CN115477613A - Method for synthesizing 2-amino imidazoline compound - Google Patents
Method for synthesizing 2-amino imidazoline compound Download PDFInfo
- Publication number
- CN115477613A CN115477613A CN202211340313.2A CN202211340313A CN115477613A CN 115477613 A CN115477613 A CN 115477613A CN 202211340313 A CN202211340313 A CN 202211340313A CN 115477613 A CN115477613 A CN 115477613A
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- Prior art keywords
- compound
- butyl
- tert
- synthesizing
- dihydro
- Prior art date
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- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 37
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- -1 2-amino imidazoline compound Chemical class 0.000 title claims description 30
- DISXFZWKRTZTRI-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-2-amine Chemical class NC1=NCCN1 DISXFZWKRTZTRI-UHFFFAOYSA-N 0.000 claims abstract description 22
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 claims abstract description 14
- PDQAZBWRQCGBEV-UHFFFAOYSA-N Ethylenethiourea Chemical compound S=C1NCCN1 PDQAZBWRQCGBEV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007098 aminolysis reaction Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 16
- 229940126142 compound 16 Drugs 0.000 claims description 16
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- 150000004982 aromatic amines Chemical class 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 8
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 150000003973 alkyl amines Chemical class 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 229940071127 thioglycolate Drugs 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229940125810 compound 20 Drugs 0.000 claims description 2
- 229940125833 compound 23 Drugs 0.000 claims description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 32
- 239000007787 solid Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 150000003568 thioethers Chemical class 0.000 abstract 3
- 150000002148 esters Chemical class 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- 238000004821 distillation Methods 0.000 description 15
- 229910021529 ammonia Inorganic materials 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 12
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 11
- 229960002896 clonidine Drugs 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- YXIMCNGUIIEJMO-UHFFFAOYSA-N tert-butyl 2-sulfanylacetate Chemical compound CC(C)(C)OC(=O)CS YXIMCNGUIIEJMO-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- PVTGORQEZYKPDK-UHFFFAOYSA-N ethenylthiourea Chemical compound NC(=S)NC=C PVTGORQEZYKPDK-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012847 fine chemical Substances 0.000 description 3
- BRADBAOVPACOQQ-UHFFFAOYSA-N hydron;methyl 1-benzyl-4-oxopiperidine-3-carboxylate;chloride Chemical compound Cl.C1CC(=O)C(C(=O)OC)CN1CC1=CC=CC=C1 BRADBAOVPACOQQ-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 3
- 229960000488 tizanidine Drugs 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 2
- ITMGVSSHWMTJRR-UHFFFAOYSA-N 11-benzyl-7-[(2,4-difluorophenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one Chemical compound FC1=CC=C(CN2C3=NCCN3C3=C(CN(CC4=CC=CC=C4)CC3)C2=O)C(F)=C1 ITMGVSSHWMTJRR-UHFFFAOYSA-N 0.000 description 2
- VLULRUCCHYVXOH-UHFFFAOYSA-N 11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one Chemical compound CC1=CC=CC=C1CN1C(=O)C(CN(CC=2C=CC=CC=2)CC2)=C2N2CCN=C21 VLULRUCCHYVXOH-UHFFFAOYSA-N 0.000 description 2
- DFULPGUTXZTYKA-UHFFFAOYSA-N 11-benzyl-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one Chemical compound C(C1=CC=CC=C1)N1CC=2C(N(C=3N(C=2CC1)CCN=3)CC1=CC=C(C=C1)C(F)(F)F)=O DFULPGUTXZTYKA-UHFFFAOYSA-N 0.000 description 2
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 description 2
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- 229940126682 ONC201 Drugs 0.000 description 2
- JHVLLYQQQYIWKX-UHFFFAOYSA-N benzyl 2-bromoacetate Chemical compound BrCC(=O)OCC1=CC=CC=C1 JHVLLYQQQYIWKX-UHFFFAOYSA-N 0.000 description 2
- 229960002925 clonidine hydrochloride Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 1
