CN103073524B - 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof - Google Patents
4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof Download PDFInfo
- Publication number
- CN103073524B CN103073524B CN201310033226.7A CN201310033226A CN103073524B CN 103073524 B CN103073524 B CN 103073524B CN 201310033226 A CN201310033226 A CN 201310033226A CN 103073524 B CN103073524 B CN 103073524B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- substituted
- formula
- dissolved
- 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
Links
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical class CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title abstract description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 117
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 96
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 84
- 239000000543 intermediate Substances 0.000 claims abstract description 38
- -1 amine hydrochloride Chemical class 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011230 binding agent Substances 0.000 claims abstract description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006698 hydrazinolysis reaction Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 239000007806 chemical reaction intermediate Substances 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 133
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 91
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 81
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 71
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 53
- 238000003756 stirring Methods 0.000 claims description 53
- 238000001035 drying Methods 0.000 claims description 51
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 32
- 229960001701 chloroform Drugs 0.000 claims description 31
- 235000019441 ethanol Nutrition 0.000 claims description 31
- 229960004756 ethanol Drugs 0.000 claims description 29
- 238000005406 washing Methods 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000001953 recrystallisation Methods 0.000 claims description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 26
- 239000012065 filter cake Substances 0.000 claims description 26
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 25
- 238000000967 suction filtration Methods 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 239000012141 concentrate Substances 0.000 claims description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 14
- NQNZNONJZASOKL-UHFFFAOYSA-N 1-phenylpiperazin-4-ium;chloride Chemical class Cl.C1CNCCN1C1=CC=CC=C1 NQNZNONJZASOKL-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 235000019253 formic acid Nutrition 0.000 claims description 11
- LAYPMCGIWDGYKX-UHFFFAOYSA-N trichloromethyl hydrogen carbonate Chemical group OC(=O)OC(Cl)(Cl)Cl LAYPMCGIWDGYKX-UHFFFAOYSA-N 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001448 anilines Chemical class 0.000 claims description 6
- 229960004132 diethyl ether Drugs 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 125000005393 dicarboximide group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 214
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 25
- 235000015320 potassium carbonate Nutrition 0.000 abstract description 24
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 abstract description 10
- 208000012902 Nervous system disease Diseases 0.000 abstract description 5
- 208000015114 central nervous system disease Diseases 0.000 abstract description 5
- 229960003920 cocaine Drugs 0.000 abstract description 5
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 206010012335 Dependence Diseases 0.000 abstract 2
- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 abstract 1
- 102000004073 Dopamine D3 Receptors Human genes 0.000 abstract 1
- 108090000525 Dopamine D3 Receptors Proteins 0.000 abstract 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- 239000007788 liquid Substances 0.000 description 45
- 238000000605 extraction Methods 0.000 description 44
- 238000001914 filtration Methods 0.000 description 44
- 238000004809 thin layer chromatography Methods 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000010992 reflux Methods 0.000 description 25
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 23
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 23
- 238000010907 mechanical stirring Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 23
- 238000013517 stratification Methods 0.000 description 23
- 238000005352 clarification Methods 0.000 description 22
- 238000002425 crystallisation Methods 0.000 description 22
- 230000008025 crystallization Effects 0.000 description 22
- 244000144992 flock Species 0.000 description 22
- 239000012452 mother liquor Substances 0.000 description 22
- 235000007715 potassium iodide Nutrition 0.000 description 22
- 229960004839 potassium iodide Drugs 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 10
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 9
- 229940127108 compound 5g Drugs 0.000 description 9
- JJXZYKARSPRNHA-UHFFFAOYSA-N Cl.COC1=CC=C(C=C1)C1NCCNC1 Chemical compound Cl.COC1=CC=C(C=C1)C1NCCNC1 JJXZYKARSPRNHA-UHFFFAOYSA-N 0.000 description 8
- 239000013067 intermediate product Substances 0.000 description 8
- 206010013663 drug dependence Diseases 0.000 description 7
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 5
- 229960003638 dopamine Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
- CYQFNNSFAGXCEC-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)piperazine;hydrochloride Chemical compound [Cl-].ClC1=CC=CC(N2CC[NH2+]CC2)=C1Cl CYQFNNSFAGXCEC-UHFFFAOYSA-N 0.000 description 2
- MHXPYWFZULXYHT-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazin-1-ium;chloride Chemical compound Cl.ClC1=CC=CC(N2CCNCC2)=C1 MHXPYWFZULXYHT-UHFFFAOYSA-N 0.000 description 2
- OIKQTWPVQQAGJG-UHFFFAOYSA-N 1-(4-fluorophenyl)piperazine;hydron;chloride Chemical compound Cl.C1=CC(F)=CC=C1N1CCNCC1 OIKQTWPVQQAGJG-UHFFFAOYSA-N 0.000 description 2
- HFJDUYKRPHHPAX-UHFFFAOYSA-N 1-(4-methoxyphenyl)piperazine;hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[NH+]1CCNCC1 HFJDUYKRPHHPAX-UHFFFAOYSA-N 0.000 description 2
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 2
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 2
- PFYFJROUSKDWOS-UHFFFAOYSA-N Cl.NCC1=CC=C(C=C1)N1CCNCC1 Chemical compound Cl.NCC1=CC=C(C=C1)N1CCNCC1 PFYFJROUSKDWOS-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 2
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- MZCZXPHMOGJQBJ-OAQYLSRUSA-L (3r)-4-[[4-(4-fluorophenyl)-2-propan-2-yl-6,7-dihydro-5h-benzo[2,3]cyclohepta[2,4-c]pyridin-3-yl]methoxy-oxidophosphoryl]-3-hydroxybutanoate Chemical compound [O-]C(=O)C[C@@H](O)CP([O-])(=O)OCC=1C(C(C)C)=NC(C2=CC=CC=C2CCC2)=C2C=1C1=CC=C(F)C=C1 MZCZXPHMOGJQBJ-OAQYLSRUSA-L 0.000 description 1
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 1
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- ITTMUMIEDXNQEQ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)piperazine;hydrochloride Chemical compound [Cl-].C1=C(Cl)C(Cl)=CC=C1N1CC[NH2+]CC1 ITTMUMIEDXNQEQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- OJKONCJPCULNOW-DYVFJYSZSA-N 5-chloro-2-fluoro-4-[(1s,2r)-2-(2-methylpyrazol-3-yl)cyclohexyl]oxy-n-pyrimidin-4-ylbenzenesulfonamide Chemical compound CN1N=CC=C1[C@@H]1[C@@H](OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2N=CN=CC=2)Cl)CCCC1 OJKONCJPCULNOW-DYVFJYSZSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- CZAFIFBJBFDMTP-UHFFFAOYSA-N N-[(4-bromophenyl)methyl]-2-[4-(2-phenylethylsulfamoyl)phenoxy]acetamide Chemical compound Brc1ccc(CNC(=O)COc2ccc(cc2)S(=O)(=O)NCCc2ccccc2)cc1 CZAFIFBJBFDMTP-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PFIWYJNBKGCVFM-UHFFFAOYSA-N n-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-9h-fluorene-2-carboxamide;hydrochloride Chemical compound Cl.ClC1=CC=CC(N2CCN(CCCCNC(=O)C=3C=C4C(C5=CC=CC=C5C4)=CC=3)CC2)=C1Cl PFIWYJNBKGCVFM-UHFFFAOYSA-N 0.000 description 1
- JVXXKQIRGQDWOJ-UHFFFAOYSA-N naphthalene-2-carboxamide Chemical class C1=CC=CC2=CC(C(=O)N)=CC=C21 JVXXKQIRGQDWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 108010092215 spiroperidol receptor Proteins 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- BHLXTPHDSZUFHR-UHFFFAOYSA-N varespladib Chemical compound CCC1=C(C(=O)C(N)=O)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 BHLXTPHDSZUFHR-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a phenyl piperazidine heterocyclic medicinal compound. The compound has high affinity to a dopamine D3 receptor, so that the compound can be used for treating addiction to and dependence on medicines such as cocaine, and a central nervous system disorder relevant to the addiction and the dependence. The compound is a 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative with a structural formula as Formula (1) as shown in the specification. A synthetic method of the derivate comprises the steps that substituted aniline and 2-(beta-chloroethyl) amine hydrochloride reacts in a solvent by taking inorganic base as an acid-binding agent to form corresponding substituted phenyl piperazidine hydrochloride 1; substituted phenyl piperazidine hydrochloride 1 and N-(delta-bromobutyl) phthalimide react in acetonitrile by taking K2CO3 as an acid-binding agent and under catalysis of KI to form a reaction intermediate 2; the intermediate 2 is subjected to hydrazinolysis to form an intermediate 3; and the intermediate 3 and an intermediate 5 are condensed by taking triethylamine as an acid-binding agent and a catalyst to form a target product I. The intermediate 5 is obtained in a manner that triphosgene and substituted aromatic phenol conduct partial condensation reaction in methylene chloride.
