2300,1637,1631,1461,1348,1238,1172cm-1
NMR(CDCl3,δ):1.31(6H,t,J=7.2Hz),2.04(3H,s),3.70(2H,s),3.84(3H,s),4.21-4.36(4H,m),6.57-6.64(2H,m),7.44(1H,d,J=8.2Hz)
MASS(APCI):406(M+H)+,316
(5)2-乙酰氨基-2-(4-氟-3-甲基苄基)丙二酸二乙酯
IR(净):3250,1740,1640,1510,1460,1370,1270,1210,1185cm-1
NMR(CDCl3,δ):1.30(6H,t,J=7.1Hz),2.03(3H,s),2.22(3H,s),3.58(2H,s),4.27(4H,q,J=7.1Hz),6.53(1H,s),6.70-6.95(3H,m)
MASS(APCI):340 (M+H)+
制备30
根据类似制备28的方法得到下述化合物。
(1)N-乙酰基-4-氯-3-甲氧基-DL-苯丙氨酸
mp:177-179℃
IR(KBr):3351,3200-2500,1735,1629,1548cm-1
MASS(APCI):272(M+H)+,230
(2) N-乙酰基-4-氟-3-甲氧基-DL-苯丙氨酸
mp:150-152℃
IR(KBr):3340,2947,1718,1603,1514,1259,1215cm-1
NMR(DMSO-d6,δ):1.79(3H,s),2.74-3.07(2H,m),3.81(3H,s),4.41(1H,m),6.77(1H,m),7.01-7.14(2H,m),8.17(1H,d,J=8.1Hz),12.68(1H,br)
MASS(APCI):256(M+H)+
(3)N-乙酰基-3,4-二氟苯基-DL-丙氨酸
IR(KBr):3360,1710,1615,1550,1530cm-1
NMR(DMSO6,δ):1.78(3H,s),2.50-2.88(2H,m),4.35-4.47(1H,m),7.07-7.41(3H,m),8.19(1H,d,J=8.2Hz)
MASS(APCI):244(M+H)+,202
(4)N-乙酰基-3-甲氧基-4-三氟甲基-DL-苯丙氨酸
mp:156-160℃
IR(KBr):3326,3200-2300,1716,1621,1552,1459cm-1
NMR(DMSO-d6,δ):1.80(3H,s),2.8 5-3.50(2H,m),3.87(3H,s),4.23-4.54(1H,m),6.94(1H,d,J=8.0Hz),7.13(1H,s),7.52(1H,d,J=8.0Hz),8.23(1H,d,J=8.1Hz),12.82(1H,br s)
MASS(APCI):306(M+H)+(游离)
(5)N-乙酰基-4-氟-3-甲基-DL-苯丙氨酸
IR(净):3350,1720,1600,1540,1500,1345cm-1
NMR(DMSO-d6,δ):1.78(3H,s),2.20(3H,s),2.71-3.03(2H,m),4.31-4.42(1H,m),6.97-8.19(3H,m),
12.68 (1H,br s)
MASS(APCI):240(M+H)+
(6)N-乙酰基-3-氟-4-甲基-DL-苯丙氨酸
IR(净):3300,1740,1720,1600,1540cm-1
制备31
根据类似制备16的方法得到下述化合物。
(1)N-乙酰基-4-氯-3-甲氧基-D-苯丙氨酸
mp:116-117℃
[α]D 27:-36.6°(C=0.37,MeOH)
IR(KBr):3500-3150,2700-2300,1733,1623cm-1MASS(APCI):272(M+H)+,230
(2)N-乙酰基-4-氟-3-甲氧基-D-苯丙氨酸
IR(净):3330,2940,1728,1618,1518,1275,1223cm-1
NMR(DMSO-d6,δ):1.79(3H,s),2.70-3.10(2H,m),3.81(3H,s),4.40(1H,m),6.78(1H,m),7.01-7.14(2H,m),8.18(1H,d,J=8.1Hz),12.63(1H,br)
MASS(APCI):256(M+H)+
(3)N-乙酰基-3,4-二氟-D-苯丙氨酸
IR(KBr):3395,1720,1615,1545,1515cm-1
(4)N-乙酰基-3-甲氧基-4-三氟甲基-D-苯丙氨酸
mp:156-160℃
IR(KBr):3326,3200-2300,1716,1621,1552,1459cm-1
NMR(DMSO-d6,δ):1.80(3H,s),2.85-3.50(2H,m),3.87(3H,s),4.23-4.54(1H,m),6.94(1H,d,J=8.0Hz),7.13(1H,s),7.52(1H,d,J=8.0Hz),8.23(1H,d,J=8.1Hz),12.82(1H,br s)
MASS(APCI):306(M+H)+(游离)
(5) N-乙酰基-4-氟-3-甲基-D-苯丙氨酸
[α]D 28:-34.60°(C=0.5,MeOH)
IR(液体石蜡):3400,1715,1605,1530,1500,1450,1240,1200,1120cm-1
NMR(DMSO-d6,δ):1.78(3H,s),2.20(3H,s),2.71-3.03(2H,m),4.31-4.42(1H,m),6.97-8.19(3H,m),12.68(1H,br s)
MASS(APCI):240(M+H)+
(6)N-乙酰基-3-氟-4-甲基-D-苯丙氨酸
[α]D 29:-46.10°(C=0.5,MeOH)
IR(液体石蜡):3300,1705,1600,1560cm-1
制备32
根据类似制备17的方法得到下述化合物。
(1)4-氯-3-甲氧基-D-苯丙氨酸盐酸盐
mp:218-222℃
[α]D 27:+3.17°(C=0.52,MeOH)
IR(KBr):3500-3150,2700-2300,1739, 1589,1488cm-1
NMR(D2O,δ):3.19(1H,dd,J=7.5 and 14.5Hz),3.33(1H,dd,J=5.7和14.5Hz),3.91(3H,s),4.28(1H,dd,J=5.7和7.5Hz),6.89(1H,dd,J=1.8和8.1Hz),7.03(1H,d,J=1.8Hz),7.42(1H,d,J=8.1Hz)
MASS(APCI):230(M+H)+
(2)4-氟-3-甲氧基-D-苯丙氨酸盐酸盐
mp:210-220℃(分解)
IR(KBr):1738,1606,1520,1487,1462,1417,1274,1223,1209,1157,1128cm-1
NMR(DMSO-d6,δ):3.13(2H,m),3.83(3H,s),4.00-4.40(1H,m),6.70-6.90(1H,m),7.00-7.30(2H,m)
MASS(APCI):214(M+H)+(游离)
(3)3-甲氧基-4-三氟甲基-D-苯丙氨酸盐酸盐
mp:156-160℃
IR(KBr):3326,3200-2300,1716,1621,1552,1459cm-1
NMR(D2O,δ):3.19(1H,dd,J=7.5和14.4Hz),3.33(1H,dd,J=5.7和14.4Hz),3.86(3H,s),4.20-4.26(1H,m),6.97(1H,d,J=8.0Hz),7.07(1H,s),7.58(1H,d,J=8.0Hz)
MASS(APCI):264(M+H)+(游离)
(4)4-氟-3-甲基-D-苯丙氨酸盐酸盐
IR(液体石蜡):1735,1485,1460,1375,1210cm-1MASS(APCI):198(M+H)+(游离)
(5)3-氟-4-甲基-D-苯丙氨酸盐酸盐
IR(液体石蜡):1730,1480,1555,1250,1220,1200cm-1
制备33
根据类似制备18的方法得到下述化合物。
(1)4-氯-3-甲氧基-D-苯丙氨酸甲酯盐酸盐
mp:165-168℃
IR(KBr):3200-2500,1745,1583,1494cm-1
NMR(D2O,δ):3.22(1H,dd,J=7.5和14.5Hz),3.35(1H,dd,J=6.8和14.5Hz),3.85(3H,s),3.92(3H,s),4.44(1H,dd,J=6.8和7.5Hz),6.89(1H,dd,J=1.9和8.1Hz),7.02(1H,d,J=1.9Hz),7.44(1H,d,J=8.1Hz)
MASS(APCI):244(M+H)+
(2)4-氟-3-甲氧基-D-苯丙氨酸甲酯盐酸盐
mp:172-173℃
IR(KBr):1745,1610,1581,1518,1452,1398,1294,1273,1242,1215,1163,1120,1061,1028cm-1
NMR(DMSO-d6,δ):3.13(2H,d,J=6.3Hz),3.71(3H,s),3.83(3H,s),4.31(1H,t,J=6.3Hz),6.70-6.90(1H,m),7.00-7.30(2H,m)
MASS(APCI):228(M+H)+(游离)
(3)3-甲氧基-4-三氟甲基-D-苯丙氨酸甲酯盐酸盐
mp:158-165℃
IR(KBr):3326,3200-2300,1739,1617,1504,1328cm-1
NMR(D2O,δ):3.29(1H,dd,J=7.5和14.4Hz),3.42(1H,dd,J=5.7和14.4Hz),3.85(3H,s),3.90(3H,s),4.46-4.55(1H,m),7.00(1H,d,J=8.0Hz),7.12(1H,s),7.65(1H,d,J=8.0Hz)
MASS(APCI):277(M+H)+(游离)
(4)4-氟-3-甲基-D-苯丙氨酸甲酯盐酸盐
IR(液体石蜡):3200,1740,1490,1450,1240cm-1
NMR(DMSO-d6,δ):2.22(3H,s),3.00-3.17(2H,m),3.68(3H,s),4.21-4.28(1H,m),7.07-7.18(3H,m),8.67(3H,s)
MASS(APCI):212(M+H)+(游离)
(5)3-氟-4-甲基-D-苯丙氨酸甲酯盐酸盐
IR(液体石蜡):1740,1580,1510,1450cm-1
NMR(DMSO-d6,δ):2.21(3H,s),3.13(2H,d,J=6.0Hz),3.69(3H,s),4.2 9(1H,t,J=6.0Hz),6.95-7.28(3H,m),8.70(3H,s)
MASS(APCI):212(M+H)+(游离)
(6)4-氟-D-苯丙氨酸甲酯盐酸盐
mp:197.3-197.8℃
IR(KBr):2989,2956,2910,1745,1741,1504,1490,1450,1240,825cm-1
NMR(DMSO-d6,δ):3.10(1H,dd,J=7.0和14.0Hz),3.18(1H,dd,J=6.4和14.0Hz),3.67(3H,s),4.26(1H,dd,J=6.4和7.0Hz),7.11-7.33(4H,m),8.67(3H,br s)
MASS:198(M+H)+(游离)
(7)4-氯-D-苯丙氨酸甲酯盐酸盐
mp:210-211℃
IR(KBr):1743,1707,1693,1645,1547,1541,1514,1495,1454,1240,1186,1147,1126,1099,1061,1024cm-1
NMR(DMSO-d6,δ):3.00-3.30(2H,m),3.68(3H,s),4.28(1H,t,J=6.5Hz),7.28(2H,d,J=8.4Hz),7.40(2H,d,J=8.4Hz)
MASS(APCI):214(M+H)+(游离)
(8)4-三氟甲基-D-苯丙氨酸甲酯盐酸盐
mp:198-199℃
IR(KBr):3199,2864,1741cm-1
NMR(DMSO-d6,δ):3.10-3.30(2H,m),3.69(3H,s),4.35(1H,t,J=6.4Hz),7.51(2H,d,J=8.1Hz),7.71(2H,d,J=8.1Hz)
MASS(APCI):248(M+H)+(游离)
制备34
根据类似制备19的方法得到下述化合物。
(1)(2R)-2-(2-氯乙酰氨基)-3-(4-氯-3-甲氧基苯基)丙酸甲酯
mp:68-69℃
IR(KBr):3303,2954,1739,1654,1538cm-1
NMR(CDCl3,δ):3.13(2H,d,J=6.0Hz),3.75(3H,s),3.88(3H,s),4.05(2H,s),4.84-4.93(1H,m),6.65(1H,dd,J=1.8和8.1Hz),6.67(1H,d,J=1.8Hz),7.28(1H,d,J=8.1Hz)
MASS(APCI):320(M+H)+,288,260
(2)(2R)-2-(2-氯乙酰氨基)-3-(4-氟-3-甲氧基苯基)丙酸甲酯
mp:86-87℃
IR(KBr):1726,1687,1 649,1614,1550,1518,1454,1423,1419,1362,331,1273,1227,1213,1186cm-1
NMR(CDCl3,δ):3.12(2H,d,J=5.8Hz),3.75(3H,s),3.87(3H,s),4.05(2H,s),4.87(1H,dt,J=8.0和5.8Hz),6.4 0-7.20(3H,m)
MASS(APCI):304(M+H)+
(3)(2R)-2-(2-氯乙酰氨基)-3-(3,4-二氟苯基)丙酸甲酯
IR(净):3305,1470,1675,1660,1515cm-1
NMR(DMSO-d6,δ):2.87-3.11(2H,m),3.63(2H,s),4.03(3H,s),4.48-4.57(1H,m),7.03-7.41(3H,m),8.68(1H,d,J=7.8Hz)
MASS(APCI):292(M+H)+
(4)(2R)-2-(2-氯乙酰氨基)-3-(3-甲氧基-4-(三氟甲基)苯基)丙酸甲酯
mp:108-109℃
IR(KBr):3315,2965,1751,1648,1536,1459,1421cm-1
NMR(CDCl3,δ):3.10-3.29(2H,m),3.76(3H,s),3.89(3H,s),4.05(2H,s),4.87-4.97(1H,m),6.73-6.77(2H,m),7.00-7.05(1H,m),7.75(1H,d,J=8.3Hz)
MASS(APCI):354(M+H)+312
(5)(2R)-2-(2-氯乙酰氨基)-3-(4-氟-3-甲基苯基)丙酸甲酯
IR(液体石蜡):3300,1730,1540,1500,1450cm-1
NMR(DMSO-d6,δ):2.19(3H,s),2.82-3.06(2H,m),3.62(3H,s),4.06(2H,s),4.32-4.53(1H,m),6.97-7.13(3H,m),8.66(1H,d,J=7.8Hz)
MASS(APCI):288(M+H)+
(6)(2R)-2-(2-氯乙酰氨基)-3-(3-氟-4-甲基苯基)丙酸甲酯
IR(液体石蜡):3300,1740,1660,1540,1450,1360cm-1
NMR(DMSO-d6,δ):2.19(3H,s),2.8 5-3.10(2H,m),3.63(3H,s),4.06(2H,s),4.45-4.56(1H,m),6.92-7.22(3H,m),8.68(1H,d,J=7.8Hz)
MASS(APCI):288(M+H)+
(7)(2R)-2-(2-氯乙酰氨基)-3-(4-氟苯基)丙酸甲酯
IR(KBr):3330,1735,1646,1538,1509,1448,1367,1226,1151cm-1
NMR(CDCl3,δ):3.09(1H,dd,J=5.8和14.0Hz),3.16(1H,dd,J=5.8和14.0Hz),3.74(3H,s),4.03(2H,s),4.85(1H,ddd,J=5.8,5.8和7.9Hz),6.95-7.12(5H,m)
MASS:274(M+H)+
(8)(2R)-2-(2-氯乙酰氨基)-3-(4-氯苯基)丙酸甲酯
mp:87-88℃
IR(KBr):1738,1662,1537,1495,1491,1446,1408,1363,1265,1209,1119,1090,1036,1016cm-1
NMR(CDCl3,δ):2.90-3.30(3H,m),3.75(3H,s),4.03(2H,s),4.70-5.00(1H,m),7.05(2H,d,J=8.0Hz),7.28(2H,d,J=8.0Hz)
MASS(APCI):290(M+H)+
(9)(2R)-2-(2-氯乙酰氨基)-3-(4-(三氟甲基)苯基)丙酸甲酯
mp:83-84℃
IR(KBr):3294,1741,1655,1547cm-1
NMR(DMSO-d6,δ):3.12-3.32(2H,m),3.7 6(3H,s),4.04(2H,s),4.86-4.96(1H,m),7.25(2H,d,J=8.1Hz),7.57(2H,d,J=8.1Hz)
MASS(APCI):324(M+H)+
制备35
根据类似制备20的方法得到下述化合物。
(1)(3R)-1-苄基-3-(4-氯-3-甲氧基苄基)哌嗪-2,5-二酮
mp:149-150℃
[α]D 27:+6.38°(C=0.47,MeOH)
IR(KBr):3253,1658,1461cm-1
NMR(DMSO-d6,δ):2.94(1H,dd,J=4.7和13.4Hz),2.96(1H,d,J=17.4Hz),3.14(1H,dd,J=4.5和13.4Hz),3.56(1H,d,J=17.4Hz),3.76(3H,s),4.21(1H,d,J=14.6Hz),4.30-4.35(1H,m),4.61(1H,d,J=14.6Hz),6.66(1H,dd,J=1.8和8.0Hz),6.91(1H,d,J=1.8Hz),7.04-7.11(2H,m),7.17(1H,d,J=8.0Hz),7.26-7.33(3H,m),8.38(1H,br s)
MASS(APCI):359(M+H)+
(2)(3R)-1-苄基-3-(4-氟-3-甲氧基苄基)哌嗪-2,5-二酮
mp:177-179℃
IR(KBr):3240,1658,1516,1464cm-1
NMR(CDCl3,δ):3.00-3.30(3H,m),3.61(1H,d,J=17.7Hz),3.84(3H,s),4.20-4.60(3H,m),6.29(1H,br s),6.60-7.50(8H,m)
MASS(APCI):343(M+H)+
(3)(3R)-1-苄基-3-(3,4-二氟苄基)哌嗪-2,5-二酮
IR(KBr):3313,3255,1650,1515,1465,1275cm-1
NMR(DMSO-d6,δ):2.90-4.70(7H,m),6.94-7.32(8H,m),8.35(1H,s)
MASS(APCI):331(M+H)+
(4)(3R)-1-苄基-3-(3-甲氧基-4-(三氟甲基)苄基)哌嗪-2,5-二酮
IR(KBr):3315,1751,1648,1536,1459,1421cm-1
NMR(DMSO-d6,δ):2.89-3.25(2H,m),3.19(1H,d,J=17.5Hz),3.62(1H,d,J=17.5Hz),3.77(3H,s),4.15(1H,d,J=14.5Hz),4.30-4.35(1H,m),4.68(1H,d,J=14.5Hz),6.80(1H,d,J=8.0Hz),7.00-7.41(7H,m),8.41(1H,br s)
MASS(APCI):393(M+H)+,351
(5)(3R)-1-苄基-3-(4-氟-3-甲基苄基)哌嗪-2,5-二酮
[α]D 28:-15.60°(C=0.5, DMF)
IR(液体石蜡):3250,3225,1650,1430,1320,1250cm-1
NMR(DMSO-d6,δ):2.13(3H,s),2.81-4.65(7H,m),6.83-7.34(8H,m),8.33(1H,s)
MASS(APCI):327(M+H)+
(6)(3R)-1-苄基-3-(3-氟-3-甲基苄基)哌嗪-2,5-二酮
[α]D 27:-16.90°(C=0.5,DMF)
IR(液体石蜡):3250,1680,1640,1460,1320cm-1
NMR(DMSO-d6,δ):2.17(3H,s),2.8 4-4.69(7H,m),6.80-7.34(8H,m),8.35(1H,s)
MASS(APCI):327(M+H)+
(7)(2R)-2-〔N-(苄基氨基乙酰基)氨基〕-3-(4-氟苯基)丙酸甲酯
MASS:345(M+H)+
(8)(3R)-1-苄基-3-(4-氟苄基)哌嗪-2,5-二酮
mp:190.1-190.8℃
IR(KBr):1671,1656, 1509,1448,1334,1162cm-1
NMR(CDCl3,δ):3.08(1H,d,J=4.4和14.0Hz),3.19(1H,d,J=5.9和14.0Hz),3.05(1H,d,J=17.7Hz),3.56(1H,d,J=17.7Hz),4.33(1H,m),4.41(1H,d,J=14.3Hz),4.54(1H,d,J=1 4.3Hz),6.38-7.35(10H,m)
MASS:313(M+H)+
(9)(3R)-1-苄基-3-(4-氯苄基)哌嗪-2,5-二酮
mp:181-182℃
IR(KBr):167 8,1649,1564,1550,1516,1489,1462,1433,1408,1325,1273,1178,1112,1090,1063cm-1
NMR(CDCl3,δ):2.80-3.30(3H,m),3.57(1H,d,J=17.6Hz),4.20-4.40(2H,m)),4.60(1H,d,J=14.3Hz),6.80-7.50(9H,m)
MASS(APCI):329(M+H)+
(10)(3R)-1-苄基-3-(4-(三氟甲基)苄基)哌嗪-2,5-二酮
mp:180-181℃
IR(KBr):3257,1678,1651cm-1
NMR(DMSO-d6,δ):2.86(1H,d,J=17.3Hz),3.00(1H,dd,J=4.8和13.5Hz),3.25(1H,d,J=4.5和13.5Hz),3.59(1H,d,J=17.3Hz),4.08(1H,d,J=14.3Hz),4.30-4.40(1H,m),4.73(1H,d,J=14.3Hz),7.05-7.32(7H,m),7.47(2H,d,J=8.2Hz)
MASS(APCI):363(M+H)+
制备36
根据类似制备21的方法得到下述化合物。
(1)(2R)-4-苄基-1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯-3-甲氧基苄基)哌嗪
IR(净):1643,1517cm-1
NMR(CDCl3,δ):2.00-5.20(14H,m),6.20-8.00(11H,m)
MASS(APCI):571(M+H)+
(2)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-2-(3,4-二氟苄基)-4-苄基哌嗪
IR(净):1645,1515,1435,1280,1180,1140cm-1
NMR(DMSO-d6,δ):2.06-4.82(11H,m),6.61-8.19(11H,m)
MASS(APCI):543(M+H)+
制备37
(2R)-4-苄基-1-〔3,5-(双三氟甲基)-苯甲酰基〕-2-(4-氯-3-甲氧基苄基)哌嗪(2.23 g)和1-氯乙基氯甲酸酯(0.61ml)的1,2-二氯乙烷(10ml)溶液回流搅拌15小时,冷却后,反应混合物减压浓缩,得到的糖浆溶解在甲醇(10ml)中,溶液回流搅拌2小时。冷却后,反应混合物减压浓缩,过滤收集得到的粉末,得到黄色粉末(2R)-1-〔3,5-(双三氟甲基)-苯甲酰基〕-2-(4-氯-3-甲氧基苄基)哌嗪盐酸盐(2.00g)。
mp:70-71℃
MASS(APCI):481(M+H)+
制备38
三溴化硼的二氯甲烷溶液(1M溶液,6.0ml)在20分钟内滴加到(2R)-1-〔3,5-双(三氟甲基)-苯甲酰基〕-2-(4-氯-3-甲氧基苄基)哌嗪盐酸盐(0.98g)的二氯甲烷(5ml)冰冷溶液中,在该温度下搅拌2小时,再于室温下搅拌2小时,再加三溴化硼的二氯甲烷(1M溶液,4.0ml)溶液,室温下再搅拌4小时,得到的混合物倾入饱和的碳酸氢钠水溶液中,混合物搅拌1小时。分离有机相,硫酸镁干燥,减压蒸发,残留物用硅胶柱层析纯化,以二氯甲烷和甲醇(20∶1)的混合溶液洗脱,收集含目的化合物的组分,减压蒸发得到(2R)-1-〔3,5-双(三氟甲基)-苯甲酰基〕-2-(4-氯-3-羟基苄基)哌嗪(0.67g)为泡状物。
IR(净):3400-3000,1635cm-1
NMR(DMSO-d6,δ):2.60-4.80(10H,m),6.28-7.20(3H,m),7.41(1H,s),7.75(1H,s),8.14(1H,d,J=8.2Hz),10.00(1H,br s)
MASS(APCI):467(M+H)+
制备39
根据类似制备38的方法得到下述化合物。
(1)(2R)-4-苄基-2-(4-氯-3-羟基苄基)哌嗪
mp:65-68℃
IR(KBr):2939,2813,1444,1429,1294,1236,1136,1047cm-1
NMR(DMSO-d6,δ):1.60-4.00(11H,m),6.60(1H,dd,J=1.6和8.0Hz),6.78(1H,d,J=1.6Hz),7.16-7.40(6H,m)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)哌嗪
mp:82-86℃
IR(KBr):3282,1637,1282,1182, 1136cm-1
NMR(CDCl3,δ):2.20-5.20(10H,m),6.10-8.10(6H,m)MASS(APCI):451(M+H)+
(3)(3R)-1-苄基-3-(3-羟基-4-甲基苄基)哌嗪
IR(KBr):1649,1516cm-1
NMR(CDCl3,δ):1.95-2.20(2H,m),2.20(3H,s),2.57-3.06(7H,m),3.51(1H,d,J=13.1Hz),3.52(1H,d,J=13.1Hz),6.60(1H,d,J=7.4Hz),6.61(1H,s),7.03(1H,d,J=7.4Hz),7.20-7.35(5H,m)
MASS(APCI):297(M+H)+
制备40
氮气氛下用冰浴冷却下于(2R)-2-(4-氯-3-羟基苄基)-4-苄基哌嗪(3.78g)和三乙胺(5.71ml)的二氯甲烷溶液中依次加入4-二甲氨基吡啶(0.29g)和叔丁基二甲基甲硅烷基氯化物(5.30g)。室温搅拌过夜后,混合物中加入水(50ml),分离有机相,用食盐水洗涤,硫酸钠干燥,真空蒸发。残留物用硅胶柱层析纯化,以二氯甲烷和甲醇(10∶1)的混合溶剂为洗脱液,得到(2R)-4-苄基-2-(4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基)哌嗪(4.11g),为油状物。
IR(净):1600,1575,1485,1420,1295,1250,1170,1140cm-1
NMR(CDCl3,δ):0.15(6H,s),0.96(9H,s),1.80(1H,t,J=10.0Hz),1.94-2.98(8H,m),3.40(1H,d,J=13.0Hz),3.48(1H,d,J=13.0Hz),6.60-7.34(8H,m)
MASS(APCI):431(M+H)+,397
制备41
室温下1-〔3-(二甲氨基)丙基〕-3-乙基碳二亚胺盐酸盐(1.93g)加至(2R)-4-苄基-2-(4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基)哌嗪(2.90 g)和3-甲氧基-5-(三氟甲基)苯甲酸(1.48g),1-羟基苯并三唑(1.14g)的二氯甲烷(18ml)混合溶液中。该温度下搅拌6小时后,反应混合物倾至水(25ml)和二氯甲烷(15ml)的混合溶剂中,水层用碳酸氢钠水溶液调pH至9,分离有机相,用食盐水洗涤,硫酸钠干燥,减压浓缩。得到的残留物用硅胶(52g)柱层析纯化,以己烷和乙酸乙酯(2∶1)的混合溶剂洗脱,收集含目的化合物的组分,减压蒸发,得到(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基)-4-苄基哌嗪(3.3g)的糖浆。
IR(净):2937,1639,1603,1421,1250,1173,1132,847cm-1
NMR(CDCl3,δ):0.13(6H,s),1.00(9H,s),1.60-5.10(11H,m),3.81(3H,s),6.30-8.20(11H,m)
MASS(APCI):633(M)+
制备42
根据类似制备37的方法得到下述化合物。
(1)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)哌嗪。
mp:154-157℃
IR(KBr):3265,2956,1624,1427,1173,1128cm-1
NMR(DMSO-d6,δ):2.20-4.90(10H,m),3.82(3H,s),6.20-7.30(6H,m),10.02(1H,br)
MASS(APCI):429(M+H)+
(2)(2R)-1-〔3-三氟甲基-5-(甲硫基)苯甲酰基〕-2-(4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基)哌嗪。
IR(净):1645,1630,1420,1170,1130cm-1
NMR(CDCl3,δ):0.18(6H,s),1.02(9H,s),2.48(3H,s),2.60-5.10(10H,m),6.28-8.26(6H,m)
MASS(APCI):559(M+H)+
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)哌嗪盐酸盐。
mp:127-134℃
IR(KBr):2970,2947,1645,1520,1281,1184,1136cm-1
NMR(DMSO-d6,δ):2.60-5.20(12H,m),6.50-8.30(6H,m),9.60(2H,br)
MASS(APCI):465(M+H)+(游离)
(4)(2R)-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪盐酸盐。
IR(KBr):1643,1606,1518,1464,1423,1377,1350,1321,1242,1215,1173,1126,1053,1038cm-1
NMR(DMSO-d6,δ):2.30-5.30(16H,m),6.30-7.50(6H,m)
MASS(APCI):427(M+H)+(游离)
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)哌嗪盐酸盐。
IR(KBr):3435,2940,2800,1645,1520,1435,1365,1280,1185,1135cm-1
NMR(DMSO-d6,δ):2.50-5.17(9H,m),6.60-8.45(6H,m),9.63(2H,br s)
MASS(APCI):453(M+H)+(游离)
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-(三氟甲基)苄基)哌嗪。
IR(净):2952,1639,1623,1461,1423,1124cm-1
NMR(CDCl3,δ):2.60-5.20(13H,m),6.40-8.00(6H,m)
MASS(APCI):515(M+H)+
(7)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-(三氟甲基)苄基)哌嗪。
IR(净):2950,1637,1461,1423,1317cm-1
NMR(CDCl3,δ):2.60-5.20(15H,m),6.60-7.60(6H,m)
MASS(APCI):477(M+H)+
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲基苄基)哌嗪。
IR(净):3350,1640,1500,1430,1380,1350,1275cm-1
NMR(DMSO-d6,δ):2.00-4.84(12H,m),6.69-8.34(7H,m)
MASS(APCI):449(M+H)+
(9)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基]-2-(3-氟-4-甲基苄基)哌嗪。
IR(净):3300,1625,1425,1275, 1120cm-1
NMR(DMSO-d6,δ):2.18(3H,s),2.40-4.86(9H,m),6.62-8.20(6H,m)
MASS(APCI):449(M+H)+
(10)(2R)-2-(4-氟苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪盐酸盐。
mp:78.8-80.3℃
IR(KBr):1513,1423,1349,1172,1126,1054cm-1
NMR(DMSO-d6,δ):2.50-5.03(9H,m),3.82(3H,s),6.94-7.25(8H,m),9.56(1H,br s)
MASS(APCI):397(M+H)+(游离)
(11)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯苄基)哌嗪盐酸盐。
mp:240-260℃
IR(净):1658,1496,1437,1387,1362,1331,1282,1186,1132,1101,1059,1018cm-1
NMR(CDCl3,δ):2.00-5.30(9H,m),6.70-8.50(7H,m)
MASS(APCI):451(M+H)+(游离)
(12)(2R)-2-(4-氯苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪盐酸盐。
IR(KBr):1643,1605,1489,1464,1423,1377,1350,1319,1271,1242,1175,1128,1097,1053cm-1
NMR(DMSO-d6,δ):2.00-5.40(13H,m),6.20-8.20(7H,m)
MASS(APCI):413(M+H)+(游离)
(13)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪。
NMR(CDCl3,δ):2.30-5.30(9H,m),7.26-7.88(7H,m)
MASS(APCI):485(M+H)+
(14)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪。
IR(净):2951,1632,1608cm-1
NMR(CDCl3,δ):2.70-5.10(9H,m),3.80(3H,s),6.72-7.87(7H,m)
MASS(APCI):447(M+H)+
(15)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔2-萘甲基〕哌嗪。
[α]D 28.8:-46.15°(C=0.26,MeOH)
IR(净):3740,1630cm-1
NMR(CDCl3,δ):2.5-5.4(9H,m),3.55(3H,s),6.51(1H,br s),6.87(1H,br s),7.06(1H,br s),6.8-7.9(7H,m)
MASS(APCI):429(M+H)+
(16)(2R)-2-〔(1H-吲哚-3-基)甲基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪。
IR(净):3280,1620,1459,1427cm-1
NMR(CDCl3,δ):2.60-3.00(10H,m),3.74(3H,s),6.70-7.40(8H,m),8.25-8.52(1H,m)
MASS(APCI):418(M+H)+
(17)(2R)-1-叔丁氧羰基-2-(3-羟基-4-甲基苄基)哌嗪。
IR(KBr):1674cm-1
NMR(CDCl3,δ):1.37(9H,s),2.20(3H,s),2.72-3.15(8H,m),3.90-3.93(1H,m),4.16(1H,br s),6.62(1H,s),6.68(1H,d,J=7.6Hz),7.02(1H,d,J=7.6Hz)
MASS(APCI):207(M+H-Boc)+
(18)(2R)-1-(叔丁氧羰基)-2-(4-氯苄基)哌嗪。
[α]D 27.2:+23.33°(C=0.39,MeOH)
IR(净):3340,2980,2870,2830, 1690,1410,1370cm-1
NMR(CDCl3,δ):1.36(9H,s),2.6-3.2(7H,m),3.90(1H,br),4.18(1H,br s),7.15(2H,d,J=8.4Hz),7.25(2H,d,J=8.4Hz)
MASS(APCI):311(M+H)+
制备43
根据类似制备41的方法得到下述化合物。
(1)(2R)-1-〔3-三氟甲基-5-(甲硫基)苯甲酰基〕-2-〔4-氯-3-(叔丁基二甲基硅烷氧基)苄基〕-4-苄基哌嗪。
IR(净):1645,1490,1420,1300,1170,1130cm-1
NMR(CDCl3,δ):0.15(6H,s),1.00(9H,s),1.95-5.02(11H,m),2.48(3H,s),6.20-8.25(11H,m)
MASS(APCI):649(M+H)+,615
(2)(2R)-4-苄基-2-〔4-氟-3-甲氧基苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪.