- BFYRXCWLDJORHM-UHFFFAOYSA-N 2-chloro-4,5-dihydro-1h-imidazole Chemical compound ClC1=NCCN1 BFYRXCWLDJORHM-UHFFFAOYSA-N 0.000 description 1
- UOUQDZFAJUNYQQ-UHFFFAOYSA-N 2-methylpropyl 2-bromoacetate Chemical compound CC(C)COC(=O)CBr UOUQDZFAJUNYQQ-UHFFFAOYSA-N 0.000 description 1
- ZZPAWQYZQVUVHX-UHFFFAOYSA-N 4-chloro-n-(4,5-dihydro-1h-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine;hydrochloride Chemical compound Cl.COC1=NC(C)=NC(Cl)=C1NC1=NCCN1 ZZPAWQYZQVUVHX-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- HTYRTGGIOAMLRR-UHFFFAOYSA-N 5-amino-4-hydroxybenzene-1,3-disulfonic acid Chemical compound NC1=CC(S(O)(=O)=O)=CC(S(O)(=O)=O)=C1O HTYRTGGIOAMLRR-UHFFFAOYSA-N 0.000 description 1
- MURNIACGGUSMAP-UHFFFAOYSA-N 5-chloro-2,1,3-benzothiadiazol-4-amine Chemical compound NC1=C(Cl)C=CC2=NSN=C12 MURNIACGGUSMAP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241001432959 Chernes Species 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- WPNJAUFVNXKLIM-UHFFFAOYSA-N Moxonidine Chemical compound COC1=NC(C)=NC(Cl)=C1NC1=NCCN1 WPNJAUFVNXKLIM-UHFFFAOYSA-N 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XTCXSNIRIUQZLY-UHFFFAOYSA-N benzyl 2-sulfanylacetate Chemical compound SCC(=O)OCC1=CC=CC=C1 XTCXSNIRIUQZLY-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- NMEGSGKCIWQRDB-UHFFFAOYSA-N butyl 2-bromoacetate Chemical compound CCCCOC(=O)CBr NMEGSGKCIWQRDB-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- FLGMAMYMYDIKLE-UHFFFAOYSA-N chloro hypochlorite;phosphane Chemical compound P.ClOCl FLGMAMYMYDIKLE-UHFFFAOYSA-N 0.000 description 1
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 229960003938 moxonidine Drugs 0.000 description 1
- GTPHHSDNEHXLJQ-UHFFFAOYSA-N n-(4-methylphenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound C1=CC(C)=CC=C1N=C1NCCN1 GTPHHSDNEHXLJQ-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 2-amino imidazoline compounds, which takes cheap bromoacetate compounds and ethylene thiourea as raw materials, synthesizes thioether through substitution reaction, and then prepares 2-amino imidazoline compounds or related drug molecules through aminolysis of thioether, and is associated with mercaptoacetate which has no odor and additional value. The method has the advantages that: 1) The raw materials are cheap and easy to obtain, and have low toxicity; 2) The obtained intermediate thioether is solid and is easy to purify and separate; 3) The product is solid and is easy to separate from the associated mercaptoacetic ester, and the two products have high yield and purity. The method has the characteristics of simple process, mild reaction conditions, low cost, environmental protection, high yield and the like, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of fine chemicals and drug molecules containing 2-amino imidazoline structural units.
Background
The 2-amino imidazoline structural unit widely exists in medical intermediates and drug molecules, and belongs to an important organic compound. Such as clonidine hydrochloride (clonidine), moxonidine hydrochloride (moxonidine), tizanidine (tizanidine), inozaline (indolizine), a nasal blood vessel contraction drug, novel targeted anticancer active molecules ONC201, ONC206, ONC212 and the like which are in clinical research stage contain 2-amino imidazoline structural units. Among them, clonidine hydrochloride and tizanidine have shown a remarkable trend of increasing domestic sales in recent years, and the market size in 2021 year is about 1.4 billion yuan and 1.2 billion yuan respectively. In addition, 2-aminoimidazolines are an important class of guanidine organic compounds and also important fine chemicals, for example, as small molecule catalysts. Therefore, the research and development of a green, efficient, safe and simple synthetic process for preparing the compound has good economic and social benefits.
As indicated above, 2-aminoimidazolines are largely comprised of two major classes, one being N-alkyl substitution, i.e., 2-alkylaminoimidazolines; another class is N-aryl substituted, 2-arylamine imidazolines. Six representative synthetic methods for such compounds are described below, taking the clonidine preparation as an example.
