【结 构 式】 |
【分子编号】35549 【品名】tert-butyl 4-aminobenzylcarbamate 【CA登记号】 |
【 分 子 式 】C12H18N2O2 【 分 子 量 】222.2872 【元素组成】C 64.84% H 8.16% N 12.6% O 14.4% |
合成路线1
该中间体在本合成路线中的序号:(VI)The known indole-2-carboxylate intermediate (I) was protected as the N-benzenesulfonyl derivative (II) using benzenesulfonyl chloride and NaH, and the tert-butyl ester group of (II) was subsequently cleaved by means of formic acid. The resulting carboxylic acid (III) was activated as the 2-pyridyl thioester (IV) upon treatment with 2,2'-dipyridyl disulfide and triphenylphosphine. Selective protection of 4-aminobenzyl amine (V) with Boc2O produced the amino carbamate (VI). This was coupled with pyridyl thioester (IV) in refluxing THF to yield amide (VII). Subsequent removal of the N-Boc group of (VII) with trifluoroacetic acid afforded the free amino derivative (VIII), which was converted to the required urea (IX) upon treatment with trimethylsilyl isocyanate. Further hydrolysis of the benzenesulfonyl group of (IX) with ethanolic NaOH furnished the deprotected indole (X).
【1】 Conti, N.; Di Fabio, R.; De Magistris, E.; Feriani, A. (Glaxo Wellcome plc); Indole derivs. as EAA antagonists. EP 0813524; JP 1999501041; US 5919811; WO 9627588 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 32148 | ethyl 3-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C18H19Cl2NO4 | 详情 | 详情 | |
(II) | 35545 | ethyl 3-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate | C24H23Cl2NO6S | 详情 | 详情 | |
(III) | 35546 | (E)-3-[4,6-dichloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indol-3-yl]-2-propenoic acid | C20H15Cl2NO6S | 详情 | 详情 | |
(IV) | 35547 | ethyl 4,6-dichloro-3-[(E)-3-oxo-3-(2-pyridinylsulfanyl)-1-propenyl]-1-(phenylsulfonyl)-1H-indole-2-carboxylate | C25H18Cl2N2O5S2 | 详情 | 详情 | |
(V) | 35548 | 4-(aminomethyl)aniline; 4-aminobenzylamine | 4403-71-8 | C7H10N2 | 详情 | 详情 |
(VI) | 35549 | tert-butyl 4-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
(VII) | 35550 | ethyl 3-[(E)-3-(4-[[(tert-butoxycarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate | C32H31Cl2N3O7S | 详情 | 详情 | |
(VIII) | 35551 | ethyl 3-[(E)-3-[4-(aminomethyl)anilino]-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate | C27H23Cl2N3O5S | 详情 | 详情 | |
(IX) | 35552 | ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate | C28H24Cl2N4O6S | 详情 | 详情 | |
(X) | 35553 | ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C22H20Cl2N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VI)The precursor ethyl ester (X) was also prepared from the unprotected indole carboxylic acid (XII). Conversion into amide (XIV) was carried out using activation of the carboxyl group via formation of the corresponding 2-pyridyl thioester (XIII) and then coupling with aniline (VI). Trifluoroacetic acid-promoted cleavage of the N-Boc group of (XIV) provided amine (XV). This was converted to urea (X) by means of trimethylsilyl isocyanate.
【1】 Provera, S.; Rovatti, L.; Sabbatini, F.M.; Reggiani, A.; Di Fabio, R.; De Magistris, M.; Conti, N.; Barnaby, R.J.; Feriani, A.; Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia. J Med Chem 1999, 42, 18, 3486. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 35549 | tert-butyl 4-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
(X) | 35553 | ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C22H20Cl2N4O4 | 详情 | 详情 | |
(XII) | 32149 | (E)-3-[4,6-dichloro-2-(ethoxycarbonyl)-1H-indol-3-yl]-2-propenoic acid | C14H11Cl2NO4 | 详情 | 详情 | |
(XIII) | 32150 | ethyl 4,6-dichloro-3-[(E)-3-oxo-3-(2-pyridinylsulfanyl)-1-propenyl]-1H-indole-2-carboxylate | C19H14Cl2N2O3S | 详情 | 详情 | |
(XIV) | 35554 | ethyl 3-[(E)-3-(4-[[(tert-butoxycarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C26H27Cl2N3O5 | 详情 | 详情 | |
(XV) | 35555 | ethyl 3-[(E)-3-[4-(aminomethyl)anilino]-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate | C21H19Cl2N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)4-Aminobenzylamine (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O. Heating of (II) with cyanamide afforded guanidine (III). The Boc protecting group of (III) was then removed by means of trifluoroacetic acid to furnish 4-guanidinobenzylamine (IV). 4-Boc-piperazine-1-carbonyl chloride (VI) (obtained by treatment of N-Boc piperazine (V) with triphosgene) was condensed with amine (IV), yielding urea (VII). The N-Boc group of (VII) was then deprotected with trifluoroacetic acid to give (VIII) (1). Dianhydromannitol (X) was converted to bischloroformate (XI) by treatment with phosgene. Then condensation of (XI) with piperazine (VIII) provided the title biscarbamate.