Description
Technical field
The present invention relates to class medicinal compound and preparation method thereof, specifically a class phenylpiperazine heterocyclic compound, such medicinal compound is to dopamine D
3acceptor presents high-affinity, can be used for the drug habits such as Cocaine and the treatment producing dependency and relative central nervous system disorder.
Background technology
Document (Science1997,278:58-63, Eur J Neurosci2002,15(12): 2016-2026, Trends Pharmacol Sci1994,15:374-379) etc. achievement in research show, D
3acceptor and middle limbic brain dopamine pathway have close dependency, and the volt nucleocapsid district dopamine D_2 receptors increase in mesolimbic system is that dependence producing drug produces critical sites that is glad and reward effect.
The achievements in research such as document (Crit Rev Neurobiol1998,12:37-67, Brain Res Brain Res Rev2000,31:277-287, Nature1999,400:371-375, Eur Psychiatry2000,15:140-146) think dopamine D
3acceptor portion agonist has good result for the treatment of to drug habits such as Cocaines.
In document (Natrue1990,347:146-151), the people such as Sokoloff P. have synthesized and have had 4-Phenylpiperazinyl structural compounds.As 9H-fluorenes-3-carboxamides derivatives NGB2904, naphthalene-2-carboxamides derivatives BP897 etc.
All D is shown as with experiment in vitro in BP897 body
3acceptor portion agonist, research shows, BP897 can suppress medicine to be strengthened and award effect, weakens the conditioned place preference of animal, reduces locomotor sensitivity, suppresses drug-seeking behavior or drug craving, and do not have strengthening effect or the KE of common dopamine-receptor stimulant or antagonist.BP897 is just being developed for the drug habits such as Cocaine and the treatment producing dependency and relative central nervous system disorder, has now entered II phase clinical stage.
Summary of the invention
The object of the present invention is to provide a kind of novel phenylpiperazine heterocyclic medicinal compound, such medicinal compound is to dopamine D
3acceptor presents high-affinity, may be used for the drug habits such as Cocaine and the treatment producing dependency and relative central nervous system disorder.
Another object of the present invention is to provide a kind of method preparing above-mentioned novel phenylpiperazine heterocyclic medicinal compound.
Phenylpiperazine heterocyclic medicinal compound of the present invention is a kind of 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative represented by formula (1):
In formula
R
1for H or the halogen, alkyl, alkoxyl group, the nitro that are in any the position of substitution of phenyl ring and any replacement number;
R
2for aryl or substituted aryl.
R in formula (1)
1be preferably o-Cl, m-Cl, p-Cl, 2,3-di-Cl, 3,4-di-Cl, p-F, p-CH
3, 2,3-di-Me, o-OCH
3or p-OCH
3.
R in formula (1)
2be preferably
or
Phenylpiperazine heterocyclic compound of the present invention is on document basis, for groping the structure activity relationship of Phenylpiperazine derivatives further, according to medicinal design principles such as isosteres, has designed and synthesized a series of R
1adjacent at phenyl, to one or more position, R
2for the novel compounds (I) of the aromatic base that different group replaces.
Note: o-, m-, p-represent the ortho position of phenyl ring, a position and contraposition respectively, and the following content representation of this patent herewith.
The present invention prepares the method for 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid aromatic ester derivative or its pharmacy acceptable salt, it is characterized in that comprising the following steps:
Step one: substituted aniline and two-(β-chloroethyl) amine hydrochlorate in organic solvent, take mineral alkali as acid binding agent, is obtained by reacting intermediate 1, be i.e. corresponding substituted phenylpiperazine hydrochloride;
Step 2: substituted phenylpiperazine hydrochloride 1 and N-(δ-bromobutyl) phthalic imidine in acetonitrile, with K
2cO
3for being obtained by reacting reaction intermediate 2 under acid binding agent, KI catalysis, i.e. N-{4-[4-(substituted-phenyl) piperazinyl-1]-butyl } the adjacent dicarboximide of benzo;
Step 3: intermediate 2 obtains intermediate 3 after hydrazinolysis, i.e. 1-(δ-aminobutyl)-4-(substituted-phenyl) piperazine;
Step 4: intermediate 3 and intermediate 5 take triethylamine as acid binding agent and catalyzer, condensation obtains target product 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aromatic ester derivative I; Wherein, intermediate 5 is trichloromethoxy formic acid substituted aromatic ester, and it is obtained with the condensation reaction of certain mol proportion generating portion in methylene dichloride by triphosgene and substituted aroma phenol.
Described step one is specially: under nitrogen protection, substituted aniline and two-(β-chloroethyl) amine hydrochlorate, with propyl carbinol, the trimethyl carbinol, chlorobenzene, DMF, DMA or ethylene glycol for solvent, preferred propyl carbinol, stirring reaction under certain temperature, preferred backflow, reaction 24-48 hour, by TLC detection reaction progress; After having reacted, be cooled to room temperature, with proper amount of methanol, reaction mixture is all dissolved, pass into hydrogen chloride gas and make reaction solution be acid, add excess diethyl ether subsequently and separate out precipitation, suction filtration, with a small amount of washed with diethylether, obtain corresponding substituted phenylpiperazine hydrochloride, crude, with organic solvent methyl alcohol, ethanol, Virahol or 95% ethyl alcohol recrystallization, preferred dehydrated alcohol, obtains sterling.
Described step 2 is specially: N-(δ-bromobutyl) reaction of phthalic imidine and substituted phenylpiperazine hydrochloride is: with acetone, acetonitrile, dimethyl formamide DMF, N, accelerine DMA, dioxane or pyridine are solvent, preferred acetonitrile; With K
2cO
3, Na
2cO
3, NaHCO
3, NaOH or CaCO
3for acid binding agent, preferred K
2cO
3; With NaI or KI for catalyzer, preferred KI; Back flow reaction 24-48 hour, by TLC detection reaction progress; Be cooled to room temperature after having reacted, by slow for reaction solution impouring frozen water under rapid stirring, separate out solid, filter after washing, dry to obtain intermediate 2.