(1) Missir, et al 1993, reported that 2, 6-dichloroaniline 1 was formylated and chlorinated to obtain the dichloroimine intermediate 3, which was reacted with ethylenediamine in 1, 2-dichloroethane to obtain clonidine (patent RO 105262), with unknown yield. In 2018, the process is improved by Wangaohua and the like (CN 107915679), the total yield of three steps is 36%, and the method is industrially adopted to prepare the clonidine at present. However, the route adopts sulfonyl chloride and sulfinyl chloride as raw materials, so that the method is strong in equipment corrosivity and large in waste water amount. With environmental governance and strict management and control, the production and environmental governance costs will increase significantly.
(2) Mundla et al, 2000, reported that ethylenethiourea 4 was used as a starting material, and was reacted with methyl iodide, methyl chloroformate, in order to obtain key intermediate 6, which was reacted with 2, 6-dichloroaniline 1 to prepare clonidine (Tetrahedron Letters,2000,41, 6563-6566). The method has simple operation and high yield of each step, and the compounds 5 and 6 are solid and easy to purify. However, methyl iodide and methyl chloroformate are highly toxic chemicals and the last step of aminolysis releases the toxic and unpleasant odor methyl mercaptan, which prevents the route from being used in industrial production.
(3) Heinelt et al, 2004, reported that Compound 1 reacted with thiophosgene 7 to give isothiocyanate intermediate 8. The latter was reacted with ethylenediamine under the action of p-toluenesulfonyl chloride and sodium hydroxide to give clonidine in 60% yield (Tetrahedron, 2004,60, 9883-9888). The method has short route, but has more impurities and low yield.
(4) Chern et al 2005 reported that 2-imidazolidinone 9 reacted with phosphine oxychloride 10 or chlorophosphate to give 2-chloroimidazoline 11, which reacted with alkylamines to produce 2-alkylaminoimidazoline (Synthetic Communications,2005,35, 2633-2639). Based on this, yangying et al synthesized clonidine using this strategy in 2021, but no yield data was available. And the phosphorus oxychloride has strong corrosivity and lacrimation property, which not only seriously harms the health of first-line personnel, but also corrodes equipment and brings a large amount of waste water and waste gas.
(5) Farajollah et al 2011 reported the reaction of Compound 1 with ammonium thiocyanate to give thiourea 12. Thiourea 12 was oxidized with sodium molybdate and hydrogen peroxide to give amidine sulfonic acid 13 in 77% yield, which was reacted with ethylenediamine in isopropanol to give clonidine in 91% yield in the last step (Chinese Journal of Chemistry,2011,29, 1055-1058). The method relates to an oxidation process, and no industrial application report is found at present.
(6) Bandgar et al, 2012 improved the route proposed by Farajollah, supra. Reaction of thiourea 12 with methyl iodide gave 14, and reaction of compound 14 with ethylenediamine produced clonidine (IN 2010MU 02956). IN 2013, bandgar further replaced methyl iodide with dimethyl sulfate, the process was optimized, and the yield of clonidine IN the last step was 96% (IN 2011MU 03307). The method avoids oxidation by hydrogen peroxide, and improves safety. However, methyl iodide and dimethyl sulfate are highly toxic and use in large quantities poses a significant risk to the health of personnel at the production front-line. At the same time, methyl mercaptan and ammonia gas are released, which is not suitable for industrial synthesis.
The latter five routes are superior to the industrial synthesis described in route 1. By systematic comparison, we believe that there is room for improvement and optimization in the synthesis of 2-aminoimidazolines starting from inexpensive ethylenethiourea (scheme 2). Therefore, the invention is improved on the basis.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2-amino imidazoline compounds, which has the advantages of simple process, low price, environmental protection, mild conditions and good yield.