IR(净):1738,1643,1628,1616,1604,1516,1464,1454,1417,1371,1342,1273,1099,1055cm-1
NMR(CDCl3,δ):0.60-5.20(17H,m),6.00-7.50(11H,m)
MASS(APCI):517(M+H)+
(3)(2R)-4-苄基-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔3-甲氧基-4-(三氟甲基)苄基〕哌嗪。
IR(净):2811,1643,1280,1180,1137cm-1
NMR(CDCl3,δ):2.20-5.20(17H,m),6.40-7.50(11H,m)
MASS(APCI):567(M+H)+
(4)(2R)-4-苄基-2-(4-氟苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪。
IR(净):1639,1509,1460,1423,1344,1128,1010cm-1
NMR(CDCl3,δ):2.07(1H,br),2.73-4.91(8H,m),6.57-7.53(12H,m)
MASS:487(M+H)+
(5)(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯苄基)哌嗪。
IR(净):1738,1676,1647,1628,1618,1498,1454,1417,1387,1273,1084,1068cm-1
NMR(CDCl3,δ):0.60-5.20(11H,m),6.40-8.70(12H,m)
MASS(APCI):541(M+H)+
(6)(2R)-4-苄基-2-(4-氯苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪。
IR(净):1707,1678,1643,1630,1618,1604,1516,1496,1489,1477,1454,1417,1392,1375,1342,1317cm-1
NMR(CDCl3,δ):0.60-5.20(14H,m),6.40-8.20(12H,m)
MASS(APCI):503(M+H)+
(7)(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-(三氟甲基)苄基)哌嗪。
IR(净):2950,2800,1765,1740,1640cm-1
(DMSO-d6,δ):1.70-4.30(11H,m),7.13(1H,d,J=7.8Hz),7.20-7.70(10H,m),8.13(1H,d,J=7.8Hz)
MASS(APCI):575(M+H)+
(8)(2R)-4-苄基-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-(三氟甲基)苄基)哌嗪。
IR(净):2945,2812,1643cm-1
NMR(CDCl3,δ):2.04-5.10(11H,m),3.81(3H,s),6.73-7.93(12H,m)
MASS(APCI):537(M+H)+
(9)(2R)-4-苄基-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘基甲基)哌嗪。
[α]D 28.8:-18.34°(C=0.35,MeOH)
IR(净):3740,1640cm-1
NMR(CDCl3,δ):1.9-2.4(2H,m),2.6-4.0(11H,m),4.4-5.2(1H,m),6.4-7.9(15H,m)
MASS(APCI):519(M+H)+
(10)(2R)-4-苄基-2-〔(1H-吲哚-3-基)甲基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪。
IR(净):3280,1620,1459cm-1
NMR(CDCl3,δ):2.00-5.20(14H,m),6.60-7.60(13H,m),7.90(1H,br s)
MASS(APCI):508(M+H)+
制备44
水浴中往4-氟-3-甲氧基苯甲醛(5g)的甲醇(25ml)溶液中滴加硼氢化钠(368 mg)的0.1N氢氧化钠水溶液(5ml),混合溶液搅拌1小时。混合物减压蒸发,加入乙酸乙酯和水。分离有机相,水相再用乙酸乙酯萃取。合并的有机相用硫酸镁干燥,真空浓缩得到4-氟-3-甲氧基苄醇(5.22 g)为油状物。
IR(净):1610,1516,1462,1417,1315,1277,1149,1115,1032cm-1
NMR(CDCl3,δ):1.75(1H,br s),3.90(3H,s),4.64(2H,s),6.70-7.20(3H,m)
制备45
根据类似制备26的方法得到下述化合物。
(1)4-氟-3-甲氧基苄基氯化物
IR(净):1608,1516,1462,1417,1325,1284,1271,1219,1155, 1119,1032cm-1
NMR(CDCl3,δ):3.91(3H,s),4.55(2H,s),6.70-7.20(3H,m)
(2)3-甲氧基-4-(三氟甲基)苄基氯化物
IR(净):1606,1459,1272,1174cm-1
NMR(CDCl3,δ):3.91(3H,s),4.73(2H,s),6.95(1H,dd,J=0.6和8.0Hz),7.04(1H,d,J=0.6Hz),7.53(1H,d,J=8.0Hz)
制备46
根据类似制备24的方法得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)哌嗪
IR(净):1641,1633,1626,1514,1475, 1462, 1452,1446,1435,1423,1417,1385,1340,1336,1273,1095,1063,1045cm-1
NMR(CDCl3,δ):0.60-5.40(12H,m),6.20-8.60(6H,m)
MASS(APCI):465(M+H)+
制备47
根据类似制备17的方法,随后再根据类似制备18的方法得到下述化合物。
3,4-二氟苯基-D-丙氨酸甲酯盐酸盐
IR(KBr):3400,1735,1610,1235cm-1
NMR(DMSO-d6,δ):3.16(2H,d,J=6.6Hz),3.70(3H,s),4.33(1H,t,J=6.6Hz),7.05-7.52(3H,m),8.65(3H,s)
MASS(APCI):216(M+H)+(游离)
制备48
28%甲醇钠的甲醇(50ml)溶液加至3-氟-4-(三氟甲基)苯甲酸(20.8g)的二甲基亚砜(200ml)溶液中,混合物在90℃下搅拌3.5小时。室温下冷却,得到的混合物倾至冰水(1.51)中,用稀盐酸酸化。搅拌30分钟后,过滤收集得到的沉淀,空气干燥得到3-甲氧基-4-(三氟甲基)苯甲酸(22.95 g)的白色粉末。
mp:203-204℃
IR(KBr):3500-3150,2700-2300,1637,1606,1459,1272,1174cm-1
NMR(DMSO-d6,δ):3.95(3H,s),7.61-7.77(3H,m),13.45(1H,s)
制备49
氮气氛下氢化铝锂(4.53g)分成,小部分加到3-甲氧基-4-(三氟甲基)苯甲酸(23.3g)的四氢呋喃(400ml)冰冷溶液中,混合物室温搅拌2小时。用冰冷却后,氮气氛下2N氢氧化钠(2ml)溶液加到混合物中,滤掉得到的沉淀,并用四氢呋喃洗涤,合并滤液和洗液,减压蒸发得到粗的油状物。油状物用硅胶柱层析纯化,用二氯甲烷和甲醇(40∶1)的混合物洗脱得到3-甲氧基-4-(三氟甲基)苄醇(20g),为无色油状物。
IR(净):3500-3150,2700-2300,1637,1606,1459,1272,1174cm-1
NMR(CDCl3,δ):2.01(1H,t,J=4.6Hz),3.88(3H,s),4.72(2H,d,J=4.6Hz),6.95(1H,dd,J=0.4和8.0Hz),7.04(1H,d,J=0.4Hz)7.52(1H,d,J=8.0Hz)
制备50
氮气氛下5-溴-2-氟甲苯(6g)的乙醚(10ml)溶液和催化量的碘加到镁(960mg)的乙醚(10ml)悬浮溶液中,混合物回流30分钟。冷却后,原甲酸乙酯(5.4g)的乙醚(20ml)溶液加到混合物中,混合物搅拌过夜。混合物中加入硫酸(10%,20ml),分离有机相,用食盐水洗涤,硫酸钠干燥,蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(10∶1)的混合物洗脱得到4-氟-3-甲基苯甲醛,为油状物。
IR(净):1695,1590,1495,1280,1245,1110cm-1
NMR(CDCl3,δ):2.36(3H,s),7.10-7.8 4(3H,m),9.93(1H,s)
得到的化合物溶解在甲醇和四氢呋喃的混合溶液中,溶液中加入硼氢化钠。搅拌1小时后,除去溶剂,残留物中加入水。混合物用10%硫酸酸化,用乙酸乙酯萃取,用食盐水洗涤,硫酸钠干燥,真空蒸发得到4-氟-3-甲基苄醇(1.33g),为油状物。
IR(净):3300,1500,1250cm-1
NMR(CDCl3,δ):2.28(3H,s),4.62(2H,s),6.93-7.26(3H,m)
制备51
四溴化碳(3.08g)分次加到4-氟-3-甲基苄醇(1.3g)和三苯基膦(2.9g)的二氯甲烷(50ml)溶液中,混合物搅拌1小时,溶液依次用饱和的碳酸氢钠水溶液和食盐水洗涤,硫酸钠干燥,真空蒸发。残留物用己烷研磨,过滤除去得到的沉淀,滤液真空蒸发,残留物用硅胶柱层析纯化,用己烷洗脱得到4-氟-3-甲基溴苄(1.28g),为油状物。
IR(净):1500,1250,1200cm-1
NMR(CDCl3,δ):2.26(3H,s),4.45(2H,s),6.91-7.26(3H,m)
制备52
根据类似制备50的方法得到下述化合物。
3-氟-4-甲基苄醇
IR(净):3350,1580,1510,1420,1250cm-1
制备53
用类似制备51的方法,再用类似制备27的方法得到下述化合物。
2-乙酰氨基-2-(3-氟-4-甲基苄基)丙二酸二乙酯
IR(液体石蜡):3250,1740,1630,1510,1360cm-1
NMR(DMSO-d6,δ):1.20(6H,t,J=7.0Hz),1.94(3H,s),
2.19(3H,s),3.40(2H,s),4.10(4H,q,J=7.0Hz),6.67-7.23(3H,m),8.13(1H,s)
MASS(APCI):340(M+H)+
制备54
根据类似制备21的前半部分的方法得到下述化合物。
(1)(2R)-4-苄基-2-〔4-氯-3-甲氧基苄基〕哌嗪二盐酸盐
mp:225-230℃(分解)
IR(KBr):3398,1460,1419,1246,1030cm-1
NMR(DMSO-d6,δ):2.80-4.60(11H,m),3.87(3H,s),6.86(1H,d,J=8.1Hz),7.10(1H,s),7.30-7.60(6H,m),9.20-10.80(3H,br)
MASS(APCI):331(M+H)+(游离)
(2)(3R)-1-苄基-3-〔4-氟-3-甲氧基苄基〕哌嗪
IR(净):1666,1608,1516,1456,1419,1321,1275,1217,1151,1126,1034cm-1
NMR(CDCl3,δ):0.60-3.20(9H,m),3.58(2H,s),3.86(3H,s),6.50-7.10(3H,m),7.10-7.60(5H,m)
MASS(APCI):315(M+H)+
(3)(2R)-4-苄基-2-〔3-甲氧基-4-(三氟甲基)苯甲酰基〕哌嗪
IR(净):2938,2809,1614,1583,1506,1459,1421cm-1
NMR(CDCl3,δ):1.84-2.16(2H,m),2.50-3.01(7H,m),3.51(2H,s),3.88(3H,s),6.83-6.85(2H,m),7.25-7.33(6H,m),7.47(1H,d,J=8.2Hz)
MASS(APCI):365(M+H)+
(4)(2R)-4-苄基-2-〔4-氟-3-甲基苄基〕哌嗪
IR(净):1500,1450,1320,1245,1205,1120cm-1
NMR(DMSO-d6,δ):1.60-3.52(14H,m),6.95-7.40(8H,m)
MASS(APCI):299(M+H)+
(5)(2R)-4-苄基-2-〔3-氟-4-甲基苄基〕哌嗪
IR(净):1575,1510,1450,1320,1250,1130,1110cm-1
(6)(2R)-4-苄基-2-〔4-氟苄基〕哌嗪
IR(净):2937,2807,1508,1450,1326,1135,827,742cm-1
NMR(CDCl3,δ):1.87(1H,t,J=10.4Hz),2.14(1H,dt,J=3.8和11.0Hz),2.35-2.94(7H,m),3.47(1H,d,J=13.0Hz),3.53(1H,d,J=13.0Hz),6.92-7.32(9H,m)
MASS(APCI):285(M+H)+
(7)(3R)-1-苄基-3-〔4-氯苄基〕哌嗪
IR(净):1670,1491,1450,1406,1360,1329,1136,1093,1036,1022cm-1
NMR(CDCl3,δ):1.70-3.80(11H,m),7.12(2H,d,J=8.4Hz),7.20-7.60(7H,m)
MASS(APCI):301(M+H)+
(8)(3R)-1-苄基-3-〔4-(三氟甲基)苄基〕哌嗪
IR(净):2939,2810,1676,1618cm-1
NMR(CDCl3,δ):1.89(1H,t,J=10.5Hz),2.09(1H,dt,J=3.9和11.0Hz),2.55-3.04(7H,m),3.49(1H,d,J=13.0Hz),3.52(1H,d,J=13.0Hz),7.25-7.32(7H,m),7.55(2H,d,J=8.1Hz)
MASS(APCI):335(M+H)+
(9)(3R)-1-苄基-3-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
mp:212-225℃
IR(KBr):3398,2673,1458,1331cm-1
NMR(DMSO-d6,δ):3.00-4.50(11H,m),7.43-7.76(9H,m)
MASS(APCI):335(M+H)+(游离)
制备55
根据类似制备21的后半部分的方法得到下述化合物。
(1)(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)哌嗪
IR(净):1736,1643,1616,1516,1462,1454,1435,1425,1377,1273,1103,1065,1038cm-1
NMR(CDCl3,δ):0.60-5.20(14H,m),6.20-8.60(11H,m)
MASS(APCI):555(M+H)+
(2)(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-(三氟甲基)苄基)哌嗪
IR(净):1643,1280,1180,1137cm-1
NMR(CDCl3,δ):2.20-5.20(14H,m),6.40-8.00(11H,m)
MASS(APCI):605(M+H)+
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲基苄基)-4-苄基哌嗪
IR(净):1640,1500,1430,1380,1350,1275,1130cm-1
NMR(DMSO-d6,δ):2.00-4.83(14H,m),6.60-8.21(11H,m)
MASS(APCI):539(M+H)+
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-氟-3-甲基苄基)-4-苄基哌嗪
IR(净):1640,1430,1280,1170,1130cm-1
NMR(DMSO-d6,δ):2.00-4.90(11H,m),2.16(3H,s),6.53-8.24(11H,m)
MASS(APCI):539(M+H)+
实施例9
根据类似实施例1的方法,用N,N-二异丙基乙胺代替碳酸钾作为碱,得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐
mp:160-169℃
[α]D 27:+10.0°(C=0.52,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1423,1282cm-1
NMR(DMSO-d6,δ):2.60-5.00(25H,m),6.30-7.25(3H,m),7.43(1H,s),7.79(1H,s),8.17-8.22(1H,m),10.13(1H,br s),11.00-12.00(2H,m)
MASS(APCI):624(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐
mp:180-190℃
[α]D 26.7:+13.90°(C=0.5,MeOH)
IR(KBr):1676,1645,1547,1516,1464,1427,1392,1387,1367,1321,1282,1217,1184,1136,1034cm-1
NMR(DMSO-d6,δ):2.00-5.40(28H,m),6.30-8.30(6H,m)
MASS(APCI):622(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-(三氟甲基)苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐
mp:146-159℃
[α]D 26.8:+10.67°(C=0.239,MeOH)
IR(KBr):3435,2656,2598,2467,1647,1429,1329,1282,1180,1132,1068cm-1
NMR(DMSO-d6,δ):2.66-5.32(27H,m),7.10-8.30(7H,m)
MASS(APCI):642(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪
IR(净):1670,1643,1583,1508,1452,1446,1435,1429,1381,1358,1350,1336,1277cm-1
NMR(CDCl3,δ):0.70-5.50(31H,m),6.20-8.60(9H,m)
MASS(APCI):695(M+H)+
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕哌嗪二盐酸盐
mp:181-186℃
[α]D 27.1:+0.571°(C=0.175,MeOH)
IR(KBr):3431,2586,1647,1431,1281,1180,1134cm-1
NMR(DMSO-d6,δ):1.32(3H,s),1.39(3H,s),2.60-5.20(19H,m),6.31-7.29(3H,m),7.54-8.21(3H,m),10.10(1H,br)
MASS(APCI):632(M)+(游离)
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐
mp:172-175℃
[α]D 28.2:-4.43°(C=0.305,MeOH)
IR(KBr):3431,2999,1647,1429,1281,1182,1140cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.60-5.20(19H,m),6.32-7.28(3H,m),7.42-8.24(3H,m),10.12(1H,br)
MASS(APCI):608(M)+(游离)
(7)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐
mp:166-170℃
[α]D 28.0:-4.25°(C=0.365,MeOH)
IR(KBr):3435,1647,1429,1281,1182,1140cm-1
NMR(DMSO-d6,δ):2.20-5.20(21H,m),6.32-7.24(3H,m),7.42-8.18(3H,m),10.10(1H,br)
MASS(APCI):614(M+H)+(游离)
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
mp:237-243℃(分解)
[α]D 26.1:-19.1°(C=0.285,MeOH)
IR(KB℃):3433,2561,1645,1427,1281,1185,1136cm-1
NMR(DMSO-d6,δ):2.60-6.10(19H,m),6.30-7.20(3H,m),7.40-8.20(3H,m),7.76(1H,dd,J=4.5和8.1Hz),8.14(1H,d,J=8.1Hz),8.71(1H,d,J=4.5Hz),10.20(1H,br)
MASS(APCI):627(M)+(游离)
(9)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
mp:160-168℃
[α]D 28.3:+14.83°(C=0.30,MeOH)
IR(KBr):3431,2586,1641,1606,1462,1425,1174,1130cm-1
NMR(DMSO-d6,δ):2.60-5.20(25H,m),3.82(3H,s),6.32-7.31(6H,m),10.11(1H,br)
MASS(APCI):586(M)+(游离)
(10)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕哌嗪二盐酸盐
mp:187-195℃
[α]D 26.9:+9.19°(C=0.37,MeOH)
IR(KBr):3423,1641,1604,1462,1425,1238,1173,1126cm-1
NMR(DMSO-d6,δ):1.33(3H,s),1.37(3H,s),2.80-5.20(19H,m),3.85(3H,s),6.30-7.30(6H,m),10.10(1H,br)
MASS(APCI):594(M)+(游离)
(11)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐
mp:177-182℃
[α]D 27.3:+9.71°(C=0.34,MeOH)
IR(KBr):3425,2613,1641,1606,1462,1425,1174,1132cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=5.8Hz),2.60-5.20(19H,m),3.82(3H,s),6.31-7.32(6H,m),9.90(1H,br)
MASS(APCI):570(M)+(游离)
(12)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐
mp:178-182℃
[α]D 27.1:+5.48°(C=0.21,MeOH)
IR(KBr):3435,1641,1606,1464,1425,1173,1134cm-1
NMR(DMSO-d6,δ):2.20-5.20(21H,m),3.83(3H,s),6.32-7.40(6H,m),10.17(1H,br)
MASS(APCI):576(M)+(游离)
(13)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
mp:22 5-240℃ (分解)
[α]D 28.3:-8.15°(C=0.27,MeOH)
IR(KBr):3435,1641,1 626,1464,1425,1238,1173,1130cm-1
NMR(DMSO-d6,δ):2.60-5.20(19H,m),3.83(3H,s),6.30-7.40(6H,m),7.71(1H,dd,J=4.6和7.6Hz),8.12(1H,d,J=7.6Hz),8.71(1H,d,J=4.6Hz),10.20(1H,br)
MASS(APCI):589(M)+(游离)
(14)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-甲氧基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐
mp:145-149℃
[α]D 27:+11.0°(C=0.5,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1423,1282cm-1
NMA(DMSO-d6,δ):2.60-5.00(28H,m),6.53-7.39(3H,m),7.45(1H,s),7.73(1H,s),8.19(1H,m)
MASS(APCI):638(M+H)+(游离)
(15)(2R)-1-〔3-三氟甲基-5-甲硫基苯甲酰基〕-2-(4-氯-3-叔丁基二甲基甲硅烷氧基苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪
IR(净):1680,1630,1490,1420,1130,1085cm-1
NMR(CDCl3,δ):0.18(6H,s),1.01(9H,s),1.15(6H,d,J=6.3Hz),1.75(2H,t,J=10.6Hz),2.08-5.10(20H,m),6.30-8.08(6H,m)
MASS(API-ES):700(M+)
(16)(2R)-1-〔3-三氟甲基-5-甲硫基苯甲酰基〕-2-(4-氯-3-叔丁基二甲基甲硅烷氧基苄基)-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘(naphthylidin)-6-基〕乙基〕哌嗪
IR(净):1635,1490,1420,1295,1170,1130,1105cm-1
NMR(CDCl3,δ):0.18(6H,s),1.01(9H,s),2.08-5.10(22H,m),6.30-8.48(9H,m)
MASS(API-ES):719(M+)
(17)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)-4-〔3-〔3-吡啶基〕-2-丙炔基〕哌嗪
IR(净):1643,1583,1508,1466,1452,1431,1377,1358,1331,1277,1086,1018cm-1
NMR(CDCl3,δ):0.70-5.60(23H,m),6.20-8.90(10H,m)
MASS(APCI):650(M+H)+
(18)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)-4-〔4-〔3,3-二甲基吗啉代〕-2-丁炔基〕哌嗪二盐酸盐。
mp:125-130℃
[α]D 26.8:+11.77°(C=0.31,MeOH)
IR(KBr):3425,2586,1647,1518,1281,1182,1132cm-1
NMR(DMSO-d6,δ):1.33(3H,s),1.40(3H,s),2.70-5.20(22H,m),6.50-7.30(3H,m),7.50-8.21(3H,m)
MASS(APCI):630(M+H)+(游离)
(19)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪二盐酸盐。
mp:205.0-208.0℃
[α]D 26.9:+14.4°(C=0.25,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1617,1517,1463,1427,1278,1133cm-1
NMR(DMSO-d6,δ):2.60-5.20(28H,m),6.60-8.40(6H,m)
MASS(APCI):606(M+H)+(游离)
(20)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)-4-〔2-〔4,4-二氟哌啶子基〕乙基〕哌嗪二盐酸盐。
mp:240-243℃
[α]D 28.3:+2.86°(C=0.315,MeOH)
IR(KBr):3384,2941,2418,1649,1518,1282,1184,1138cm-1
NMR(DMSO-d6,δ):2.20-5.20(24H,m),6.50-7.30(3H,m),7.43-8.20(3H,m)
MASS(APCI):612(M+H)+(游离)
(21)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲氧基苄基)-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐。
mp:175-185℃
[α]D 27:-10.0°(C=0.16,MeOH)
IR(KBr):3500-3150,2700-2300,1641,1562,1459,1432,1282cm-1
NMR(DMSO-d6,δ):2.60-5.2 0(22H,m),6.60-8.70(9H,m)
MASS(APCI):625(M+H)+(游离)
(22)(2R)-2-(4-氟-3-甲氧基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
[α]D 26.7:+29.52°(C=0.31,MeOH)
IR(KBr):1643,1635,1618,1606,1518,1462,1419,1273,1169,1132,1103,1041cm-1
NMR(DMSO-d6,δ):0.70-5.40(31H,m),6.30-7.50(6H,m)
MASS(APCI):584(M+H)+(游离)
(23)(2R)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
[α]D 28.0:+26.67°(C=0.24,MeOH)
IR(KBr):1676,1645,1635,1628,1616,1516,1464,1423,1346,1273,1171,1126,1101,1049cm-1
NMR(DMSO-d6,δ):1.10-5.30(31H,m),6.40-7.50(6H,m)
MASS(APCI):592 (M+H)+(游离)
(24)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
[α]D 26.3:+23.54°(C=0.24,MeOH)
IR(KBr):1645,1612,1516,1464,1423,1398,1352,1315,1275,1213,1173,1130,1092,1055,1036cm-1
NMR(DMSO-d6,δ):0.80-5.30(31H,m),6.30-7.50(6H,m)
MASS(APCI):568(M+H)+(游离)
(25)(2R)-4-〔2-(4,4-二氟哌啶子基)乙基〕-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
[α]D 26.4:+24.63°(C=0.27,MeOH)
IR(KBr):2538,2488,1641,1604,1516,1464,1417,1387,1346,1290,1242,1171,1134,1047,1024cm-1
NMR(DMSO-d6,δ):1.70-5.40(27H,m),6.30-7.50(6H,m)
MASS(APCI):574(M+H)+(游离)
(26)(2R)-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
[α]D 25.8:+5.22°(C=0.345,MeOH)
IR(KBr):1643,1635,1630,1516,1464,1423,1350,1317,1275,1173,1128,1051,1038cm-1
NMR (DMSO-d6,δ):0.8 0-5.50(25H,m),6.20-8.70(9H,m)
MASS(APCI):587(M+H)+(游离)
(27)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐。
mp:156-168℃
[α]D 27.6:+5.14°(C=0.36,MeOH)
IR(KBr):3458,1647,1518,1433,1282,1184,1140cm-1
NMR(DMSO-d6,δ):2.60-5.20(2 5H,m),6.30-7.20(3H,m),7.43-8.23(3H,m),9.77(1H,br)
MASS(APCI):608(M+H)+(游离)
(28)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕哌嗪二盐酸盐。
mp:180-184℃
[α]D 26.8:+2.20°(C=0.25,MeOH)
IR(KBr):3435,2931,2584,1645,1435,1281,1182,1136cm-1
NMR(DMSO-d6,δ):1.32(3H,s),1.39(3H,s),2.60-5.20(19H,m),6.30-7.20(3H,m),7.50-8.21(3H,m),9.76(1H,br)
MASS(APCI):616(M+H)+(游离)
(29)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐。
mp:170-195℃
[α]D 27:+6.77°(C=0.27,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1519,1434,1371,1282,1184cm-1
NMR(DMSO-d6,δ):0.80-5.20(25H,m),6.60-8.20(7H,m),11.40-11.80(2H,br)
MASS(APCI):592(M+H)+(游离)
(30)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐。
mp:190-200℃
[α]D 27:+0.83°(C=0.3,MeOH)
IR(KBr):3500-3150,2700-2300,1646,1517,1432,1373,1282,1139cm-1
NMR(DMSO-d6,δ):2.60-5.20(21H,m),6.20-8.30(7H,m),9.00-10.40(2H,br)
MASS(APCI):598(M+H)+(游离)
(31)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-羟基苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:240.0-241.0℃
[α]D 26:-11.66°(C=0.57,MeOH)
IR(KBr):3500-3150,2700-2300,1641,1517,1432,1282,1137cm-1
NMR(DMSO-d6,δ):2.60-5.20(19H,m),6.20-8.80(10H,m),9.00-10.50(2H,br)
MASS(APCI):611(M+H)+(游离)
(32)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐。
mp:196-198℃
[α]D 27:+8.3°(C=0.5,MeOH)
IR(KBr):3365,2590,2475,1645,1520,1440,1280cm-1
NMR(DMSO-d6,δ):2.73-5.07(22H,m),3.27(3H,s),6.88-8.21(6H,m)
MASS(APCI):610(M+H)+(游离)
(33)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕哌嗪二盐酸盐。
[α]D 27:+4.2°(C=0.5,MeOH)
IR(KBr):2435,1645,1520,1430,1280cm-1
NMR(DMSO-d6,δ):1.32(3H,s),1.38(3H,s),2.76-5.17(19H,m),6.79-8.26(6H,m)
MASS(APCI):618(M+H)+(游离)
(34)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐。
mp:223-228℃
[α]D 27:+5.1°(C=0.5,MeOH)
IR(KBr):3435,3390,2600,2495,1650,1520,1435,1280cm-1
NMR(DMSO-d6,δ):1.45(6H,d,J=6.0Hz),2.60-5.20(19H,m),6.80-8.28(6H,m)
MASS(APCI):594(M+H)+(游离)
(35)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐。
[α]D 27:+9.1°(C=0.5,MeOH)
IR(KBr):2380,1645,1520,1430,1280cm-1
NMR(DMSO-d6,δ):2.10-5.14(21H,m),6.78-8.26(6H,m)
MASS(APCI):600(M+H)+(游离)
(36)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔1-甲基-1H-吡唑-4-基〕甲基〕哌嗪盐酸盐。
mp:230℃
[α]D 27:-1.6°(C=0.5,MeOH)
IR(KBr):2520,2470,1645,1525,1440,1365,1275cm-1
NMR(DMSO-d6,δ):2.72-5.12(11H,m),3.86(3H,s),6.74-8.31(8H,m)
MASS(APCI):547(M+H)+(游离)
(37)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:203-208℃
[α]D 27:+5.3°(C=0.5,MeOH)
IR(KBr):2560,1640,1520,1430,1370,1280cm-1
NMR(DMSO-d6,δ):2.80-5.14(11H,m),6.72-9.10(10H,m)
MASS(APCI):544(M+H)+(游离)
(38)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-(3-〔3-吡啶基〕丙基)哌嗪二盐酸盐。
mp:215-220℃
[α]D 27:+2.6°(c=0.5,MeOH)
IR(KBr):2650,1645,1550,1520,1430,1280cm-1
NMR(DMSO-d6,δ):2.13-5.15(15H,m),6.78-8.95(10H,m)
MASS(APCI):572(M+H)+(游离)
(39)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3,4-二氟苄基)-4-(2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基)哌嗪三盐酸盐。
[α]D 27:-2.0°(C=0.5,MeOH)
IR(KBr):2620,1645,1515,1430,1280cm-1
NMR(DMSO-d6,δ):2.59-5.17(19H,m),6.76-8.69(9H,m)
MASS(APCI):613(M+H)+(游离)
(40)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-(三氟甲基)苄基)-4-(2-〔顺-2,6-二甲基吗啉代〕乙基)哌嗪二盐酸盐。
mp:160.0-170.0℃
[α]D 27:+17.16°(C=0.44,MeOH)
IR(KBr):3500-3150,2700-2300,1648,1623,1587,1511,1463,1280,1132cm-1
NMR(DMSO-d6,δ):2.60-5.20(28H,m),6.40-8.20(6H,m)
MASS(APCI):656(M+H)+(游离)
(41)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-甲氧基-4-(三氟甲基)苄基)-4-(2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基)哌嗪三盐酸盐。
mp:195-200℃
[α]D 27:+1.76°(C=0.34,MeOH)
IR(KBr):3500-3150,2700-2300,1646,1625,1511,1465,1427,1369,1280,1130cm-1
NMA(DMSO-d6,δ):2.60-5.20(22H,m),6.60-8.80(9H,m)
MASS(APCI):675(M+H)+(游离)
(42)(2R)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)-2-(3-甲氧基-4-(三氟甲基)苄基)-4-(2-〔(2S)-2-甲氧基甲基吗啉代〕乙基)哌嗪二盐酸盐。
mp:135-140℃
[α]D 27:+20.3°(C=0.15,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1623,1463,1423,1321,1128,1045cm-1
NMR(DMSO-d6,δ):2.80-5.20(31H,m),6.60-8.20(6H,m),10.60-12.20(2H,br)
MASS(APCI):634(M+H)+(游离)
(43)(2R)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)-2-(3-甲氧基-4-(三氟甲基)苄基)-4-(2-〔顺-2,6-二甲基吗啉代〕乙基)哌嗪二盐酸盐。
mp:125-135℃
[α]D 27:+35.0°(C=0.18,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1623,1511,1463,1423,1351,1274,1128cm-1
NMR(DMSO-d6,δ):2.60-5.20(31H,m),6.50-8.20(6H,m),11.20-11.80(2H,br)
MASS(APCI):618(M+H)+(游离)
(44)(2R)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)-2-(3-甲氧基-4-(三氟甲基)苄基)-4-(2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基)哌嗪三盐酸盐。
mp:190-200℃
[α]D 27:+7.5°(C=0.16,MeOH)
IR(KBr):3500-3150,2700-2300,1623,1614,1511,1463,1321,1126cm-1
NMR(DMSO-d6,δ):2.80-5.20(25H,m),6.60-8.80(9H,m)
MASS(APCI):637(M+H)+(游离)
(45)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-2-(3-氟-4-甲基苄基)-4-(2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基)哌嗪二盐酸盐。
mp:148-160℃
[α]D 26.5:-2.25°(C=0.222,MeOH)
IR(KBr):3435,2661,2593,2465,1645,1514,1429,1363,1324,1282,1184,1140cm-1
NMR(DMSO-d6,δ):2.20(3H,s),2.64-5.28(25H,m),6.62-8.28(6H,m)
MASS(APCI):606(M+H)+(游离)
(46)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟-3-甲基苄基)-4-(2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基)哌嗪二盐酸盐。
mp:151-156℃
[α]D 27:+2.96°(C=0.355,MeOH)
IR(KBr):3435,2941,1647,1510,1281,1184,1138cm-1
NMR(DMSO-d6,δ):2.10-2.21(3H,m),2.65-5.25(25H,m),6.70-8.30(6H,m)
MASS(APCI):606(M+H)+(游离)
(47)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)-4-〔4-((2S)-2-(甲氧基甲基)吗啉代)-2-丁炔基〕哌嗪。
IR(净):1643,1583,1510,1452,1446,1433,1379,1277,1095,1014cm-1
NMR(CDCl3,δ):0.60-5.40(37H,m),6.20-8.20(6H,m)
MASS(ESI):716.3(M+H)+
(48)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(4-〔3,3-二甲基吗啉代〕-2-丁炔基)-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:110-130℃
[α]D 24:+9.20°(C=0.25,MeOH)
IR(KBr):1647cm-1
NMR(DMSO-d6,δ):1.33-1.41(6H,m),2.80-5.30(19H,m),7.20-8.17(7H,m)
MASS(APCI):650(M+H)+(游离)
(49)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-〔顺-2,6-二甲基吗啉代〕乙基)-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:148-159℃
[α]D 27:+10.60°(C=0.25,MeOH)
IR(KBr):3437,1645,1516,1427cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),6.60-5.30(19H,m),7.25-8.19(7H,m)
MASS(APCI):626(M+H)+(游离)
(50)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-〔4,4-二氟哌啶子基〕乙基)-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:209-253℃