Described step 3 is specially: described intermediate 2 hydrazinolysis reaction is: using water, methyl alcohol, ethanol, Virahol or the trimethyl carbinol as solvent, preferred alcohol; 30%-80% hydration hydrazinolysis, preferably 50% hydrazine hydrate; 20-85 DEG C of reaction, preferably refluxes; By TLC detection reaction progress, reacted rear concentrated solvent, solid, with water dissolution, gets three times with methylene dichloride, trichloromethane, ethyl acetate, toluene or 1,2-dichloroethane solvent, preferred methylene dichloride; Collect organic phase, filter with after anhydrous sodium sulphate or anhydrous magnesium sulfate drying, concentrated, obtain intermediate 3.
Described step 4 is specially: be dissolved in appropriate monochloro methane, methylene dichloride, trichloromethane or 1,2-dichloroethane solvent with described intermediate 3, preferred trichloromethane; Add catalyst of triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide, preferred triethylamine; Separately dissolve intermediate 5 with appropriate same solvent, it is slowly added dropwise in intermediate 3 solution, dropping terminates rear continuation and stirs after 15-30 minute, is warming up to back flow reaction, and TLC monitors, until complete should completely after, stopped reaction, reaction solution with water washing 2-3 time, anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, concentrate to obtain crude product; Crude product, with the mixed solvent recrystallization of methyl alcohol, ethanol, Virahol or they and methylene dichloride, trichloromethane, obtains target product I.
In described step 4, the preparation of intermediate 5 is specially:
Triphosgene and the condensation of substituted aroma phenol moieties obtain trichloromethoxy formic acid substituted aromatic ester: at monochloro methane, methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride or their mixed solvent, with triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide for acid binding agent, preferred triethylamine; Reaction under room temperature to backflow; Wherein triphosgene and substituted aroma phenol mol ratio are 1.0:1.0 ~ 3.0, preferred 1:2.5; Reaction 2-10 hour, TLC detection reaction progress, add water washing reaction solution after completion of the reaction 2-3 time, anhydrous sodium sulfate drying, filter, concentration and recovery solvent, obtains trichloromethoxy formic acid substituted aromatic ester, is not purifiedly directly used in next step and reacts.
N-(δ-bromobutyl in described step 2) preparation of phthalic imidine is specially:
Get the adjacent dicarboximide potassium of appropriate benzo and be dissolved in a certain amount of acetone, separately get appropriate Isosorbide-5-Nitrae-dibromobutane and be dissolved in acetone, be added drop-wise in three-necked bottle in one hour, drip and finish, backflow is spent the night; Concentrated, in slow impouring frozen water, leave standstill 30 minutes, filter, filter cake is washed, and dries, to obtain final product.
Above synthesis step separately represents with synthetic route can such as formula shown in II:
The beneficial effect of synthesis 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative of the present invention is embodied in:
(1) the present invention obtains the special new compound 4-of a class formation [4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid aromatic ester derivative, and show through pharmacological evaluation, such medicinal compound is to dopamine D
3acceptor presents high-affinity, can be effective to the drug habits such as Cocaine and the treatment producing dependency and relative central nervous system disorder.
(2) adopt solvent of the present invention and reaction conditions, can higher yields obtain target product, and convenient post-treatment, multiple intermediate is without the need to further purifying be separated can directly as next step raw material.
(3) intermediate is as wanted purifying, without the need to adopting the method such as column chromatography or thin-layer chromatography, only need with the solvent had fewer environmental impacts in right amount as ethanol carry out recrystallizing and refining, and requirement is also very limited.
(4) technological operation is simple, reaction conditions is gentle, security is high, and reaction yield is stable, product purity is high, and environmental pollution is little.
Embodiment
Below by specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Although do not embodied in an embodiment one by one solvent, acid binding agent, catalyzer and reaction conditions etc. that each step reaction disclosed in summary of the invention adopts in the specific embodiment of the invention, but our experiments show that, in fact all can realize the object of the invention, only be presented as preferred version in embodiment.
One, the preparation of intermediate 1-substituted phenylpiperazine hydrochloride (1a-1k)
Implement 1
Phenylpiperazine hydrochloride (1a)
1, in the 100ml there-necked flask that mechanical stirring, reflux exchanger, thermometer are housed, add two-(β-chloroethyl) amine hydrochlorate 8.93g(0.05mol), aniline 4.65g(0.05mol), 20ml propyl carbinol, salt of wormwood 13.8g(0.10mmol), N
2protection, back flow reaction, by TLC detection reaction progress.After having reacted, filtered while hot, filtrate is down to room temperature, separates out solid, adding proper amount of methanol makes solid all dissolve, passing into hydrogen chloride gas makes solution be acid, adds excess diethyl ether subsequently and separates out precipitation, suction filtration, filter cake is with a small amount of washed with diethylether, obtain 1-php hydrochloride, crude, crude product can be directly used in next step reaction, then obtains sterling with dehydrated alcohol recrystallization.(U.S. wears peace U3000, HPLC:t
r=2.50min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.5%), fusing point: 245 ~ 249 DEG C.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831。
Other substituted phenylpiperazine hydrochloride is prepared as stated above: (other substituted aniline amount of substances are identical with above-mentioned aniline, and respective quality presses amount of substance and this substituted aniline molar mass converts)
(4-fluorophenyl) piperazine hydrochloride (1b)
(U.S. wears peace U3000, HPLC:t
r=2.63min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.8%), fusing point: 230 ~ 234 DEG C.IRυ
max(KBr)/cm
-1:3350,3037,2942,2845,1638,1553,1498,1435,1368,830。
(4-chloro-phenyl-) piperazine hydrochloride (1c)
(U.S. wears peace U3000, HPLC:t
r=2.58min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.7%), fusing point: 215 ~ 218 DEG C.IRυ
max(KBr)/cm
-1:3350,3039,2944,2845,1639,1555,1497,1435,1369,832。
(4-p-methoxy-phenyl) piperazine hydrochloride (1d)
(U.S. wears peace U3000, HPLC:t
r=2.71min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 99.0%), fusing point: 190 ~ 192 DEG C.IRυ
max(KBr)/cm
-1:3350,3036,2940,2847,1639,1553,1496,1432,1366,830。
(4-aminomethyl phenyl) piperazine hydrochloride (1e)
(U.S. wears peace U3000, HPLC:t
r=2.65min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.7%), fusing point: 220 ~ 223 DEG C.IRυ
max(KBr)/cm
-1:3349,3033,2941,2847,1640,1552,1498,1433,1368,829。
(2,3-dichlorophenyl) piperazine hydrochloride (1f)
(U.S. wears peace U3000, HPLC:t
r=2.71min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.5%), fusing point: 246 ~ 248 DEG C.IRυ
max(KBr)/cm
-1:3354,3038,2942,2847,1638,1550,1498,1433,1366,825。
(3,4-dichlorophenyl) piperazine hydrochloride (1g)
(U.S. wears peace U3000, HPLC:t
r=2.71min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.0%), fusing point: 206 ~ 208 DEG C.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831。
(2-p-methoxy-phenyl) piperazine hydrochloride (1h)
(U.S. wears peace U3000, HPLC:t
r=2.71min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 99.2%), fusing point: 213 ~ 217 DEG C.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831.