Aiming at the purposes, the technical scheme adopted by the invention comprises the following steps:
1. reacting ethylene thiourea 4 with a bromoacetate compound 15 in a solvent to prepare a compound 16;
in the formula R 1 Represents C 1 ~C 7 An alkyl group or a benzyl group, preferably any one of an ethyl group, an isopropyl group, a n-butyl group, a tert-butyl group and a benzyl group;
2. the compound 16 is used for preparing the 2-amino imidazoline compound by any one of the following two methods:
the method comprises the following steps: aminolysis of compound 16 with alkylamine or arylamine 17 to obtain 2-aminoimidazoline compound 18 accompanied with mercaptoacetate compound 19 with additional value;
in the formula R 2 Represents C 1 ~C 7 Alkyl (specifically, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), para-or meta-C 1 ~C 4 Alkyl substituted aryl, para or meta C 1 ~C 3 Alkoxy-substituted aryl groups, etc.;
the second method comprises the following steps: reacting the compound 16 with methyl chloroformate or di-tert-butyl dicarbonate to obtain an acylate 20, aminolyzing the acylate 20 by using arylamine 21 to obtain a 2-aminoimidazoline compound 23 accompanied with a thioglycollate compound 19 with an additional value;
in the formula R 3 Represents methyl or tert-butyl, R 4 Represents aryl or substituted aryl.
In the step 1, the mol ratio of the ethylene thiourea 4 to the bromoacetate compound 15 is preferably 1: 1.1-1.3, and the solvent is preferably any one of methanol, ethanol and isopropanol.
In the first method of step 2, the molar ratio of the compound 16 to the alkylamine or arylamine 17 is preferably 1:1.0 to 1.3.
In the second method of the above step 2, the molar ratio of the compound 16 to the methyl chloroformate or di-tert-butyl dicarbonate is preferably 1:1.0 to 1.3, preferably the molar ratio of compound 20 to aromatic amine 21 is 1:1.0 to 1.3.
In the step 2, the solvent used for the ammonolysis is preferably any one of tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, acetonitrile, 1, 2-dichloroethane, acetic acid and the like.
The invention has the following beneficial effects:
1. according to the invention, bromoacetate compounds such as tert-butyl bromoacetate or benzyl bromoacetate with the same price are used for replacing methyl iodide to prepare the compound 16, and the compound 16 is solid and is simple to prepare; then aminolysis compound 16 such as alkylamine or arylamine with higher activity is adopted, or methyl chloroformate or di-tert-butyl dicarbonate is adopted to acylate compound 16, then aminolysis acylate is carried out on the acylate by arylamine with lower activity, and the target product 2-amino imidazoline compound is obtained with high yield, meanwhile, mercaptoacetic acid tert-butyl ester or benzyl ester with additional value is associated, and the latter has no peculiar smell. The method can obtain various aryl-substituted 2-amino imidazoline drug molecules with high yield, not only avoids the use of high-toxicity methyl iodide, but also avoids the generation of methyl mercaptan in the route, and solves the link pollution problem of toxic and unpleasant gas. Therefore, the invention obviously improves the safety of the route and has the characteristic of environmental protection.
2. The invention realizes two-step synthesis of 2-amino imidazoline fine chemicals or drug molecules, and has the advantages of short reaction steps, mild conditions and high yield compared with the existing industrial synthesis method.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
1. A1L one-neck flask was charged with 20g (0.196 mol) of ethylenethiourea 4 and 300mL of anhydrous ethanol, and further charged with 46g (0.235 mol) of t-butyl bromoacetate 15-1, and reacted at room temperature for 20 hours. After the reaction was completed, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of dichloromethane, followed by addition of petroleum ether and stirring to obtain 56g of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 as a white solid in a yield of 94%.
2. In a 250mL single-necked flask, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 and 100mL of tetrahydrofuran were charged, and 9.0g (74.0 mmol) of 2-methylbenzylamine 17-1 was further added, followed by reaction at 80 ℃ for 20 hours. After the reaction is finished, the solvent tetrahydrofuran is directly filtered out, the filter cake is washed by dichloromethane, then the filter cake is transferred to a beaker, dichloromethane and 0.5mol/L aqueous solution of sodium hydroxide are added for stirring and extraction, an organic phase is separated, the aqueous phase is extracted by dichloromethane for 3 times, the combined organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and 11g of N- (2-methylbenzyl) -4, 5-dihydro-1-hydrogen-imidazole-2-ammonia 18-1 is obtained by drying, the yield is 86 percent, and the purity is more than 99 percent. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to obtain 6g of tert-butyl thioglycolate 19-1 in a yield of 61%.