[α]D 26:+15.60°(C=0.25,MeOH)
IR(KBr):1647cm-1
NMR(DMSO-d6,δ):2.60-5.20(21H,m),7.21-8.19(7H,m)
MASS(APCI):632(M+H)+(游离)
(51)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(〔1-甲基-1H-吡唑-4-基)甲基〕-2-〔4-(三氟甲基)苄基〕哌嗪盐酸盐。
mp:200-229℃
[α]D 24:+5.07°(C=0.25,MeOH)
IR(KBr):1647cm-1
NMR(DMSO-d6,δ):2.84-5.20(14H,m),7.14-7.72(7H,m),7.94-7.96(1H,m),8.21(1H,s)
MASS(APCI):579(M+H)+(游离)
(52)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(〔3-吡啶基〕甲基)-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:198-223℃
[α]D 27:+6.60°(C=0.25,MeOH)
IR(KBr):1645cm-1
NMR(DMSO-d6,δ):2.80-5.20(11H,m),7.13-7.91(7H,m),8.34(1H,s),8.62(1H,d,J=7.7Hz),8.87(1H,d,J=5.2Hz),9.05(1H,s)
MASS(APCI):576(M+H)+(游离)
(53) (2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(3-〔3-吡啶基〕-2-丙炔基)-2-〔4-(三氟甲基)苄基〕哌嗪。
mp:142-143℃
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):2.20-5.20(11H,m),7.19-7.64(7H,m),7.80-7.90(1H,m),8.16(1H,br s),8.55-8.58(1H,m),8.66(1H,br s)
MASS(APCI):600(M+H)+
(53′)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(3-〔3-吡啶基〕-2-丙炔基)-2-〔4-(三氟甲基)苄基〕哌嗪。
mp:142-143℃
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):2.20-5.20(11H,m),7.19-7.64(7H,m),7.80-7.90(1H,m),8.16(1H,brs),8.35-8.58(1H,m),8.66(1H,br s)
MASS (APCI):600(M+H)+
(54)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基)-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐。
mp:174-180℃
[α]D 27:-2.80°(C=0.25,MeOH)
IR(KBr):3438,1645,1516cm-1
NMR(DMSO-d6,δ):2.60-5.30(19H,m),7.20-8.67(10H,m)
MASS(APCI):645(M+H)+(游离)
(55)(2R)-4-(2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:126-155℃
[α]D 26:+20.60°(C=0.25,MeOH)
IR(KBr):3460,1645,1464cm-1
NMR(DMSO-d6,δ):2.80-5.30(25H,m),3.82(3H,s),6.31-7.80(7H,m)
MASS(APCI):604(M+H)+(游离)
(56)(2R)-4-(4-〔3,3-二甲基吗啉代〕-2-丁炔基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:158-165℃
[α]D 26:+19.93°(C=0.25,MeOH)
IR(KBr):3430,1645,1516,1462,1421cm-1
NMR(DMSO-d6,δ):1.33(3H,s),1.38(3H,s),2.90-5.30(19H,m),3.83(3H,s),6.30-7.70(7H,m)
MASS(APCI):612(M+H)+(游离)
(57)(2R)-4-(2-〔顺-2,6-二甲基吗啉代〕乙基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:139-151℃
[α]D 27:+19.00°(C=0.25,MeOH)
IR(KBr):3435,1645,1464,1423cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.60-5.30(19H,m),3.82(3H,s),6.30-7.80 (7H,m)
MASS(APCI):588(M+H)+(游离)
(58)(2R)-4-(2-〔4,4-二氟哌啶子基〕乙基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:~230℃
[α]D 27:+19.80°(C=0.25,MeOH)
IR(KBr):1643,1464,1421cm-1
NMR(DMSO-d6,δ):2.30-5.30(21H,m),3.80(3H,s),6.30-7.80(7H,m)
MASS(APCI):594(M+H)+(游离)
(59)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-(3-吡啶基)-2-丙炔基〕-2-〔4-(三氟甲基)苄基〕哌嗪。
IR(净):3585,1637cm-1
NMR(DMSO-d6,δ):2.20-5.20(11H,m),3.82(3H,s),6.81-7.70(9H,m),8.55(1H,d,J=3.5Hz),8.66(1H,s)
MASS(APCI):562(M+H)+
(60)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐。
mp:185-191℃
[α]D 27:+4.00°(C=0.25,MeOH)
IR(KBr):1645,1423cm-1
NMR(DMSO-d6,δ):2.90-5.30(19H,m),3.83(3H,s),6.30-7.80(8H,m),8.11(1H,d,J=7.7Hz),8.70(1H,d,J=4.7Hz)
MASS(APCI):607(M+H)+(游离)
(61)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐。
mp:90-120℃
[α]D 27.7:+5.18°(C=0.28,MeOH)
IR(KBr):1707,1693,1676,1645,1547,1539,1516,1498,1489,1477,1464,1454,1427,1392,1387,1367,1281,1182,1138,1101cm-1
NMR(DMSO-d6,δ):2.00-5.40(25H,m),6.80-8.40(7H,m)
MASS(APCI):608(M+H)+(游离)
(62)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯苄基〕-4-〔4-〔3,3-二甲基吗啉代〕-2-丁炔基〕哌嗪二盐酸盐。
mp:120-150℃
[α]D 27.6:-0.69°(C=0.29,MeOH)
IR(KBr):2578,2515,1645,1496,1489,1431,1362,1319,1281,1217,1182,1136,1099,1066cm-1
NMR(DMSO-d6,δ):1.10-1.50(6H,m),2.60-5.30(19H,m),6.80-8.40(7H,m)
MASS(APCI):616(M+H)+(游离)
(63)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-[顺-2,6-二甲基吗啉代〕乙基〕-2-(4-氯苄基)哌嗪二盐酸盐。
mp:150-175℃(分解)
[α]D 27.4:-2.86°(C=0.28,MeOH)
IR(KBr):1693,1687,1645,1514,1508,1498,1489,1464,1454,1429,1329,1281,1182,1142,1099,1038cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),1.80-5.40(19H,m),6.80-8.30(7H,m)
MASS(APCI):592(M+H)+(游离)
(64)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐。
mp:250-255℃
[α]D 28.2:-3.52°(C=0.27,MeOH)
IR(KBr):1707,1693,1678,1647,1628,1547,1539,1516,1498,1464,1454,1425,1367,1279,1176,1140,1101,1061,974cm-1
NMR(DMSO-d6,δ):1.80-5.40(21H,m),6.80-8.40(7H,m)
MASS(APCI):598(M+H)+(游离)
(65)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:172-203℃(分解)
[α]D 27.4:-16.12°(C=0.245,MeOH)
IR(KBr):1674,1645,1630,1558,1550,1539,1516,1498,1489,1464,1427,1392,1387,1367,1281,1182,1136,1101,1043cm-1
NMR(DMSO-d6,δ):1.10-5.60(19H,m),6.80-8.80(10H,m)
MASS(APCI):611(M+H)+(游离)
(66)(2R)-2-(4-氯苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:70-90℃
[α]D 28.2:+13.00°(C=0.227,MeOH)
IR(KBr):1643,1606,1514,1508,1496,1423,1387,1350,1315,1271,1242,1174,1130,1097,1051cm-1
NMR(DMSO-d6,δ):2.50-5.40(28H,m),6.30-7.60(7H,m)
MASS(APCI):570(M+H)+(游离)
(67)(2R)-2-(4-氯苄基)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:110-140℃
[α]D 28.2:+8.96°(C=0.24,MeOH)
IR(KBr):1676,1645,1539,1535,1516,1498,1464,1423,1348,1317,1271,1242,1173,1126,1097,1049cm-1
NMR(DMSO-d6,δ):1.10-1.60(6H,m),2.60-5.40(22H,m),6.40-7.60(7H,m)
MASS(APCI):578(M+H)+(游离)
(68)(2R)-2-(4-氯苄基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:90-120℃
[α]D 27.9:+10.80°(C=0.25,MeOH)
IR(KBr):1676,1645,1606,1516,1498,1464,1423,1387,1381,1377,1350,1317,1271,1242,1209,1174,1130,1095,1051cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.40-5.40(22H,m),6.30-7.60(7H,m)
MASS(APCI):554(M+H)+(游离)
(69)(2R)-2-(4-氯苄基)-4-〔2-(4,4-二氟哌啶子基)乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:220-250℃
[α]D 28.3:+13.18°(C=0.425,MeOH)
IR(KBr):1641,1635,1604,1539,1516,1498,1464,1417,1344,1292,1269,1242,1174,1138,1097,1047cm-1
NMR(DMSO-d6,δ):2.00-5.40(24H,m),6.30-7.60(7H,m)
MASS(APCI):560(M+H)+(游离)
(70)(2R)-2-(4-氯苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:140-170℃
[α]D 28.7:-6.11°(C=0.36,MeOH)
IR(KBr):1645,1635,1630,1516,1498,1464,1477,1350,1315,1271,1240,1207,1174,1128,1097,1053cm-1
NMR(DMSO-d6,δ):2.40-5.40(22H,m),6.30-8.90(10H,m)
MASS(APCI):573(M+H)+(游离)
(71)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(4-(3,3-二甲基吗啉代)-2-丁炔基)-2-〔4-氟苄基〕哌嗪二盐酸盐。
mp:76.5-130.6℃
[α]D 26.3:+7.53°(C=0.25,MeOH)
IR(KBr):1644,1513,1430,1282,1182,1133cm-1
NMR(DMSO-d6,δ):1.32,1.39(6H,2br s),2.50-4.58(19H,m),6.99-8.20(7H,m)
MASS:600(M+H)+(游离)
(72)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-(顺-2,6-二甲基吗啉子基)乙基)-2-〔4-氟苄基〕哌嗪二盐酸盐。
mp:89.0-110.2℃
[α]D 28:+7.80°(C=0.25,MeOH)
IR(KBr):1644,1513,1282,1182,1137cm-1
NMR(DMSO-d6,δ):1.13(6H,d,J=6.05Hz),2.73-4.55(19H,m),7.00-8.17(7H,m)
MASS:576(M+H)+(游离)
(73)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-(4,4-二氟哌啶子基)乙基)-2-〔4-氟苄基〕哌嗪二盐酸盐。
mp:264.0-270.6℃
[α]D 26.6:+5.07°(C=0.25,MeOH)
IR(KBr):1644,1513,1427,1278,1187,1141cm-1
NMR(DMSO-d6,δ):2.30-5.00(21H,m),6.99-8.17(7H,m)
MASS:582(M+H)+(游离)
(74)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟苄基〕-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪。
NMR(CDCl3,δ):2.42-4.96 (11H,m),6.95-8.66(11H,m)
MASS:550(M+H)+
(75)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟苄基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:155.5-170.1℃
[α]D 28:-81.20°(C=0.50,MeOH)
IR(KBr):1644,1513,1427,1282,1184,1135cm-1
NMR(DMSO-d6,δ):2.60-4.85(19H,m),7.03-8.69(11H,m)
MASS:595(M+H)+(游离)
(76)(2R)-2-(4-氟苄基)-4-〔2-((2S)-2-(甲氧基甲基)-吗啉代)乙基〕-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐。
mp:109.5-119.2℃
[α]D 26.8:+24.73°(C=0.46,MeOH)
IR(KBr):1643,1513,1463,1423,1172,1130,1101cm-l
NMR(DMSO-d6,δ):2.73-4.10(24H,m),3.26(3H,s),3.87(3H,s),6.45-7.41(7H,m)
MASS:554(M+H)+(游离)
(77)(2R)-4-〔4-(3,3-二甲基吗啉代〕-2-丁炔基〕-2-(4-氟苄基)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐。
mp:137.5-140.7℃
[α]D 27.0:+15.18°(C=0.48,MeOH)
IR(KBr):1643,1465,1423,1348,1126cm-1
NMR(DMSO-d6,δ):1.32和1.37(6H,s),1.37(6H,sx2),3.10-5.00(19H,m),3.83(3H,s),6.99-12.0(8H,m)
MASS:562(M+H)+(游离)
(78)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-2-(4-氟苄基)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐。
mp:70.3-85.2℃
[α]D 27.2:+19.03°(C=0.49,MeOH)
IR(KBr):1645,1513,1463,1423,1174,1130cm-1
NMR(DMSO-d6,δ):1.03和1.14(6H,d,J=6.1Hz),2.89-5.10(19H,m),3.83(3H,s),6.4 6-7.40(7H,m)
MASS:538(M+H)+(游离)
(79)(2R)-4-〔2-(4,4-二氟哌啶子基)乙基〕-2-(4-氟苄基)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐。
mp:258.4-261.4℃
[α]D 27.3:+20.40°(C=0.43,MeOH)
IR(KBr):1637,1604,1417,1346,1240,1047,970cm-1
NMR(DMSO-d6,δ):2.7 3-5.09(21H,m),3.82(3H,s),6.45-7.38(7H,m)
MASS:544(M+H)+(游离)
(80)(2R)-4-(4-氟苄基)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪。
NMR(CDCl3,δ):2.38-5.06(11H,m),3.82(3H,s),6.41-8.66(11H,m)
MASS:512(M+H)+
(81)(2R)-2-(4-氟苄基)-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)-4-〔2-(5,6,7,8-四氢-1,6二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:148.7-152.3℃
[α]D 27.1:-0.737°(C=0.48,MeOH)
IR(KBr):1643,1635,1514,1464,1421,1350,1173,1128cm-1
NMR(DMSO-d6,δ):2.65-5.10(19,m),3.83(3H,s),6.50-8.69(10H,m)
MASS:557(M+H)+(游离)
(82)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-(顺-2,6-二甲基吗啉代)乙基)-2-〔2-萘甲基〕哌嗪二盐酸盐。
mp:168-195℃
[α]D 26.4:-27.26°(C=0.31,MeOH)
IR(KBr):3410,1640cm-1
NMR(DMSO-d6,δ):1.16(6H,d,J=6.0Hz),2.6-5.3(19H,m),7.0-8.2(10H,m)
MASS(APCI):608(M+H)+(游离)
(83)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-(4,4-二氟哌啶子基)乙基)-2-〔2-萘甲基〕哌嗪二盐酸盐。
mp:>250℃
[α]D 27.3:-33.11°(C=0.37,MeOH)
IR(KBr):3740,2400,1650cm-1
NMR(DMSO-d6,δ):2.9-5.4(21H,m),7.0-8.2(10H,m)
MASS(APCI):614(M+H)+(游离)
(84)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔2-萘甲基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:189-194℃
[α]D 28.1:-34.93°(C=0.28,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.9-5.4(19H,m),6.9-8.2(12H,m),8.66(1H,d,J=4.4Hz)
MASS(APCI):627(M+H)+(游离)
(85)(2R)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)哌嗪二盐酸盐。
mp:134-140℃
[α]D 28.5:+0.78°(C=0.35,MeOH)
IR(KBr):3750,1640cm-1
NMR(DMSO-d6,δ):2.8-5.4(28H,m),6.3-8.0(10H,m)
MASS(APCI):586(M+H)+(游离)
(86)(2R)-4-〔4-〔3,3-二甲基吗啉代〕-2-丁炔基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)哌嗪二盐酸盐。
mp:190-199℃
[α]D 28.7:-2.16°(C=0.26,MeOH)
IR(KBr):3750,3400,1640cm-1
NMR(DMSO-d6,δ):1.32(3H,s),1.37(3H,s),3.0-5.4(22H,m),6.3-8.0(1H,m)
MASS(APCI):594(M+H)+(游离)
(87)(2R)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)哌嗪二盐酸盐。
mp:188-193℃
[α]D 28.5:-7.70°(C=0.31,MeOH)
IR(KBr):3430,3400,1640cm-1
NMR(DMSO-d6,δ):1.16(6H,d,J=6.0Hz),2.6-5.4(22H,m),6.3-8.0(1H,m)
MASS(APCI):570(M+H)+(游离)
(88)(2R)-4-〔2-〔4,4-二氟哌啶子基〕乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)哌嗪二盐酸盐。
mp:243-260℃
[α]D 28.7:-10.36°(C=0.28,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.2-5.4(24H,m),6.3-8.0(10H,m)
MASS(APCI):576(M+H)+(游离)
(89)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)-4-〔3-(3-吡啶基)-2-丙炔基〕哌嗪。
[α]D 28.7:-5.37°(C=0.27,MeOH)
IR(KBr):3740,1640cm-1
N-MR(DMSO-d6,δ):2.1-5.2(1 4H,m),6.5-8.0(12H,m),8.57(1H,m),8.64(1H,s)
MASS(APCI):544(M+H)+
(90)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘甲基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:173-183℃
[α]D 27.9:-2 0.91°(C=0.26,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.8-5.4(22H,m),6.4-8.0(11H,m),8.03(1H,d,J=8.5Hz),8.67(1H,d,J=4.9Hz)
MASS(APCI):58 9(M+H)+(游离)
(91)(2R)-1-〔3,5-双(三氟甲基)〕-2-((1H-吲哚-3-基)甲基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:190-200℃
[α]D 27:-25.25°(C=0.2,MeOH)
IR(KBr):3500-3150,2700-2300,1646,1519,1434,1371,1272,1236cm-1
NMR(DMSO-d6,δ):2.60-5.20(25H,m),6.60-8.70(11H,m),11.17(1H,s)
MASS(APCI):616(M+H)+(游离)
(92)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-((2R)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐。
mp:200-210℃
[α]D 25.6:+34.4°(C=0.27,MeOH)
IR(KBr):3400-3000,2900-2500,1637,1607,1461,1423cm-1
NMR(DMSO-d6,δ):2.81-5.20(28H,m),6.60-9.20(8H,m),10.98(1H,s),11.60-12.20(2H,m)
MASS(APCI):575(M+H)+(游离)
(93)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕哌嗪二盐酸盐。
mp:190-200℃
[α]D 25.6:+23.6°(C=0.25,MeOH)
IR(KBr):3400-3000,2900-2500,1644,1608,1457,1421cm-1
NMR(DMSO-d6,δ):1.32-1.37(6H,m),3.20-5.20(22H,m),6.60-8.00(8H,m),10.96(1H,s),12.00-12.40(2H,m)
MASS(APCI):583(M+H)+(游离)
(94)(2R)-2-((1H-吲哚-3-基)甲基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:188-200℃
[α]D 26:+28.4°(C=0.19,MeOH)
IR(KBr):3500-3150,2700-2300,1637,1606,1459,1272,1174cm-1
NMR(DMSO-d6,δ):0.80-5.20(28H,m),6.60-8.20(8H,m),10.96(1H,s),11.40-11.80(2H,br)
MASS(APCI):559(M+H)+(游离)
(95)(2R)-4-(2-(4,4-二氟哌啶子基)乙基)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐。
mp:130-140℃
[α]D 25.6:+22.9°(C=0.22,MeOH)
IR(KBr):3400-3000,2900-2500,1635,1608,1461,1423cm-1
NMR(DMSO-d6,δ):2.20-5.20(24H,m),6.60-8.80(8H,m),10.97(1H,s),11.20-12.20(2H,m)
MASS(APCI):565(M+H)+(游离)
(96)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:210-220℃
[α]D 25.6:+18.58°(C=0.24,MeOH)
IR(KBr):3400-3000,2900-2500,1639,1609,1459,1419,1321cm-1
NMR(DMSO-d6,δ):2.70-5.20(17H,m),6.50-8.80(8H,m),7.63(1H,s),7.94(1H,s),10.88-10.93(1H,m),11.59(1H,br s)
MASS(APCI):512(M+H)+(游离)
(97)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:190-200℃
[α]D 25.6:+22.0°(C=0.34,MeOH)
IR(KBr):3400-3000,2900-2500,1637,1606,1463,1421cm-1
NMR(DMSO-d6,δ):2.80-5.50(14H,m),6.50-8.00(8H,m),7.74-7.92(1H,m),8.67(1H,d,J=8.0Hz),8.86(1H,d,J=4.4Hz),9.07(1H,s),10.87(1H,br s),12.00-12.40(2H,m)
MASS(APCI):509(M+H)+(游离)
(98)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-(3-吡啶基)丙基〕哌嗪二盐酸盐。
mp:135-145℃
[α]D 26.3:+21.2°(C=0.29,MeOH)
IR(KBr):3400-3000,2900-2500,1635,1607,1463,1421cm-1
NMR(DMSO-d6,δ):2.20-5.20(18H,m),6.60-8.80(11H,m),11.80-12.00(2H,m)
MASS(APCI):537(M+H)+(游离)
(99)(2R)-2-((1H-吲哚-3-基)甲基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐。
mp:180-190℃
[α]D 27:-8.3°(C=0.15,MeOH)
IR(KBr):3500-3150,1700-2300,1637,1631,1461,1348,1238,1172cm-1
NMR(DMSO-d6,δ):3.20-5.20(22H,m),6.60-8.20(11H,m),10.98(1H,s)
MASS(APCI):578(M+H)+(游离)
(100)1-(3,5-双(三氟甲基)苯甲酰基)-2-〔3-羟基-4-甲基苄基〕-4-〔2-(4,4-二氟哌啶子基)乙基〕哌嗪二盐酸盐。
mp:250-255℃
IR(KBr):3400-3000,2900-2500,1646,1427,1280cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.35-5.20(21H,m),6.05-8.20(7H,m),8.90-9.50(2H,m)
MASS(APCI):594(M+H)+(游离)
(101)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔2-〔(2R)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪。
IR(净):1643,1508,1435,1381,1354,1331,1279,1130,1101,1012cm-1
NMR(CDCl3,δ):1.90-5.60(37H,m),6.20-8.20(6H,m)
MASS(APCI):692(M+H)+
(102)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-4-〔2-〔(3S,5S)-3,5-二甲基吗啉代〕乙基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕哌嗪。
IR(净):1643,1583,1508,1435,1379,1356,1329,1279,1132,1099,1012cm-1
NMR(CDCl3,δ):1.01(6H,d,J=6.4Hz),1.90-5.50(31H,m),6.2 0-8.20(6H,m)
MASS(APCI):676(M+H)+
(103)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-4-〔 2-〔顺-3,5-二甲基吗啉代〕乙基〕-2-〔 3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕哌嗪。
IR(净):1643,1583,1508,1452,1435,1406,1379,1356,1325,1277,1099,1012cm-1
NMR(CDCl3,δ):0.51-5.70(37H,m),6.10-8.20(6H,m)
MASS(APCI):676(M+H)+
(104)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-(3-〔(2S)-2-(甲氧基甲基)吗啉代〕丙基)哌嗪。
IR(净):1643,1583, 1508,1437,1406,1379,1354,1331,1279,1097,1014cm-1
NMR(CDCl3,δ):1.60-5.40(39H,m),6.30-7.90(6H,m)
MASS(APCI):706.3(M+H)+,728.3(M+Na)+
(105)(2R)-1-(3,5-双(三氟甲基)苯甲酰基)-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-((E)-4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁烯基)哌嗪。
IR(净):1643,1510,1454,1435,1406,1379,1352,1331,1281,1134,1101,1012cm-1
NMR(CDCl3,δ):0.70-5.40(37H,m),6.30-7.90(8H,m)
MASS(ESI):718.3(M+H)+,740.3(M+Na)+
(106)(2S)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基)乙基〕哌嗪
IR(净):1678,1645,1628,1618,1510,1477,1462,1454,1435,1427,1385,1381,1275cm-1
NMR(CDCl3,δ):0.70-5.40(31H,m),6.20-8.20(8H,m)
MASS(APCI):700(M+H)+
(107)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔(喹啉-6-基)甲基〕哌嗪
IR(净):1693,1678,1645,1630,1618,1547,1539,1514,1464,1454,1427,1392,1387,1381,1277cm-1
NMR(CDCl3,δ):0.70-5.50(23H,m),6.20-9.00(12H,m)
MASS(APCI):676(M+H)+
(108)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔(3-溴-1,2,4-噁二唑-5-基)甲基〕哌嗪
NMR(CDCl3,δ):2.19(3H,s),2.40-5.40(15H,m),3.38(3H,s),3.78(2H,s),6.30-8.00 (6H,m)
MASS(APCI):695(M+H)+,621,609
实施例10
根据类似实施例1的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐。
mp:129-133℃
[α]D 28.0:+6.96°(C=0.28,MeOH)
IR(KBr):1645,1516,1281,1182,1138cm-1
NMR(DMSO-d6,δ):2.70-5.20(25H,m),7.00-8.22(7H,m)
MASS(APCI):592(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔2-萘甲基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐。
mp:145-148℃
[α]D 28.9:-16.6°(C=0.49,MeOH)
IR(KBr):1645,1429,1281,1182,1134cm-1
NMR(DMSO-d6,δ):2.80-5.40(25H,m),7.05-8.20(10H,m)
MASS(APCI):624(M+H)+(游离)
(3)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔4-((2S,5S)-2-甲氧基甲基-5-甲基吗啉代)-2-丁炔基〕哌嗪。
IR(KBr):1643cm-1
NMR(CDCl3,δ):1.20(3H,d,J=6.3Hz),2.19(3H,brs),1.92-2.12(2H,m),2.60-5.40(25H,m),3.36(6H,s),6.67-7.81(6H,m)
MASS(ESI+):730.3(M+H)+,752(M+Na)+
(4)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔2-((1R,4S)-3,3-二甲基-2-氧-5-氮杂双环[2.2.1]庚烷-5-基)乙基〕哌嗪。
IR(净):1643,1437cm-1
NMR(CDCl3,δ):1.10-1.12(3H,m),1.31(3H,s),1.60-1.75(1H,m),1.92(1H,d,J=10.0Hz),2.20-(3H,s),2.28(1H,d,J=10.0Hz),2.20-4.60(19H,m),3.36(3H,s),4.43(1H,br s),5.00-5.40(2H,m),6.30-7.79(6H,m)
MASS(APCI):688(M+H)+
实施例11
三乙酰氧基硼氢化钠(0.3g)分次加至(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕哌嗪(0.5g)和1-甲基-1H-吡唑-4-甲醛(0.12g)的二氯甲烷(10ml)的混合物中,该混合物室温搅拌1小时。混合物用碳酸氢钠水溶液洗涤,硫酸镁干燥,减压蒸发,残留物用硅胶柱层析纯化,用乙酸乙酯作为洗脱剂。收集含目的化合物的组分,减压蒸发得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪(0.54g),为油状物。
IR(净):1641,1579,1508,1435,1381,1352,1329,1277,1097,1088,1014cm-1
NMR(CDCl3,δ):1.75-5.40(26H,m),6.2 5-7.95(8H,m)
MASS(APCI):629(M+H)+
实施例12
根据类似实施例11的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔3-吡啶基甲基〕哌嗪。
IR(净):1643,1583,1508,1431,1379,1356,1352,1331,1279,1097cm-1
NMR(CDCl3,δ):0.70-5.60(23H,m),6.20-8.80(10H,m)
MASS(APCI):626(M+H)+
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:159-163℃
[α]D 28:-5.25°(C=2.0,MeOH)
IR(KBr):3398,1647,1427,1281,1178,1138cm-1
NMR(DMSO-d6,δ):2.60-5.10(11H,m),3.85(3H,s),6.26-7.21(3H,m),7.51-8.23(5H,m),10.20(1H,br)
MASS(APCI):561(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:187-192℃
[α]D 27.3:-8.11°(C=0.185,MeOH)
IR(KBr):3435,1645,1429,1281,1182,1136cm-1
NMR(DMSO-d6,δ):2.60-6.10(11H,m),6.29-7.20(3H,m),7.47-8.24(4H,m),8.61-9.03(3H,m),10.13(1H,br)
MASS(APCI):558(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
mp:65-70℃
[α]D 27.9:-7.68°(C=0.28,MeOH)
IR(KBr):1647,1427,1279,1180,1136cm-1
NMR(DMSO-d6,δ):2.10-5.10(15H,m),6.30-7.29(3H,m),7.48(1H,s),7.84(1H,s),7.95-8.89(5H,m),10.20(1H,br)
MASS(APCI):586(M+H)+(游离)
(5)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔〔1-甲基-1H-吡唑-4-基〕甲基〕哌嗪二盐酸盐。
mp:140-150℃
[α]D 28.3:+4.17°(C=0.36,MeOH)
IR(KBr):3411,2600,1641,1604,1462,1423,1240,1173,1128cm-1
NMR(DMSO-d6,δ):2.70-5.10(11H,m),3.85(6H,s),6.30-7.32(6H,m),7.60(1H,s),7.95(1H,s),10.18(1H,br)
MASS.(APCI):523(M+H)+(游离)
(6)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔3-吡啶甲基〕哌嗪二盐酸盐。
mp:215-224℃
[α]D 28.3:+7.60°(C=0.25,MeOH)
IR(KBr):3400,1639,1606,14 64,1425,1173,1128cm-1
NMR(DMSO-d6,δ):2.60-5.10(11H,m),3.84(3H,s),6.26-7.33(6H,m),7.92(1H,dd,J=4.8和7.9Hz),8.65(1H,d,J=7.9Hz),8.88(1H,d,J=4.8Hz),9.04(1H,s),10.13(1H,br)
MASS(APCI):520(M+H)+(游离)
(7)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔3-(3-吡啶基)丙基〕哌嗪二盐酸盐。
mp:90-110℃
[α]D 28.3:+0.27°(C=0.185,MeOH)
IR(KBr):2952,2600,1645,1606,1464,1425,1238,1171,1126cm-1
NMR(DMSO-d6,δ):2.10-5.20(15H,m),3.83(3H,s),6.30-7.33(6H,m),7.61(1H,dd,J=4.2和8.0Hz),8.01(1H,d,J=8.0Hz),8.58(1H,d,J=4.2Hz),8.65(1H,s),10.20(1H,br)
MASS(APCI):54 8(M)+(游离)
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-〔〔1-甲基-1H-吡唑-4-基〕甲基〕哌嗪盐酸盐。
mp:127-135℃
[α]D 28.1:+2.75°(C=0.20,MeOH)
IR(KBr):3400,1645,1516,1282,1182,1136cm-1
NMR(DMSO-d6,δ):2.8 0-5.20(14H,m),3.85(3H,s),6.40-7.30(3H,m),7.58-8.30(5H,m)
MASS(APCI):559(M+H)+(游离)
(9)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:143-147℃
[α]D 28.1:+0.889°(C=0.225,MeOH)
IR(KBr):3400,1645,1516,12 82,1182,1134cm-1
NMR(DMSO-d6,δ):2.80-5.20(14H,m),6.40-7.30(3H,m),7.50-8.30(4H,m),8.65(1H,d,J=8.3Hz),8.88(1H,d,J=5.0Hz),9.08(1H,s)
MASS(APCI):556(M+H)+(游离)
(10)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
mp:125-130℃
[α]D 27.7:+2.50°(C=0.18,MeOH)
IR(KBr):3400,1645,1516,1281,1182,1134cm-1
NMR(DMSO-d6,δ):2.00-5.20(18H,m),6.40-7.40(3H,m),7.50-8.50(5H,m),8.70-9.00(2H,m)
MASS(APCI):584(M+H)+(游离)
(11)(2R)-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
[α]D 28:+23.27°(C=0.245,MeOH)
IR(KBr):1741,1707,1693,1678,1645,1628,1616,1562,1547,1516,1464,1423,1344,1317,1273,1242,1215,1169,1126,1051cm-1
NMR(DMSO-d6,δ):2.00-5.20(20H,m),6.30-8.00(8H,m)
MASS(APCI):521(M+H)+(游离)
(12)(2R)-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
[α]D 28:+24.20°(C=0.345,MeOH)
IR(KBr):1643,1635,1616,1516,1466,1423,1350,1273,1171,1126,1051cm-1