(2,3-3,5-dimethylphenyl) piperazine hydrochloride (1i)
(U.S. wears peace U3000, HPLC:t
r=2.70min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 99.5%) fusing point: 220 ~ 223 DEG C.IRυ
max(KBr)/cm
-1:3349,3035,2940,2846,1638,1551,1496,1433,1366,831.
(2-chloro-phenyl-) piperazine hydrochloride (1j)
(U.S. wears peace U3000, HPLC:t
r=2.65min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 98.9%), fusing point: 219 ~ 221 DEG C.IRυ
max(KBr)/cm
-1:3356,3050,2940,2846,1630,1545,1490,1433,1366,836.
(3-chloro-phenyl-) piperazine hydrochloride (1k)
(U.S. wears peace U3000, HPLC:t
r=2.65min, λ=254nm, CH
3cN:H
2o=9:1, T
f=1.0ml/min, content 99.1%), fusing point: 209 ~ 211 DEG C.IRυ
max(KBr)/cm
-1:3354,3050,2942,2846,1629,1545,1490,1431,1365,837.
Two, intermediate product 5-trichloromethoxy formic acid replaces the preparation of phenyl ester (5a-5g)
Implement 2
Intermediate product trichloromethoxy formic acid is to fluorobenzene ester (5a)
Get 17.78g triphosgene (0.06mol), be dissolved in 100mL methylene dichloride, be placed in 250mL three-necked bottle altogether, electric stirring; Separately get 16.86g(0.15mol) p-fluorophenol, 16.9mL triethylamine, is dissolved in 45mL methylene dichloride, is slowly added dropwise in triphosgene solution, after dropping terminates, stir 30 minutes, reflux, after TLC monitoring reaction terminates, stop heating, after cool to room temperature, add 50mL water, stir 30 minutes, stratification, organic layer is with 20mL water washing 2 times, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure recycling design, obtain white solid, dry weighing 13.38g, yield 80.5%.(U.S. wears peace U3000, HPLC:t
r=10.5min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 98.5%), fusing point: 114-118 DEG C.IRυ
max(KBr)/cm
-1:3064,1770,1598,1508,1466,1289,1023,830.
1HNMR(CDCl
3,TMS,400MHz,δppm):7.05(dd,J=8.9,2.7Hz,2H,Ar-H),6.94(dd,J=8.9,2.8Hz,2H,Ar-H).EIMS m/z(%):272(M
+,100),274(96),276(32),273(9),275(9),278(3),277(3)。
Other trichloromethoxy formic acid substituted aromatic ester is prepared as stated above: (other substituted aroma phenol amount of substances are identical with above-mentioned p-fluorophenol, and respective quality presses amount of substance and this substituted aroma phenol molar mass converts).
Intermediate product trichloromethoxy formic acid is to chlorobenzene ester (5b)
Yield: 84.8%, product is liquid.(U.S. wears peace U3000, HPLC:t
r=9.9min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 99.2%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831.
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS m/z(%):290(M
+,100),288(78),292(49),294(10),291(9),289(7),293(4)。
Intermediate product trichloromethoxy formic acid p-nitrophenyl ester (5c)
Yield: 91.5%, fusing point: 128-132 DEG C.(U.S. wears peace U3000, HPLC:t
r=9.5min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 99.1%).IRυ
max(KBr)/cm
-1:3116,3084,1783,1592,1520,1489,1348,1227,1010,859,838.
1HNMR(CDCl
3,TMS,400MHz,δppm):8.16(dd,J=9.5,2.7Hz,2H,Ar-H),7.01(dd,J=9.5,2.8Hz,2H,Ar-H);EIMS m/z(%):299(M
+,100),301(96),303(31),300(9),302(9),305(4),304(3),301(1),303(1)。
Intermediate product trichloromethoxy formic acid is to methoxyl group phenyl ester (5d)
Yield: 79.6%, fusing point: 84-86 DEG C.(U.S. wears peace U3000, HPLC:t
r=10.5min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 97.5%).IRυ
max(KBr)/cm
-1:3050,1724,1590,1482,1420,1228,1017,830.
1HNMR(CDCl
3,TMS,400MHz,δppm):6.96(dd,J=8.3,2.6Hz,2H,Ar-H),6.74(dd,J=8.3,2.7Hz,2H,Ar-H),3.73(s,3H,OCH
3);EIMSm/z(%):284(M
+,100),286(96),288(32),285(10),287(10),290(3),289(3),286(1)。
Intermediate product trichloromethoxy formic acid-2-naphthalene ester (5e)
Yield: 84.3%, fusing point: 164-168 DEG C.(U.S. wears peace U3000, HPLC:t
r=10.5min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 98.1%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831;
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS m/z(%):304(M
+,100),306(97),308(32),305(14),307(13),309(4),310(4)。
Intermediate product trichloromethoxy formic acid-1-naphthalene ester (5f)
Yield: 80.6%, fusing point: 129-132 DEG C.(U.S. wears peace U3000, HPLC:t
r=10.4min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 98.3%).IRυ
max(KBr)/cm
-1:3063,1769,1599,1509,1464,1389,1238,1215,799;
1HNMR(CDCl
3,TMS,400MHz,δppm):6.64(dd,J=8.3,2.3Hz,1H,Ar-H),7.17(dd,J=8.3,8.5Hz,1H,Ar-H),7.31(dd,J=8.5,2.3Hz,1H,Ar-H),7.68(dd,J=8.3,8.5Hz,1H,Ar-H),7.35(dd,J=8.3,8.5Hz,1H,Ar-H),7.38(dd,J=8.3,8.5Hz,1H,Ar-H),8.08(dd,J=8.3,8.5Hz,1H,Ar-H);EIMSm/z(%):304(M
+,100),306(96),308(31),305(14),307(13),309(4),310(4),306(1),308(1)。
Intermediate product trichloromethoxy phenyl formate (5g)
Yield 76.5%.Fusing point: 113-115 DEG C.(U.S. wears peace U3000, HPLC:t
r=10.3min, λ=254nm, CH
3oH:H
2o=7:3, T
f=1.0ml/min, content 98.5%).IRυ
max(KBr)/cm
-1:3064,1768,1596,1508,1464,1289,1023,831;
1HNMR(CDCl
3,TMS,400MHz,δppm):7.23(dd,J=8.8,2.6Hz,2H,Ar-H),7.01(dd,J=8.8,2.7Hz,2H,Ar-H);EIMS m/z(%):290(M
+,100),288(78),292(49),294(10),291(9),289(7),293(4)。
Three, compound 4-N-(δ-bromobutyl) preparation of phthalic imidine
Get the adjacent dicarboximide potassium of appropriate benzo and be dissolved in a certain amount of acetone, separately get appropriate Isosorbide-5-Nitrae-dibromobutane and be dissolved in acetone, be added drop-wise in three-necked bottle in one hour, drip and finish, backflow is spent the night.Concentrated, in slow impouring frozen water, leave standstill 30 minutes, filter, filter cake is washed, and dries, obtains white powdery solids compound 4.
Four, the preparation of target product 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative (6a-6v)
Embodiment 3: the preparation of compound 6a
Step 1: such as formula in II shown in steps A, obtains compound 1a according to example 1 synthesis;
Step 2: such as formula the 2a(of synthetic compound shown in step B in II and intermediate 2a, similar below).Specific as follows:
By compound 1a15.6g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2a25.8g, yield 90%.