Example 2
Step 1 of this example is the same as step 1 of example 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 and 100mL of tetrahydrofuran were charged in a 250mL single-necked flask, and 10.6g (74 mmol) of 2, 4-difluorobenzylamine 17-2 was further added, followed by reaction at 80 ℃ for 20 hours. After the reaction is finished, the solvent tetrahydrofuran is directly removed under reduced pressure, then the residual liquid is stirred and diluted by dichloromethane and 1mol/L diluted hydrochloric acid, an organic phase is separated, the pH of an aqueous phase is adjusted to 11, the dichloromethane is continuously used for extraction for 3 times, the organic phases are combined and dried by anhydrous sodium sulfate, the solvent is removed after filtration, and 10g of N- (2, 4-difluorobenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-2 is obtained by drying, the yield is 71%, and the purity is more than 99%. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to give 6g of tert-butyl mercaptoacetate 19-1 in a yield of 61%.
Example 3
In step 2 of this example, 2, 4-difluorobenzylamine 17-2 in example 2 was replaced with an equimolar amount of 4-trifluoromethylbenzylamine 17-3, and the other steps were the same as in example 2 to obtain 12.5g of N- (4-trifluoromethylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-3 in a yield of 77% and a purity of >99%. The filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to obtain 6g of tert-butyl mercaptoacetate 19-1 in a yield of 61%.
Example 4
Step 1 of this example is the same as step 1 of example 1. In step 2 of this example, 2.52g (8.48 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 and 20mL of tetrahydrofuran were charged in a 100mL single-necked flask, and 1.00g (9.33 mmol) of p-toluidine 17-4 was further added, followed by reaction at 80 ℃ for 20 hours. After the reaction is finished, the solvent tetrahydrofuran is directly removed under reduced pressure, then the residual liquid is stirred and diluted by dichloromethane and 1mol/L dilute hydrochloric acid, an organic phase is separated, the pH of an aqueous phase is adjusted to 11, the extraction is continuously carried out for 3 times by dichloromethane, the combined organic phase is dried by anhydrous sodium sulfate, and the solvent is removed after filtration. The crude product was washed with ether and dried to give 1.00g of N- (p-tolyl) -4, 5-dihydro-1H-imidazole-2-ammonia 18-4 in 70% yield with a purity of >99%. The ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to obtain 0.76g of tert-butyl mercaptoacetate 19-1 in 55% yield.
Example 5
Step 1 of this example is the same as step 1 of example 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1, 100mL of methylene chloride and 15.7g (154.8 mmol) of triethylamine were charged in a 250mL single-neck flask, and 8.3g (87.5 mmol) of methyl chloroformate was added in an ice-water bath and reacted at room temperature for 6 hours. After the completion of the reaction, the organic phase was washed with water, the solvent was removed under reduced pressure, and the residue was dried to obtain 14.7g of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate 20-1 in 84% yield. A100 mL single-neck flask was charged with 20-1 g (8.48 mmol) of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate, 15mL of methanol, and 1.5mL of acetic acid, followed by addition of 21-1 g (9.33 mmol) of p-toluidine, and the reaction was carried out at 80 ℃ for 20 hours. After the reaction, the solvents methanol and acetic acid were removed under reduced pressure. The residue was then diluted with dichloromethane and water with stirring, the organic phase was separated off, the aqueous phase was adjusted to pH 11, extraction was continued for 3 times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and the solvent was removed. The crude product was washed with ether and dried to give 1.15g of N- (p-tolyl) -4, 5-dihydro-1H-imidazol-2-amine 22-1 in 78% yield with a purity of >99%. The ether filtrate was concentrated, and the residue was concentrated by distillation under reduced pressure (100Pa, 30 ℃ C.) to obtain 0.76g of tert-butyl mercaptoacetate 19-1 in 55% yield.
Example 6
In step 2 of this example, 2.03g (7.38 mmol) of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate 20-1, methanol 15mL, and acetic acid 1.5mL were charged in a 100mL single-neck flask, and 1.00g (8.12 mmol) of p-anisidine 21-2 was further added, and the reaction was carried out at 80 ℃ for 20 hours. The other steps were the same as in example 5, to give 1.13g of N- (p-methoxyphenyl) -4, 5-dihydro-1H-imidazole-2-ammonia 22-2 in 80% yield with a purity of >99%. The ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to obtain 0.70g of tert-butyl mercaptoacetate 19-1 in 58% yield.