NMR(DMSO-d6,δ):0.80-5.30(17H,m),6.00-9.00(10H,m)
MASS(APCI):518(M+H)+(游离)
(13)(2R)-2-(4-氟-3-甲氧基苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
[α]D 27.1:+25.77°(C=0.26,MeOH)
IR(KBr):1645,1635,1628,1618,1516,1464,1425,1171,1128,1088,1047cm-1
NMR(DMSO-d6,δ):1.60-5.30(21H,m),6.00-9.00(10H,m)
MASS(APCI):54 6(M+H)+(游离)
(14)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-羟基苄基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:160-170℃
[α]D 27.6:-4.45°(C=0.55,MeOH)
IR(KBr):1693,1674,1645,1630,1533,1516,1477,1446,1437,1429,1392,1387,1365,1282,1180,1138,1057cm-1
NMR(DMSO-d6,δ):0.80-5.20(14H,m),6.00-8.40(8H,m)
MASS(APCI):545(M+H)+(游离)
(15)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-羟基苄基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:50-60℃
[α]D 27.6:-0.95°(C=0.37,MeOH)
IR(KBr):1707,1693,1676,1645,1628,1618,1558,1547,1533,1516,1477,1466,1454,1429,1392,1387,1367,1281,1180,1136cm-1
NMR(DMSO-d6,δ):0.80-5.20(11H,m),6.00-9.20(10H,m)
MASS(APCI):542(M+H)+(游离)
(16)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-羟基苄基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
mp:80-95℃
[α]D 26.5:-3.51°(C=0.285,MeOH)
IR(KBr):1647,1518,1281,1180,1136cm-1
NMR(DMSO-d6,δ):2.00-5.20(15H,m),6.30-7.20(3H,m),7.40-8.40(5H,m),8.60-8.80(2H,m),9.78(1H,br)
MASS(APCI):570(M+H)+(游离)
(17)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯苄基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:210-245℃(分解)
[α]D 27.6:-8.83°(C=0.283,MeOH)
IR(KBr):1647,151 6,1508,1498,1464,1454,1446,1427,1362,1281,1182,1138,1057,1020cm-1
NMR(DMSO-d6,δ):2.00-5.40(14H,m),6.80-8.30(9H,m)
MASS(APCI):54 5(M+H)+(游离)
(18)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯苄基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:220-228℃(分解)
[α]D 27.7:-5.58°(C=0.26,MeOH)
IR(KBr):1643,1495,1489,1468,1429,1363,1319,1284,1279,1186,1136,1053cm-1
NMR(DMSO-d6,δ):2.00-5.80(11H,m),6.70-9.10(11H,m)
MASS(APCI):542(M+H)+(游离)
(19)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯苄基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
mp:60-100℃
[α]D 28.3:-5.74°(C=0.27,MeOH)
IR(KBr):1645,1551,1514,1498,1468,1429,1363,1319,1281,1184,1136,1103,1039,1024cm-1
NMR(DMSO-d6,δ):2.00-5.40(15H,m),6.80-9.00(11H,m)
MASS(APCI):570(M+H)+(游离)
(20)(2R)-2-〔4-氯苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:70-100℃
[α]D 27.8:+1.84°(C=0.435,MeOH)
IR(KBr):1693,1641,1635,1628,1604,1550,1547,1539,1516,1498,1466,1437,1414,1352,1269,1169,1128,1092,1051cm-1
NMR(DMSO-d6,δ):2.60-5.20(17H,m),6.50-8.10(9H,m)
MASS(APCI):507(M+H)+(游离)
(21)(2R)-2-〔4-氯苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:60-80℃
[α]D 27.8:+10.56°(C=0.27,MeOH)
IR(KBr):1643,1610,1496,1466,1421,1373,1350,1315,1271,1242,1174,1130,1097,1049cm-1
NMR(DMSO-d6,δ):2.60-5.20(14H,m),6.40-9.20(11H,m)
MASS(APCI):504(M+H)+(游离)
(22)(2R)-2-〔4-氯苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐。
mp:60-100℃
[α]D 28.3:+4.08°(C=0.245,MeOH)
IR(KBr):1643,1606,1558,1550,1516,1496,1466,1421,1350,1317,1271,1242,1173,1128,1097,1051cm-1
NMR(DMSO-d6,δ):1.80-5.40(18H,m),6.40-9.00(11H,m)
MASS(APCI):532(M+H)+(游离)
(23)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟苄基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:143.3-146.4℃
[α]D 26.6:-5.60°(C=0.25,MeOH)
IR(KBr):1647,1513,1427,1282,1182,1135cm-1
NMR(DMSO-d6,δ):2.80-5.04(14H,m),6.96-8.23(9H,m)
MASS:529(M+H)+(游离)
(24)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟苄基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:130.0-137.3℃
[α]D 26:-13.03°(C=0.33,MeOH)
IR(KBr):1645,1427,1282,1184,1133cm-1
NMR(DMSO-d6,δ):2.84-5.01(11H,m),6.94-9.05(11H,m)
MASS:526(M+H)+(游离)
(25)(2R)-2-〔4-氟苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕哌嗪盐酸盐。
mp:225.6-228.4℃
[α]D 27.5:+8.84°(C=0.25,MeOH)
IR(KBr):1635,1413,1351,1238,1158,1122,1049cm-1
NMR(DMSO-d6,δ):2.85-5.03(17H,m),6.59-8.45(9H,m)
MASS:491(M+H)+(游离)
(26)(2R)-2-〔4-氟苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:81.4-84.3℃
[α]D 27.1:+15.58°(C=0.50,MeOH)
IR(KBr):1643,1606,1513,1465,1423,1349,1172,1128cm-1
NMR(DMSO-d6,δ):2.95-5.00(14H,m),6.58-7.32(7H,m),7.80-9.03(4H,m)
MASS:488(M+H)+(游离)
(27)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕-2-〔2-萘基甲基〕哌嗪盐酸盐。
mp:>250℃
[α]D 25.2:-19.62°(C=0.26,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.8-5.3(11H,m),3.78(3H,s),6.96(1H,d,J=8.1Hz),7.4-8.2(11H,m)
MASS(APCI):561(M+H)+(游离)
(28)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔2-萘基甲基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:198-208℃
[α]D 24.8:-12.81°(C=0.26,MeOH)
IR(KBr):3430,2590,1640cm-1
NMR(DMSO-d6,δ):3.0-5.2(11H,m),6.95(1H,d,J=7.7Hz),7.4-8.0(9H,m),8.17(1H,m),8.54(1H,d,J=8.0Hz),8.80(1H,br s),9.00(1H,s)
MASS(APCI):558(M+H)+(游离)
(29)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔(1-甲基-1H-吡唑-4-基)甲基〕-2-〔2-萘基甲基〕哌嗪盐酸盐。
mp:226-228℃
[α]D 27.2:-2.55°(C=0.28,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.9-5.3(17H,m),6.6-8.0(12H,m)
MASS(APCI):523(M+H)+(游离)
(30)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-〔2-萘基甲基〕-4-〔3-吡啶基甲基〕哌嗪二盐酸盐。
mp:162-168℃
[α]D 27.6:-1.41°(C=0.29,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.8-5.3(11H,m),3.65和3.73(3H,s),6.5-8.0(11H,m),8.51(1H,d,J=8.7Hz),8.80(1H,m),8.98(1H,s)
MASS(APCI):520(M+H)+(游离)
(31)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔2-〔3-吡啶基〕乙基〕哌嗪。
IR(净):1674,1643,1581,1547,1510,1429,1381,1356,1350,1333,1279,1132,1097,1012cm-1
NMR(CDCl3,δ):0.70-5.50(25H,m),6.20-8.80(10H,m)
MASS(APCI):640(M+H)+
(32)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-〔3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪-4-基〕乙基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕哌嗪。
IR(净):167 8,1645,1628,1618,1510,1477,1462,1454,1435,1427,1385,1381,1275cm-1
NMR(CDCl3,δ):0.70-5.60(29H,m),6.20-8.00(9H,m)
MASS(APCI):697(M+H)+
(33)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔(三苯甲基-1H-吡唑-4-基)甲基〕哌嗪。
[α]D 27.2:-26.15°(C=0.260,MeOH)
IR(净):1645,1450,1280,1130,1020cm-1
NMR(CDCl3,δ):1.86-5.40(23H,m),6.30-7.90(23H,m)
MASS(API-ES):857(M+)
(34)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔1-甲基-1H-吡唑-4-基甲基〕-2-〔4-(三氟甲基)苄基〕哌嗪盐酸盐。
mp:218-223℃
[α]D 27:+18.73°(C=0.25,MeOH)
IR(KBr):3437,3400,1645cm-1
NMR(DMSO-d6,δ):2.80-5.30(11H,m),3.80(3H,s),3.85(3H,s),6.48-7.94(9H,m)
MASS(APCI):541(M+H)+(游离)
(35)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-吡啶基甲基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐。
mp:101-108℃
[α]D 27:+15.60°(C=0.25,MeOH)
IR(KBr):3431,1643,1518cm-1
NMR(DMSO-d6,δ):2.80-5.20(11H,m),3.83(3H,s),6.42-7.90(8H,m),8.56(1H,d,J=7.6Hz),8.84(1H,d,J=5.2Hz),9.01(1H,s)
MASS(APCI):538(M+H)+(游离)
实施例13
5℃下(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(651.9mg)的四氢呋喃(6.5ml)溶液中加入氟化四丁基铵(1M的四氢呋喃溶液,0.85ml),室温搅拌后,混合物蒸发,柱层析(硅胶,65ml,甲醇∶二氯甲烷=3∶97)纯化得到油状物(381.5mg)。油状物的甲醇(3ml)溶液中加入2.17M的氯化氢的甲醇(1.43ml)溶液,混合物浓缩得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐,为固体。该固体室温下用丙酮(4.55ml)和水(13.9ul)的混合溶液重结晶,然后0℃下重结晶,在45℃下减压干燥,得到纯品(393.9mg)粉末。
mp:206-224.5℃
IR(KBr):1635cm-1
NMR(D2O,δ):2.16(3H,s),2.60-5.30(22H,m),3.40(3H,s),6.30-8.10(6H,m)
MASS(APCI):604(M+H)+(游离)
实施例14
根据类似实施例13的方法得到下述化合物。
(1)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-硝基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:181-185℃
[α]D 23:+24.00°(C=0.25,MeOH)
IR(KBr):1641cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.80-5.10(25H,m),6.18-8.55(6H,m)
MASS(APCI):581(M+H)+(游离)
(2)(2R)-1-〔3-二甲氨基-5-(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
mp:182-186℃
[α]D 23:+27.00°(C=0.25,MeOH)
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):2.06(3H,s),2.94(6H,br s),2.70-5.20(25H,m),6.24-7.00(6H,m)
MASS(APCI):579(M+H)+(游离)
(3)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-甲基氨基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:159-170℃
[α]D 22:+23.60°(C=0.125,MeOH)
IR(KBr):3433,3400,1643cm-1
NMR(DMSO-d6,δ):2.06(3H,s),2.68(3H,br s),2.80-5.10(25H,m),6.10-7.00(6H,m)
MASS(APCI):565.37(M+H)+(游离)
(4)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-(吡咯-1-基)-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:159-170℃
[α]D 24:+1.20°(C=0.125,MeOH)
IR(KBr):3433,3400,1636,1494cm-1
NMR(DMSO-d6,δ):2.05(3H,s),2.80-5.10(25H,m),6.10-8.02(10H,m)
MASS(APCI):601.4(M+H)+(游离)
(5)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-甲氧基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:160-169℃
[α]D 24:+6.80°(C=0.125,MeOH)
IR(KBr):3430,3400,1643,1461cm-1
NMR(DMSO-d6,δ):2.07(3H,s),3.27(3H,s),3.93(3H,br s),2.40-4.10(22H,m),6.10-7.40(6H,m)
MASS(APCI):566(M+H)+(游离)
(6)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-甲硫基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:154-168℃
[α]D 24:+5.87°(C=0.125,MeOH)
IR(KBr):3431,3400,1639cm-1
NMR(DMSO-d6,δ):2.09(3H,s),3.27(3H,s),2.40-5.10(25H,m),6.17-7.60(6H,m)
MASS(APCI):582(M+H)+(游离)
(7)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-甲基磺酰基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:173.5-178.0℃
[α]D 25:-19.07°(C=0.125,MeOH)
IR(KBr):3437,3402,1645cm-1
NMR(DMSO-d6,δ):2.08 (3H,s),3.27(3H,s),3.37(3H,s),2.20-5.10(22H,m),6.21-8.31(6H,m)
MASS(APCI):614(M+H)+(游离)
(8)(2R)-1-(3-二甲基氨磺酰基-5-(三氟甲基)苯甲酰基)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
mp:153.5-160℃
[α]D 25:-15.60°(C=0.125,MeOH)
IR(KBr):3400,1643,1516cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.66(6H,s),2.40-5.20(25H,m),6.18-8.01(6H,m)
MASS(APCI):643.3 6(M+H)+(游离)
(9)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-甲基氨磺酰基-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:120-187℃
[α]D 25:-15.07°(C=0.125,MeOH)
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.60-5.10(28H,m),6.17-8.10(6H,m)
MASS(APCI):629(M+H)+(游离)
(10)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-(1-吡咯烷基磺酰基)-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:125-177℃
[α]D 24:-11.10°(C=0.25,MeOH)
IR(KBr):1645cm-1
NMR(DMSO-d6,δ):1.60-1.76(4H,m),2.07(3H,s),2.4 9-5.20(29H,m),6.20-8.02(6H,m)
MASS(APCI):6 69(M+H)+(游离)
(11)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-吗啉子基磺酰基)-5-(三氟甲基)苯甲酰基)哌嗪二盐酸盐
mp:130-175℃
[α]D 25:-8.60°(C=0.25,MeOH)
IR(KBr):1645cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.60-5.10(33H,m),6.20-8.01(6H,m)
MASS(APCI):685(M+H)+(游离)
(12)(2R)-2-(3-羟基-4-甲基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-(3-(4-吡啶基)-5-(三氟甲基)苯甲酰基)哌嗪三盐酸盐
mp:169-173℃
[α]D 28:-1.60°(C=0.125,MeOH)
IR(KBr):1635cm-1
NMR(DMSO-d6,δ):1.91-2.04(3H,m),2.84-5.20(25H,m),
6.17-8.37(8H,m),8.96(2H,d,J=5.9Hz)
MASS(APCI):613(M+H)+(游离)
(13)(2R)-1-(3-三氟甲基-5-(甲硫基)苯甲酰基)-2-〔4-氯-3-羟基苄基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐
mp:162-178℃
[α]D 26.2:+6.42°(C=0.226,MeOH)
IR(KBr):3400,2665,2600,2488,1643,1425,1331,1311,1174,1130,1043cm-1
NMR(DMSO-d6-D2O,δ):1.17(6H,d,J=6.2Hz),2.40-5.20(21H,m),6.26-7.70(6H,m)
MASS(APCI):586(M+H)+(游离),552
(14)(2R)-1-(3-三氟甲基-5-(甲硫基)苯甲酰基)-2-〔4-氯-3-羟基苄基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
mp:169-178℃
[α]D 26.4:-7.99°(C=0.263,MeOH)
IR(KBr):3400,2679,2561,1645,1425,1173,1130,1053cm-1
NMR(DMSO-d6-D2O,δ):2.40-5.40(22H,m),6.20-8.80(9H,m)
MASS(APCI):605(M+H)+(游离),571
(15)(2R)-1-(3-(2,5-二甲基吡咯-1-基磺酰基)-5-(三氟甲基)苯甲酰基)-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪
IR(KBr):1637cm-1
NMR(DMSO-d6,δ):2.05(3H,s),2.30(6H,s),1.78-4.80(25H,m),6.05(2H,s),6.00-9.17(6H,m)
MASS(APCI):693(M+H)+
(16)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(1-(2-羟乙基)-1H-吡唑-4-基)甲基〕哌嗪盐酸盐
mp:140-156℃
[α]D 22.3:-15.68°(C=0.204,MeOH)
IR(KBr):3400,1645,1427,1279,1180,1134cm-1
NMR(DMSO-d6-D2O,δ):2.02-5.20(18H,m),6.14-8.26(8H,m)
MASS(APCI):571(M+H)+(游离)
实施例15
根据实施例3的类似方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(1-甲基-1H-吡唑-4-基)-甲基〕哌嗪盐酸盐
mp:160-180℃
[α]D 27.0:-13.28°(C=0.32,MeOH)
IR(KBr):2976,1643,1446,1427,1381,1363,1323,1281,1217,1182,1142,1088,1049cm-1
NMR(DMSO-d6,δ):1.60-5.20(17H,m),5.90-8.30(8H,m)
MASS(APCI):541(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-吡啶基甲基〕哌嗪二盐酸盐
mp:110-130℃
[α]D 27.0:-7.75°(C=0.4,MeOH)
IR(KBr):1643,1558,1550,1541,1516,1464,1454,1427,1365,1319,1281,1242,1184,1138,1053cm-1
NMR(DMSO-d6,δ):1.70-5.80(14H,m),6.00-9.50(1H,m)
MASS(APCI):538(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
mp:255-270℃
[α]D 25.1:-22.88°(C=0.295,MeOH)
IR(KBr):1643,1635,1562,1550,1516,14 62,1427,1365,1327,1282,1244,1184,1138,1041,1003cm-1
NMR(DMSO-d6,δ):0.80-5.40(22H,m),6.00-8.8 0(9H,m)
MASS(APCI):607(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(Z)-3-〔3-吡啶基〕-2-丙烯基〕哌嗪二盐酸盐
mp:85-130℃
[α]D 22.9:+2.86°(C=0.28,MeOH)
IR(KBr):1643,1550,1516,1462,1427,1362,1325,1282,1184,1136,1045,1001cm-1
NMR(DMSO-d6,δ):0.70-5.20(14H,m),6.00-10.00(12H,m)
MASS(APCI):5 64(M+H)+(游离)
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁炔基〕哌嗪
IR(KBr):1741,1707,1693,1678,1645,1562,15581547,1539,1516,1454,1141,1109cm-1
NMR(DMSO-d6,δ):0.70-5.00(28H,m),6.00-8.20(6H,m)
MASS(APCI):628(M+H)+
(6)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔4-〔(2S,5S)-2-甲氧基甲基-5-甲基吗啉代〕-2-丁炔基〕哌嗪二盐酸盐
mp:110-135℃
[α]D 29:+3.40°(C=0.25,MeOH)
IR(KBr):1645cm-1
NMR(DMSO-d6,δ):1.16(3H,d,J=6.2Hz),2.08(3H,br s),3.25(3H,s),2.52-5.20(21H,m),6.17-8.20(6H,m)
MASS(APCI):642(M+H)+(游离)
(7)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-〔(1R,4S)-3,3-二甲基-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基〕乙基〕哌嗪二盐酸盐
mp:173-185℃
[α]D 27:+14.20°(C=0.25,MeOH)
IR(KBr):3400,2981,1643cm-1
NMR(DMSO-d6,δ):1.18(3H,s),1.49(3H,s),2.09(3H,s),2.20-5.10(19H,m),6.20-8.25(6H,m)
MASS(APCI):600(M+H)+(游离)
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-〔(2R)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐
mp:225-235℃
[α]D 26.6:-13.02°(C=0.315,MeOH)
IR(KBr):1645,151 ,1454,1425,1365,1321,1281,1190,1134,1001cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.50-5.20(25H,m),6.00-8.30(6H,m)
MASS(APCI):604(M+H)+(游离)
(9)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-〔(3S,5S)-3,5-二甲基吗啉代〕乙基〕-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐
mp:240-250℃
[α]D 26.7:+10.24°(C=0.21,MeOH)
IR(KBr):1645,1516,1454,1427,1387,1365,1327,1281,1184,1136,1041cm-1
NMR(DMSO-d6,δ):1.00-1.60(6H,m),2.08(3H,s),2.30-5.20(19H,m),6.10-8.30(6H,m)
MASS(APCI):588(M+H)+(游离)
(10)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-〔顺-3,5-二甲基吗啉代〕乙基〕-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐
mp:210-220℃
[α]D 25.2:-9.81°(C=0.26,MeOH)
IR(KBr):1676,1643,1533,1516,1454,1425,1387,1367,1327,1281,1236,1182,1134,1057cm-1
NMR(DMSO-d6,δ):0.80-5.30(28H,m),6.10-8.40(6H,m)
MASS(APCI):588(M+H)+(游离)
(11)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔3-〔(2S)-2-(甲氧基甲基)吗啉代)丙基〕哌嗪二盐酸盐
mp:150-170℃
[α]D 25:-10.50°(C=0.30,MeOH)
IR(KBr):1678,1655,1649,1531,1514,1454,1446,1429,1392,1387,1365,1327,1321,1282,1186,1136cm-1
NMR(DMSO-d6,δ):1.60-5.30(30H,m),5.90-8.50(6H,m)
MASS(APCI):618(M+H)+(游离)
(12)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(E)-4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁烯基〕哌嗪二盐酸盐
mp:50-70℃
[α]D 25:-4.79°(C=0.24,MeOH)
IR(KBr):1772,1739,1678,1514,1498,1454,1429,1363,1325,1282,1186,1134cm-1
NMR(DMSO-d6,δ):1.80-5.20(30H,m),5.70-8.40(6H,m)
MASS(APCI):630 (M+H)+(游离)
(13)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-(3-吡啶基)乙基〕哌嗪二盐酸盐
mp:90-120℃
[α]D 26.9:-4.19°(C=0.215,MeOH)
IR(KBr):1643,1550,1516,1466,1454,1427,1365,1327,1281,1184,1138cm-1
NMR(DMSO-d6,δ):0.70-5.20(16H,m),
6.00-8.90(10H,m)
MASS(APCI):552(M+H)+(游离)
(14)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-(4,5,6,7-四氢噻吩并[3,2-c]-吡啶-5-基)乙基〕哌嗪二盐酸盐
mp:245-265℃
[α]D 27.9:-2.78°(C=0.27,MeOH)
IR(KBr):1693,1674,1645,1547,1533,1516,1454,1427,1365,1329,1281,1182,1138,1041cm-1
NMR(DMSO-d6,δ):1.60-5.50(22H,m),6.00-8.40(8H,m)
MASS(APCI):612(M+H)+(游离)
(15)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(3,4,-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪-4-基)乙基〕-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐
mp:190-200℃
[α]D 26.9:+6.7 9°(C=0.265,MeOH)
IR(KBr):1641,1618,1566,1454,1427,1281,1184,1132,1066,1032cm-1
NMR(DMSO-d6,δ):0.70-5.60(20H,m),6.00-8.40(9H,m)
MASS(APCI):609 (M+H)+(游离)
(16)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔6-喹啉基甲基〕哌嗪二盐酸盐
mp:170-200℃
[α]D 25.8:-28.54°(C=0.247,MeOH)
IR(KBr):1724,1707,1645,1514,1454,1427,1385,1365,1311,1281,1180,1136cm-1
NMR(DMSO-d6,δ):0.70-5.10(15H,m),6.00-9.40(12H,m)
MASS(APCI):588(M+H)+(游离)
实施例16
根据制备41类似的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪
NMR(CDCl3,δ):1.09(9H,s),1.89-4.90(22H,m),2.35(3H,s),3.38(3H,s),6.10-7.92(16H,m)
MASS(ESO+):842.4(M+H)+
(2)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-硝基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(Neat):1641cm-1
NMR(CDCl3,δ):1.09(9H,s),2.37(3H,s),1.89-4.80(22H,m),3.35(3H,s),6.00-8.40(16H,m)
MASS(ESI+):819.3(M+H)+
(3)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-1-〔3-二甲基氨基-5-(三氟甲基)苯甲酰基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪
IR(KBr):1641,1608cm-1
NMR(CDCl3,δ):1.50(9H,s),2.25(3H,br s),2.95(6H,br s),3.35(3H,s),1.80-4.80(22H,m),6.05-7.80(16H,m)
MASS(ESI+):817.4(M+H)+
(4)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲基氨基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1614cm-1
NMR(DMSO-d6,δ):1.03(9H,s),1.70-4.80(28H,m),2.26(3H,br s),6.00-7.70(16H,m)
MASS(ESI+):803.4(M+H)+,825.3(M+Na)+
(5)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-(1-吡咯基)-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):1.00-1.04(9H,m),1.70-4.80(28H,m),6.00-8.00(20H,m)
MASS(ESI+):839.4(M+H)+,861.4(M+Na)+
(6)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):2939,1643,1512,1462,1423cm-1
NMR(DMSO-d6,δ):1.04(9H,s),2.22(3H,s),1.71-4.60(28H,m),5.99-7.75(16H,m)
MASS(ESI+):804.4(M+H)+,826.3(M+Na)+
(7)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲基硫基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):2933,1641,1510,1421cm-1
NMR(DMSO-d6,δ):1.04(9H,s),2.29(3H,s),3.18(3H,s),1.70-4.70(25H,m),6.00-7.80(16H,m)
MASS(ESI+):820.3(M+H)+,842.3(M+Na)+
(8)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲基磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1643cm-1
NMR(CDCl300,δ):1.03(9H,br s),1.72-4.60(28H,m),2.28(3H,br s),6.02-8.28(16H,m)
MASS(ESI+):852.3(M+H)+,874.3(M+Na)+
(9)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-1-〔3-二甲基氨基磺酰基-5-(三氟甲基)苯甲酰基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪
IR(KBr):1639cm-1
NMR(DMSO-d6,δ):1.04(9H,s),1.71-4.70(31H,m),2.28(3H,br s),6.04-8.00(16H,m)
MASS(ESI+):881.4(M+H)+,904.3(M+Na)+
(10)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-甲基氨基磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):1.04-1.05(9H,m),1.70-4.60(28H,m),2.28(3H,br s),6.03-8.07(16H,m)
MASS(ESI+):867.3(M+H)+
(11)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-吡咯烷子基磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1643cm-1
NMR(CDCl3,δ):1.09(9H,s),1.75-1.82(4H,m),2.35(3H,s),2.05-4.80(29H,m),6.00-8.65(16H,m)
MASS(ESI+):907(M+H)+
(12)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-吗啉代磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1645cm-1
NMR(CDCl3,δ):1.09(9H,s),2.35(3H,s),2.46-4.80(33H,m),6.00-8.56(16H,m)
MASS(ESI+):923.4(M+H)+
(13)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1645cm-1
NMR(CDCl3,δ):0.99-1.02(9H,m),1.80-4.80(28H,m),6.00-8.16(18H,m),8.70(2H,d,J=5.6Hz)
MASS(ESI+):851.4(M+H)+,873.3(M+Na)+
(14)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-硝基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:133.3-136.2℃
[α]D 26:+5.62°(C=0.61,MeOH)
IR(KBr):1645,1547,1327,1182,1143cm-1
NMR(DMSO-d6,δ):1.02 and 1.14(6H,d,J=6.2Hz),2.71-4.53(19H,m),6.95-8.52(7H,m)
MASS:569(M+)(游离)
(15)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-甲基氨基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:245.6-248.7℃
[α]D 26.4:+21.44°(C=0.26,MeOH)
IR(KBr):1612,1494,1427,1182,1143,1095cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.0Hz),2.68(3H,s),3.20-4.30(19H,m),6.14-7.47(7H,m)
MASS:553(M+)(游离)
(16)(2R)-2-(4-氯苄基)-1-〔3-二甲基氨基-5-(三氟甲基)苯甲酰基〕-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪二盐酸盐
mp:148.2-153.3℃
[α]D 26.6:+19.82°(C=0.36,MeOH)
IR(KBr):1645,1464,1425,1182,1138cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.0Hz),2.94(6H,s),3.40-4.20(19H,m),6.20-7.38(7H,m)
MASS:567(M+)(游离)
(17)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-甲基硫基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:138.4-142.5℃
[α]D 26.6:+7.55°(C=0.26,MeOH)
IR(KBr):1643,1417,1330,1176,1128,1099cm-1
NMR(DMSO-d6,δ):1.02和1.15(6H,d,J=6.2Hz),2.54(3H,s),2.71-3.99(19H,m),6.69-7.91(7H,m)
MASS:570(M+)(游离)
(18)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-甲基磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:138.4-142.5℃
[α]D 26.7:+7.55°(C=0.26,MeOH)
IR(KBr):1645,1462,1423,1328,1303,1182,1144cm-1
NMR(DMSO-d6,δ):1.16(6H,d,J=6.1Hz),2.55-4.05(19H,m),3.38(3H,s),6.98-8.32(7H,m)
MASS:602(M+)(游离)