【2】 Gangloff, A.R.; Kuo, E.Y.-L.; Dener, J.M.; Rice, K.D. (Axys Pharmaceuticals, Inc.); Compsns. and methods for treating mast-cell inflammatory condition. US 6022969; WO 9609297 . |
【1】 Putnam, D.; Dener, J.M.; Gangloff, A.R.; Wong, M.; Rice, K.D.; Wng, V.R.; Young, W.B.; Simpson, P.J.; Kuo, E.Y.-L.; Cregar, L.; Newcomb, W.S.; Dibasic inhibitors of human mast cell tryptase. Part 2: Structure-activity relationships and requirements for potent activity. Bioorg Med Chem Lett 2000, 10, 20, 2361. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 35548 | 4-(aminomethyl)aniline; 4-aminobenzylamine | 4403-71-8 | C7H10N2 | 详情 | 详情 |
(II) | 35549 | tert-butyl 4-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
(III) | 45504 | tert-butyl 4-[[amino(imino)methyl]amino]benzylcarbamate | C13H20N4O2 | 详情 | 详情 | |
(IV) | 45505 | N-[4-(aminomethyl)phenyl]guanidine | C8H12N4 | 详情 | 详情 | |
(V) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
(VI) | 28999 | tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate | C10H17ClN2O3 | 详情 | 详情 | |
(VII) | 45507 | N-(4-[[amino(imino)methyl]amino]benzyl)-1-piperazinecarboxamide | C13H20N6O | 详情 | 详情 | |
(VIII) | 45506 | tert-butyl 4-[[(4-[[amino(imino)methyl]amino]benzyl)amino]carbonyl]-1-piperazinecarboxylate | C18H28N6O3 | 详情 | 详情 | |
(IX) | 45508 | (3R,3aR,6R,6aR)hexahydrofuro[3,2-b]furan-3,6-diol | 3261-62-9 | C6H10O4 | 详情 | 详情 |
(X) | 45509 | (3R,3aS,6R,6aS)-3,6-bis[(chlorocarbonyl)oxy]hexahydrofuro[3,2-b]furan | 67-73-2 | C8H8Cl2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)Guanidilation of substituted aniline (I) with protected guanidine (II) provides derivative (III), whose Boc group is removed by treatment with TFA or HCl to afford (4-aminomethyl)phenyl-2,3-di(benzyloxycarbonyl)guanidine (IV). Finally, the target product is obtained by coupling of (IV) with 1-adamantyl-isocyanate (V), followed by removal of the protecting group by hydrogenation over Pd/C.
【2】 Magdolen, V.; Moroder, L.; Sperl, S.; Sturzebecher, J.; Wilhelm, O. (Wilex Biotechnology GmbH); Selective inhibitors of the urokinase plasminogene activators. DE 19940389; WO 0114324 . |
【1】 Stürzebecher, J.; Jacob, U.; Magdolen, V.; Huber, R.; Wilhelm, O.G.; Sperl, S.; Moroder, L.; Bode, W.; Arroyo de Prada, N.; (4-Aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 10, 5113. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 35549 | tert-butyl 4-aminobenzylcarbamate | C12H18N2O2 | 详情 | 详情 | |
(II) | 47207 | benzyl [[(benzyloxy)carbonyl]amino][[(trifluoromethyl)sulfonyl]imino]methylcarbamate | C18H16F3N3O6S | 详情 | 详情 | |
(III) | 47208 | benzyl (Z)-[[(benzyloxy)carbonyl]amino](4-[[(tert-butoxycarbonyl)amino]methyl]anilino)methylidenecarbamate | C29H32N4O6 | 详情 | 详情 | |
(IV) | 47209 | benzyl (Z)-[4-(aminomethyl)anilino][[(benzyloxy)carbonyl]amino]methylidenecarbamate | C24H24N4O4 | 详情 | 详情 | |
(V) | 47210 | 1-isocyanatoadamantane; 1-adamantyl isocyanate | 4411-25-0 | C11H15NO | 详情 | 详情 |
(VI) | 47211 | benzyl (Z)-[4-([[(1-adamantylamino)carbonyl]amino]methyl)anilino][[(benzyloxy)carbonyl]amino]methylidenecarbamate | C35H39N5O5 | 详情 | 详情 |