Example 7
In step 2 of this example, 1.54g (5.61 mmol) of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate 20-1, 15mL of methanol, and 1.5mL of acetic acid were charged in a 100mL single-neck flask, and 1.0g (6.17 mmol) of 2, 6-dichloroaniline 21-3 was further added, and the reaction was carried out at 80 ℃ for 20 hours. The other steps were the same as in example 5, to give 0.96g of 2, 6-dichloro-N- (2-imidazolin-2-yl) aniline 22-3 in a yield of 75% and a purity of >99%. The ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to give 0.5g of tert-butyl mercaptoacetate 19-1 in 54% yield.
Example 8
In step 2 of this example, 1.34g (4.90 mmol) of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate 20-1, 15mL of methanol, and 1.5mL of acetic acid were charged in a 100mL single-neck flask, and 1.00g (5.39 mmol) of 4-amino-5-chloro-2, 1, 3-benzothiadiazole 21-4 was further added, and reacted at 80 ℃ for 20 hours. The other steps are the same as in example 5, 0.97g 5-chloro-4- (4, 5-dihydro-1H-imidazol-2-yl) -2,1, 3-benzothiadiazol-4-amine 22-4 is obtained with a yield of 79% and a purity of >99%. The ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to give 0.44g of tert-butyl mercaptoacetate 19-1 in 55% yield.
Example 9
In step 2 of this example, 1.87g (6.83 mmol) of tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) mercaptoacetate 20-1, 15mL of methanol, and 1.5mL of acetic acid were charged in a 100mL single-neck flask, and 1.00g (7.51 mmol) of (4, 5-dihydro-1H-imidazol-2-yl) -4-indanamine 21-5 was further added, and reacted at 80 ℃ for 20 hours. The other steps were the same as in example 5 to give 1.03g of (4, 5-dihydro-1H-imidazol-2-yl) -4-indanamine 22-5 in 75% yield and >99% purity. The ether filtrate was concentrated, and the residue was purified by distillation under reduced pressure (100Pa, 30 ℃ C.) to give 0.61g of tert-butyl mercaptoacetate 19-1 in 55% yield.
Example 10
Step 1 of this example is the same as step 1 of example 1. In step 2 of this example, 20g (67.3 mmol) of tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1, 100mL of tetrahydrofuran, and 100mL of water were charged into a 250mL single-neck flask, and 17.6g (80.6 mmol) of di-tert-butyl dicarbonate was added under an ice-water bath and reacted at room temperature for 6 hours. After the reaction is finished, inorganic salt is filtered, then tetrahydrofuran is removed under reduced pressure, the residual liquid is filtered to obtain a crude product, petroleum ether is added for recrystallization after water washing, and 17g of tert-butyl 2- (4, 5-dihydro-1-formic acid tert-butyl ester-imidazole) mercaptoacetate 20-2 is obtained with the yield of 81%. Then, the same procedure as in step 2 of example 5 was repeated except for replacing tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) thioglycolate 20-1 in step 2 of example 5 with equimolar tert-butyl 2- (4, 5-dihydro-1-carboxylate-imidazole) thioglycolate 20-2 to give N- (p-tolyl) -4, 5-dihydro-1H-imidazole-2-ammonia 22-1.
Example 11
In step 1 of this example, 5.0g (49 mmol) of ethylenethiourea 4 and 100mL of absolute ethanol were put into a 250mL single-neck flask, and 9.8g (59 mmol) of ethyl bromoacetate 15-2 was further added and reacted at room temperature for 20 hours. After the reaction, the solvent ethanol was removed under reduced pressure, after the reaction, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, a small amount of dichloromethane was added to dilute the viscous liquid, and then petroleum ether was added to stir the diluted liquid to obtain 12g of ethyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-2 in a yield of 92%.