(19)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-二甲基氨基磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:209.6-213.7℃
[α]D 26.5:+4..44°(C=0.31,MeOH)
IR(KBr):1645,1461,1423,1344,1173,1146,1103cm-1
NMR(DMSO-d6,δ):1.17(6H,d,J=6.0Hz),2.66(6H,s),3.00-4.46(19H,m),7.03-8.00(7H,m)
MASS:631(M+)(游离)
(20)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-(1-吡咯基)-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:152.7-157.9℃
[α]D 26.2:+5.96°(C=0.55,MeOH)
IR(KBr):1345,1496,1178,1130cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=5.9Hz),2.70-4.20(19H,m),6.34(2H,s),6.96-7.91(9H,m)
MASS:589(M+)(游离)
(21)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-(4-吡咯基)-5-(三氟甲基)苯甲酰基〕哌嗪三盐酸盐
mp:287.7-289.1℃
[α]D 26.9:-3.00°(C=0.36,MeOH)
IR(KBr):1641,1635,1427,1270,1178,1130cm-1
NMR(DMSO-d6,δ):1.08(6H,d,J=6.0Hz),2.73-5.15(19H,m),6.94-8.97(11H,m)
MASS:601(M+)(游离)
(22)(2R)-2-(4-氯苄基)-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪二盐酸盐
mp:136.4-141.0℃
[α]D 26.8:+1.06°(C=0.45,MeOH)
IR(KBr):1644,1417,1326,1178,1135,1095cm-1
NMR(DMSO-d6,δ):1.02 and 1.15(6H,d,J=6.1Hz),2.60-4.12(19H,m),6.93-7.96(7H,m)
MASS:560(M+H)+(游离)
(23)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-氟-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:80.1-82.5℃
[α]D 27.0:+3.54°(C=0.30,MeOH)
IR(KBr):1645,1427,1344,1178,1136,1091cm-1
NMR(DMSO-d6,δ):1.16(6H,d,J=6.1Hz),2.60-4.53(19H,m),6.78-7.78(7H,m)
MASS:542(M+)(游离)
(24)(2R)-2-(4-氯苄基)-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕-1-〔3-甲基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
mp:82.3-88.2℃
[α]D 26.5:+4.05°(C=0.315,MeOH)
IR(KBr):1643,1635,1425,1174,1128cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.32-4.10(22H,m),6.68-7.57(7H,m)
MASS:539(M+H)+(游离)
(25)(2R)-2-(4-氯苄基)-1-〔3,5-二氯苯甲酰基〕-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪二盐酸盐
mp:140.1-143.8℃
[α]D 25.7:+3.25°(C=0.55,MeOH)
IR(KBr):1643,1452,1446,1409,1330,1277,1092,1036cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.2Hz),2.72-4.15(19H,m),6.56-7.64(7H,m)
MASS:524(M+)(游离)
(26)(2R)-2-(4-氯苄基)-1-〔3-硝基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:221-228℃
[α]D 27.2:-11.50°(C=0.30,MeOH)
IR(KBr):3430,3400,1640,1550,1470,1420cm-1
NMR(DMSO-d6,δ):2.6-5.2(19H,m),6.8-8.8(10H,m)
MASS(APCI):588(M+H)+(游离)
(27)(2R)-2-(4-氯苄基)-1-〔3-甲基氨基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:199-245℃
[α]D 27.1:+2.31°(C=0.26,MeOH)
IR(KBr):3430,3400,1630,1510,1460,1430cm-1
NMR(DMSO-d6,δ):2.69(3H,s),2.8-5.3(19H,m),6.41(1H,s),6.83(1H,s),6.9-7.5(5H,m),7.71(1H,dd,J=5,8Hz),8.11(1H,d,J=8Hz),8.70(1H,d,J=5Hz)
MASS(APCI):572(M+H)+(游离)
(28)(2R)-2-(4-氯苄基)-1-〔3-甲基硫基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:182-195℃
[α]D 26.8:-9.58°(C=0.24,MeOH)
IR(KBr):3430,3400,1640,1460,1420cm-1
NMR(DMSO-d6,δ):2.55(3H,s),2.6-5.2(19H,m),6.6-8.7(10H,m)
MASS(APCI):58 9(M+H)+(游离)
(29)(2R)-2-(4-氯苄基)-1-〔3-甲磺酰基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:198-213℃
[α]D 26.8:-13.71°(C=0.28,MeOH)
IR (KBr):3430,3400,1640,14 60,1420cm-1
NMR(DMSO-d6,δ):2.6-5.2(19H,m),3.39(3H,s),6.9-8.2(8H,m),8.33(1H,s),8.67(1H,d,J=5Hz)
MASS:621(M+H)+(游离)
(30)(2R)-2-(4-氯苄基)-1-〔3-二甲基氨磺酰基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:209-226℃
[α]D 26.8:-8.38°(C=0.24,MeOH)
IR(KBr):3740,1680,1640,1520,1460cm-1
NMR(DMSO-d6,δ):2.67(6H,s),2.8-5.2(19H,m),6.9-8.7(10H,m)
MASS:650(M+H)+(游离)
(31)(2R)-2-(4-氯苄基)-1-〔3-(1-吡咯基)-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:184-191℃
[α]D 26.7:-12.13°(C=0.40,MeOH)
IR(KBr):3400,1640,1500,1430cm-1
NMR(DMSO-d6,δ):2.8-5.3(19H,m),6.2-8.7(14H,m)
MASS:608(M+H)+(游离)
(32)(2R)-2-(4-氯苄基)-1-〔3-(4-吡啶基)-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪四盐酸盐
mp:206-217℃
[α]D 25.8:-20.08°(C=0.27,MeOH)
IR(KBr):3430,3400,1640,1510,1430cm-1
NMR(DMSO-d6,δ):2.7-6.2(19H,m),6.8-8.1(8H,m),8.10(1H,d,J=8.5Hz),8.41(2H,d,J=6.5Hz),8.70(1H,d,J=4.4Hz),9.04(2H,d,J=6.5Hz)
MASS(API-ES):620(M+H)+(游离)
(33)(2R)-2-(4-氯苄基)-1-〔3-氯-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:130.6-135.7℃
[α]D 26.6:-12.12°(C=0.60,MeOH)
IR(KBr):1643,1635,1417,1326,1321,1178,1135cm-1
NMR(DMSO-d6,δ):2.79-4.78(19H,m),7.02-8.66(10H,m)
MASS:577(M+)(游离)
(34)(2R)-2-(4-氯苄基)-1-〔3-氟-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:127.3-130.9℃
[α]D 26.4:-10.20°(C=0.51,MeOH)
IR(KBr):1643,1635,1629,1425,1178,1135cm-1
NMR(DMSO-d6,δ):2.80-4.60(19H,m),6.80-8.63(10H,m)
MASS:561(M+)(游离)
(35)(2R)-2-(4-氯苄基)-1-〔3-甲基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:102.5-110.4℃
[α]D 26.8:-13.35°(C=0.310,MeOH)
IR(KBr):1643,1635,1423,1419,1173,1128cm-1
NMR(DMSO-d6,δ):2.35(2H,m),2.51-4.49(20H,m),7.03-8.69(10H,m)
MASS:557(M+)(游离)
(36)(2R)-2-(4-氯苄基)-1-〔3-二甲基氨基-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪三盐酸盐
mp:209-214℃
[α]D 27.1:+1.51°(C=0.27,MeOH)
IR(KBr):3430,3400,1640,1500,1460,1420cm-1
NMR(DMSO-d6,δ):2.8-5.3(19H,m),2.95(6H,s),6.1-7.5(7H,m),7.65(1H,dd,J=5,8Hz),8.05(1H,d,J=8Hz),8.67(1H,d,J=5Hz)
MASS:586(M+H)+(游离)
(37)(2R)-2-(3-叔丁基二苯基甲硅烷氧基-4-甲基苄基)-1-〔3-(2,5-二甲基吡咯基-1-基磺酰基)-5-(三氟甲基)-苯甲酰基〕-4-〔2-〔(2S)-2-(甲氧基甲基)-吗啉代〕乙基〕哌嗪
IR(KBr):1643cm-1
NMR(DMSO-d6,δ):1.04(9H,s),2.30(6H,br s),2.30(3H,br s),1.91-4.60(25H,m),6.05(2H,s),6.60-7.98(16H,m)
MASS(ESI+):931.3(M+H)+
实施例17
根据类似实施例11的方法,再根据类似实施例3的方法得到下述化合物。
(1)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(E)-3-(3-吡啶基)-2-丙烯基〕-哌嗪二盐酸盐
mp:60-80℃
IR(KBr):1707,1693,1676,1645,1628,1550,1539,1516,1477, 1464,1454,1427,1392,1365,1281,1182,1136,1049cm-1
NMR(DMSO-d6,δ):1.90-5.60(16H,m),6.10-9.10(10H,m)
MASS(APCI):564(M+H)+(游离)
(2)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔1-甲基-1H-吡唑-4-基〕甲基〕-哌嗪盐酸盐
IR(KBr):1707,1693,1676,1645,1562,1550,1547,1533,1516,1454,1427,1392,1363,1319,1281,1182,1138,1057cm-1
NMR(DMSO-d6,δ):1.60-5.20(17H,m),5.90-8.30(8H,m)
MASS(APCI):541(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(2-氨基噻唑-4-基)甲基〕-哌嗪二盐酸盐
mp:205-215℃
[α]D 27:-12.13°(C=0.40,MeOH)
IR(KBr):3500-3000,2700-2300,1639,1428,1280cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.60-5.20(11H,m),6.20-8.20(7H,m),8.00-9.00(2H,m)
MASS(APCI):559(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(5-氨基-1,2,4-噻二唑-3-基)甲基〕哌嗪二盐酸盐
mp:1777-182℃
[α]D 27:-31.5°(C=0.18,MeOH)
IR(KBr):3500-3000,2700-2300,1644,1278cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.60-5.20(11H,m),6.20-8.2 0(8H,m),8.00-9.00(2H,m)
MASS(APCI):560(M+H)+(游离),447
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(2-(二甲基氨基)噻唑-4-基)甲基〕哌嗪二盐酸盐
mp:162-165℃
[α]D 27:-17.6°(C=0.5,MeOH)
IR(KBr):3500-3000,2700-2300,1639,1427,1365,1280cm-1
NMR(DMSO-d6,δ):1.80-1.90(6H,m),2.07(3H s),2.60-5.20(11H,m),4.50-5.80(2H,m),5.90-8.20(7H,m)
MASS(APCI):587(M+H)+(游离)
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(3-(甲基氨基)-1,2,4-噁二唑-5-基)甲基〕哌嗪二盐酸盐
mp:145-160℃
[α]D 26:-23.1°(C=0.55,MeOH)
IR(KBr):3500-3150,2700-2300,1644,1428,1363,1280cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.66-5.20(14H,m),6.10-8.30(7H,m)
MASS(APCI):558(M+H)+(游离)
实施例18
根据类似实施例1的方法,再根据类似实施例3的方法得到下述化合物。
1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-〔(2S)-5,5-二甲基-2-(甲氧基甲基)吗啉代〕乙基〕-2-(3-羟基-4-甲基苄基)哌嗪二盐酸盐
mp:150-180℃
IR(KBr):1707,1693, 1678,1645,1628,1562,1547,1539,1533,1516,1477,1464,1454,1427,1392,1367,1281,1182,1138cm-1
NMR(DMSO-d6,δ):1.10-1.60(6H,m),2.08(3H,s),2.30-5.20(23H,m),6.10-8.30(6H,m),9.15(1H,brs)
MASS(APCI):632(M+H)+(游离)
实施例19
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁炔基〕哌嗪(0.33 g)的甲醇(10ml)溶液以Lindlar催化剂(63mg)氢化。过滤除去催化剂,滤液减压蒸发。残留物用硅胶柱层析纯化,以甲醇/二氯甲烷(1∶9)为洗脱液。收集含目的化合物的组分,减压蒸发得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔(Z)-4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁烯基〕哌嗪(0.22g)为油状物。
IR(净):1707,1693,1678,1645,1635,1547,1539,1535,1516,1464,1454,1423,1417,1405,1387cm-1
NMR(CDCl3,δ):0.60-5.20(28H,m),5.40-5.90(2H,m),6.10-8.10(6H,m)
MASS(APCI):630(M+H)+
实施例20
根据类似实施例19的方法得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基)-4-〔(Z)-3-〔3-吡啶基〕-2-丙烯基〕哌嗪。
IR(净):1670,1641,1585,1550,1510,1431,1379,1350,1329,1279,1130,1101,1012cm-1
NMR(CDCl3,δ):0.70-5.50(23H,m),5.70-6.10(1H,m),6.10-8.80(11H,m)
MASS(APCI):652(M+H)+
实施例21
根据类似实施例8的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔3-〔3-吡啶基〕丙基〕-2-(4-(三氟甲基)苄基)哌嗪二盐酸盐
mp:64-74℃
[α]D 27:+7.47°(C=0.5,MeOH)
IR(KBr):1645cm-1
NMR(DMSO-d6,δ):2.10-2.40(2H,m),2.80-5.40(13H,m),7.19-7.69(6H,m),7.97-8.03(1H,m),8.19-8.22(1H,m),8.42-8.58(1H,m),8.81(1H,d,J=5.5Hz),8.90-9.00(1H,m)
MASS(APCI):604(M+H)+(游离)
(2)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-〔3-吡啶基〕丙基〕-2-(4-(三氟甲基)苄基)哌嗪二盐酸盐
mp:70-80℃
[α]D 27:+19.49°(C=0.0065,MeOH)
IR(KBr):1643,1466,1423cm-1
NMR(DMSO-d6,δ):2.10-2.40(2H,m),2.80-5.30(13H,m),3.82(3H,s),6.41-7.70(7H,m),7.97(1H,dd,J=5.5和8.0Hz),8.45(1H,d,J=8.0Hz),8.79(1H,d,J=5.5Hz),8.88(1H,s)
MASS(APCI):566(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氟苄基)-4-〔3-〔3-吡啶基〕丙基〕哌嗪
mp:110.2-117.5℃
[α]D 28:+19.46°(C=0.34,MeOH)
IR(KBr):1644,1513,1280,1184,1135cm-1
NMR(DMSO-d6,δ):1.03(2H,d,J=6.07Hz),2.23(2H,m),2.86-5.05(11H,m),6.99-8.85(11H,m)
MASS:554(M+H)+(游离)
(4)(2R)-2-(4-氟苄基)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐
mp:111.5-118.3℃
[α]D 27.3:+11.3°(C=0.26,MeOH)
IR(KBr):1643,1511,1465,1421,1049cm-1
NMR(DMSO-d6,δ):2.21(1H,br),2.88-5.41(18H,m),6.56-8.86(11H,m),11.5(1H,br)
MASS:516(M+H)+(游离)
(5)(2R)-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-2-(2-萘基甲基)-4-〔3-〔3-吡啶基〕丙基〕哌嗪二盐酸盐
[α]D 28.2:-9.96°(C=0.24,MeOH)
IR(KBr):3400,1640cm-1
NMR(DMSO-d6,δ):2.1-2.4(2H,m),2.7-5.3(13H,m),3.61和3.71(3H,s),6.5-8.9(14H,m)
MASS:548(M+H)+(游离)
实施例22
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔〔1-三苯甲基-1H-吡唑-4-基〕甲基〕哌嗪(1.184g)的1,4-二氧六环(118ml)溶液中加入1N盐酸(71ml),得到的混合物于40℃搅拌7小时。冷却后,混合物的pH值用4N氢氧化钠溶液调至7,并将氯化钠加至混合物中,分离有机相,硫酸镁干燥,真空蒸发。残留物用硅胶柱层析纯化,以二氯甲烷和甲醇的混合溶液(30∶1)为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔〔1H-吡唑-4-基〕甲基〕哌嗪(575mg)。
IR(净):3250,1645,1280,1130cm-1
NMR(CDCl3,δ):1.95-5.22(23H,m),6.24-7.90(8H,m)
MASS(APCI):615(M+H)+(游离)
实施例23
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔〔1H-吡唑-4-基〕甲基〕哌嗪(254mg),2-溴乙醇(259mg),碳酸钾(228mg)和溴化四丁基铵(13mg)的N,N-二甲基甲酰胺(2.5ml)溶液于100℃搅拌2天。冷却后,混合物于真空中蒸发,残留物中加入水和乙酸乙酯,分离有机相,用食盐水洗涤,硫酸镁干燥,真空中蒸发,残留物用铝柱层析纯化,以二氯甲烷和甲醇(100∶1)的混合溶液为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-((2-甲氧基乙氧基)甲氧基)-4-甲基苄基〕-4-〔〔1-(2-羟乙基)-1H-吡唑-4-基〕甲基〕哌嗪(185mg)。
IR(净):3400,1640,1440,1280,1135cm-1
NMR(CDCl3,δ):1.84-5.38(27H,m),6.30-7.90(8H,m)
MASS(APCI):659(M+H)+(游离)
实施例24
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁炔基〕哌嗪(0.05g)的乙酸乙酯(5ml)溶液与4N氯化氢的乙酸乙酯(1ml)溶液反应,混合物减压浓缩,残留物用二氯甲烷和二异丙醚的混合溶液研磨,减压除去有机溶剂,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁炔基〕哌嗪二盐酸盐(0.05g)粉末。
mp:110-130℃
[α]D 25.5:-7.89°(C=0.40,MeOH)
IR(KBr):1687,1645,1516,1454,1429,1362,1327,1281,1184,1138cm-1
NMR(DMSO-d6,δ):1.70-5.30(28H,m),6.00-8.40(6H,m)
MASS(APCI):628(M+H)+(游离)
实施例25
根据类似实施例24的方法得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔(Z)-4-〔(2S)-2-(甲氧基甲基)吗啉代〕-2-丁烯基〕哌嗪二盐酸盐
mp:180-200℃
[α]D 25.6:+0.49°(C=0.205,MeOH)
IR(KBr):1693,1687,1645,1531,1516,1454,1427,1363,1321,1281,1184,1140,1003cm-1
NMR(DMSO-d6,δ):0.80-5.30(30H,m),5.80-8.40(6H,m)
MASS(APCI):630(M+H)+(游离)
实施例26
5℃和氮气氛中,2-〔3-甲氧基-4-(三氟甲基)苄基〕哌嗪二溴酸盐(109mg),碘化钾(109mg)和N,N-二异丙基乙胺(0.26ml)的N,N-二甲基甲酰胺(4ml)悬浮液中于搅拌下加入(2R)-4-(2-氯乙基)-2-〔甲氧基甲基〕吗啉盐酸盐(29mg),混合物逐步升温至室温过夜。5℃时上述搅拌着的悬浮液中加入3,5-双(三氟甲基)苯甲酰氯(118mg),并在该温度下搅拌1小时。混合物用乙酸乙酯萃取,萃取液用水洗涤,硫酸镁干燥。通常,随后进行的后处理用闪式硅胶柱层析方法,以二氯甲烷和甲醇的混合溶液(60∶1)为洗脱液,得到纯品,该纯品溶解在乙酸乙酯中,用4N氯化氢的乙酸乙酯溶液处理得到1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-甲氧基-4-(三氟甲基)苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐(22mg)粉末。
NMR(DMSO-d6,δ):2.80-5.20(28H,m),6.60-8.50(8H,m)
MASS(APCI):672(M+H)+(游离)
实施例27
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-〔(2-甲氧基乙氧基)甲氧基〕-4-甲基苄基〕-4-〔(3-溴-1,2,4-噁二唑-5-基)甲基〕哌嗪(250mg)溶解在2M氨的四氢呋喃(10ml)中,室温贮存1天,溶液减压蒸发,残留物在乙酸乙酯和食盐水之间分配,分离有机相,并用食盐水洗涤,硫酸镁干燥,减压浓缩。残留物用硅胶柱层析纯化,以二氯甲烷和甲醇的混合溶液(30∶1)洗脱,收集含目的化合物的组分,减压蒸发,用4N氯化氢的乙酸乙酯溶液处理,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔(3-氨基-1,2,4-噁二唑-5-基)甲基〕哌嗪二盐酸盐(40mg)。
mp:160-170℃
[α]D 26:-20.1°(C=0.38,MeOH)
IR(KBr):3500-3150,2700-2300,1635,1428,1280cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.60-5.20(13H,m),6.10-8.20(7H,m),8.60-9.40(2H,m)
MASS(APCI):544(M+H)+(游离)
实施例28
根据类似实施例27的方法得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔(3-(二甲基氨基)-1,2,4-噁二唑-5-基)甲基〕哌嗪二盐酸盐
mp:140-150℃
[α]D 27:-20.14°(C=0.35,MeOH)
IR(KBr):3500-3000,2700-2300,1635,1606,1430cm-1
NMR(DMSO-d6,δ):2.07(3H,s),2.92(3H,s),2.94(3H,s),2.60-5.20(11H,m),6.10-8.20(7H,m),8.60-9.60(2H,m)
MASS(APCI):572(M+H)+(游离)
实施例29
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪二盐酸盐(0.50g)在乙酸乙酯和饱和碳酸氢钠水溶液之间分配,分离有机相,用食盐水洗涤,硫酸镁干燥,真空蒸发,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(0.437g)。氮气氛和冰浴冷却下于得到的化合物的二氯甲烷溶液中依次加入4-(二甲氨基)吡啶(9mg)和trifuric酸酐(0.22ml)。搅拌1小时后,混合物中加入饱和的碳酸氢钠溶液,分离有机相,水层用二氯甲烷萃取。合并的有机相用食盐水洗涤,硫酸镁和硅胶(1.1g)干燥,真空蒸发,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-三氟甲磺酰氧基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(358mg),为油状物。
IR(净):1645,1425,1280,1210,1135cm-1
NMR(CDCl30,δ):1.90-5.14(28H,m),6.60-8.20(6H,m)
MASS(APCI):736(M+H)+
实施例30
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-三氟甲磺酰氧基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(0.10g),二苯酮亚胺(30.5mg),碳酸铯(62mg),醋酸钯(3mg),和2,2’-双(二苯基膦基)-1,1’-联萘(12.7mg)的甲苯溶液在80℃和氮气氛下搅拌22小时,冷却后,水和乙酸乙酯加入到混合物中,分离有机相,真空蒸发,用食盐水洗涤,硫酸钠干燥,真空蒸发。残留物用硅胶柱层析(NH-DM1020,Fuji Silysia Chemical Ltd.)纯化,用己烷和乙酸乙酯混合溶液(3∶1)为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-(二苯基亚甲基氨基)-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(75mg),为油状物。
[α]D 23.7:-63.51°(C=0.222,MeOH)
IR(净):2620,1625,1435cm-1
NMR(CDCl3,δ):1.86-4.84(2 8H,m),6.00-7.95(16H,m)
MASS(APCI):767(M+H)+
实施例31
50℃下(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-(二苯基亚甲基氨基)-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(65mg)的甲醇溶液用10%钯碳(6mg,50%)氢解(3个氢气压)16小时。冷却后,混合物过滤,滤液真空蒸发,残留物中加入乙酸乙酯和水,分离有机相,硫酸镁干燥,真空蒸发。残留物用硅胶柱层析(NH-DM1020,Fuji SilysiaChemical Ltd.)纯化,用己烷和乙酸乙酯混合溶液(1∶1)为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-氨基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(18mg)。得到的化合物的甲醇溶液中加入4N氯化氢的乙酸乙酯溶液(0.05ml),混合物真空蒸发,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-氨基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪三盐酸盐(20mg)。
mp:180-186℃
[α]D 24.4:+9.41°(C=0.085,MeOH)
IR(KBr):3435,2600,1645,1514,1454,1429,1365,1282,1182,1105cm-1
NMR(D2O,δ):2.20-5.35(28H,m),6.80-8.30(6H,m)
MASS(APCI):604(M+H)+(游离)
实施例32
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-氨基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(0.10g),琥珀酰亚胺(30mg)和甲醛水溶液(28mg)的乙醇混合溶液在100℃下搅拌24小时。冷却后,混合物真空蒸发,下述化合物的残留物不经纯化直接用于下步反应:
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔((2,5-二氧代吡咯烷基子基)甲基)氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪
IR(净):1705,1640,1280,1130cm-1
NMR(CDCl3,δ):1.50-5.20(34H,m),6.02-7.90(6H,m)
MASS(API-ES):714(M+)(游离)
实施例33
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔((2,5-二氧代吡咯烷基子基)甲基)氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(0.14g)的二甲基亚砜(0.42ml)溶液中加入硼氢化钠(10mg),该混合物在80℃下搅拌15小时。冷却后,混合物中加入水和乙酸乙酯,分离有机相,用食盐水洗涤,硫酸钠干燥,真空蒸发。残留物用硅胶柱层析纯化,用二氯甲烷和甲醇的混合溶液(30∶1至10∶1)洗脱,分别得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔甲基氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(37mg)和(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔((5-羟基-2-氧代吡咯烷基子基)甲基)氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(45mg)。以常规方法将每一个化合物转变为它的三盐酸盐。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔甲基氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪三盐酸盐。
mp:156-163℃
[α]D 25.9:-1.79°(C=0.003,MeOH)
IR(KBr):3425,2669,2605,2451,1647,1516,1462,1429,1281,1134,1105cm-1
NMR(D2O,δ):2.05-5.57(31H,m),6.74-8.25(6H,m)
MASS(APCI):617(M+H)+(游离),581
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-〔((5-羟基-2-氧代吡咯烷基子基)甲基)氨基〕苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪三盐酸盐
mp:163-176℃
IR(KBr):3400,2586,2443,1647,1454,1427,1369,1281,1174,1134,1103cm-1
NMR(D2O,δ):1.70-6.50(35H,m),6.70-8.30(6H,m)
MASS(APCI):716(M+H)+(游离)
实施例34
根据类似实施例30的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-吡咯烷基子基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪三盐酸盐
mp:160-165℃
[α]D 24.6:+20.83°(C=0.108,MeOH)
IR(KBr):3438,2665,2586,2482,1645,1516,1454,1429,1282,1182,1138,1105cm-1
NMR(D2O,δ):2.05-5.50(36H,m),6.74-8.30(6H,m)
MASS(APCI):657(M+H)+(游离),588
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-吗啉代苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪三盐酸盐
mp:150-170℃
[α]D 24.7:-4.48°(C=0.067,MeOH)
IR(KBr):3437,2667,2576,2457,1645,1514,1454,1429,1282,1182,1136cm-1
NMR(D2O,δ):2.15-5.50(36H,m),6.74-8.30(6H,m)
MASS(APCI):673(M+H)+(游离),588
实施例35
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-氨基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(132mg)的二氯甲烷溶液中依次加入4-(二甲氨基)吡啶(2mg)和三氟乙酸酐(0.05ml),混合物室温搅拌过夜。混合物真空蒸发,残留物中加入乙酸乙酯和水,分离有机相,用食盐水洗涤,硫酸镁干燥,真空蒸发。残留物用根据柱层析纯化,用二氯甲烷和甲醇的混合溶液(25∶1)为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-(三氟乙酰氨基)苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(134mg)
MASS(APCI):699(M+H)+
实施例36
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-(三氟乙酰氨基)苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(131mg)的四氢呋喃(2ml)溶液中加入氢化钠(10mg),得到的混合物搅拌20分钟。混合物中加入碘甲烷(28mg),混合物室温搅拌过夜。混合物中加入食盐水,分离有机相,硫酸镁干燥,真空蒸发,残留物用HPLC纯化得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲基-3-(N-甲基-N-三氟乙酰氨基)苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(31mg),为油状物。得到的混合物按常规方法转变为它的二盐酸盐。
[α]D 27.3:-10.94°(C=0.032,MeOH)
IR(KBr):3425,1695,1647,1282,1207,1180,1140,1101cm-1
NMR(DMSO-d6,δ):1.95-5.32(31H,m),6.75-8.34(6H,m)
MASS(APCI):713(M+H)+(游离)
实施例37
(2R)-1-〔3-〔2,5-二甲基吡咯-1-基磺酰基〕-5-(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕哌嗪(160.6mg)的6N盐酸(10ml)悬浮溶液在70℃搅拌2小时。混合物倾到饱和的碳酸氢钠水溶液(150ml)中,用乙酸乙酯(50ml×3)萃取。合并的萃取液用食盐水洗涤,硫酸镁干燥,减压蒸发得到油状物(163.4mg)。该油状物溶解在乙酸乙酯(1.6ml)中,然后室温下依次往该溶液中加入4N氯化氢的乙酸乙酯溶液(0.17ml)和己烷(50ml)。过滤收集得到的粉末,减压干燥得到(2R)-2-〔3-羟基-4-甲基苄基〕-4-〔2-〔(2S)-2-(甲氧基甲基)吗啉代〕乙基〕-1-〔3-氨磺酰基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐(149.3g)粉末。
mp:166-206℃
[α]D 25:-11.93°(C=0.25,MeOH)
IR(KBr):3431,3402,1641cm-1
NMR(DMSO-d6,δ):2.08(3H,s),2.60-5.20(25H,m),6.18-9.20(6H,m)
MASS(APCI):615(M+H)+(游离)
制备56
在0℃时(3R)-1-苄基-3-〔3-羟基-4-甲基苄基〕哌嗪(840mg)溶解于1,4-二氧六环(7.5ml),水(5ml)和1N盐酸(2.8ml)混合溶剂的溶液中依次加入二叔丁基二碳酸酐(740mg)的1,4-二氧六环(2.5ml)和2N氢氧化钠溶液(1.9ml),0℃搅拌1小时后,溶液中加入二叔丁基二碳酸酐(123mg)的1,4-二氧六环溶液,0℃搅拌2小时。混合物用1N盐酸(0.99ml)调pH7-8,用二氯甲烷(×3)萃取。合并的萃取液用食盐水洗涤,硫酸镁干燥,减压蒸发得到油状物(1.74g)。用柱层析纯化(硅胶,50ml,乙酸乙酯∶己烷(1∶5-1∶4))得到(2R)-4-苄基-1-叔丁氧羰基-2-〔3-羟基-4-甲基苄基〕哌嗪(1.08g),为泡沫状。
IR(净):1664cm-1
NMR(CDCl3,δ):1.40(9H,s),1.92(1H,dd,J=3.8和11.4Hz),2.15(3H,s),2.05-2.20(1H,m),2.64-3.10(4H,m),3.19(1H,dt,J=3.5和12.6Hz),3.25(1H,d,J=12.8Hz),3.59(1H,d,J=12.8Hz),3.80-4.15(2H,m),4.77(1H,br s),6.15(1H,br s),6.55(1H,d,J=7.5Hz),6.91(1H,d,J=7.5Hz),7.2 6-7.37(5H,m)
MASS(APCI):397(M+H)+
制备57
室温下(2R)-1-叔丁氧羰基-2-〔3-羟基-4-甲基苄基〕哌嗪(7.73g)和4-二甲氨基吡啶(620mg)的二氯甲烷(90ml)溶液中依次加入三乙胺(15.82ml)和叔丁基二苯基硅甲基氯化物(26.24ml)。回流搅拌27.5小时,混合物中加入水,混合物用二氯甲烷(100ml,50ml×2)萃取。合并的有机萃取液依次用水和食盐水洗涤,硫酸镁干燥,减压蒸发得到粗品油状物。该油状物用柱层析(硅胶,500ml,甲醇∶二氯甲烷=5∶95)纯化,得到(2R)-1-叔丁氧羰基-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕哌嗪(12.07g)为固体。
mp:64.5-65.5℃
IR(KBr):2962,2933,1693cm-1
NMR(CDCl3,δ):1.07-1.09(9H,m),1.26-1.50(9H,m),2.00-3.80(9H,m),2.36(3H,s),6.13-6.20(1H,m),6.67(1H,d,J=7.6Hz),7.03(1H,d,J=7.6Hz),7.26-7.34(6H,m),7.65-7.73(4H,m)
MASS(APCI):545(M+H)+
制备58
用类似实施例1的方法,以N,N-二异丙基乙胺代替碳酸钾作为碱,得到下述混合物。
(1)(2R)-1-叔丁氧羰基-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-((2S)-2-甲氧基甲基吗啉代)乙基〕哌嗪
IR(净):1695cm-1
NMR(CDCl3,δ):1.10(9H,s),1.21(9H,s),1.60-3.00(17H,m),2.34(3H,s),3.37(3H,s),3.37-4.00(5H,m),6.23(1H,s),6.64(1H,d,J=7.6Hz),7.38(1H,d,J=7.6Hz),7.34-7.42(6H,m),7.66-7.73(4H,m)
MASS(ESI):702.5(M+H)+
(2)(2R)-1-叔丁氧羰基-2-〔4-氯苄基〕-4-〔2-〔顺-2,6-二甲基吗啉代〕乙基〕哌嗪
IR(净):1693,1410,1367,1087cm-1
NMR(CDCl3,δ):1.16(6H,d,J=6.3Hz),1.38(9H,s),1.76(1H,t,J=11.0Hz),2.03(2H,m),2.51(4H,m),2.60-3.20(8H,m),3.50-4.15(4H,m),7.12-7.27(4H,m)
MASS:452(M+)
(3)(2R)-1-叔丁氧羰基-2-〔4-氯苄基〕-4-〔2-〔5,6,7,8-四氢-1,6-二氮杂萘-6-基〕乙基〕哌嗪
[α]D 27.2:+4.89°(C=0.32,MeOH)
IR(净):2970,2930,2810,1690,1580cm-1
NMR(CDCl3,δ):1.39(9H,s),1.9-2.2(2H,m),2.4-3.3(13H,m),3.67(2H,s),3.8-4.3(2H,m),7.07(1H,dd,J=4.7和7.6Hz),7.13(2H,d,J=8.4Hz),7.22(2H,d,J=8.4Hz),7.33(1H,d,J=7.6Hz),8.40(1H,d,J=4.7Hz)
MASS(APCI):471(M+H)+
制备59
0℃下(2R)-1-叔丁氧羰基-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-((2S)-2-甲氧基甲基吗啉代)乙基〕哌嗪(13.43g)的二氯甲烷(67.0ml)溶液中加入三氟乙酸(67.0ml)。室温搅拌30分钟,混合物浓缩,并滴加饱和的碳酸氢钠水溶液。室温搅拌30分钟后,混合物用二氯甲烷(100ml×1,50ml×2)萃取。合并的有机萃取液用硫酸镁干燥,减压蒸发得到(2R)-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-((2S)-2-甲氧基甲基吗啉代)乙基〕哌嗪(11.63g)为棕色油状物。
IR(净):1676,1614,1579cm-1
NMR(CDCl3,δ):1.10(9H,s),1.60-2.80(17H,m),2.36(3H,s),3.37(3H,s),3.37-3.41(2H,m),3.60-3.95(3H,m),6.22(1H,d,J=1.4Hz),6.60(1H,dd,J=1.4和7.6Hz),7.06(1H,d,J=7.6Hz),7.31-7.42(6H,m),7.68-7.73(4H,m)
MASS(APCI):602(M+H)+
制备60