Step 3: such as formula the 3a(of synthetic compound shown in step C in II and intermediate 3a, similar below).Specific as follows:
Get compound 2a25.4g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 12.2g, yield 73.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6a of synthetic compound shown in step e in II.Specific as follows:
Get compound 3a1.17g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filter, concentrated, obtain brown solid.With ethyl alcohol recrystallization, obtain 6a.Fusing point: 74-77 DEG C, yield 74.5%.IRυ
max(KBr)/cm
-1:3425,3056, 2922,1760,1590,1490,1456,1180,1156;
1H NMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):352.20(M
+,100),353.21(23.1),354.21(3.0),353.20(1.1)。
Embodiment 4: the preparation of compound 6b
Step 1: such as formula in II shown in steps A, obtains compound 1f according to example 1 synthesis;
Step 2: such as formula the 2f of synthetic compound shown in step B in II.Specific as follows:
By compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2f29.0g, yield 88%.
Step 3: such as formula the 3f of synthetic compound shown in step C in II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.3g, yield 75.3%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6b of synthetic compound shown in step e in II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6b.Fusing point: 174-178 DEG C, yield 90.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):420.12(M
+,100),422.13(64),421.13(23),423.12(15),424.12(10),422.13(3),425.12(2.5),424.13(1.9),421.12(1.1)。
Embodiment 5: the preparation of compound 6c
Step 1: such as formula in II shown in steps A, obtains compound 1j according to example 1 synthesis;
Step 2: such as formula the 2j of synthetic compound shown in step B in II.Specific as follows:
By compound 1j18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2j28.1g, yield 89.5%.
Step 3: such as formula the 3j of synthetic compound shown in step C in II.Specific as follows:
Get compound 2j27.8g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.2g, yield 75.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6c of synthetic compound shown in step e in II.Specific as follows:
Get compound 3j1.34g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6c.Fusing point: 72-76 DEG C, yield 89.0%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40,(m,2H,CH
2);EIMS m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 6: the preparation of compound 6d
Step 1: such as formula in II shown in steps A, obtains compound 1k according to example 1 synthesis;
Step 2: such as formula the 2k of synthetic compound shown in step B in II.Specific as follows:
By compound 1k18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2k27.5g, yield 87.5%.
Step 3: such as formula the 3k of synthetic compound shown in step C in II.Specific as follows:
Get compound 2k27.8g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.6g, yield 77.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6d of synthetic compound shown in step e in II.Specific as follows:
Get compound 3k1.34g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound trichloromethoxy phenyl formate 1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6d.Fusing point: 163-165 DEG C, yield 86.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 7: the preparation of compound 6e
Step 1: such as formula in II shown in steps A, obtains compound 1g according to example 1 synthesis;
Step 2: such as formula the 2g of synthetic compound shown in step B in II.Specific as follows:
By compound 1g21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2g30.4g, yield 89%.
Step 3: such as formula the 3g of synthetic compound shown in step C in II.Specific as follows:
Get compound 2g28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.4g, yield 73.6%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6e of synthetic compound shown in step e in II.Specific as follows:
Get compound 3g1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6e.Fusing point: 73-75 DEG C, yield 88.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):421(M
+,100),423(67),422(25),424(16),425(12),426(3)。
Embodiment 8: the preparation of compound 6f
Step 1: such as formula in II shown in steps A, obtains compound 1c according to example 1 synthesis;
Step 2: such as formula the 2c of synthetic compound shown in step B in II.Specific as follows:
By compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2c28.7g, yield 91.5%.
Step 3: such as formula the 3c of synthetic compound shown in step C in II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.8g, yield 78.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6f of synthetic compound shown in step e in II.Specific as follows:
Get compound 3g1.34g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6f.Fusing point: 207-210 DEG C, yield 84.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t, 4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):387(M
+,100),389(32),388(25),390(8),389(3)。
Embodiment 9: the preparation of compound 6g
Step 1: such as formula in II shown in steps A, obtains compound 1e according to example 1 synthesis;
Step 2: such as formula the 2e of synthetic compound shown in step B in II.Specific as follows:
By compound 1e16.8g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2e27.7g, yield 93.1%.
Step 3: such as formula the 3e of synthetic compound shown in step C in II.Specific as follows:
Get compound 2e26.4g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 13.6g, yield 78.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6g of synthetic compound shown in step e in II.Specific as follows:
Get compound 3e1.24g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6g.Fusing point: 181-183 DEG C, yield 84.5%.IRυ
max(KBr)/cm
-1:3432,3059,2927,1756,1590,1490,1456,1180,1156;
1H NMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):367(M
+,100),368(25),369(4),390(8),368(1)。
Embodiment 10: the preparation of compound 6h
Step 1: such as formula in II shown in steps A, obtains compound 1e according to example 1 synthesis;
Step 2: such as formula the 2e of synthetic compound shown in step B in II.Specific as follows:
By compound 1e16.8g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2e27.7g, yield 93.1%.
Step 3: such as formula the 3e of synthetic compound shown in step C in II.Specific as follows:
Get compound 2e26.4g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 13.6g, yield 78.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5a according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6h of synthetic compound shown in step e in II.Specific as follows:
Get compound 3e1.24g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5a1.35g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6h.Fusing point: 134-138 DEG C, yield 83.5%.IRυ
max(KBr)/cm
-1:3432,3059,2927,1756,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),7.07(dd,J=8.7,2.4Hz,1H,Ar-H),6.93(m,1H,Ar-H),6.55(m,1H,Ar-H),6.52(dd,J=8.8,2.5Hz,1H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.56(m,2H,CH
2),1.40(m,2H,CH
2);EIMSm/z(%):385(M
+,100),386(25),387(4),386(1)。
Embodiment 11: the preparation of compound 6i
Step 1: such as formula in II shown in steps A, obtains compound 1f according to example 1 synthesis;
Step 2: such as formula the 2f of synthetic compound shown in step B in II.Specific as follows:
By compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2f29.0g, yield 88%.
Step 3: such as formula the 3f of synthetic compound shown in step C in II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.3g, yield 75.3%.
Step 4: such as formula method shown in step D in II, obtains compound 5a according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6a of synthetic compound shown in step e in II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5a1.35g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6i.Fusing point: 80-84 DEG C, yield 84.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMSm/z(%):454(M
+,100),456(64),455(25),457(16),458(10),456(4),459(3),458(2),455(1)。
Embodiment 12: the preparation of compound 6j
Step 1: such as formula in II shown in steps A, obtains compound 1i according to example 1 synthesis;
Step 2: such as formula the 2i of synthetic compound shown in step B in II.Specific as follows:
By compound 1i17.9g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2i29.3g, yield 95.0%.
Step 3: such as formula the 3i of synthetic compound shown in step C in II.Specific as follows:
Get compound 2i27.4g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.6g, yield 79.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6a of synthetic compound shown in step e in II.Specific as follows:
Get compound 3i1.29g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6j.Fusing point: 191-194 DEG C, yield 86.0%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):381(M
+,100),382(27),384(4)。
Embodiment 13: the preparation of compound 6k
Step 1: such as formula in II shown in steps A, obtains compound 1a according to example 1 synthesis;
Step 2: such as formula the 2a of synthetic compound shown in step B in II.Specific as follows:
By compound 1a15.6g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2a25.8g, yield 90%.