In step 2 of this example, t-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1 was replaced with equimolar ethyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-2 and the other steps were the same as in step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 12
In step 1 of this example, 5.0g (49 mmol) of vinylthiourea 4 and 100mL of absolute ethanol were put into a 250mL single-neck flask, and 10.7g (59 mmol) of isopropyl bromoacetate 15-3 was further added to the flask, followed by reaction at room temperature for 20 hours. After the reaction was completed, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride, and then petroleum ether was added thereto and stirred to obtain 12.5g of isopropyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-3 in a yield of 90%.
In step 2 of this example, tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1 was replaced with equimolar isopropyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-3 and the other steps were the same as in step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Example 13
In step 1 of this example, 5.0g (49 mmol) of ethylenethiourea 4 and 100mL of absolute ethanol were put into a 250mL single-neck flask, and 11.5g (59 mmol) of n-butyl bromoacetate 15-4 was further added to the flask and reacted at room temperature for 20 hours. After the reaction was completed, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride and stirred with petroleum ether to obtain 12.6g of n-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-4 in 87% yield.
In step 2 of this example, N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1 was obtained by replacing tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1 with equimolar N-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-4 in step 2 of example 1 and the other steps were the same as in step 2 of example 1.
Example 14
In step 1 of this example, 5.0g (49 mmol) of vinylthiourea 4 and 100mL of absolute ethanol were put into a 250mL single-neck flask, and 11.5g (59 mmol) of isobutyl bromoacetate 15-5 was further added to the flask, followed by reaction at room temperature for 20 hours. After the reaction was completed, the solvent ethanol was removed under reduced pressure to obtain a colorless viscous liquid, which was diluted with a small amount of methylene chloride and stirred with petroleum ether to obtain 13.2g of isobutyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-5 in a yield of 91%.
In step 2 of this example, N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1 was obtained by replacing tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1 with an equimolar amount of isobutyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-5 in step 2 of example 1 and by following the same procedure as in step 2 of example 1.
Example 15
In step 1 of this example, 5.0g (49 mmol) of vinylthiourea 4 and 100mL of absolute ethanol were put into a 250mL single-neck flask, and 13.5g (59 mmol) of benzyl bromoacetate 15-6 were further added to the flask and reacted at room temperature for 20 hours. After the reaction was completed, the solvent ethanol was removed under reduced pressure to obtain a white solid, which was stirred and washed with petroleum ether, and the filter cake was filtered and dried to obtain 15g of benzyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-6 in 92% yield.
In step 2 of this example, tert-butyl 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-1 in step 2 of example 1 was replaced with equimolar 2- (4, 5-dihydro-1-hydro-imidazole) mercaptoacetate hydrobromide 16-6 and the other steps were the same as in step 2 of example 1 to give N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1.
Examples of applications of the synthesis of biologically active molecules
Application example 1
In a 250mL single-neck flask were charged 10g (52.8 mmol) of N- (2-methylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-1, 100mL of methanol, 5.7g (105.6 mmol) of sodium methoxide, and further 13.63g (48.0 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, and the reaction was carried out at 80 ℃ for 20 hours. After the reaction is finished, methanol is removed by reduced pressure distillation, then the residual solid is extracted by dichloromethane and water, and after organic phase is dried by reduced pressure distillation, 17.7g of light yellow solid product ONC201 is obtained, wherein the yield is 86% and the purity is more than 99%.
Application example 2
In a 250mL single-neck flask were charged 10g (47.3 mmol) of N- (2, 4-difluorobenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-2, 100mL of methanol, 5.12g (94.7 mmol) of sodium methoxide, and further 12.2g (43.0 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, and the reaction was carried out at 80 ℃ for 20 hours. After the reaction is finished, methanol is removed by reduced pressure distillation, then the residual solid is extracted by dichloromethane and water, and 15.5g of light yellow solid product ONC206 is obtained after organic phase is dried by reduced pressure distillation, the yield is 80 percent, and the purity is more than 99 percent.
Application example 3
In a 250mL single-neck flask were charged 10g (41.3 mmol) of N- (4-trifluoromethylbenzyl) -4, 5-dihydro-1-hydro-imidazole-2-ammonia 18-3, 100mL of methanol, 4.46g (82.6 mmol) of sodium methoxide, and 10.7g (37.6 mmol) of 1-benzyl-3-methoxycarbonyl-4-piperidone hydrochloride, followed by reaction at 80 ℃ for 20 hours. After the reaction is finished, methanol is removed by reduced pressure distillation, then the residual solid is extracted by dichloromethane and water, and 15.5g of light yellow solid product ONC212 is obtained after organic phase is dried by reduced pressure distillation, the yield is 85 percent, and the purity is more than 99 percent.