0℃下(2R)-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-((2S)-2-甲氧基甲基吗啉代)乙基〕哌嗪(9.38g)的乙酸乙酯(40ml)溶液中加入4N氯化氢的乙酸乙酯溶液(11.7ml),然后滴加己烷(200ml)。室温搅拌2小时,混合物冷却至0℃下,得到的沉淀过滤收集,用己烷洗涤,减压干燥得到(2R)-2-〔3-叔丁基二苯基甲硅烷氧基-4-甲基苄基〕-4-〔2-((2S)-2-甲氧基甲基吗啉代)乙基〕哌嗪三盐酸盐(10.75g)粉末。
mp:173-185℃
IR(KBr):3398,2935,1647,1510cm-1
NMR(DMSO-d6,δ):1.07(9H,s),2.31(3H,s),1.80-4.3025H,m),6.15 (1H,br s),6.70(1H,d,J=7.7Hz),7.17(1H,d,J=7.7Hz),7.42-7.50(6H,m),7.65-7.70(4H,m)
NMR(D2O,δ):1.03(9H,s),2.27(3H,s),2.90-4.20(22H,m),3.39(3H,s),6.32(1H,s),6.80-6.87(1H,m),7.19(1H,d,J=7.8Hz),7.37-7.76(10H,m)
MASS(APCI):602(M+H)+(游离)
制备61
N,O-二甲基羟基胺盐酸盐(5.37g)加到3-甲氧基-4-(三氟甲基)苯甲酸(11.0g),1-羟基苯并三氮唑(6.76g),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(9.59g)和N,N-二异丙基乙胺(9.6ml)的二氯甲烷(200ml)混合溶液中,该混合物室温搅拌18小时。混合物中加入饱和的碳酸氢钠水溶液,分离有机相,硫酸镁干燥,真空蒸发。残留物用硅胶柱层析纯化,用25%的乙酸乙酯的己烷溶液洗脱,得到3-甲氧基-N-甲氧基-N-甲基-4-(三氟甲基)-苯甲酰胺(12.0g)为无色油状物。
NMR(CDCl3,δ):3.38(3H,s),3.56(3H,s),3.94(3H,s),7.28(2H,m),7.60(1H,d,J=8.3Hz)
MASS(APCI):264(M+H)+
制备62
搅拌的3-甲氧基-N-甲氧基-N-甲基-4-(三氟甲基)苯甲酰胺(2.63g)的无水四氢呋喃(26ml)溶液在-40℃和氮气氛中加入氢化铝锂(380mg)。5℃下搅拌1小时后,混合物中加入2N氢氧化钠。用Celite过滤除去不溶物,并用乙酸乙酯洗涤。合并滤液和洗液,减压蒸发得到粗品3-甲氧基-4-(三氟甲基)苯甲醛,为无色油状物。5℃下搅拌着的粗品3-甲氧基-4-(三氟甲基)苯甲醛和1,4-二乙酰基哌嗪-2,5-二酮(1.98g)的N,N-二甲基甲酰胺(10ml)和叔丁醇(10ml)的混合溶液中加入叔丁醇钾(1.12g),混合物室温搅拌18小时。混合物中加入水(30ml)和乙酸乙酯(100ml),分离有机相,水层用乙酸乙酯萃取。合并的萃取液用水洗涤,硫酸镁干燥,真空蒸发。残留物用硅胶柱层析纯化,用50%的乙酸乙酯的己烷溶液洗脱,得到1-乙酰基-3-〔(3-甲氧基-4-(三氟甲基)苯基)亚甲基〕哌嗪-2,5-二酮(2.11g)粉末。
NMR(DMSO-d6,δ):3.33(3H,s),3.90(3H,s),4.37(2H,s),6.98(1H,s),7.26(1H,d,J=8.1Hz),7.38(1H,s),7.63(1H,d,J=8.1Hz),10.55(1H,s)
MASS(APCI):343(M+H)+
制备63
1-乙酰基-3-〔(3-甲氧基-4-(三氟甲基)苯基)亚甲基〕哌嗪-2,5-二酮(1.8g)的四氢呋喃(50ml)溶液在于大气压下用10%钯碳(50%湿,180mg)氢化5小时,过滤除去催化剂,滤液中加入一水合肼(395mg)。室温下混合物搅拌1.5小时,减压浓缩。残留物用异丙醚(12ml)研磨,过滤收集沉淀,用异丙醚洗涤得到3-〔3-甲氧基-4-(三氟甲基)苄基〕哌嗪-2,5-二酮(1.29g)粉末。
NMR(DMSO-d6,δ):2.94-3.19(3H,m),3.51(1H,m),3.84(3H,s),4.15(1H,m),6.90(1H,d,J=7.9Hz),7.08(1H,s),7.52(1H,d,J=7.9Hz),7.99(1H,m),8.20(1H,m)
MASS(APCI):303(M+H)+
制备64
搅拌的3-〔3-甲氧基-4-(三氟甲基)苄基〕哌嗪-2,5-二酮(1.2g)的四氢呋喃(100ml)悬浮溶液中在氮气氛和室温下注射加入硼烷-四氢呋喃复合物(1M的四氢呋喃,39.7ml),混合物加热回流18小时。冷却后,反应混合物过滤,滤液慢慢加入12%溴化氢的醋酸(16ml)溶液。该混合溶液中加入异丙醚(300ml),该混合物在5℃下搅拌1小时。得到的沉淀过滤收集,减压干燥得到2-〔3-甲氧基-4-(三氟甲基)苄基〕哌嗪二溴化氢盐(1.73mg)粉末。
NMR(DMSO-d6,δ):2.70-3.9 0(9H,m),3.92(3H,s),6.50(1H,m),7.03(1H,d,J=7.9Hz),7.2 5(1H,s),7.62(1H,d,J=7.9Hz),8.10(1H,br s),9.07(2H,br s)
MASS(APCI):275(M+H)+(游离)
制备65
根据类似制备56的方法得到下述化合物。
(2R)-4-苄基-1-(叔丁氧羰基)-2-(4-氯苄基)哌嗪
mp:139-140℃
[α]D 26.8:-2.96°(C=0.27,MeOH)
IR(KBr):3740,2970,2810,1700,1650cm-1
NMR(CDCl3,δ):1.38(9H,s),1.9-2.2(2H,m),2.58(1H,d,J=11.5Hz),2.7-3.3(4H,m),3.32(1H,d,J=12.9Hz),3.56(1H,d,J=12.9Hz),3.7-4.3(2H,m),6.93(2H,d,J=8.2Hz),7.12(2H,d,J=8.2Hz),7.33(5H,s)
MASS(APCI):401(M+H)+
制备66
根据类似制备59的方法得到下述化合物。
(1)(2R)-2-(4-氯苄基-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪三盐酸盐
IR(KBr):1645,1454,1425,1120,1086cm-1
NMR(DMSO-d6,δ):1.11(6H,d,J=6.2Hz),2.59-4.60(19H,m),7.34(2H,d,J=8.5Hz),7.44(2H,d,J=8.5Hz),9.47-10.0(1H,br),9.50(0.5H,br),10.5(0.5H,br)
MASS:352(M+)
(2)(2R)-2-(4-氯苄基-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪四盐酸盐
[α]D 27.2:+13.10°(C=0.35,MeOH)
IR(KBr):3400,1640,1630,1550,1520cm-1
NMR(DMSO-d6,δ):2.8-6.2(16H,m),4.53(2H,s),7.34(2H,d,J=8Hz),7.43(2H,d,J=8Hz),7.80(1H,dd,J=5和8Hz),8.23(1H,d,J=8Hz),8.75(1H,d,J=5Hz),9.7-10.0(1H,br),10.1-10.3(1H,br)
MASS(APCI):371(M+H)+
制备67
0℃下3-氯磺酰基-5-(三氟甲基)苯甲酸(0.4g)中加入28%氨水溶液(5.0ml),混合溶液在0℃下搅拌,然后回升至室温过夜。混合物浓缩至干,然后混合物中加入1N盐酸(5ml),0℃搅拌30分钟。过滤收集得到的粉末,减压干燥得到3-氨磺酰基-5-(三氟甲基)苯甲酸(299.4mg),为浅黄色粉末。
mp:244-246℃
IR(KBr):1713cm-1
NMR(DMSO-d6,δ):7.73(2H,s),8.34(1H,s),8.37(1H,s),8.62(1H,s)
MASS(ESI-):268.1(M-H)
制备68
3-氨磺酰基-5-(三氟甲基)苯甲酸(200 mg)和2,5-己二酮(0.26ml)的甲苯(1ml)溶液中加入对甲苯磺酸一水合物(28mg),混合物用Dean-Stark阱搅拌回流24小时。然后,混合物中加入2,5-己二酮(0.26ml)和对甲苯磺酸一水合物(30mg),混合物在相同条件下搅拌24小时。混合物蒸发,用柱层析纯化(硅胶,50 ml,甲醇∶二氯甲烷(5∶95-20∶80)得到3-〔(2,5-二甲基吡咯-1-基)-磺酰基〕-5-(三氟甲基)苯甲酸(280 mg)为粗品固体。该固体溶解在1N氢氧化钠水溶液(10ml)和水(20ml)中,然后用1N盐酸(20ml)调pH1-2,得到的粉末过滤收集,减压干燥,得到纯品(191.1mg)。
mp:150-153℃
IR(KBr):1701cm-1
NMR(DMSO-d6,δ):2.33(6H,s),6.07(2H,s),8.13(1H,s),8.23(1H,s),8.46(1H,s)
MASS(APCI):348(M+H)+
制备69
3-氯磺酰基-5-三氟甲基苯甲酸(0.5g)和吡咯烷(0.72ml)的二氯甲烷(5ml)混合溶液在室温搅拌过夜,蒸发至干后,残留物中加入水(50ml),并用1N盐酸调pH至1。过滤收集得到的沉淀,45℃减压干燥3-(吡咯烷代磺酰基-5-三氟甲基苯甲酸(0.514g)粉末。
mp:198-199℃
IR(KBr):1697cm-1
NMR(DMSO-d6,δ):1.64-1.77(4H,m),3.18-3.29(4H,m),8.28(1H,s),8.45(1H,s),8.46(1H,s)
MASS(APCI):324(M+H)+
制备70
根据类似制备69的方法得到下述化合物。
(1)3-(吗啉代磺酰基)-5-(三氟甲基)苯甲酸
mp:210-213℃
IR(KBr):1707cm-1
NMR(DMSO-d6,δ):2.96-3.01(4H,m),3.62-3.67(4H,m),8.22(1H,s),8.41(1H,s),8.48(1H,s)
MASS(ESI-):338.1(M-H)
(2)3-甲基氨磺酰基-5-(三氟甲基)苯甲酸
mp:194-197℃
IR(KBr):1705cm-1
NMR(DMSO-d6,δ):2.46(3H,s),7.8 4-7.94(1H,m),8.28(1H,s),8.41(1H,s),8.55(1H,s)
NMR(CD3OD,δ):2.57(3H,s),8.29(1H,s),8.48(1H,s),8.65(1H,s)
MASS(ESI-):282(M-H)
(3)3-二甲基氨磺酰基-5-(三氟甲基)苯甲酸
mp:145-155℃
IR(KBr):1705cm-1
NMR(DMSO-d6,δ):2.70(6H,s),8.2 4(1H,s),8.42(1H,s),8.46(1H,s)
MASS(APCI):298(M+H)+
制备71
3-氨基-5-(三氟甲基)苯甲酸(2.0g)和2,5-二甲氧基四氢呋喃(1.52ml)溶解在乙酸(10ml)和1,4-二氧六环(10ml)的混合溶剂中,在100℃搅拌2小时,冷却至室温后,混合物浓缩,柱层析(硅胶,50ml,甲醇∶二氯甲烷=10∶90)纯化,得到粗品固体。该固体用乙酸乙酯(5.0ml)和己烷(200ml)重结晶得到3-(吡咯-1-基)-5-(三氟甲基)苯甲酸(1.72g)粉末。
mp:191-192.5℃
IR(KBr):1705,1614,1496cm-1
NMR(CDCl3,δ):6.43(2H,s),7.19(2H,s),7.87(1H,s),8.22(1H,s),8.31(1H,s)
MASS(ESI-):254(M-H),509.1(2M-1)
制备72
-30℃时,10分钟期间将氯甲酸乙酯(1.4ml)的二氯甲烷(2.0ml)溶液滴加到3-碘-5-(三氟甲基)苯甲酸(2.32g)和三乙胺(1.13ml)的二氯甲烷(20ml)溶液中,混合物在-30℃时搅拌1小时,在-30℃时,5分钟期间将2-氨基-2-甲基-1-丙醇滴加到混合物中,混合物在-30℃时搅拌30分钟,然后在室温搅拌1小时。0℃时混合物中加入氯化铵水溶液终止反应,用二氯甲烷(×2)萃取。合并的有机萃取溶液依次用饱和的碳酸氢钠水溶液、1N乙酸和食盐水洗涤,然后用硫酸镁干燥,蒸发,用柱层析(硅胶,乙酸乙酯∶己烷=20∶80)纯化,得到N-(2-羟基-1,1-二甲基乙基)-3-碘-5-(三氟甲基)苯甲酰胺(2.10g)为油状物。
IR(净):3400,1640,1550cm-1
NMR(CDCl3,δ):1.44(6H,s),3.69(2H,d,J=5.9Hz),4.02(1H,t,J=5.9Hz),7.93(1H,d,J=0.6Hz),8.05(1H,d,J=0.6Hz),8.22(1H,s)
NMR(DMSO-d6,δ):3.33(6H,s),3.53(2H,d,J=5.7Hz),4.81(1H,t,J=5.7Hz),8.12(1H,s),8.22(1H,s),8.45(1H,s)
MASS(ESI+):410.1(M+Na)+
制备73
N-(2-羟基-1,1-二甲基乙基)-3-碘-5-(三氟甲基)苯甲酰胺(2.11g)中加入氯化亚砜(1.29ml),混合物室温搅拌4小时。混合物减压浓缩,用饱和的碳酸氢钠水溶液终止反应,用乙酸乙酯(×2)萃取。合并的萃取液用硫酸镁干燥,蒸发,用柱层析(硅胶,乙酸乙酯∶己烷=2.5∶97.5)纯化,得到2-〔3-碘-5-(三氟甲基)苯基〕-4,4-二甲基-4,5-二氢噁唑(1.66g)固体。
mp:73-74.5℃
IR(KBr):2968,1645,1566cm-1
NMR(CDCl3,δ):1.39(6H,s),4.14(2H,s),8.03(1H,d,J=0.7Hz),8.16(1H,d,J=0.7Hz),8.48(1H,s)
MASS(APCI):370(M+H)+
制备74
-70℃时,2-〔3-碘-5-(三氟甲基)苯基〕-4,4-二甲基-4,5-二氢噁唑(2.11g)和硼酸三异丙酯(1.26g)的四氢呋喃(21ml)溶液中滴加丁基锂(1.6M的己烷溶液),搅拌4小时后,混合物用2N盐酸终止反应,用乙酸乙酯萃取。合并的萃取液用食盐水洗涤,硫酸镁干燥,真空蒸发,得到3-(4,4-二甲基-4,5-二氢噁唑-2-基)-5-(三氟甲基)苯基硼酸(1.65g)为黄色油状物。该油状物不稳定,不经纯化立刻直接用于下步反应。
制备75
氮气氛下,3-(4,4-二甲基-4,5-二氢噁唑-2-基)-5-(三氟甲基)苯基硼酸(0.58g)和4-溴吡啶盐酸盐(0.39g)的碳酸钠水溶液(2M,6ml)和1,2-二甲氧基乙烷(4ml)的混合溶液的悬浮液中加入四(三苯基膦)钯盐(0.116g)。80℃搅拌12小时后,混合物用水终止反应,用乙酸乙酯萃取2次。合并的萃取液用硫酸镁干燥,蒸发,用柱层析(硅胶,乙酸乙酯∶己烷=1∶3-2∶1-1∶2)纯化,得到4-〔3-(4,4-二甲基-4,5-二氢噁唑-2-基)-5-(三氟甲基)苯基〕吡啶(0.61g)为糖浆状。
IR(KBr):2972,1651,1597,1446cm-1
NMR(CDCl3,δ):1.42(6H,s),4.14(2H,s),7.57(2H,d,J=6.2Hz),7.96(1H,s),8.28(1H,s),8.40(1H,s),8.72(2H,d,J=6.2Hz)
MASS(ESI+):321.1(M+H)+
制备76
4-〔3-(4,4-二甲基-4,5-二氢噁唑-2-基)5-(三氟甲基)苯基〕吡啶(0.60g)和6N盐酸(6ml)的混合溶液在90℃时搅拌5小时。冷却至室温后,混合物浓缩,少量水加入到残留物中,过滤收集apperaed结晶,减压干燥得到5-(4-吡啶基)-3-(三氟甲基)苯甲酸盐酸盐(0.33g)粉末。类似地从母液中得到第二次结晶(0.1g)。
mp:~230℃
IR(KBr):2534,1703,1641,1608,1514cm-1
NMR(DMSO-d6,δ):8.36(1H,s),8.50(2H,d,J=6.7Hz),8.60(1H,s),8.69(1H,s),9.01(2H,d,J=6.7Hz)
MASS(ESI+):268.2(M+H)+
制备77
根据类似制备11的方法得到下述化合物。
2-苄基氨基-2-甲基-1-丙醇
NMR(CDCl3,δ):1.14(6H,s),3.34(2H,s),3.67(2H,s),7.20-7.34(5H,m)
MASS(APCI):180(M+H)+
制备78
根据类似制备12的方法得到下述化合物。
2-甲基-〔2-(N-苄基-N-((2S)-2-羟基-3-甲氧基丙基)氨基)-1-丙醇
IR(净):3400,2973,2881,1643,1454cm-1
NMR(CDCl3,δ):1.03(3H,s),1.13(3H,s),2.49(1H,dd,J=3.5 和14.0Hz),2.79(1H,dd,J=9.2和14.0Hz),3.28(3H,s),2.92-3.32(3H,m),3.38-3.48(1H,m),3.48-3.61(2H,m),4.02(1H,d,J=15.3Hz),7.17-7.41(5H,m)
MASS(APCI):268(M+H)+
制备79
根据类似制备13的方法得到下述化合物。
(1)(2S)-1-〔N-苄基-N-(2-氯-1,1-二甲基乙基)氨基〕-3-甲氧基-2-丙醇
IR(净):2933,1645,1456cm-1
NMR(CDCl3,δ):1.08-1.53(6H,m),2.46-4.10(9H,m),3.34(3H,s),7.23-7.40(5H,m)
MASS(APCI):286(M+H)+
(2)(1R,4S)-3,3-二甲基-5-(2-氯乙基)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐
IR(KBr):2945,2603,1514,1462cm-1
NMR(DMSO-d6,δ):1.16(3H,s),1.45(3H,s),2.20-2.40(2H,m),3.21(1H,d,J=11.9Hz),3.40-3.80(3H,m),3.90-4.15(2H,m),4.31(1H,s),4.56(1H,s)
MASS(APCI):190(M+H)+(游离)
制备80
根据类似制备14的方法得到下述化合物。
(2S)-4-苄基-5,5-二甲基-2-(甲氧基甲基)吗啉
NMR(CDCl3,δ):1.10(3H,s),1.12(3H,s),2.21(1H,dd,J=10.5和11.7Hz),2.37(1H,dd,J=3.0和11.7Hz),3.00(1H,d,J=13.8Hz),3.32(3H,s),3.24-3.56(4H,m),3.61-3.71(1H,m),4.02(1H,d,J=13.8Hz),7.20-7.36(5H,m)
MASS(APCI):250(M+H)+
制备81
根据类似制备15的方法得到下述化合物。
(1)(2S)-5,5-二甲基-2-(甲氧基甲基)吗啉盐酸盐
IR(净):3398,2947,1458,1390cm-1
NMR(CDCl3,δ):1.26(3H,s),1.33(3H,s),2.90-3.00(2H,m),3.27(3H,s),3.35-3.50(2H,m),3.49-3.64(2H,m),3.82-3.94(1H,m)
MASS(APCI):1.60(M+H)+(游离)
(2)(1R,4S)-3,3-二甲基-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐
mp:237-238℃
IR(KBr):2895,2727,1587,1464cm-1
NMR(DMSO-d6,δ):1.11(3H,s),1.31(3H,s),1.92(1H,d,J=11.3Hz),2.28(1H,d,J=11.3Hz),3.00-3.15(2H,m),4.08(1H,s),4.53(1H,s)
MASS(APCI):128(M+H)+(游离)
制备82
根据类似制备7的方法得到下述化合物。
(1)(2S)-5,5-二甲基-4-(2-羟乙基)-2-(甲氧基甲基)吗啉
IR(KBr):3433,2970, 2875,1458, 1365cm-1
NMR(CDCl3,δ):0.98(3H,s),1.06(3H,s),2.12(1H,ddd,J=2.2,3.2和12.9Hz),2.31(1H,dd,J=10.8and 11.8Hz),2.63(1H,dd,J=2.8和11.8Hz),2.96(1H,ddd,J=5.3,10.7和12.9Hz),3.39(3H,s),3.33-3.60(6H,m),3.60-3.80(1H,m)
MASS(APCI):204(M+H)+
(2)(1R,4S)-3,3-二甲基-5-(2-羟乙基)-2-氧杂-5-氮杂双环[2.2.1]庚烷
IR(KBr):3433,2978,1460cm-1
NMR(CDCl3,δ):1.13(3H,s),1.34(3H,s),1.63(1H,dd,J=1.7和10.2Hz),1.99(1H,ddd,J=1.1,1.1和10.2Hz),2.32(1H,dd,J=1.7和10.4Hz),2.52(1H,ddd,J=4.1,5.4和12.3Hz),2.85(1H,ddd,J=4.8,6.8和12.3Hz),2.98(1H,br s),3.00(1H,d,J=10.4Hz),3.40-3.75(2H,m),4.38(1H,br s)
MASS(APCI):172(M+H)+
(3)4,4-二氟-1-(2-羟乙基)哌啶
NMR(CDCl3,δ):1.85-2.05(5H,m),2.55-2.65(6H,m),3.62(2H,t,J=5.3Hz)
MASS(APCI):166(M+H)+
制备83
干冰丙酮浴冷却和氮气氛下,溴化甲基镁盐(0.93M的四氢呋喃溶液,120ml)加至N-苄基-反式-4-羟基-L-脯氨酸甲酯(5.0g)的四氢呋喃(50ml)溶液中,混合物搅拌30分钟。混合物中加入饱和的氯化铵水溶液,分离有机相,用食盐水洗涤,硫酸钠干燥,真空蒸发得到(2S,4R)-1-苄基-2-(1-羟基-1-甲基乙基)-4-羟基吡咯烷(5.0g)为油状物。
IR(净):3400,1455,1370,1120cm-1
NMR(CDCl3-D2O,δ):1.15(3H,s),1.30(3H,s),1.8 0-2.02(2H,m),2.52-2.66(1H,m),3.02(1H,dd,J=11.9和3.8Hz),3.15(1H,d,J=8.0Hz),3.92(1H,d,J=13.6Hz),4.17(1H,d,J=13.6Hz),4.32-4.45(1H,m),7.15-7.44(5H,m)
MASS(APCI):236(M+H)+
制备84
0℃下,三乙胺(4.32ml)和(2S,4R)-1-苄基-2-(1-羟基-1-甲基乙基)-4-羟基吡咯烷(4.87g)的二氯甲烷(50ml)溶液中加入甲磺酰氯(2.4ml)。室温搅拌4小时后,混合物中加入水终止反应,用乙酸乙酯(×2)萃取。合并的萃取液用食盐水洗涤,硫酸镁干燥,减压蒸发,用柱层析(硅胶,500ml,甲醇∶二氯甲烷=4∶96)纯化,得到(2S,4R)-1-苄基-2-(1-羟基-1-甲基乙基)-4-(甲磺酰氧基)吡咯烷(3.34 g),为淡黄色固体。
IR(净):3431,3402,1647,1458cm-1
NMR(CDCl3,δ):1.15(3H,s),1.32(3H,s),2.04-2.35(2H,m),2.93-3.21(3H,m),3.02(3H,s),3.89(1H,d,J=13.9Hz),4.13(1H,d,J=13.9Hz),5.14(1H,brs),7.23-7.35(5H,m)
MASS(APCI):314(M+H)+
制备85
0℃下(2S,4R)-1-苄基-2-(1-羟基-1-甲基乙基)-4-(甲磺酰氧基)吡咯烷(3.65 g)的N,N-二甲基甲酰胺(36ml)的溶液中加入氢化钠(1.12g,60%的矿物油中)。混合物在室温搅拌2.5小时,并维持该条件过夜。混合物中加入甲醇(20ml)终止反应,然后搅拌30分钟,蒸发。残留物加水(300ml),用乙酸乙酯(100ml×3)萃取。合并的萃取液依次用水和食盐水洗涤,有机相用硫酸镁干燥,蒸发,用柱层析(硅胶,125ml,乙酸乙酯∶己烷=5∶95-20∶80)纯化得到(1R,4S)-2-苄基-3,3-二甲基-2-氧杂-5-氮杂双环[2.2.1]-庚烷(2.32g)为无色油状物。
IR(净):2978,1676,1647cm-1
NMR(CDCl3,δ):1.08(3H,s),1.40(3H,s),1.73(1H,dd,J=1.9和10.1Hz),1.92(1H,ddd,J=1.1,1.1和10.1Hz),2.3 0(1H,dd,J=1.6和10.5Hz),2.92(1H,br s),2.98(1H,d,J=10.5Hz),3.62(1H,d,J=13.6Hz),3.77(1H,d,J=13.6Hz),4.36(1H,br s),7.19-7.42(5H,m)
MASS(APCI):218(M+H)+
制备86
根据类似实施例1的方法得到下述化合物。
(2S,5S)-4-(4-氯-2-丁炔基)-2-甲氧基甲基-5-甲基吗啉
IR(净):2877,1454,1381,1327cm-1
NMR(CDCl3,δ):1.20(3H,d,J=6.3Hz),1.94-2.14(2H,m),2.69-2.79(2H,m),3.35(2H,t,J=2.0Hz),3.38(3H,s),3.38-3.51(2H,m),3.68-3.81(2H,m),4.17(2H,t,J=2.0Hz)
MASS(APCI):232(M+H)+
制备87
3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪(0.4g)的N,N-二甲基甲酰胺(5ml)溶液中分次加入氢化钠(60%油悬浮液;0.24g),数分钟后,2-氯甲基-1,3-二氧戊环(0.43g)的N,N-二甲基甲酰胺(2ml)溶液滴加至混合物中,搅拌2小时后,混合物倾到水和乙酸乙酯的混合溶剂中,分离有机相,用水洗涤2次,硫酸镁干燥,减压浓缩。残留物用硅胶柱层析纯化,用乙酸乙酯和己烷(1∶1)的混合溶剂洗脱,得到3,4-二氢-4-〔(1,3-二氧戊环-2-基)甲基〕-2H-吡啶并[3,2-b]-1,4-噁嗪(0.28g)为油状物。
NMR(CDCl3,δ):3.30-4.40(10H,m),5.10(1H,t,J=4.4Hz),6.49(1H,dd,J=4.9和7.6Hz),6.91(1H,dd,J=1.5和7.6Hz),7.73(1H,dd,J=1.5和4.9Hz)
MASS(APCI):223(M+H)+
制备88
3,4-二氢-4-〔(1,3-二氧戊环-2-基)甲基〕-2H-吡啶并[3,2-b]-1,4-噁嗪(0.12g)的丙酮(10ml)和水(1ml)的溶液在对甲苯磺酸(2.24g)的存在下加热回流3天。混合物真空浓缩,残留物倾至碳酸氢钠水溶液中,,水层用乙酸乙酯萃取3次,合并的有机相用硫酸镁干燥,真空浓缩,残留物用硅胶柱层析纯化,用甲醇和二氯甲烷(1∶10)的混合溶剂为洗脱液。收集含目的化合物的组分,减压蒸发得到2-〔3,4-二氢-2H-吡啶并[3,2-b]-1,4-噁嗪-4-基〕乙醛(0.09g),为油状物。
NMR(CDCl3,δ):3.56(2H,t,J=4.5Hz),4.00-4.40(4H,m),6.57(1H,dd,J=5.5和8Hz),6.97(1H,dd,J=1.4和8.0Hz),7.69(1H,dd,J=1.4和5.5Hz),9.73(1H,s)
MASS(APCI):179(M+H)+
制备89
4,5,6,7-四氢噻吩并[3,2-c]吡啶(0.86g),2-溴乙醇(0.66g),碳酸钾(2.58g)和碘化钾(3.10g)的N,N-二甲基甲酰胺(20ml)的混合溶液于70℃搅拌2小时。冷却后,混合溶液中加入乙酸乙酯和水。分离有机相,用水洗涤2次,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用甲醇和二氯甲烷(1∶10)混合溶剂为洗脱剂,收集含目的化合物的组分,减压蒸发得到5-(2-羟乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶(0.53g),为油状物。
IR(净):1664,1456,1441,1406,1360,1327,1111,1065,1043cm-1
NMR(DMSO-d6,δ):2.60-3.10(6H,m),3.50-3.90(4H,m),6.74(1H,d,J=5.1Hz),7.10(1H,d,J=5.1Hz)
MASS(APCI):184(M+H)+
制备90
5-(2-羟乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶(0.49g)的二氯甲烷(20ml)的溶液中滴加氯化亚砜(0.39ml)。混合溶液于40℃搅拌1.5小时。混合物减压蒸发后,残留物用二异丙醚研磨,过滤收集得到的粉末,用二异丙醚洗涤,真空干燥,得到5-(2-氯乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐(0.44g)。
mp:205-215℃
IR(KBr):2667,257 6,2544,2467,2397,1693,1645,1547,1539,1516,1452,1437,1184,1155,1086,1066cm-1
NMR(DMSO-d6,δ):2.80-4.80(10H,m),6.91(1H,d,J=5.2Hz),7.49(1H,d,J=5.2Hz)
MASS(ESI):202.2(M+H)+(游离)
制备91
根据类似制备90的方法得到下述化合物。
(1)1-(2-氯乙基)-4,4-二氟哌啶盐酸盐
mp:158-159℃
IR(KBr):2700-2300,1477,1388cm-1
NMR(DMSO-d6,δ):2.20-2.60(4H,m),3.00(4H,m),3.55(2H,t,J=7.0Hz),4.07(2H,t,J=7.0Hz)
(2)(2S)-4-(2-氯乙基)-5,5-二甲基-2-(甲氧基甲基)吗啉盐酸盐
IR(KBr):1562,1558,1547,1539,1516,1498,1464,1456,1198,1180,1126,1105,1041cm-1
NMR(DMSO-d6,δ):1.41(3H,s),1.54(3H,s),2.60-4.70(14H,m)
MASS(APCI):222(M+H)+(游离)
制备92
根据类似制备7的方法,随后再根据类似制备90的方法得到下述化合物。
(1)(3S,5S)-4-(2-氯乙基)-3,5-二甲基吗啉盐酸盐
mp:190-195℃(分解)
IR(KBr):1516,1454,1398,1371,1342,1250,1205,1153,1132,1103,1074, 1024cm-1
NMR(DMSO-d6,δ):0.90-1.50(6H,m),3.00-4.50(10H,m)
MASS(APCI):178(M+H)+(游离)
(2)顺-4-(2-氯乙基)-3,5-二甲基吗啉盐酸盐
mp:70-80℃(分解)
IR(KBr):2559,2478,2407,1477,1466,1454,1429,1390,1146,1120,1074,1030cm-1
NMR(DMSO-d6,δ):1.27(6H,d,J=6.1Hz),3.20-4.40(10H,m),11.58(1H,br s)
MASS(APCI):178(M+H)+(游离)
(3)(2R)-4-(2-氯乙基)-2-(甲氧基甲基)吗啉盐酸盐
mp:150-155℃(分解)
[α]D 27.5:-9.69°(C=0.485,MeOH)
IR(KBr):2673,2590,2476,1516,1477,1454,1400,1201,1132,1107,1084cm-1
NMR(DMSO-d6,δ):2.80-3.20(2H,m),3.28(3H,s),3.30-4.40(11H,m)
MASS(APCI):194(M+H)+(游离)
制备93
(2S)-2-(甲氧基甲基)吗啉盐酸盐(0.5g),1-溴-3-氯丙烷(1.47ml),和碳酸钾(2.06g)的N,N-二甲基甲酰胺(6ml)的混合溶液室温搅拌1小时。混合物中加入乙酸乙酯和水后,分离有机相,用水洗涤2次,硫酸镁干燥,减压蒸发,残留物用硅胶柱层析纯化,用乙酸乙酯为洗脱液,收集含目的化合物的组分,减压蒸发。得到的油状物用4N氯化氢的乙酸乙酯处理,得到(2S)-4-(3-氯丙基)-2-(甲氧基甲基)吗啉盐酸盐(0.44g)。
mp:165-170℃(分解)
IR(KBr):1547,1539,1516,1454,1192,1142,1111,1092,1066cm-1
NMR(DMSO-d6,δ):2.10-2.40(2H,m),2.70-4.20(16H,m),11.53(1H,br s)
MASS(APCI):208(M+H)+(游离)
制备94
根据类似制备93的方法得到下述化合物。
(1)(2S)-4-〔(E)-4-氯-2-丁炔基〕-2-(甲氧基甲基)吗啉盐酸盐
IR(净):1722,1450,1400,1360,1286,1255,1201,1136,1090,1030cm-1
NMR(DMSO-d6,δ):2.60-3.60(10H,m),3.60-4.20(4H,m),4.28(2H,d,J=5.9Hz),5.80-6.30(2H,m),11.87(1H,br s)
MASS(APCI):220(M+H)+(游离)
(2)(2S)-4-〔4-氯-2-丁炔基〕-2-(甲氧基甲基)吗啉盐酸盐
mp:70-75℃(分解)
IR(KBr):1516,1464,1454,1427,1398,1273,1194,1136,1086,1032cm-1
NMR(DMSO-d6,δ):2.60-4.80(16H,m)
MASS(APCI):218(M+H)+(游离)
制备95
根据类似制备27的方法得到下述化合物。
2-乙酰氨基-2-(4-苄氧基)-3-甲氧基苄基〕丙二酸二乙酯
mp:105-106℃
IR(KBr):3224,2977,1752,1635,1519,1301,1236cm-1
NMR(CDCl3,δ):1.29(6H,t,J=7.2Hz),2.02(3H,s),3.58(2H,s),3.82(3H,s),4.12-4.32(4H,m),5.11(2H,s),6.48(1H,dd,J=2.0和8.1Hz),6.55(1H,d,J=2.0Hz),6.56(1H,s),6.76(1H,d,J=8.1Hz),7.29-7.40(5H,m)
MASS(APCI):444(M+H)+,402,354
制备96
根据类似制备28的方法得到下述化合物。
(D,L)-N-乙酰基-4-苄氧基-3-甲氧基-DL-苯丙氨酸
mp:125.0-130.0℃
IR(KBr):3316,3200-2500,1714,1652,1544cm-1
NMR(DMSO-d6,δ):1.79(3H,s),2.76(1H,dd,J=9.6和13.7Hz),2.96(1H,dd,J=4.8和13.7Hz),3.74(3H,s),4.35-4.37(1H,m),5.02(2H,s),6.71(1H,dd,J=1.8和8.2Hz),6.8 6(1H,d,J=1.8Hz),6.92(1H,d,J=8.2Hz),7.31-7.45(5H,m),8.15(1H,d,J=8.0Hz),12.63(1H,br s)
MASS(APCI):344(M+H)+,302
制备97
(D)-N-乙酰基-4-苄氧基-3-甲氧基-D-苯丙氨酸
[α]D 26:-14.3°(C=0.5,DMF)
mp:148.0-149.0℃
IR(KBr):3324,3200-2700,1741,1616,1550,1513,1398cm-1
NMR(DMSO-d6,δ):1.79(3H,s),2.76(1H,dd,J=9.2和13.9Hz),2.97(1H,dd,J=4.8和13.9Hz),3.74(3H,s),4.31-4.42(1H,m),5.02(2H,s),6.71(1H,dd,J=1.8和8.2Hz),6.8 6(1H,d,J=1.8Hz),6.92(1H,d,J=8.2Hz),7.28-7.45(5H,m),8.14(1H,d,J=8.2Hz),12.85(1H,br s)
MASS(APCI):344(M+H)+,372
制备98
根据类似制备17的方法得到下述化合物。
4-羟基-3-甲氧基-D-苯丙氨酸盐酸盐
mp:188-200℃
IR(KBr):3500-3150,2700-2300,1739,1589,1488cm-1
NMR(D2O,δ):3.13(1H,dd,J=7.6和14.6Hz),3.28(1H,dd,J=5.8和14.6Hz),3.85(3H,s),4.28(1H,dd,J=5.8和7.6Hz),6.77-6.95(3H,m)
MASS(APCI):212(M+H)+,(游离)
制备99
二叔丁基二碳酸酯(2.55g)加至4-羟基-3-甲氧基-D-苯丙氨酸盐酸盐(2.2g)和三乙胺(2.9ml)的丙酮(25ml)和水(25ml)的溶液中,室温搅拌5小时后,反应混合物用水稀释,用乙酸乙酯萃取。分离有机相,硫酸镁干燥,减压蒸发得到N-叔丁氧羰基-4-羟基-3-甲氧基-D-苯丙氨酸(2.6g),为油状物。
NMR(CDCl3,δ):1.42(9H,s),2.82-3.20(2H,m),3.83(3H,s),4.20-5.50(2H,m),6.56-6.68(2H,m),6.83(1H,d,J=8.5Hz),7.23(1H,s)
MASS(APCI):212(M+H-Boc)+,195
制备100
溴苄(2.34ml,19.8ml)加至N-叔丁氧羰基-4-羟基-3-甲氧基-D-苯丙氨酸(3.44g)和N,N-二异丙基乙胺(3.85ml)的N,N-二甲基甲酰胺(20ml)溶液中,室温搅拌6小时后,反应混合物用水稀释,用乙酸乙酯萃取。分离有机相,硫酸镁干燥,减压蒸发,残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(4∶1)的混合溶剂洗脱得到(2R)-2-(叔丁氧羰基氨基)-3-(4-羟基-3-甲氧基苯基)丙酸苄酯(2.98g),为白色粉末。
IR(KBr):3438,3378,2700-2300,1725,1683,1521,1488cm-1
NMR(CDCl3,δ):1.41(9H,s),3.03(2H,d,J=5.8Hz),3.76(3H,s),4.45-4.55(1H,m),4.95-5.05(1H,m),5.09(1H,d,J=12.5Hz),5.18(1H,d,J=12.5Hz),5.53(1H,s),6.56-6.68(2H,m),6.76(1H,d,J=8.0Hz),7.25-7.36(5H,m)
MASS(APCI):302(M+H-Boc)+
制备101
4N氯化氢的1,4-二氧六环溶液(9ml)加至(2R)-2-(叔丁氧羰基氨基)-3-(4-羟基-3-甲氧基苯基)丙酸苄酯(2.90g)的二氯甲烷(29ml)冰冷溶液中,该温度下搅拌2小时,混合物减压浓缩得到(2R)-2-氨基-3-(4-羟基-3-甲氧基苯基)丙酸苄酯盐酸盐(2.8g),为油状物。
NMR(DMSO-d6,δ):3.00-3.10(2H,m),3.70(3H,s),4.31(1H,t,J=6.2Hz),5.1 8(2H,s),6.54(1H,dd,J=1.7and 8.0Hz),6.68(1H,d,J=8.0Hz),6.81(1H,d,J=1.7Hz),7.29-7.39(5H,m),8.57(3H,br s),8.97(1H,s)
MASS(APCI):301(M+H)+(游离)
制备102
根据类似制备19的方法得到下述化合物。
(2R)-2-(N-(氯乙酰基)氨基)-3-(4-羟基-3-甲氧基苯基)丙酸苄酯
制备103
根据类似制备20的方法的前半部分得到下述化合物。
(2R)-2-(N-(苄基氨基)乙酰基)氨基)-3-(4-羟基-3-甲氧基苯基)丙酸苄酯
制备104
根据类似制备20的方法的第二部分得到下述化合物。
(3R)-1-苄基-3-(4-羟基-3-甲氧基苄基)哌嗪-2,5-二酮
[α]D 26:-5.2°(C=0.5,DMF)
mp:225.0-226.0℃
IR(KBr):3335,1677,1515,1463,1276,1185cm-1
NMR(DMSO-d6,δ):2.73(1H,d,J=17.2Hz),2.78(1H,dd,J=4.6和13.6Hz),3.04(1H,dd,J=4.6和13.6Hz),3.42(1H,d,J=17.2Hz),3.66(3H,s),4.28(1H,m),4.27(1H,d,J=14.6Hz),4.47(1H,d,J=14.6Hz),6.43(1H,dd,J=1.8和8.0Hz),6.54(1H,d,J=8.0Hz),6.67(1H,d,J=1.8Hz),7.05-7.31(5H m),8.31(1H,br s),8.84(1H,s)
MASS(APCI):341(M+H)+
制备105
室温下将氢化铝锂(614mg)加至悬浮的(3R)-1-苄基-3-(4-羟基-3-甲氧基苄基)哌嗪-2,5-二酮(1.1g)四氢呋喃(40ml)溶液中,回流搅拌5小时后,反应混合物在氮气氛下用2N氢氧化钠溶液(5ml)处理,反应混合物用水(40ml)稀释,反应混合物在冰浴冷却下滴加3,5-双(三氟甲基)苯甲酰氯(1.6ml),搅拌30分钟后,得到的混合物用乙酸乙酯萃取,分离有机相,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,用己烷和乙酸乙酯(4∶1)的混合溶剂洗脱,得到目的物(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-羟基-3-甲氧基苄基)哌嗪和它的3,5-双(三氟甲基)苯甲酸盐,其再用1N氢氧化钠和甲醇的混合溶液转变为目的化合物。
NMR(CDCl3,δ):2.20-4.55(14H,m),6.20-7.90(12H,m)
MASS(APCI):553(M+H)+
制备106
30分钟内将三氟甲磺酸酐(5.25ml)在10℃以下滴加到(2R)-4-苄基-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-羟基-3-甲氧基苄基)哌嗪(14.3 g)和4-(二甲氨基)吡啶(0.47g)和2,6-二甲基吡啶(3.6ml)的二氯甲烷冰冷溶液中,该温度下搅拌2小时,反应混合物倾到水中。整个混合物的pH用稀盐酸调至7,分离有机相,硫酸镁干燥,残留物用硅胶柱层析纯化,用甲苯和乙酸乙酯(100∶1-5∶1)洗脱得到目的物三氟甲磺酸4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-苄基哌嗪-2-基)甲基〕-2-甲氧基苯基酯,为油状物。
制备107
室温下于1小时将一氧化碳用鼓泡法导入至三氟甲磺酸4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-苄基哌嗪-2-基)甲基〕-2-甲氧基苯基酯(15.0g),醋酸钯(150mg),1,3-双(二苯基膦)丙烷(275mg)和三乙胺(4.28ml)溶解在甲醇(30ml)和N,N-二甲基甲酰胺(75ml)的混合溶剂中的混合溶液。混合溶液升温至70℃,于一氧化碳气氛下搅拌3小时,得到的混合物通过Celite过滤,残留物用乙酸乙酯洗涤,合并滤液和洗液,减压蒸发。残留物溶解在乙酸乙酯中,该溶液依次用水和食盐水洗涤,硫酸镁干燥,减压蒸发。残留物用硅胶柱层析纯化,以甲苯和己烷的混合溶剂为洗脱液,收集含目的化合物的组分,减压蒸发得到糖浆,该糖浆用4N氯化氢的乙酸乙酯溶液处理得到4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-苄基哌嗪-2-基)甲基〕-2-甲氧基苯甲酸甲酯盐酸盐(7.71g)
mp:100-102℃
IR(KBr):3335,1720,1648,1614,1459,1427,1185cm-1
NMR(DMSO-d6,δ):2.95-5.20(11H,m),3.41(3H,s),3.75(3H,s),6.40-8.25(11H,m),11.50-11.80(1H,m)
MASS(API-ES):617(M+Na,游离)+,595(M+H,游离)+
制备108
根据类似制备22的方法得到下述化合物。
4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-苄基哌嗪-2-基)甲基〕-2-羟基苯甲酸甲酯
IR(净):1677,1643,1438,1280cm-1
NMR(CDCl3,δ):2.00-5.10(11H,m),3.93(3H,s),6.20-7.90(11H,m),10.71(1H,br s)
MASS(API-ES):603(M+Na)+,581(M+H)+
制备109
室温下将叔丁基二甲基硅甲基氯化物(2.34g)加至4-〔((2R)-1-(3,5-双(三氟甲基)苯甲酰基)哌嗪-2-基)甲基〕-2-羟基苯甲酸甲酯(2.56g),4-(二甲氨基)吡啶(126mg)和三乙胺(2.51ml)的二氯甲烷(50ml)溶液中。室温搅拌15小时后,再加入三乙胺(2.51ml)和叔丁基二甲基硅甲基氯化物(2.34g),整个反应混合物再搅拌1天。混合物中加入水(200ml),得到的混合物用二氯甲烷萃取,有机萃取液依次用水和食盐水洗涤,硫酸镁干燥,减压蒸发得到粗品油状物。该油状物用硅胶柱层析纯化,用二氯甲烷和甲醇的混合溶剂洗脱得到4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-哌嗪-2-基)甲基〕-2-叔丁基二甲基甲硅烷氧基)苯甲酸甲酯(1.72g)。
IR(净):2955,1727,1639,1436,1280cm-1
NMR(CDCl3,δ):0.10-0.30(6H,m),1.00(9H,s),2.80-5.10(9H,m),3.85(3H,s),6.30-7.90(6H,m)
MASS(APCI):605(M+H)+,573,491
制备110
冰浴冷却下(2R)-2-叔丁氧羰基氨基-3-(4-甲氧基苯基)丙酸(5.14g)的二氯甲烷(50ml)溶液中加入三乙胺(8.49ml),N苄基甘氨酸苄酯盐酸盐(5.08g),和2-氯-1-甲基碘化吡啶盐(4.89g)。室温搅拌90分钟后,反应混合物减压浓缩,搅拌下残留物中加入乙酸乙酯和水,用稀盐酸调pH至1。分离有机相,用食盐水洗涤,硫酸镁干燥,减压浓缩。得到的残留物用硅胶(100g)柱层析纯化,用甲苯和乙酸乙酯的混合溶剂(10∶1)洗脱,收集含目的化合物的组分,减压蒸发,得到N-苄基-N-(苄氧羰基甲基)-(2R)-2-(叔丁氧羰基氨基)-3-(4-甲氧基苯基)丙酰胺(8.57g),为糖浆状。
[α]D 24.0:+6.60°(C=0.50,MeOH)
IR(净):3300,1740,1700,1650,1240cm-1
NMR(DMSO-d6,δ):1.27和1.31(9H,s,s),2.76(2H,m),3.69和3.70(3H,s,s),3.95-4.90(5H,m),5.13(2H,m),6.70-7.36(15H,m)