Step 3: such as formula the 3a of synthetic compound shown in step C in II.Specific as follows:
Get compound 2a25.4g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 12.2g, yield 73.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5d according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6k of synthetic compound shown in step e in II.Specific as follows:
Get compound 3a1.17g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5d1.42g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6k.Fusing point: 92-95 DEG C, yield 83.0%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):383(M
+,100),384(26),385(4)。
Embodiment 14: the preparation of compound 6l
Step 1: such as formula in II shown in steps A, obtains compound 1c according to example 1 synthesis;
Step 2: such as formula the 2c of synthetic compound shown in step B in II.Specific as follows:
By compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2c28.7g, yield 91.5%.
Step 3: such as formula the 3c of synthetic compound shown in step C in II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.8g, yield 78.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5d according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6l of synthetic compound shown in step e in II.Specific as follows:
Get compound 3c1.34g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5d1.42g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with alcohol recrystallization, obtains 6l.Fusing point: 125-130 DEG C, yield 89.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):383(M
+,100),384(26),385(4)。
Embodiment 15: the preparation of compound 6m
Step 1: such as formula in II shown in steps A, obtains compound 1c according to example 1 synthesis;
Step 2: such as formula the 2c of synthetic compound shown in step B in II.Specific as follows:
By compound 1c18.4g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2c28.7g, yield 91.5%.
Step 3: such as formula the 3c of synthetic compound shown in step C in II.Specific as follows:
Get compound 2c27.8g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.8g, yield 78.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5b according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6m of synthetic compound shown in step e in II.Specific as follows:
Get compound 3c1.34g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5b1.45g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6m.Fusing point: 145-149 DEG C, yield is 88.7%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):421(M
+,100),423(67),422(25),424(16),425(12),426(3)。
Embodiment 16: the preparation of compound 6n
Step 1: such as formula in II shown in steps A, obtains compound 1f according to example 1 synthesis;
Step 2: such as formula the 2f of synthetic compound shown in step B in II.Specific as follows:
By compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2f29.0g, yield 88%.
Step 3: such as formula the 3f of synthetic compound shown in step C in II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.3g, yield 75.3%.
Step 4: such as formula method shown in step D in II, obtains compound 5f according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6n of synthetic compound shown in step e in II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5f1.52g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6n.Fusing point: 86-90 DEG C, yield 87.6%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):471(M
+,100),473(68),472(29),474(18),475(13),476(3)。
Embodiment 17: the preparation of compound 6o
Step 1: such as formula in II shown in steps A, obtains compound 1f according to example 1 synthesis;
Step 2: such as formula the 2f of synthetic compound shown in step B in II.Specific as follows:
By compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2f29.0g, yield 88%.
Step 3: such as formula the 3f of synthetic compound shown in step C in II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.3g, yield 75.3%.
Step 4: such as formula method shown in step D in II, obtains compound 5e according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6o of synthetic compound shown in step e in II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5e1.52g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6o.Fusing point: 179-183 DEG C, yield 87.2%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):471(M
+,100),473(68),472(29),474(18),475(13),476(3)。
Embodiment 18: the preparation of compound 6p
Step 1: such as formula in II shown in steps A, obtains compound 1f according to example 1 synthesis;
Step 2: such as formula the 2f of synthetic compound shown in step B in II.Specific as follows:
By compound 1f21.0g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2f29.0g, yield 88%.
Step 3: such as formula the 3f of synthetic compound shown in step C in II.Specific as follows:
Get compound 2f28.1g(0.065mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.3g, yield 75.3%.
Step 4: such as formula method shown in step D in II, obtains compound 5c according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6p of synthetic compound shown in step e in II.Specific as follows:
Get compound 3f1.51g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5c1.50g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6p.Fusing point: 174-178 DEG C, yield 84.5%.IRυ
max(KBr)/cm
-1:3427,3060,2926,1756,1590,1488,1458,1180,1090;
1HNMR(CDCl
3,TMS,400MHz,δppm):8.00(t,1H,N-H),7.08-7.24(m,5H,Ar-H),6.90(dd,J=8.8,8.7Hz,1H,Ar-H),6.56(dd,J=8.8,2.5Hz,1H,Ar-H),6.41(dd,J=8.7,2.5Hz,1H,Ar-H),2.95(dt,2H,CH
2),2.38(t,2H,CH
2),1.57(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):465(M
+,100),467(68),466(24),468(15),469(13),470(3)。
Embodiment 19: the preparation of compound 6q
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5g according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6q of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5g1.27g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6q.Fusing point: 130-132 DEG C, yield 84.5%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):352(M
+,100),354(25),355(3)。
Embodiment 20: the preparation of compound 6r
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5a according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6r of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5a1.35g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6r.Fusing point: 113-117 DEG C, yield 87.4%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2).EIMSm/z(%):400(M
+,100),401(25),402(3)。
Embodiment 21: the preparation of compound 6s
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5f according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6s of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5f1.50g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6s.Fusing point: 112-116 DEG C, yield 89.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):432(M
+,100),433(30),434(4)。
Embodiment 22: the preparation of compound 6t
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5e according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6t of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5e1.50g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6t.Fusing point: 98-101 DEG C, yield 88.4%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):432(M
+,100),433(30),434(4)。
Embodiment 23: the preparation of compound 6u
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5d according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6u of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5d1.42g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6u.Fusing point: 123-125 DEG C, yield 91.2%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):412(M
+,100),413(26),414(4)。
Embodiment 24: the preparation of compound 6v
Step 1: such as formula in II shown in steps A, obtains compound 1h according to example 1 synthesis;
Step 2: such as formula the 2h of synthetic compound shown in step B in II.Specific as follows:
By compound 1h18.1g(0.079mol), compound 426.7g(0.095mol), potassiumiodide 15.7g(0.095mol), salt of wormwood 21.8g(0.158mol) and 500mL acetonitrile join in 1000mL three-necked bottle, after mechanical stirring back flow reaction 4h, cold filtration, mother liquor leaves standstill crystallization.Suction filtration, filter cake dries to obtain 2h29.9g, yield 96.2%.
Step 3: such as formula the 3h of synthetic compound shown in step C in II.Specific as follows:
Get compound 2h27.5g(0.070mol) be dissolved in 500mL dehydrated alcohol, be placed in 1000mL three-necked bottle, slowly drip 85% hydrazine hydrate, drip complete being heated to and reflux, solution has suspendible to become clarification, occurs flocks after reaction for some time.Reaction solution concentrates, and is dissolved in water, chloroform extraction three times, extraction liquid anhydrous magnesium sulfate drying, concentrated after filtering, and obtains colloidal liquid and is about 14.9g, yield 80.8%.
Step 4: such as formula method shown in step D in II, obtains compound 5b according to the 2-in-1 one-tenth of example.