Claims (7)
1. A method for synthesizing 2-amino imidazoline compounds is characterized by comprising the following steps:
(1) Reacting ethylene thiourea 4 with a bromoacetate compound 15 in a solvent to prepare a compound 16;
in the formula R 1 Represents C 1 ~C 7 Alkyl or benzyl;
(2) The compound 16 is used for preparing the 2-amino imidazoline compound by any one of the following two methods:
the method comprises the following steps: aminolysis of a compound 16 by alkylamine or arylamine 17 to obtain a 2-aminoimidazoline compound 18 accompanied by a thioglycolate compound 19 with an additional value;
in the formula R 2 Represents C 1 ~C 7 Alkyl, para or meta C 1 ~C 4 Alkyl substituted aryl, para or meta C 1 ~C 3 Any one of alkoxy substituted aryl;
the second method comprises the following steps: reacting the compound 16 with methyl chloroformate or di-tert-butyl dicarbonate to obtain an acylate 20, aminolyzing the acylate 20 by using arylamine 21 to obtain a 2-aminoimidazoline compound 23 accompanied with a thioglycollate compound 19 with an additional value;
in the formula R 3 Represents methyl or tert-butyl, R 4 Represents aryl or substituted aryl.
2. The method for synthesizing 2-aminoimidazolines according to claim 1, characterized in that: in the step (1), the molar ratio of the ethylene thiourea 4 to the bromoacetate compound 15 is 1:1.1 to 1.3.
3. The method for synthesizing 2-aminoimidazolines according to claim 1, characterized in that: in step (1), R 1 Represents any one of ethyl, isopropyl, n-butyl, tert-butyl and benzyl.
4. The method for synthesizing 2-aminoimidazolines according to claim 1, characterized in that: in the step (1), the solvent is any one of methanol, ethanol and isopropanol.
5. The method for synthesizing 2-aminoimidazolines according to claim 1, wherein: in the first method in the step (2), the molar ratio of the compound 16 to the alkylamine or arylamine 17 is 1:1.0 to 1.3.
6. The method for synthesizing 2-aminoimidazolines according to claim 1, characterized in that: in the second method in the step (2), the molar ratio of the compound 16 to the methyl chloroformate or the di-tert-butyl dicarbonate is 1:1.0 to 1.3, the molar ratio of the compound 20 to the arylamine 21 is 1:1.0 to 1.3.
7. The method for synthesizing 2-aminoimidazolines according to claim 1, characterized in that: in the step (2), the solvent used for aminolysis is any one of tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, acetonitrile, 1, 2-dichloroethane and acetic acid.
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BE555210A (en) * | 1956-02-23 | |||
CN1242004A (en) * | 1996-11-25 | 2000-01-19 | 普罗克特和甘保尔公司 | Process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives |
US20070112020A1 (en) * | 2005-11-11 | 2007-05-17 | Pharmacia Italia S.P.A. | Azaindolylidene derivatives as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
CN101687812A (en) * | 2007-07-02 | 2010-03-31 | 弗·哈夫曼-拉罗切有限公司 | The 2-imidazolinium compounds that trace amine associated receptors (TAAR) is had good affinity |
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BE555210A (en) * | 1956-02-23 | |||
US2819965A (en) * | 1956-02-23 | 1958-01-14 | Eastman Kodak Co | Carboxymethylmercapto compounds as stabilizers for photographic emulsions |
CN1242004A (en) * | 1996-11-25 | 2000-01-19 | 普罗克特和甘保尔公司 | Process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives |
US20070112020A1 (en) * | 2005-11-11 | 2007-05-17 | Pharmacia Italia S.P.A. | Azaindolylidene derivatives as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
CN101687812A (en) * | 2007-07-02 | 2010-03-31 | 弗·哈夫曼-拉罗切有限公司 | The 2-imidazolinium compounds that trace amine associated receptors (TAAR) is had good affinity |
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