MASS(APCI):533(M+H)+
制备111
冰浴冷却下将4N氯化氢的1,4-二氧六环溶液(48ml)滴加到N-苄基-N-苄氧羰基甲基-(2R)-2-(叔丁氧羰基氨基)-3-(4-甲氧基苯基)丙酰胺(8.48g)的二氯甲烷(48ml)。该温度下搅拌2小时后,反应混合物减压浓缩,残留物加至碳酸氢钠水溶液(50ml)和二氯甲烷(50ml)中,分离有机相,用食盐水洗涤,硫酸钠干燥,减压蒸发得到(3R)-1-苄基-3-(4-甲氧基苄基)哌嗪-2,5-二酮(3.65g)。
[α]D 27.9:-38.6°(C=0.50,MeOH)
IR(液体石蜡):3250,1680,1640,1245cm-1
NMR(DMSO-d6,δ):2.60(1H,d,J=17Hz),2.80(1H,dd,J=4.7和14Hz),3.09(1H,dd,J=3.8和14Hz),3.46(1H,d,J=17Hz),3.67(3H,s),4.11(1H,d,J=14Hz),4.22(1H,br),4.65(1H,d,J=14Hz),6.63(2H,d,J=8.7Hz),6.93(2H,d,J=8.7Hz),7.10-7.40(5H,m),8.30(1H,br)
MASS(APCI):325(M+H)+
制备112
氮气氛和冰浴冷却下,氢化铝锂(0.85g)的四氢呋喃(65ml)的悬浮溶液中分次加入(3R)-1-苄基-3-(4-甲氧基苄基)哌嗪-2,5-二酮(3.65g)。反应混合物搅拌回流1小时,冷却后,连续加入水(0.85ml)、15%氢氧化钠水溶液(0.85ml)和水(2.5ml)终止反应,反应混合物室温搅拌30分钟。过滤除去得到的不溶物,滤液加至乙酸乙酯(50ml)和食盐水(70ml)的混合溶液中,分离有机相,硫酸镁干燥,减压浓缩得到(2R)-2-(4-甲氧基苄基)-4-苄基哌嗪(3.51g),为糖浆。
IR(净):3250,1240cm-1
NMR(DMSO-d6,δ):1.60-2.00(4H,m),2.40-2.90(5H,m),3.30-3.50(2H,m),3.70(3H,s),6.81(2H,d,J=8.6Hz),7.07(2H,d,J=8.6Hz),7.15-7.40(6H,m)
MASS(APCI):297(M+H)+
制备113
5分钟内3,5-双(三氟甲基)苯甲酸(3.04g)和吡啶(0.030ml)的四氢呋喃(9ml)溶液中滴加草酰氯(1.80g),反应混合物搅拌下55℃加热1小时。冷却后,氮气氛和5℃以下,30分钟内将该溶液滴加到(2R)-2-(4-甲氧基苄基)-4-苄基哌嗪(3.47g)和三乙胺(3.55g)的二氯甲烷(35ml)溶液中,反应混合物室温搅拌1小时,减压浓缩,搅拌下残留物中加入乙酸乙酯(40ml)和水(20ml),分离有机相,用食盐水洗涤,硫酸镁干燥。蒸发除去溶剂,得到的残留物用硅胶(70g)柱层析纯化,用甲苯和乙酸乙酯(5∶1)的混合溶剂洗脱。收集含目的化合物的组分,减压蒸发,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-甲氧基苄基)-4-苄基哌嗪(5.03g),为糖浆。
[α]D 28.0:-21.4°(C=0.50,MeOH)
IR(净):1740,1640,1270cm-1
NMR(DMSO-d6,δ):1.70-2.40(3H,m),2.60-3.80(11H,m),6.60-7.60(10H,m),7.65-8.55(2H,m)
MASS(APCI):537(M+H)+
制备114
氮气氛下(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-甲氧基苄基)-4-苄基哌嗪(4.90g)的乙醇(50ml)溶液中加入水(5ml),甲酸铵(1.44g),和10%活性钯碳(50%湿)(0.49g)。反应混合物搅拌,60℃加热2小时。过滤除去不溶物质,滤液减压浓缩,残留物中加入乙酸乙酯(40ml)和水(40ml),分离有机相,用食盐水洗涤,硫酸镁干燥。蒸发除去溶剂,得到的残留物用硅胶(70g)柱层析纯化,用乙酸乙酯和甲醇(10∶1)的混合溶剂洗脱。收集含目的化合物的组分,减压蒸发,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-甲氧基苄基)哌嗪(3.18g),为糖浆。
[α]D 28.1:-32.6°(C=0.50,MeOH)
IR(净):3300,1630,1280cm-1
NMR(DMSO-d6,δ):2.40-3.55(9H,m),3.72(3H,s),6.70-8.45(7H,m)
MASS(APCI):447(M+H)+
制备115
根据类似制备56的方法得到下述化合物。
(1)(2R)-4-苄基-1-(叔丁氧羰基)-2-〔4-(三氟甲基)苄基〕哌嗪
NMR(CDCl3,δ):1.36(9H,s),1.98(1H,dd,J=11.5和3.7Hz),2.10(1H,td,J=12.0和3.4Hz),2.58(1H,d,J=11.5Hz),2.83-3.13(3H,m),3.20(1H,td,J=12.8和3.4Hz),3.26(1H,d,J=12.8Hz),3.58(1H,d,J=12.8Hz),3.80-4.30(2H,m),7.12(2H,d,J=7.7Hz),7.26-7.42(7H,m)
MASS(APCI):435(M+H)+
(2)(2R)-4-苄基-2-〔4-氟-3-甲氧基苄基〕-1-(叔丁氧羰基)哌嗪
IR(净):1516,1458,1400,1327,1275,1217,1169cm-1
NMR(CDCl3,δ):1.39(9H,s),1.95-2.13(2H,m),2.60-3.24(5H,m),3.32-3.57(2H,m),3.79(3H,s),3.90-4.14(2H,m),6.S2-7.35(8H,m)
MASS(APCI):415(M+H)+
(3)(2R)-4-苄基-1-(叔丁氧羰基)-2-〔4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基〕哌嗪
IR(净):1695,1480,1415,1250,1170cm-1
(4)(3S,4S)-1-(叔丁氧羰基)吡咯烷-3,4-二醇
mp:156-158℃
IR(KBr):3398,3334,1662,1431,1174,1122,1082,985cm-1
NMR(DMSO-d6,δ):1.42(9H,s),3.10(2H,br d,J=11.3Hz),3.25-3.44(2H,m),3.86(2H,br s),5.05(2H,d,J=3.2Hz)
MASS(ES+):429.3(2M+Na)+,226.2(M+Na)+(游离)
制备116
根据类似制备37的方法得到下述化合物。
(1)4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕哌嗪-2-基)甲基〕-2-羟基苯甲酸甲酯
IR(净):3083,1677,1639,1438,1280cm-1
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕哌嗪
mp:95-97℃
IR(KBr):1954,1628,1481,1437cm-1
NMR(CDCl3,δ):0.17(3H,s),0.20(3H,s),1.01(9H,s),2.50-5.10(9H,m),6.30-7.70(5H,m),7.87(1H,s)
MASS(APCI):581(M+H)+
(3)(2R)-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕哌嗪
IR(净):2954,2933,1635,1483,1419cm-1
NMR(CDCl3,δ):0.18(3H,s),0.21(3H,s),1.02(9H,s),2.50-5.20(9H,m),6.20-7.70(6H,m)
MASS(APCI):547(M+H)+
(4)(2R)-1-〔叔丁氧羰基〕-2-〔4-氯-3-(叔丁基二甲基甲硅烷氧基)苄基〕哌嗪
NMR(DMSO-d6,δ):0.99(9H,s),1.24(9H,s),2.15(6H,s),2.2 0-4.10(9H,m),6.78-7.33(3H,m)
MASS(APCI):441(M+H)+
制备117
根据类似制备24的方法得到下述化合物。
(1)(2R)-1-〔叔丁氧羰基〕-2-〔4-(三氟甲基)苄基〕哌嗪
mp:61-62℃
IR(KBr):2981,2952,1682,1417,1330cm-1
NMR(CDCl3,δ):1.33(9H,s),2.67-4.40(9H,m),7.35(2H,d,J=8.0Hz),7.54(2H,d,J=8.0Hz)
MASS(ESI):345.3(M+H)+,289.2(M-Bu)+
(2)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-〔叔丁氧羰基〕哌嗪
IR(净):1689,1515,1414,1273,1165,1115cm-1
NMR(CDCl3,δ):1.38(9H,s),2.70-3.14(8H,m),3.87(3H,s),3.88-4.18(2H,m),6.74-7.26 3H,m)
MASS(APCI):225(M-Boc+1)+,269(M-tBu+1)+
(3)(2R)-1-〔3-(二甲基氨磺酰基)-5-(三氟甲基)-苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪
IR(KBr):2956,1639,1462,1423,1329cm-1
NMR(CDCl3,δ):2.60-5.20(9H,m),2.72(6H,s),7.00-7.60(5H,m),7.67(1H,s),8.00(1H,s)
MASS(APCI):524(M+H)+
(4)(2R)-1-〔3-(甲基磺酰基)-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪盐酸盐
mp:94.5-101℃
IR(KBr):3433,1645cm-1
NMR(DMSO-d6,δ):2.80-5.30(12H,m),7.00-8.31(7H,m)
MASS(APCI):495(M+H)+(游离)
(5)(2R)-2-〔3-叔丁基二甲基甲硅烷氧基-4-甲基苄基〕-1-〔3甲氧基-5-(三氟甲基)-苯甲酰基〕哌嗪
IR(KBr):2956,2935,1641,1606cm-1
NMR(CDCl3,δ):0.14,0.17(6H,s),0.99(9H,s),2.15(3H,s),2.50-5.20(9H,m),3.81(3H,s),6.75-7.13(6H,m)
MASS(APCI):523(M+H)+
制备118
根据类似实施例1的方法,用N,N-二异丙基乙胺代替碳酸钾作为碱,得到下述化合物。
(1)(2R)-1-(叔丁氧羰基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪
IR(KBr):2974,2935,2814,1693cm-1
NMR(CDCl3,δ):1.35(9H,s),2.04-2.17(2H,m),2.50-4.30(17H,m),7.07(1H,dd,J=4.8和7.6Hz),7.27-7.34(3H,m),7.50(2H,d,J=8.0Hz),8.40(1H,d,J=4.8Hz)
MASS(APCI):505(M+H)+
(2)(2R)-1-(叔丁氧羰基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪
IR(净):2974,1693,1680cm-1
NMR(CDCl3,δ):1.19,1.20(6H,d,J=6.2Hz),1.32(9H,s),2.02-2.21(4H,m),2.71-3.31(11H,m),3.90-4.50(4H,m),7.34(2H,d,J=7.9Hz),7.54(2H,d,J=7.9Hz)
MASS(APCI):486(M+H)+
(3)(2R)-1-(叔丁氧羰基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪
IR(净):3438,2816,1691cm-1
NMR(CDCl3,δ):1.33(9H,s),2.02-4.30(22H,m),3.37(3H,s),7.35(2H,d,J=8.0Hz),7.54(2H,d,J=8.0Hz)
MASS(APCI):502(M+H)+
(4)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-(叔丁氧羰基)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪
IR(净):1515,1458,1414,1367,1323,1115,1086cm-1
NMR(CDCl3,δ):1.14(6H,d,J=1.2Hz),1.40(9H,s),1.70-2.10(4H,m),2.36-3.20(12H,m),3.61-4.18(3H,m),3.88(3H,s),6.74-7.02(3H,m)
MASS(APCI):466(M+H)+
(5)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-(叔丁氧羰基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪
IR(净):1516,1456,1414,1273,1165,1111,1036cm-1
NMR(CDCl3,δ):1.40(9H,s),1.90-4.25(22H,m),3.38(3H,s),3.87(3H,s),6.69-7.27(3H,m)
MASS:482(M+H)+
(6)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-(叔丁氧羰基)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪
NMR(DMSO-d6,δ):1.40(9H,s),1.99-2.15(2H,m),2.51-3.18(14H,m),3.67-4.18(3H,m),3.86(3H,s),6.73-8.40(6H,m)
MASS:485(M+H)+
(7)(2R)-1-(叔丁氧羰基)-2-〔4-氯-3-羟基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪
制备119
根据类似制备41的方法得到下述化合物。
(1)(2R)-4-苄基-1-〔3-(二甲基氨磺酰基)-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪
IR(净):1645,1456,1419,1319cm-1
NMR(CDCl3,δ):2.00-2.40(2H,m),2.70-5.10(9H,m),2.73(6H,s),6.90-7.60(10H,m),7.73(1H,s),8.01(1H,s)
MASS(APCI):614(M+H)+
(2)(2R)-4-苄基-1-〔3-甲基磺酰基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪
NMR(CDCl3,δ):2.00-2.40(2H,m),2.70-3.71(8H,m),3.06(3H,s),4.50-5.10(1H,m),6.80-7.60(10H,m),7.86(1H,s),8.19(1H,s)
MASS(APCI):585(M+H)+
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-苄基-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕哌嗪
IR(净):2935,2860,2812,1645,1483,1423cm-1
NMR(CDCl3,δ):0.10-0.30( 6H,br),1.00(9H,s),1.80-5.10(11H,m),6.20-8.00(10H,m),7.87(1H,s)
MASS(APCI):671(M+H)+
(4)(2R)-4-苄基-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕哌嗪
IR(净):2935,1641,1483,1417cm-1
NMR(CDCl3,δ):0.10-0.30(6H,br),1.01(9H,s),1.80-5.00(11H,m),6.20-7.70(10H,m),7.59(1H,s)
MASS(APCI):637(M+H)+
(5)(2R)-4-苄基-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-甲基苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(KBr):1643,1464,1421,1267cm-1
NMR(CDCl3,δ):0.09(6H,br s),0.98(9H,s),2.04-2.21(2H,m),2.14(3H,s),2.60-5.1 0(12H,m),6.24-7.36(11H,m)
MASS(APCI):613(M+H)+
制备120
根据类似制备59的方法得到下述化合物。
(1)(2R)-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪
NMR(DMSO-d6,δ):3.03-4.00(19H,m),7.57(2H,d,J=8.1Hz),7.75(2H,d,J=8.1Hz),7.85(1H,dd,J=7.7和5.6Hz),8.29(1H,d,J=7.7Hz),8.78(1H,d,J=5.6Hz)
MASS(APCI):405(M+H)+(游离)
(2)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐
mp:>250℃
IR(KBr):2563,2426,1456,1327cm-1
NMR(CDCl3,δ):1.11(6H,d,J=6.2Hz),2.59-4.50(19H,m),7.56(2H,d,J=8.1Hz),7.75(2H,d,J=8.1Hz)
MASS(APCI):386(M+H)+(游离)
(3)(2R)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐
mp:80-95℃
IR(KBr):1695,1516cm-1
NMR(DMSO-d6,δ):2.80-4.60(25H,m),7.56(2H,d,J=8.1Hz),7.75(2H,d,J=8.1Hz)
MASS(APCI):402(M+H)+(游离)
(4)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪三盐酸盐
IR(KBr):1610,1517,1452,1425,1367,1326,1274cm-1
NMR(DMSO-d6,δ):1.11(6H,d,J=6.0Hz),2.49-4.40(21H,m),3.86(3H,s),6.87-7.24(3H,m),9.55-10.06(2H,m)
MASS:366(M+H)+(游离)
(5)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪三盐酸盐
IR(KBr):3465,3435,3400,1615,1515,1455,1270,1235cm-1
NMR(DMSO-d6,δ):2.65-4.20(22H,m),3.27(3H,s),3.86(3H,s),6.82-7.23(3H,m)
MASS(APCI):382(M+H)+(游离)
(6) 2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪四盐酸盐
IR(KBr):1515,1464,1269,1153,1095cm-1
NMR(CDCl3,δ):2.60-4.50(22H,m),3.84(3H,s),6.85-10.0(8H,m)
MASS:385(M+H)+(游离)
(7)(2R)-2-〔4-氯-3-羟基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪三盐酸盐
IR(KBr):1645,1450,1425,1370,1236,1140cm-1
NMR(DMSO-d6,δ):2.64-4.50(22H,m),3.27(3H,s),6.71-7.32(3H,s)
MASS(APCI):384(M+H)+(游离)
(8)(3S,4S)-3,4-二甲氧基吡咯烷盐酸盐
mp:168℃
IR(KBr):3464,2900-2350,1198,1109,1065,1024cm-1
NMR(DMSO-d6,δ):3.05-3.35(4H,m),3.31(6H,s),4.00(2H,d,J=3.5Hz),9.67(2H,br s)
MASS(APCI):132(M+H)+(游离)
制备121
2-溴乙醇(310 mg)加至(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪(1g)的乙腈(10ml)溶液中,反应混合物70℃搅拌19小时。混合物过滤,滤液中的残留物用二氯甲烷洗涤2次,合并的滤液和洗液真空浓缩,残留物用硅胶柱层析纯化,以甲醇的二氯甲烷溶液(2%,然后5%)为洗脱液,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-羟基乙基)-2-〔4-(三氟甲基)苄基〕哌嗪(927mg),为非晶型粉末。
IR(净):3462,3435,2949,2817,1637,1439cm-1
NMR(CDCl3,δ):2.1-5.2(14H,m),6.9-8.0(7H,m)
MASS(APCI):529(M+H)+
制备122
根据类似制备121的方法得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-(2-羟基乙基)哌嗪
IR(净):2945,2817,1639,1518,1442cm-1
NMR(CDCl3,δ):2.20-5.10(13H,m),4.52(3H,s),6.30-7.89(6H,m)
MASS(APCI):509(M+H)+
制备123
根据类似制备9的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-氯乙基)-2-〔4-(三氟甲基)苄基〕哌嗪盐酸盐
IR(KBr):3437,3429,2561,1649,1427cm-1
NMR(DMSO-d6,δ):2.20-5.40(13H,m),7.10-8.30(7H,m)
MASS(APCI):547(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-(2-氯乙基)-2-〔4-氟-3-甲氧基苄基〕哌嗪盐酸盐
mp:75-79℃
IR(KBr):1647,1518,1427cm-1
NMR(DMSO-d6,δ):2.75-5.20(13H,m),4.49(3H,s),6.50-8.23(6H,m)
MASS(APCI):527(M+H)+(游离)
制备124
根据类似制备57的方法得到下述化合物。
(2R)-4-苄基-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-甲基苄基〕哌嗪
IR(净):2952,2933,2856,1504cm-l
NMR(DMSO-d6,δ):0.21(6H,s),1.02(9H,s),1.66-2.00(2H,m),2.13(3H,s),2.49-2.85(4H,m),3.37-3.41(5H,m),6.63(1H,s),6.69(1H,d,J=7.6Hz),7.05(1H,d,J=7.6Hz),7.25-7.40(5H,m)
MASS(ESI+):411.4(M+H)+
制备125
(2S,4R)-1-苄基-4-羟基-2-(羟甲基)吡咯烷(1.49g)的N,N-二甲基甲酰胺(10ml)溶液于室温滴加至氢化钠(60%分散与矿物油中)的N,N-二甲基甲酰胺(5ml)悬浮溶液中。反应混合物在该温度下搅拌1小时,向该混合溶液中滴加入碘化钾(2.55g)的N,N-二甲基甲酰胺(3ml),室温搅拌2小时。该反应混合物倾至冰水中,该混合溶液用乙酸乙酯萃取2次,合并的有机相依次用饱和碳酸氢钠水溶液和5%硫代硫酸钠水溶液的混合溶液、饱和的氯化钠水溶液洗涤,硫酸镁干燥,真空干燥。残留物用硅胶柱层析纯化得到,以1%,再以2%的甲醇的二氯甲烷溶液为洗脱液,得到(2S,4R)-1-苄基-4-甲氧基-2-(甲氧基甲基)吡咯烷(1.07g),为油状物。
IR(净):2877,2817,1452cm-1
NMR(CDCl3,δ):1.79-2.02(2H,m),2.26(1H,dd,J=9.9和5.6Hz),2.88-3.01(1H,m),3.19-3.49(4H,m),3.25(3H,s),3.35(3H,s),3.86(1H,m),4.10(1H,d,J=13.1Hz),7.20-7.33(5H,m)
MASS(APCI):236(M+H)+
制备126
根据类似制备15的方法得到下述化合物。
(1)(2S,4R)-4-甲氧基-2-(甲氧基甲基)吡咯烷IR(净):3342,2881,1668,1444cm-1
NMR(CDCl3,δ):1.55(1H,m),1.93(1H,dd,J=13.6和7.1Hz),2.88-3.09(2H,m),3.24-3.52(3H,m),3.29(3H,s),3.36(3H,s),3.89(1H,m)
MASS(APCI):146(M+H)+
(2)(3S,4S)-吡咯烷-3,4-二醇盐酸盐
mp:69-73℃
IR(KBr):3400,1622,1442,1238,1109,1030,989cm-1
NMR(DMSO-d6-D2O,δ):3.05(2H,d,J=12.1Hz),3.28(2H,dd,J=12.1和3.2Hz),4.10(2H,d,J=3.2Hz)
MASS(APCI):104(M+H)+(游离)
(3)顺-2,6-二甲氧基甲基哌啶盐酸盐
mp:200-202℃
IR(KBr):3402,2941,2821,2735,1645,1516,1456cm-1
NMR(DMSO-d6,δ):1.30-1.90(6H,m),3.10-3.40(2H,m),3.30(6H,s),3.54(4H,d,J=5.3Hz)
MASS(APCI):1.74(M+H)+(游离)
(4)顺-3,5-二甲氧基甲基哌啶盐酸盐
mp:220-222℃
IR(KBr):2939,2806,2783,1460,1392cm-1
NMR(DMSO-d6,δ):0.99(1H,q,J=12.4Hz),1.69(1H,m),1.90-2.25(2H,m),2.50(2H,t,J=12.3Hz),3.10-3.40(6H,m),3.23(6H,s)
MASS(APCI):174(M+H)+(游离)
(5)顺-2,6-二甲氧基甲基吗啉盐酸盐
IR(净):2935,2819,1595,1513,1456cm-1
NMR(CDCl3,δ):2.73(2H,t,J=12.0Hz),3.18(2H,d,J=12.0Hz),3.35(6H,s),3.35-3.46(4H,m),3.92-4.05(2H,m)
MASS(APCI):176(M+H)+(游离)
(6)2,2-二甲氧基甲基吗啉盐酸盐
IR(净):2935,2522,1594,1454cm-1
NMR(CDCl3,δ):2.92-3.00(4H,m),3.29(6H,s),3.46(2H,d,J=10.2Hz),3.51(2H,d,J=10.2Hz),3.81-3.86(2H,m)
MASS(APCI):176(M+H)+(游离)
(7)8-氧杂-3-氮杂双环[3.2.1]辛烷盐酸盐
mp:205-207.5℃
IR(KBr):2920,2792,1591,1442cm-1
NMR(DMSO-d6,δ):1.85-2.18(4H,m),2.97-3.08(4H,m),4.39-4.40(2H,m)
MASS(APCI):114(M+H)+(游离)
制备127
根据类似制备89的方法得到下述化合物。
(1)(2S,4R)-1-(2-羟乙基)-4-甲氧基-2-(甲氧基甲基)吡咯烷
IR(净):3400,2881,1660,1458,1379cm-1
NMR(CDCl3,δ):1.77(1H,m),2.00(1H,m),2.45(1H,dd,J=10.4,4.5Hz),2.62(1H,dt,J=12.7,3.7Hz),2.95-3.11(2H,m),3.29-3.45(3H,m),3.30(3H,s),3.36(3H,s),3.50-3.70(2H,m),3.90(1H,m)
MASS(APCI):190(M+H)+
(2)2,2-二甲基-4-(2-羟乙基)吗啉
IR(净):2972,2941,1458,1387cm-1
NMR(CDCl3,δ):1.26(6H,s),2.31(2H,s),2.45-2.54(4H,m),3.63(2H,t,J=5.1Hz),3.77(2H,t,J=5.1Hz)
MASS(APCI):160(M+H)+
(3)(3S,4S)-1-(2-溴乙基)-3,4-二甲氧基吡咯烷盐酸盐
制备128
根据类似制备90的方法得到下述化合物。
(1)(2S,4R)-1-(2-氯乙基)-4-甲氧基-2-(甲氧基甲基)吡咯烷盐酸盐
IR(净):3400,2939,1645,1450cm-1
NMR(DMSO-d6,δ):1.80(1H,m),2.23(1H,m),3.26(3H,s),3.32(3H,s),3.20-4.20(10H,m)
MASS(APCI):208(M+H)+(游离)
(2)2,2-二甲基-4-(2-氯乙基)吗啉盐酸盐
mp:180-185℃
IR(KBr):2978,2677,2630,2584,1456cm-1
NMR(DMSO-d6,δ):1.18(3H,s),1.44(3H,s),2.80-3.10(2H,m),3.30-3.91(6H,m),4.10(2H,t,J=6.9Hz)
MASS(APCI):178(M+H)+(游离)
(3)(3S,4S)-1-(2-氯乙基)-3,4-二甲氧基吡咯烷盐酸盐
IR(净):3400,2563,2440,1637,1460,1113cm-1
NMR(DMSO-d6,δ):3.20-3.86(6H,m),3.32(6H,s),3.92-4.16(4H,m),11.44(1H,s)
MASS(APCI):194(M+H)+(游离)
制备129
3-二甲氨基-1H-吡咯并[3,2-b]吡啶(1.53g)和六亚甲基四胺(1.22g)的6.68g的66%丙酸溶液滴加至回流的2.44g六亚甲基四胺的8.92g溶解在相同溶剂中的溶液中,该滴加过程进行1小时,该溶液回流3.5小时以上,该溶液真空浓缩,然后其中加入水(30ml),乙酸乙酯(25ml),和四氢呋喃(20ml)。分离有机相,硫酸钠干燥,减压浓缩。得到的残留物用硅胶(12g)柱层析纯化,以二氯甲烷和甲醇(15∶1)的混合溶剂为洗脱液,收集含目的化合物的组分,减压蒸发得到3-甲酰基-1H-吡咯并[3,2-b]吡啶(0.45g)粉末。
mp:230℃(分解)
IR(KBr):2744,1658,1466,1408,1142,1113,777cm-1
NMR(DMSO-d6,δ):7.27(1H,dd,J=4.6和8.3Hz),7.921H,d,J=8.3Hz),8.44(1H,s),8.50(1H,d,J=4.6Hz),10.19(1H,s),12.38(1H,s)
MASS(APCI):147(M+H)+
制备130
根据类似制备125的方法得到下述化合物。
(1)(3S,4S)-1-(叔丁氧羰基)-3,4-二甲氧基吡咯烷
IR(净):1690,1410,1365,1165,1100cm-1
NMR(CDCl3,δ):1.45(9H,s),3.37(6H,s),3.30-3.56(4H,m),3.72-3.85(2H,m)
MASS(APCI):132(M-Boc+H)+
(2)顺-2,6-二甲氧基甲基-1-苄基哌啶
IR(净):2924,2883,1489,1450cm-1
NMR(CDCl3,δ):1.30-1.85(6H,m),2.68-2.78(2H,m),3.13(6H,s),3.18(2H,dd,J=9.6,6.2Hz),3.35(2H,dd,J=9.6,4.4Hz),3.84(2H,s),7.17-7.42(5H,m)
MASS(APCI):264(M+H)+
(3)顺-3,5-二甲氧基甲基-1-苄基哌啶
IR(净):2920,2829,1454,1389cm-1
NMR(CDCl3,δ):0.68(1H,q,J=12.2Hz),1.61(2H,t,J=11.1Hz),1.78(1H,m),1.85-2.20(2H,m),2.90-3.05(2H,m),3.19(4H,d,J=6.2Hz),3.29(6H,s),3.52(2H,s),7.20-7.32(5H,m)
MASS(APCI):264(M+H)+
制备131
(S)-甲基缩水甘油醚(10g)和苄胺(3.62g)的甲醇(50ml)溶液于55℃搅拌2小时。混合物中加入(S)-甲基缩水甘油醚(1g),该混合物于55℃搅拌2小时,然后减压蒸发。残留物中加入甲苯,减压蒸发,得到(2S)-1-〔N-苄基-N-〔(2S)-2-羟基-3-甲氧基丙基〕氨基〕-3-甲氧基丙-2-醇(8.84g),为浅黄色油状物。
IR(净):3430,3402,2889,1454cm-1
NMR(CDCl3,δ):2.52-2.70(4H,m),3.34(6H,s),3.26-3.44(4H,m),3.61(1H,d,J=13.7Hz),3.81-3.92(2H,m),3.84(1H,d,J=13.7Hz),7.20-7.33(5H,m)
MASS(APCI):284(M+H)+
制备132
三苯基膦(10.2g),偶氮二羧酸二乙酯(6.12ml),和(2S)-1-〔N-苄基-N-((2S)-2-羟基-3-甲氧基丙基)氨基〕-3-甲氧基丙-2醇(7.34g)的四氢呋喃(70ml)混合溶液于0℃搅拌5小时,该混合溶液中依次加入三苯基膦(2.04g)和偶氮二羧酸二乙酯(1.2ml),该混合溶液于0℃搅拌3小时。该混合溶液倾至水中,用二氯甲烷(×3)萃取。合并的萃取溶液用食盐水洗涤,硫酸钠干燥,蒸发。残留物中加入异丙醚(50ml),室温搅拌30分钟。过滤掉不溶的沉淀,溶液蒸发。用柱层析(第-次:硅胶800ml,乙酸乙酯∶异丙醚=2∶8-3∶7)(第二次:硅胶30ml,乙酸乙酯∶异丙醚=3∶97-10∶90)纯化2次,得到4-苄基-顺-2,6-二甲氧基甲基吗啉(2.65g),为油状物。
IR(净):2883,1514,1458,1099cm-1
NMR(CDCl3,δ):1.93(2H,t,J=11.0Hz),2.77(2H,d,J=11.0Hz),3.34(6H,s),3.36-3.50(4H,m),3.51(2H,s),3.75-3.87(2H,m),7.25-7.32(5H,m)
MASS(APCI):266(M+H)+
制备133
30分钟内将N-苄基乙醇胺(302g)的水(8.92ml)和甲苯(1510ml)和二甘醇二甲醚(151ml)的混合溶液中滴加硫酸(128ml),该混合溶液回流搅拌6小时。冷却至室温后混合溶液中加入甲醇(300ml),然后混合物搅拌1小时,过滤沉淀,用甲醇(300ml×4)洗涤,干燥得到2-(N-苄基氨基)乙基硫酸氢盐(352.6g),为白色粉末。
MASS(APCI):232(M+H)+
Elemental Analysis Calcd.for C9H13N1O4S:
Calcd.C:46.74%,H:5.67%,N:6.06%
Found.C:46.42%,H:5.63%,N:5.93%
制备134
室温下于30分钟向2-(N-苄基氨基)乙基硫酸氢盐(28g)的水(36.3ml)和40%氢氧化钠水溶液(12.1ml)的混合溶液中加入2,2-双(甲氧基甲基)环氧乙烷(16.0g),室温搅拌87小时后,20分钟将40%氢氧化钠水溶液(73ml)滴加至该混合溶液中。该混合溶液室温搅拌1小时,然后40℃搅拌20小时,用乙酸乙酯(100ml×3)萃取,有机相用1N盐酸萃取(×6)。合并的萃取液用氢氧化钠中和,然后加入氯化钠,用乙酸乙酯(100ml×3)萃取。合并的萃取液用食盐水洗涤,硫酸镁干燥,减压蒸发,得到4-苄基-2,2-二甲氧基甲基吗啉(31.79g),为橙色油状物。
IR(净):2922,2877,2812,1454cm-1
NMR(CDCl3,δ):2.38-2.44(4H,m),3.27-3.45(4H,m),3.37(6H,s),3.65(2H,d,J=9.6Hz),3.77-3.84(2H,m),7.20-7.34(5H,m)
MASS(APCI).266(M+H)+
制备135
2,5-双(羟甲基)四氢呋喃-双(对甲苯磺酸盐)(10g)和苄胺(9.7g)的混合溶液70℃搅拌24小时,该混合物中加入氢氧化钠(1.85g)的甲醇(30ml)溶液,室温搅拌30分钟,混合物过滤。滤液蒸发,加入二氯甲烷,过滤,滤液减压蒸发。用柱层析(硅胶,250ml,乙酸乙酯∶己烷=1∶4)纯化,得到3-苄基-8-氧杂-3-氮杂双环[3.2.1]辛烷(4.05g),为油状物。
IR(净):2951,2800,1452cm-1
NMR(CDCl3,δ):1.78-2.07(4H,m),2.33(2H,dd,J=11.1和1.8Hz),2.54(2H,br d,J=11.1Hz),3.45(2H,s),4.25-4.28(2H,m),7.18-7.34(5H,m)
MASS(APCI):204(M+H)+
实施例38
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(2,2-二甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 26:+11.00°(C=0.25,MeOH)
mp:215-231℃
IR(KBr):3438,1645,1329,1281cm-1
NMR(DMSO-d6,δ):1.25,1.33(6H,s),2.60-5.30(19H,m),7.21-8.19(7H,m)
MASS(APCI):626(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S,5S)-2-甲氧基甲基-5-甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 26:+12.33°(C=0.25,MeOH)
mp:142-182℃
IR(KBr):1647,1281cm-1
NMR(DMSO-d6,δ):1.16(3H,d,J=6.2Hz),2.70-5.30(24H,m),7.21-8.19(7H,m)
MASS(APCI):656(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲氧基甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 24:+9.00°(C=0.25,MeOH)
mp:130-138℃
IR(KBr):3437,1647,1427,1329,1282cm-1
NMR(DMSO-d6,δ):2.80-5.30(2 9H,m),7.21-8.18(7H,m)
MASS(APCI):686(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(2,2-二甲氧基甲基吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 26:+5.27°(C=0.25,MeOH)
mp:123-149℃
IR(KBr):3435,1647cm-1
NMR(DMSO-d6,δ):2.70-5.30(29H,m),7.21-8.19(7H,m)
MASS(APCI):686(M+H)+(游离)
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 25:+11.67°(C=0.25,MeOH)
mp:232-250℃
IR(KBr):3438,1645,1281cm-1
NMR(DMSO-d6,δ):1.91-2.27(4H,m),2.80-5.40(19H,m),7.21-8.19(7H,m)
MASS(APCI):624(M+H)+(游离)
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(2,2-二甲基吗啉代)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 26:+9.73°(C=0.25,MeOH)
mp:152-162℃
IR(KBr):3438,1645,1516,1282cm-1
NMR(DMSO-d6,δ):1.30(6H,br s),2.60-5.30(22H,m),6.40-8.20(6H,m)
MASS(APCI):606(M+H)+(游离)
(7)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S,5S)-2-甲氧基甲基-5-甲基吗啉代)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 24:+12.33°(C=0.25,MeOH)
mp:140-164℃
IR(KBr):3437,1645,1282cm-1
NMR(DMSO-d6,δ):1.16( 3H,d,J=6.1Hz),2.70-5.30(27H,m),6.50-8.20(6H,m)
MASS(APCI):636(MH)+(游离)
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲氧基甲基吗啉代)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 26:+10.60°(C=0.25,MeOH)
mp:148-156℃
IR(KBr):1645,1516,1281cm-1
NMR(DMSO-d6,δ):2.60-5.20(32H,m),6.40-8.20(6H,m)
MASS(APCI):666(M+H)+(游离)
(9)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(2,2-二甲氧基甲基吗啉代)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 23:+6.60°(C=0.25,MeOH)
mp:132-150℃
IR(KBr):3437,1645,1516,1282cm-1
NMR(DMSO-d6,δ):2.60-5.30(32H,m),6.4S-8.20(6H,m)
MASS(APCI):666(M+H)+(游离)
(10)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(8-氧杂-3-氮杂双环)[3.2.1]辛烷-3-基)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 23:+13.20°(C=0.25,MeOH)
mp:163-178℃
IR(KBr):3431,1645,1518,1427,1282cm-1
NMR(DMSO-d6,δ):1.91-2.30(4H,m),2.70-5.30(22H,m),6.45-8.25(6H,m)
MASS(APCI):604(M+H)+(游离)
实施例39
根据类似实施例1的方法,用N,N-二异丙基乙胺代替碳酸钾作为碱,得到下述化合物。
(1)4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪-2-基)甲基〕-2-〔叔丁基二甲基甲硅烷氧基〕苯甲酸甲酯
IR(净):1677,1643,1438,1280cm-1
NMR(CDCl3,δ):0.10-0.30(6H,m),0.99(9H,s),2.00-5.10(22H,m),3.38(3H,s),3.87(3H,s),6.30-7.90(6H,m)
MASS(APCI):784(M+Na)+,763(M+H)+
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-甲氧基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 25:-5.16°(C=0.32,MeOH)
mp:146-149℃
IR(KBr):1645,1282,1182,1136cm-1
NMR(DMSO-d6,δ):2.60-5.20(28H,m),6.75-6.90(4H,m),7.29-8.21(3H,m)
MASS(APCI):604(M+H)+(游离)
(3)(2R)-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-甲基苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪
IR(净):2935,1641,1464,1421cm-1
NMR(CDCl3,δ):0.13(6H,br s),0.99(9H,s),2.15(3H,s),2.10-5.10(19H,m),3.81(3H,s),6.20-7.10(7H,m),7.32(1H,d,J=6.7Hz),8.40(1H,d,J=3.8Hz)
MASS(APCI):683(M+H)+
(4)(2R)-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-甲基苄基〕-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪
IR(净):2952,1645,1510cm-1
NMR(CDCl3,δ):0.14(6H,br s),0.99(9H,s),1.05(6H,s),2.15(3H,s),2.20-5.20(19H,m),3.81(3H,s),6.20-7.58(6H,m)
MASS(APCI):688(M+H)+
(5)(2R)-1-〔3-(二甲基氨磺酰基)-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐
[α]D 26:+1.33°(C=0.25,MeOH)
mp:190-194℃
IR(KBr):3398,1647cm-1
NMR(DMSO-d6,δ):2.66(6H,s),2.80-5.30(19H,m),6.90-8.71(10H,m)
MASS(APCI):684(M+H)+(游离)