Step 5: such as formula the 6v of synthetic compound shown in step e in II.Specific as follows:
Get compound 3h1.32g(5mmol), be dissolved in 50mL methylene dichloride, add 5mL triethylamine, be placed in 150mL three-necked bottle; Separately get compound 5b1.45g(5mmol), be dissolved in 15mL methylene dichloride, be slowly added drop-wise in three-necked bottle under rapid stirring, be warmed up to backflow after dropping terminates, TLC monitors reaction process, and having treated should be complete, add 20ml water, stir after 15 minutes, stratification, after organic layer 10ml water washing, anhydrous sodium sulfate drying, filters, concentrated, residue, with ethyl alcohol recrystallization, obtains 6v.Fusing point: 134-136 DEG C, yield 87.1%.IRυ
max(KBr)/cm
-1:3425,3056,2922,1760,1590,1490,1456,1180,1156;
1HNMR(CDCl
3,TMS,400MHZ,δppm):8.00(t,1H,N-H),6.68-7.24(m,10H,Ar-H),3.44(t,4H,CH
2),2.60(t,4H,CH
2),2.38(t,2H,CH
2),2.94(t,2H,CH
2),1.62(m,2H,CH
2),1.40(m,2H,CH
2);EIMS m/z(%):416(M
+,100),417(25),418(36),419(8),420(1)。
Pharmacological evaluation
Compound is to mankind D
3the affinity of acceptor by [
3h] spiperone combination (spiperone binding) mensuration (see table 4).
Chinese hamster ovary celI transfection coding mankind D
3acceptor (Hd
3) cDNA.In the medium containing 120mM NaCl, 5mM KCl and 50mM Tris HCl pH7.4, under the condition containing 2.5-5 μ g membranin, carry out [
3h] spiperone (0.5-2nM) combination; Incubation at room temperature 60 minutes.Non-specific binding is assessed under the existence of 10 μMs of haloperidol.Without any specific binding in non-transfected cells.LIGAND formula is used to borrow nonlinear regression analysis to measure K
ivalue.
The list of table 1. intermediate phenylpiperazine hydrochloride
compd | R 1 | formula | M.w.mp,℃ |
1a | H | C 10H 14N 2·HCl | 198.69245~249 |
1b | p-F | C 10H 13N 2F·HCl | 216.68230~234 |
1c | p-Cl | C 10H 13N 2Cl·HCl | 233.14215~218 |
1d | p-OCH 3 | C 11H 16N 2O·HCl | 228.72190~192 |
1e | p-CH 3 | C 11H 16N 2·HCl | 212.72220~223 |
1f | 2,3-di-Cl | C 10H 12N 2Cl 2·HCl | 266.13246~248 |
1g | 3,4-di-Cl | C 10H 12N 2Cl 2·HCl | 266.13206~208 |
1h | o-OCH 3 | C 11H 16N 2O·HCl | 228.72213~217 |
1i | 2,3-di-CH 3 | C 12H 18N 2·HCl | 226.75220~223 |
1j | o-Cl | C 10H 13N 2Cl·HCl | 233.14219~221 |
1k | m-Cl | C 10H 13N 2Cl·HCl | 233.14209~211 |
The list of table 2. intermediate trichloromethoxy formic acid aromatic ester
The list of table 3. target compound
Table 4. target compound is to mankind D
3receptor affinity list
compd | Ki(nM) | compd | Ki(nM) |
6a | 243.8 | 6l | 9.5 |
6b | 48.0 | 6m | 441.8 |
6c | 23.6 | 6n | 657.6 |
6d | 68.9 | 6o | 36.2 |
6e | 371.2 | 6p | 774.4 |
6f | 142.5 | 6q | 52.1 |
6g | 45.3 | 6r | 321.0 |
6h | 228.7 | 6s | 25.5 |
6i | 56.0 | 6t | 830.9 |
6j | 668.1 | 6u | 1024.7 |
6k | 1132.0 | 6v | 117.6 |
Claims (8)
1. the 4-represented by formula (1) [4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aroma ester derivative:
In formula
R
1for H or R
1for halogen, wherein halogen be o-Cl, m-Cl, p-Cl, 2,3-di-Cl, 3,4-di-Cl, p-F; Or R
1for alkyl, wherein alkyl is p-CH
3or 2,3-di-Me; Or R
1for alkoxyl group, wherein alkoxyl group is o-OCH
3or p-OCH
3; R
2for
2. prepare a method for 4-as claimed in claim 1 [4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid aromatic ester derivative, it is characterized in that comprising the following steps:
Step one: substituted aniline and two-(β-chloroethyl) amine hydrochlorate in organic solvent, take mineral alkali as acid binding agent, is obtained by reacting intermediate 1, be i.e. corresponding substituted phenylpiperazine hydrochloride;
Step 2: substituted phenylpiperazine hydrochloride 1 and N-(δ-bromobutyl) phthalic imidine in acetonitrile, with K
2cO
3for being obtained by reacting reaction intermediate 2 under acid binding agent, KI catalysis, i.e. N-{4-[4-(substituted-phenyl) piperazinyl-1]-butyl } the adjacent dicarboximide of benzo;
Step 3: intermediate 2 obtains intermediate 3 after hydrazinolysis, i.e. 1-(δ-aminobutyl)-4-(substituted-phenyl) piperazine;
Step 4: intermediate 3 and intermediate 5 take triethylamine as acid binding agent and catalyzer, and condensation obtains target product 4-[4-(substituted-phenyl) piperazinyl-1]-butylamine formic acid substituted aromatic ester derivative I; Wherein, intermediate 5 is trichloromethoxy formic acid substituted aromatic ester, and it is obtained with certain mol proportion generation condensation reaction in methylene dichloride by triphosgene and substituted aroma phenol.
3. method as claimed in claim 2, is characterized in that described step one is specially:
Under nitrogen protection, substituted aniline and two-(β-chloroethyl) amine hydrochlorate, with propyl carbinol, the trimethyl carbinol, chlorobenzene, DMF, DMA or ethylene glycol for solvent, stirring reaction under certain temperature, reaction 24-48 hour, by TLC detection reaction progress; After having reacted, be cooled to room temperature, with methyl alcohol, reaction mixture is all dissolved, passing into hydrogen chloride gas makes reaction solution be acid, adds excess diethyl ether subsequently and separates out precipitation, suction filtration, with washed with diethylether, obtain corresponding substituted phenylpiperazine hydrochloride, crude, with organic solvent methyl alcohol, dehydrated alcohol, Virahol or 95% ethyl alcohol recrystallization, obtain sterling.
4. method as claimed in claim 2, is characterized in that described step 2 is specially:
The reaction of N-(δ-bromobutyl) phthalic imidine and substituted phenylpiperazine hydrochloride is: with acetone, acetonitrile, dimethyl formamide DMF, DMA DMA, dioxane or pyridine for solvent; With K
2cO
3, Na
2cO
3, NaHCO
3, NaOH or CaCO
3for acid binding agent; With NaI or KI for catalyzer; Back flow reaction 24-48 hour, by TLC detection reaction progress; Be cooled to room temperature after having reacted, by slow for reaction solution impouring frozen water under rapid stirring, separate out solid, filter after washing, dry to obtain intermediate 2.
5. method as claimed in claim 2, is characterized in that described step 3 is specially:
Described intermediate 2 hydrazinolysis reaction is: using water, methyl alcohol, ethanol, Virahol or the trimethyl carbinol as solvent; 30%-80% hydration hydrazinolysis; 20-85 DEG C of reaction; By TLC detection reaction progress, reacted rear concentrated solvent, solid, with water dissolution, gets three times with methylene dichloride, trichloromethane, ethyl acetate, toluene or 1,2-dichloroethane solvent; Collect organic phase, filter with after anhydrous sodium sulphate or anhydrous magnesium sulfate drying, concentrated, obtain intermediate 3.
6. method as claimed in claim 2, is characterized in that described step 4 is specially:
Monochloro methane, methylene dichloride, trichloromethane or 1,2-dichloroethane solvent is dissolved in described intermediate 3; Add catalyst of triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide; Separately dissolve intermediate 5 with appropriate same solvent, it is slowly added dropwise in intermediate 3 solution, dropping terminates rear continuation and stirs after 15-30 minute, is warming up to back flow reaction, and TLC monitors, until complete should completely after, stopped reaction, reaction solution with water washing 2-3 time, anhydrous sodium sulphate or anhydrous magnesium sulfate drying, filter, concentrate to obtain crude product; Crude product, with the mixed solvent recrystallization of methyl alcohol, ethanol, Virahol or they and methylene dichloride, trichloromethane, obtains target product I.
7. method as claimed in claim 2, is characterized in that the preparation of intermediate 5 in described step 4 is specially:
Triphosgene and the condensation of substituted aroma phenol obtain trichloromethoxy formic acid substituted aromatic ester: at monochloro methane, methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride or their mixed solvent, with triethylamine, pyridine, diisopropyl ethyl amine or dimethyl formamide for acid binding agent; Reaction under room temperature to backflow; Wherein triphosgene and substituted aroma phenol mol ratio are 1.0:1.0 ~ 3.0; Reaction 2-10 hour, TLC detection reaction progress, add water washing reaction solution after completion of the reaction 2-3 time, anhydrous sodium sulfate drying, filter, concentration and recovery solvent, obtains trichloromethoxy formic acid substituted aromatic ester, is not purifiedly directly used in next step and reacts.
8. method as claimed in claim 2, is characterized in that the preparation method of N-in described step 2 (δ-bromobutyl) phthalic imidine is:
Get the adjacent dicarboximide potassium of appropriate benzo and be dissolved in a certain amount of acetone, separately get appropriate Isosorbide-5-Nitrae-dibromobutane and be dissolved in acetone, be added drop-wise in three-necked bottle in one hour, drip and finish, backflow is spent the night; Concentrated, in slow impouring frozen water, leave standstill 30 minutes, filter, filter cake is washed, and dries, to obtain final product.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310033226.7A CN103073524B (en) | 2013-01-25 | 2013-01-25 | 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310033226.7A CN103073524B (en) | 2013-01-25 | 2013-01-25 | 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103073524A CN103073524A (en) | 2013-05-01 |
CN103073524B true CN103073524B (en) | 2015-06-10 |
Family
ID=48150243
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310033226.7A Expired - Fee Related CN103073524B (en) | 2013-01-25 | 2013-01-25 | 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103073524B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3452029A4 (en) * | 2016-05-04 | 2019-10-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9828352B2 (en) | 2013-07-18 | 2017-11-28 | Fondazione Istituto Italiano Di Tecnologia | Phenyl carbamates and their use as inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR) |
CN104829558B (en) * | 2014-02-10 | 2020-03-03 | 江苏豪森药业集团有限公司 | Preparation method of diaryl thioether amine compound |
CN103980229B (en) * | 2014-05-30 | 2016-03-23 | 宁波市微循环与莨菪类药研究所 | A kind of preparation method of N-phenylpiperazine |
CN107011288B (en) * | 2017-04-20 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of aripiprazole intermediate 1- (2,3- dichlorophenyl) piperazine hydrochloride |
CN108299337A (en) * | 2018-01-15 | 2018-07-20 | 吴江信凯医药科技有限公司 | The preparation method of one kind 2,3- dichlorophenylpiperazine hydrochlorides |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200634009A (en) * | 2004-12-08 | 2006-10-01 | Solvay Pharm Bv | Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition |
WO2008047883A1 (en) * | 2006-10-13 | 2008-04-24 | Otsuka Pharmaceutical Co., Ltd. | Piperazine-substituted benzothiophenes for treatment of mental disorders |
CN1948298B (en) * | 2006-11-09 | 2010-09-01 | 东南大学 | Dopamine D3 acceptor portion agonist and its application |
AU2007354861B2 (en) * | 2007-06-15 | 2013-03-21 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | 4-phenylpiperazine derivatives with functionalized linkers as dopamine D3 receptor selective ligands and methods of use |
US8829001B2 (en) * | 2008-10-10 | 2014-09-09 | The Institute of Pharmacology and Toxicology Academy of Military Medical Science P.L.A. China | Dopamine D3 receptor ligands and preparation and medical uses of the same |
-
2013
- 2013-01-25 CN CN201310033226.7A patent/CN103073524B/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3452029A4 (en) * | 2016-05-04 | 2019-10-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
Also Published As
Publication number | Publication date |
---|---|
CN103073524A (en) | 2013-05-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103073524B (en) | 4-[4-(substituted phenyl) piperazine piperazinyl-1]-butylcarbamic acid substituted aromatic ester derivative and preparation method thereof | |
Wang et al. | Synthesis of [11C] Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase | |
US4430343A (en) | Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same | |
RU2096411C1 (en) | Derivatives of benzimidazolone, mixture of their isomers or their acid additive salts as antagonist of receptor 5htia and 5ht2 | |
IE54619B1 (en) | 2-(4-((4,4-dialkyl-2,6-piperidinedion-1-yl) butyl) -1-piperazinyl) pyrimidines | |
Goodson et al. | Diphenylethylamines. I. The Preparation of Tertiary Amines by the Grignard Reaction1, 2 | |
NO144885B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZODIAZEPINE DERIVATIVES | |
Handzlik et al. | Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties | |
Jiang et al. | Synthesis and biological evaluation of novel 2-(2-arylmethylene) hydrazinyl-4-aminoquinazoline derivatives as potent antitumor agents | |
EP1194415B1 (en) | Novel piperazinylalkylthiopyrimidine derivatives, pharmaceutical compositions containing the same, and a process for their preparation | |
EP0058779B1 (en) | Carboxamides, their preparation and their use as medicines | |
HU190827B (en) | Process for preparing 2-/4/-/4,4-dialkyl-1,2,6-piperidindion-1-yl/-butyl/-1-piperazinyl/-pyridines | |
CN109485638B (en) | Preparation method of oxitinib intermediate | |
CN103880822B (en) | Containing 2,4,6-trisubstituted pyrimidine compounds of 1,2,3-triazole, preparation method and application thereof | |
JPH02138266A (en) | 6-phenyl-3-(piperazinylalkyl)-2,4(1h,3h)-pyrimidine dione derivative | |
Penjišević et al. | 1‐Cinnamyl‐4‐(2‐methoxyphenyl) piperazines: Synthesis, Binding Properties, and Docking to Dopamine (D2) and Serotonin (5‐HT1A) Receptors | |
CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
CN103497146B (en) | 2-(N-arylmethyl piperidines-4-is amino)-4-(fortified phenol) phenyl ring derivative and preparation method thereof and application | |
CN107935997B (en) | Synthesis method of Ostinib | |
GB1571242A (en) | 3,3 - dichloro - 2 - azetidinone derivatives | |
PL125663B1 (en) | Process for preparing novel derivatives of n-(trimethoxybenzyl)-piperazine | |
EP0123962B1 (en) | Benzimidazole derivative, process for the preparation thereof and pharmaceutical composition | |
JPS60112778A (en) | Morpholine derivatives, manufacture and medicinal composition | |
GB1567313A (en) | 2,3-dihydro-3-hydroxy-1h-benz-(de)isoquinolin-1-one derivatives | |
Reitz et al. | N-aryl-N'-benzylpiperazines as potential antipsychotic agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150610 |