(6)(2R)-1-〔3-甲基磺酰基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
[α]D 26:-2.33°(C=0.25,MeOH)
mp:192-197℃
IR(KBr):3433,3400,1647cm-1
NMR(DMSO-d6,δ):2.70-5.30(22H,m),7.05-8.68(10H,m)
MASS(APCI):655(M+H)+(游离)
(7)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2R)-2-(甲氧基甲基)吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 26.5:+5.18°(C=0.28,MeOH)
mp:188-194℃
IR(KBr):3438,1645,1516,1464,1456cm-1
NMR(DMSO-d6,δ):2.50-5.30(22H,m),3.27(3H,s),7.10-8.30(7H,m)
MASS(API-ES positive):642(M+H)+(游离)
(8)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S,4R)-4-甲氧基-2-(甲氧基甲基)吡咯烷子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 26.7:-17.43°(C=0.23,MeOH)
mp:56.59℃
IR(KBr):3438,1647,1427cm-1
NMR(DMSO-d6,δ):1.70-5.40(21H,m),3.29(3H,s),3.35(3H,s),7.10-7.80(6H,m),8.19(1H,br s)
MASS(APCI):656(M+H)+(游离)
(9)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((3S,4S)-3,4-二甲氧基吡咯烷子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 23.1:+5.94°(C=0.202,MeOH)
mp:203-208℃
IR(KBr):3437,2565,2440,1647,1429,1331,1282,1178,1128,1066cm-1
NMR(DMSO-d6,δ):2.76-5.32(25H,m),7.10-8.26(7H,m)
MASS(APCI):642(M+H)+(游离)
(10)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧苄基〕-4-〔2-((2S,4R)-4-甲氧基-2-(甲氧基甲基)吡咯烷子基)乙基〕哌嗪二盐酸盐
[α]D 26.6:-12.27°(C=0.30,MeOH)
mp:128-134℃
IR(KBr):3437,3400,1645,1516cm-1
NMR(DMSO-d6,δ):1.70-5.30(21H,m),3.29(3H,s),3.35(3H,s),3.57(3H,s),6.40-8.30(6H,m)
MASS(APCI):636(M+H)+(游离)
(11)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧苄基〕-4-〔2-((2R)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 26.8:+6.24°(C=0.33,MeOH)
mp:139-148℃
IR(KBr):3438,1644,1516,1464,1427cm-1
NMR(DMSO-d6,δ):2.60-5.30(25H,m),3.27(3H,s),6.40-8.30(6H,m)
MASS(APCI):622(M+H)+(游离)
(12)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((3S,4S)-3,4-二甲氧基吡咯烷子基)乙基〕-2-〔4-氟-3-甲氧苄基〕哌嗪二盐酸盐
[α]D 23.5:+8.05°(C=0.205,MeOH)
mp:112-120℃
IR(KBr):3431,2561,2436,1645,1516,1464,1427,1282,1182,1134,1034cm-1
NMR(DMSO-d6,δ):2.65-5.24(28H,m),6.44-8.30(6H,m)
MASS(APCI):622(M+H)+(游离)
(13) (2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔2-((2R)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 26.5:-11.28°(C=0.27,MeOH)
mp:204-214℃
IR(KBr):1645,1539,1516cm-1
NMR(DMSO-d6,δ):2.50-5.20(22H,m),3.27(3H,s),6.30-8.30(6H,m),9.90-10.30(1H,br)
MASS(API-ES positive):624(M+H)+(游离)
(14)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔2-((2S,4R)-4-甲氧基-2-(甲氧基甲基)吡咯烷子基)乙基〕哌嗪二盐酸盐
[α]D 26.4:-25.54°(C=0.33,MeOH)
mp:95-105℃
IR(KBr):3400,1645,1516,1429cm-1
NMR(DMSO-d6,δ):1.70-5.30(21H,m),3.28(3H,s),3.35(3H,s),6.20-8.30(6H,m),10.07-11.26(1H,br)
MASS(APCI):638(M+H)+(游离)
(15)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔2-((3S,4S)-3,4-二甲氧基吡咯烷子基)乙基〕哌嗪二盐酸盐
[α]D 23.8:-6.49°(C=0.23,MeOH)
mp:150-155℃
IR(KBr):3398,2600,2436,1645,1429,1281,1180,1136,1107,1047cm-1
NMR(DMSO-d6,δ):2.55-5.15(25H,m),6.24-8.30(6H,m)
MASS(APCI):624(M+H)+(游离)
(16)(2R)-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪
IR(净):2935,1641,1417cm-1
NMR(CDCl3,δ):0.18(6H,br s),1.02(9H,s),1.16(6H,d,J=6.3Hz),1.76(2H,t,J=10.7Hz),2.00-5.10(17H,m),6.30-7.50(5H,m),7.61(1H,s)
MASS(APCI):688(M+H)+
(17)(2R)-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-氯苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪
IR(KBr):2954,2935,1643,1419cm-1
NMR(DMSO-d6,δ):0.00-0.07(6H,br),0.83(9H,s),1.70-5.00(19H,m),6.20-8.10(8H,m),8.18(1H,d,J=4.7Hz)
MASS(API-ES positive):707(M+H)+
实施例40
(2R)-4-〔2-氯乙基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪盐酸盐与(2S)-2-(羟甲基)吡咯烷反应,以类似实施例1的反应条件,用N,N-二异丙基乙胺代替碳酸钾作为碱,得到下述化合物。
(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(羟甲基)吡咯烷子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 24.0:+6.43°(C=0.28,MeOH)
mp:221-224℃
IR(KBr):1643,1516,1427cm-1
NMR(DMSO-d6,δ):1.65-2.30(4H,m),2.60-5.40(19H,m),7.10-8.30(7H,m)
MASS(APCI):612(M+H)+(游离)
实施例41
根据类似实施例40的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二羟甲基哌啶子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 24.2:+10.36°(C=0.14,MeOH)
mp:164-167℃
IR(KBr):3396,3369,1645,1516,1427cm-1
NMR(DMSO-d6,δ):1.30-2.10(6H,m),2.40-5.60(21H,m),7.00-8.30(7H,m)
MASS(APCI):656(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲氧基甲基哌啶子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 23.1:+5.12°(C=0.21,MeOH)
mp:147-151℃
IR(KBr):1645,1516,1454,1427cm-1
NMR(DMSO-d6,δ):1.40-2.00(6H,m),2.80-5.30(25H,m),7.10-8.40(7H,m)
MASS(APCI):684(M+H)+(游离)
(3)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-3,5-二甲氧基甲基哌啶子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 23.4:+8.28°(C=0.32,MeOH)
mp:157-160℃
IR(KBr):3438,1647,1464,1427cm-1
NMR(DMSO-d6,δ):1.05(1H,q,J=12.4Hz),1.70(1H,m),2.10-5.40(23H,m),3.24(6H,s),7.10-8.30(7H,m)
MASS(APCI):684(M+H)+(游离)
(4)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((3S,4S)-3,4-二羟基吡咯烷子基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 23.9:+7.37°(C=0.29,MeOH)
mp:154-159℃
IR(KBr):3398,3369,1645,1427cm-1
NMR(DMSO-d6,δ):2.20-5.40(21H,m),7.1-8.3(7H,m)
MASS(APCI):614(M+H)+(游离)
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-〔2-((2S)-2-(羟甲基)吡咯烷子基)乙基〕哌嗪二盐酸盐
[α]D 24.1:+4.76°(C=0.25,MeOH)
mp:198-201℃
IR(KBr):1645,1516,1464,1425cm-1
NMR(DMSO-d6,δ):1.60-5.40(23H,m),3.59(3H,s),6.40-8.30(6H,m)
MASS(APCI):592(M+H)+(游离)
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二羟基甲基哌啶子基)乙基〕-2-〔4-氟-3-甲氧基苄基〕哌嗪二盐酸盐
[α]D 24.3:+11.33°(C=0.27,MeOH)
mp:159-161℃
IR(KBr):3367,1645,1516,1464,1427cm-1
NMR(DMSO-d6,δ):1.40-2.00(6H,m),2.60-5.30(24H,m),6.40-8.30(6H,m)
MASS(APCI):636(M+H)+(游离)
(7)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-3,5-二甲氧基甲基哌啶子基)乙基〕-2-〔4-氟-3-甲氧基苄基〕哌嗪二盐酸盐
[α]D 23.7:+9.45°(C=0.28,MeOH)
mp:150-156℃
IR(KBr):3438,2939,1645,1518,1464,1427cm-1
NMR(DMSO-d6,δ):1.05(1H,q,J=12.3Hz),1.70(1H,m),2.10-5.30(26H,m),3.24(6H,s),6.40-8.30(6H,m)
MASS(APCI):664(M+H)+(游离)
实施例42
根据类似实施例13的方法得到下述化合物。
(1)(2R)-2-〔3-羟基-4-甲基苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
[α]D 27:-17.11°(C=0.15,MeOH)
mp:192-208℃
IR(KRr):1643,1628,1464cm-1
NMR(DMSO-d6,δ):2.06(3H,s),2.60-5.10(22H,m),6.20-7.30(6H,m),7.62-7.69(1H,m),8.05(1H,d,J=7.8Hz),8.67(1H,d,J=4.0Hz)
MASS(APCI):569(M+H)+(游离)
(2)(2R)-4-〔4-(3,3-二甲基吗啉代)-2-丁炔基〕-2-〔3-羟基-4-甲基苄基〕-1-〔3-甲氧基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 27:+13.87°(C=0.25,MeOH)
mp:181-188℃
IR(KBr):1645,1464,1425cm-1
NMR(DMSO-d6,δ):1.25-1.32(6H,m),2.07(3H,s),2.70-5.20(22H,m),6.20-7.29(6H,m)
MASS(APCI):574(M+H)+(游离)
(3)(2R)-2-〔4-氯-3-羟基苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕哌嗪二盐酸盐
[α]D 26.5:-12.04°(C=0.25,MeOH)
mp:196-199℃
IR(KBr):3398,1643,1514,1456,1425cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.60-5.20(19H,m),6.30-8.10(6H,m),10.08(1H,br s)
MASS(APCI):574(M+H)+(游离)
(4)(2R)-2-〔4-氯-3-羟基苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
[α]D 26.5:-20.57°(C=0.2 8,MeOH)
mp:200-204℃
IR(KBr):3430,3400,1645,1514,1464,1425cm-1
NMR(DMSO-d6,δ):2.60-5.20(19H,m),6.30-8.10(8H,m),8.63(1H,d,J=4.6Hz),10.09(1H,br)
MASS(APCI):593(M+H)+(游离)
实施例43
根据类似实施例41的方法得到下述化合物。
(1)(2R)-2-〔4-氯苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕哌嗪三盐酸盐
[α]D 27:+1.5°(C=0.5,MeOH)
IR(KBr):1645,1510,1460,1425,1270,1240,1175,1135cm-1
NMR(DMSO-d6,δ):2.62-5.15(22H,m),3.28(3H,s),6.16-9.01(11H,m)
MASS(APCI):617(M)+(游离)
(2)(2R)-2-〔4-氯苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-甲基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 27:+10.9°(C=0.5,MeOH)
mp:148-151℃
IR(KBr):1645,1510,1465,1425,1270,1230cm-1
NMR(DMSO-d6,δ):2.33(3H,s),3.28(3H,s),2.66-5.24(22H,m),6.16-7.70(7H,m)
MASS(APCI):554(M)+(游离)
(3)(2R)-2-〔4-氯苄基〕-1-〔3-环戊基磺酰基-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 27:+12.1°(C=0.5,DMF)
mp:>230℃
IR(KBr):1650,1465,1425,1335,1305,1235,1135cm-1
NMR(DMSO-d6,δ):1.45-1.93(9H,m),2.80-5.20(22H,m),3.27(3H,s),6.14-8.30(7H,m)
MASS(APCI):672(M)+(游离)
(4)(2R)-2-〔4-氯苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 27:+13.3°(C=0.5,MeOH)
mp:140-146℃
IR(KBr):1625,1415,1320,1270,1225,1175cm-1
NMR(DMSO-d6,δ):2.54(3H,s),2.66-5.20(22H,m),3.27(3H,s),6.66-7.64(7H,m)
MASS(APCI):58 6(M)+(游离)
(5)(2R)-2-〔4-氯苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 27:+7.0°(C=0.5,MeOH)
mp:148-153℃
IR(KBr):1645,1460,1420,1315,1270,1230,1175cm-1
NMR(DMSO-d6,δ):2.66-5.20 (22H,m),3.28(3H,s),6.02-8.00(7H,m)
MASS(APCI):574(M)+(游离)
(6)(2R)-2-〔4-氯苄基〕-1-〔3-氟-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 27:+10.0°(C=0.5,MeOH)
mp:199-204℃
IR(KBr):1645,1425,1235,1175,1135cm-1
NMR(DMSO-d6,δ):2.70-5.16(22H,m),3.28(3H,s),6.16-7.90(7H,m)
MASS(APCI):558(M)+(游离)
(7)(2R)-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 22:+21.93°(C=0.25,MeOH)
mp:153-170℃
IR(KBr):3433,1645cm-1
NMR(DMSO-d6,δ):2.54(3H,s),2.70-5.30(25H,m),6.50-7.80(7H,m)
MASS(APCI):620(M+H)+(游离)
(8)(2R)-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 22:+29.60°(C=0.21,MeOH)
mp:168-173℃
IR(KBr):3433,1647cm-1
NMR(DMSO-d6,δ):2.80-5.30(25H,m),6.87-8.00(7H,m)
MASS(APCI):608(M+H)+(游离)
(9)(2R)-1-〔3-氟-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 27:+17.47°(C=0.25,MeOH)
mp:173-176℃
IR(KBr):1647cm-1
NMR(DMSO-d6,δ):2.80-5.30(25H,m),6.70-7.90(7H,m)
MASS(APCI):592(M+H)+(游离)
(10)(2R)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐
[α]D 26:+13.60°(C=0.25,MeOH)
mp:81-91℃
IR(KBr):3435,1643cm-1
NMR(DMSO-d6,δ): 2.80-5.30(25H,m),6.88-8.98(11H,m)
MASS(APCI):651(M+H)+(游离)
(11)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 27:+19.00°(C=0.25,MeOH)
mp:154-156℃
IR(KBr):3435,1647cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.54(3H,s),2.60-5.30(19H,m),6.50-7.70(7H,m)
MASS(APCI):604(M+H)+(游离)
(12)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-甲磺酰基-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 25:+12.60°(C=0.25,MeOH)
mp:188-195℃
IR(KBr):1647cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.60-5.30(22H,m),7.00-8.32(7H,m)
MASS(APCI):636(M+H)+(游离)
(13)(2R)-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕-2-〔4-(三氟甲基)苄基〕哌嗪三盐酸盐
[α]D 26:+8.40°(C=0.25,MeOH)
mp:135-145℃
IR(KBr):3433,3402,1641cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.2Hz),2.60-5.30(19H,m),6.80-9.02(11H,m)
MASS(APCI):635(M+H)+(游离)
(14)(2R)-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪二盐酸盐
[α]D 27:+1.53°(C=0.25,MeOH)
mp:190-210℃
IR(KBr):3431,1643cm-1
NMR(DMSO-d6,δ):2.54(3H,s),2.80-5.30(19H,m),6.50-8.71(10H,m)
MASS(APCI):623(M+H)+(游离)
(15)(2R)-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕-2-〔4-(三氟甲基)苄基〕哌嗪四盐酸盐
[α]D 26:-5.73°(C=0.25,MeOH)
mp:205-218℃
IR(KBr):3400,1641cm-1
NMR(DMSO-d6,δ):2.60-5.30(19H,m),6.85-9.02(14H,m)
MASS(APCI):654(M+H)+(游离)
(16)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 27.3:+23.47°(C=0.36,MeOH)
mp:62.5-82.4℃
IR(KBr):1645,1518,1421,1176,1126cm-1
NMR(DMSO-d6,δ):1.15(6H,d,J=6.1Hz),2.60-4.20(27H,m),6.50-7.56(6H,m)
MASS:584(M+H)+(游离)
(17)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕哌嗪三盐酸盐
[α]D 27.4:+14.30°(C=0.37,MeOH)
mp:137.6-142.5℃
IR(KBr):1641,1515,1425,1270,1176,1145,1132cm-1
NMR(DMSO-d6,δ):1.14(6H,d,J=6.0Hz),2.60-4.20(25H,m),6.52-8.90(10H,m)
MASS(APCI):615(M+H)+(游离)
(18)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪三盐酸盐
[α]D 27.4:-3.51°(C=0.39,MeOH)
mp:143.3-147.5℃
IR(KBr):1645,1516,1417,1173,1126cm-1
NMR(DMSO-d6,δ):3.80-5.20(28H,m),6.53-8.68(9H,m)
MASS(APCI):603(M+H)+(游离)
(19)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕-4-〔2-(5,6,7,8-四氢-1,6-二氮杂萘-6-基)乙基〕哌嗪四盐酸盐
[α]D 27.9:-9.07°(C=0.46, MeOH)
mp:236.8-248.5℃
IR(KBr):1641,1635,1516,1423,1273,1130cm-1
NMR(DMSO-d6,δ):2.65-5.10(26H,m),6.51-9.00(13H,m)
MASS:634(M+H)+(游离)
(20)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-(4-吡啶基)-5-(三氟甲基)苯甲酰基〕哌嗪三盐酸盐
[α]D 28:+32.5°(C=0.5,MeOH)
IR(KBr):1645,1515,1425,1270,1235cm-1
NMR(DMSO-d6,δ):2.66-5.24(25H,m),3.27(3H,s),6.45-8.93(10H,m)
MASS(APCI):631(M+H)+(游离)
(21)(2R)-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-2-〔4-氟-3-甲氧基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 28:+25.4°(C=0.5,MeOH)
mp:139-142℃
IR(KBr):1645,1515,1460,1420,1315,1270,1230cm-1
NMR(DMSO-d6,δ):2.72-5.21(22H,m),3.29(3H,s),3.44(3H,s),6.17-8.00(6H,m)
MASS(APCI):588(M)+(游离)
(22)(2R)-2-〔4-氟-3-甲氧基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 28:+28.1°(C=0.5,MeOH)
mp:132-135℃
IR(KBr):1645,1515,1460,1420,1315,1270,1230,1130cm-1
NMR(DMSO-d6,δ):2.54(3H,s),2.73-5.27(22H,m),3.28(3H,s),3.41(3H,s),6.15-7.83(6H,m)
MASS(APCI):600(M+H)+(游离)
(23)(2R)-2-〔4-氟-3-甲氧基苄基〕-1-〔3-氟-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 27:+21.4°(C=0.5,MeOH)
IR(KBr):1640,1515,1465,1425,1345,1275,1230,1135cm-1
NMR(DMSO-d6,δ):2.76-5.20(22H,m),3.29(3H,s),3.42(3H,s),6.16-7.86(6H,m)
MASS(APCI):572(M+H)+(游离)
实施例44
根据类似制备21下半部分的方法得到下述化合物。
(1)(2R)-2-〔4-氯-3-羟基苄基〕-1-〔3-氯-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 28:+6.1°(C=0.5,MeOH)
IR(KBr):1645,1510,1425,1235,1175cm-1
NMR(DMSO-d6,δ):2.55-5.10(22H,m),3.27(3H,s),6.31-8.03(6H,m),10.07(1H,br s)
MASS(APCI):590(M)+(游离)
(2)(2R)-2-〔4-氯-3-羟基苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-1-〔3-甲硫基-5-(三氟甲基)苯甲酰基〕哌嗪二盐酸盐
[α]D 28:+15.0°(C=0.5,MeOH)
mp:169-174℃
IR(KBr):3475,3420,1640,1425,1320,1270,1230,1135cm-1
NMR(DMSO-d6,δ):2.54(3H,s),2.56-5.10(22H,m),3.27(3H,s),6.29-7.69(6H,m),10.10(1H,br s)
MASS(APCI):602(M)+(游离)
(3)(2R)-2-〔4-氯-3-羟基苄基〕-1-〔3-氟-5-(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐
[α]D 27:+7.6°(C=0.5,MeOH)
mp:176-178℃
IR(KBr):1645,1510,1460,1425,1235,1175cm-1
NMR(DMSO-d6,δ):2.52-4.98(22H,m),3.28(3H,s),6.34-7.77(7H,m)
MASS(APCI):574(M)+(游离)
实施例45
根据类似实施例11的方法得到下述化合物。
(1)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔(1H-吡咯并[3,2-b]吡啶-3-基)甲基〕哌嗪二盐酸盐
[α]D 25.0:+5.42°(C=0.60,MeOH)
mp:208-211℃
IR(KBr):1647,1281,1180,1138cm-l
NMR(DMSO-d6,δ):2.60-5.10(11H,m),6.26-7.20(3H,m),7.43-7.82(3H,m),8.18-8.72(4H,m),10.08(1H,br),13.11(1H,s)
MASS(APCI):597(M+H)+(游离)
(2)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔4-氯-3-羟基苄基〕-4-〔(1H-吡咯并[2,3-b]吡啶-3-基)甲基〕哌嗪二盐酸盐
[α]D 24.9:-0.90°(C=0.50,MeOH)
mp:197-200℃
IR (KBr):1647,1281,1180,1136cm-1
NMR(DMSO-d6,δ):2.60-5.20(11H,m),6.24-7.40(4H,m),7.45(1H,s),7.76(1H,s),7.95-8.55(4H,m),11.60(1H,br),12.45(1H,s)
MASS(APCI):597(M+H)+(游离)
实施例46
1M碘化甲基镁盐的乙醚溶液(3.15ml)加至4-〔((2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪-2-基)甲基〕-2-〔叔丁基二甲基甲硅烷氧基〕苯甲酸甲酯(0.8g)的甲苯(8ml)溶液中,45℃搅拌4小时后,混合溶液用饱和的氯化铵水溶液终止反应,该混合溶液用乙酸乙酯萃取,分有机相,依次用水和食盐水洗涤,硫酸镁干燥,减压蒸发得到粗品油状物。该油状物用硅胶柱层析纯化,用二氯甲烷和甲醇(40∶1)的混合溶剂洗脱,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-(1-羟基-1-甲基乙基)苄基-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪(0.333g)
IR(净):1643,1438,1280cm-l
NMR(CDCl3,δ):0.10-0.50(6H,m),1.03(9H,s),1.58(6H,s),2.00-5.10(22H,m),3.38(3H,s),6.30-7.90(6H,m)
MASS(API-ES):784(M+Na)+,763(M+H)+
实施例47
甲磺酰氯(0.115ml)加至(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-(叔丁基二甲基甲硅烷氧基)-4-(1-羟基-1-甲基乙基)苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪(0.76g)和三乙胺(0.35ml)的二氯甲烷(9ml)冰冷溶液中,该温度下搅拌2小时,混合物用水洗涤2次。分离有机相,用食盐水洗涤,硫酸镁干燥,减压蒸发得到甲磺酰化和非甲磺酰化的化合物的混合物。该混合物未经纯化溶解在甲醇中,该溶液用20%钯氢氧化物-活性炭(0.1g)于室温和3个大气压下氢化5小时。反应混合物用Celite过滤,用甲醇洗涤。合并滤液和洗液,减压蒸发。得到的糖浆溶解在四氢呋喃(6.5ml)中,10℃以下该溶液中加入氟化四丁基铵(1M的四氢呋喃溶液,0.1ml)。室温搅拌后,混合溶液减压蒸发,残留物用柱层析纯化,用二氯甲烷和甲醇(40∶1)的混合溶剂作为洗脱液,得到油状物。该油状物用4N氯化氢的乙酸乙酯溶液处理,得到(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-〔3-羟基-4-(1-甲乙基)苄基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪二盐酸盐(150mg)的粉末。
[α]D 26:-1.25°(C=0.2,MeOH)
mp:218-228℃
IR(KBr):3500-3150,2700-2300,1644,1498,1461,1282,1174cm-1
NMR(DMSO-d6,δ):1.00-1.30(6H m),2.60-5.10(26H,m),6.20-8.20(6H,m),9.22(1H,br s)
MASS(APCI):632(M+H)+(游离)
Claims (6)
1.下述通式的化合物以及它们的药用可接受盐
其中
Y是C1-C6亚烷基;
R1是被1或2个相同或不同取代基取代的苯基,取代基选自下列基团:卤素、C1-C6烷基、C1-C6烷氧基、单、二或三-卤代C1-C6烷基、硝基、氨基、C1-C6烷基氨基、二C1-C6烷基氨基、C1-C6烷硫基、C1-C6烷基磺酰基、环C3-C6烷基磺酰基、氨基磺酰基、C1-C6烷基氨基磺酰基、二C1-C6烷基氨基磺酰基、吡咯烷基磺酰基、吗啉基磺酰基、吡咯基磺酰基、吡啶基磺酰基、吡咯基和吡啶基;
R2是被取代的苯基,取代基为羟基和选自下述的基团:C1-C6烷基、单、二或三卤代C1-C6烷基、单、二或三卤代C1-C6烷基磺酰氧基、卤素、C1-C6亚烷基二氧基、C1-C6烷氧基、C1-C6烷氧羰基、C1-C6烷氧C1-C6烷氧基C1-C6烷氧基、羟基、二苯基C1-C6烷基甲硅烷氧基、三C1-C6烷基甲硅烷氧基、羟基C1-C6烷基、氰基、氨基、单、二或三卤代C1-C6烷基羰基氨基、C1-C6烷基氨基、N-C1-C6烷基-单、二或三卤代C1-C6烷基羰基氨基、吡咯烷基和吗啉基,其可被C1-C6烷氧基C1-C6烷基或C1-C6烷基取代;
R3是氢;和
R4是2,6-二甲基吗啉代C1-C6烷基;
3,3-二甲基吗啉代C1-C6烷基;
顺-3,5-二甲基吗啉代C1-C6烷基;
(3S,5S)-3,5-二甲基吗啉代C1-C6烷基;
(3S,5R)-3,5-二甲基吗啉代C1-C6烷基;
2-甲氧基甲基吗啉代C1-C6烷基;
3-甲氧基甲基吗啉代C1-C6烷基;
2-甲氧基甲基-5-甲基吗啉代C1-C6烷基;
2-甲氧基甲基-5,5-二甲基吗啉代C1-C6烷基;
3,5-二甲氧基甲基吗啉代C1-C6烷基;或
2,3-二甲氧基甲基吗啉代C1-C6烷基。
2.权利要求1的化合物,其中
Y是C1-C4亚烷基;
R1是双单、二或三卤代C1-C4烷基苯基;
R2是被取代的苯基,取代基为羟基和选自下述的基团:C1-C4烷基、单、二或三卤代C1-C4烷基、卤素、C1-C4烷氧基和羟基;
R3是氢;和
R4是2,6-二甲基吗啉代C1-C4烷基;
2-甲氧基甲基吗啉代C1-C4烷基;
3-甲氧基甲基吗啉代C1-C4烷基;或
2-甲氧基甲基-5-甲基吗啉代C1-C4烷基。
3.权利要求2的化合物,选自如下化合物:
(1)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-((3R)-3-(甲氧基甲基)吗啉代)乙基〕哌嗪,
(2)1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-(顺-2,6-二甲基吗啉代)乙基〕-2-(3-羟基-4-甲基苄基)哌嗪,
(3)1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(3-羟基-4-甲基苄基)-4-〔2-((2 S,5 S)-2-甲氧基甲基-5-甲基吗啉代)乙基〕哌嗪,
(4)1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-2-(3-羟基-4-甲基苄基)哌嗪,
(5)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕-2-(3-羟基-4-甲基苄基)哌嗪,和
(6)(2R)-1-〔3,5-双(三氟甲基)苯甲酰基〕-2-(4-氯-3-羟基苄基)-4-〔2-((2S)-2-(甲氧基甲基)吗啉代)乙基〕哌嗪,或它们的药用可接受的盐。
4.制备权利要求1的化合物或它们的药用可接受盐的方法,包括:
使通式(II)的化合物或其盐,
其中R1、R2、R3和Y各自如权利要求1中的定义,与通式(III)的化合物或其盐反应,
W1-R4 (III)其中R4如权利要求1的定义,和
W1是离去基,得到通式(I)的化合物或其盐,
其中R1、R2、R3、R4和Y各自如权利要求1中的定义。
5.一种用于治疗或预防速激肽介导的疾病的药用组合物,其中包含作为活性成份的权利要求1的化合物或它们的药用可接受的盐与与之混合的药用可接受的载体。
6.权利要求1的化合物在制备治疗或预防速激肽介导的疾病的药品中的应用。
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TR200101649T2 (tr) * | 1998-12-14 | 2001-10-22 | Fujisawa Pharmaceutical Co., Ltd. | Piperazin türevleri. |
GB9923748D0 (en) * | 1999-10-07 | 1999-12-08 | Glaxo Group Ltd | Chemical compounds |
TW591025B (en) * | 2000-06-13 | 2004-06-11 | Fujisawa Pharmaceutical Co | Production of the piperazine derivative |
IT1317049B1 (it) * | 2000-06-23 | 2003-05-26 | Sigma Tau Ind Farmaceuti | Composti utili per la preparazione di medicamenti ad attivita'inibitrice della fosfodiesterasi iv. |
US6974818B2 (en) * | 2002-03-01 | 2005-12-13 | Euro-Celtique S.A. | 1,2,5-thiadiazol-3-YL-piperazine therapeutic agents useful for treating pain |
UA77515C2 (en) * | 2002-04-04 | 2006-12-15 | Diazabicyclo alkane derivatives possessing neuroldnin-nk1 receptor antagonistic activity | |
WO2007092475A2 (en) | 2006-02-06 | 2007-08-16 | Franklin And Marshall College | Site-specific incorporation of fluorinated amino acids into proteins |
ES2522827T3 (es) | 2009-10-30 | 2014-11-18 | Domain Therapeutics | Nuevos derivados de oximas y su uso como moduladores alostéricos de los receptores del glutamato metabotrópico |
BR112012013431B1 (pt) | 2009-12-04 | 2022-04-12 | Sunovion Pharmaceuticals, Inc. | Composto e seu uso, composição farmacêutica |
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JP2019523279A (ja) | 2016-07-29 | 2019-08-22 | サノビオン ファーマシューティカルズ インクSunovion Pharmaceuticals Inc. | 化合物および組成物ならびにそれらの使用 |
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IL303177A (en) | 2017-02-16 | 2023-07-01 | Sunovion Pharmaceuticals Inc | Treatment of schizophrenia |
SG11202000669VA (en) | 2017-08-02 | 2020-02-27 | Sunovion Pharmaceuticals Inc | Isochroman compounds and uses thereof |
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US11136304B2 (en) | 2019-03-14 | 2021-10-05 | Sunovion Pharmaceuticals Inc. | Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof |
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US5541054B1 (en) * | 1995-04-20 | 1998-11-17 | Imation Corp | Spectral sensitizing dyes for photothermographic elements |
BR9610277A (pt) * | 1995-08-31 | 1999-07-06 | Schering Corp | Derivados de piperazino como antagonistas de neurowuinina |
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TW509688B (en) | 2002-11-11 |
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US20060014948A1 (en) | 2006-01-19 |
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HK1043998A1 (en) | 2002-10-04 |
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IL143577A0 (en) | 2002-04-21 |
DE69930543T2 (de) | 2006-11-09 |
CN1334812A (zh) | 2002-02-06 |
PT1140924E (pt) | 2006-08-31 |
JP3454427B2 (ja) | 2003-10-06 |
EP1140924A1 (en) | 2001-10-10 |
BR9917047A (pt) | 2002-07-30 |
HK1043998B (zh) | 2005-03-18 |
JP2002532499A (ja) | 2002-10-02 |
CZ20012130A3 (cs) | 2001-10-17 |
KR20010086104A (ko) | 2001-09-07 |
HUP0203651A2 (en) | 2003-02-28 |
TR200101649T2 (tr) | 2001-10-22 |
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Owner name: ASTELLAS PHARMA INC. Free format text: FORMER NAME OR ADDRESS: FUJISAWA PHARMACEUTICAL CO., LTD. |
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CP03 | Change of name, title or address |
Address after: Tokyo, Japan Patentee after: ASTELLAS PHARMA Inc. Address before: Osaka City, Osaka of Japan Patentee before: Fujisawa Pharmaceutical Co.,Ltd. |
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C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |