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【结 构 式】 
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【分子编号】35252 【品名】(E)-1-bromo-2-butene 【CA登记号】29576-14-5 |
【 分 子 式 】C4H7Br 【 分 子 量 】135.00358 【元素组成】C 35.59% H 5.23% Br 59.19% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of the acetyl-protected dipeptide (I) with N2H4 in acetonitrile followed by treatment with Boc2O, 4-dimethylaminopyridine (DMAP) and Et3N in dichloromethane affords the Boc-protected dipeptide (II). Oxazolone cleavage of (II) by means of Cs2CO3 in MeOH yields the methyl ester (III), which is converted into the crotyl ester (V) by a first hydrolysis with LiOH in THF/H2O followed by treatment with crotyl bromide (IV) and Et3N in acetone. Removal of the allyl moiety from peptide (VI) by means of Pd(PPh3)4 and dimedone in THF allows obtention of the carboxylic acid derivative (VII), which is then esterified with (V) by means of dicyclohexylcarbodiimide (DCC) and DMAP in CH2Cl2 to furnish (VIII). Removal of the crotyl moiety from (VIII) by means of Pd(PPh3)4 and dimedone in THF gives (IX), whose azide group is reduced with PPh3 in THF/H2O to afford amine (X). Self-assembling of (X) by spontaneous cyclodimerization when treated with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (DEC) and 1-hydroxy-7-aza-1H-benzotriazole (HOAt) produces dimer (XI), which is reduced by hydrogenation over PtO2 in EtOAc to provide (XII).
| 【1】 Ciufolini, M.A.; et al.; Total synthesis of luzopeptin E2. Angew Chem. Int Ed Engl 2000, 39, 14, 2493. |
| 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) | 43044 | methyl (3S)-2-[[(4R)-3-acetyl-2-oxo-1,3-oxazolidin-4-yl]carbonyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C12H15N3O6 | 详情 | 详情 | |
| (II) | 43045 | methyl (3S)-2-[[(4R)-3-(tert-butoxycarbonyl)-2-oxo-1,3-oxazolidin-4-yl]carbonyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C15H21N3O7 | 详情 | 详情 | |
| (III) | 43046 | methyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C14H23N3O6 | 详情 | 详情 | |
| (IV) | 35252 | (E)-1-bromo-2-butene | 29576-14-5 | C4H7Br | 详情 | 详情 |
| (V) | 43047 | (E)-2-butenyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C17H27N3O6 | 详情 | 详情 | |
| (VI) | 43048 | allyl (2S,3S)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoate | C15H24N4O5 | 详情 | 详情 | |
| (VII) | 43049 | (2S,3S)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoic acid | C12H20N4O5 | 详情 | 详情 | |
| (VIII) | 43050 | (E)-2-butenyl (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C29H46N8O10 | 详情 | 详情 | |
| (IX) | 43051 | (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid | C25H40N8O10 | 详情 | 详情 | |
| (X) | 43052 | (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-aminoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid | C25H42N6O10 | 详情 | 详情 | |
| (XI) | 43053 | tert-butyl (4aS,13S,17R,23aS,32S,36R)-36-[(tert-butoxycarbonyl)amino]-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethyl-5,8,11,14,18,24,27,30,33,37-decaoxo-4,4a,5,6,7,8,9,10,11,12,13,14,17,18,23,23a,24,25,26,27,28,29,30,31,32,33,36,37-octaco | C48H76N12O18 | 详情 | 详情 | |
| (XII) | 43054 | tert-butyl (4aS,13S,17R,23aS,32S,36R)-36-[(tert-butoxycarbonyl)amino]-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethyl-5,8,11,14,18,24,27,30,33,37-decaoxodotriacontahydro-1H,16H,20H,35H-dipyridazino[6,1-l:6,1-b_1_][1,17,4,7,10,13,20,23,26,2 | C48H80N12O18 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)A novel synthetic route to pemetrexed disodium has been reported: The reaction of 3,4-dimethoxybenzylamine with methyl chloroformate gives the corresponding carbamate (II), which is alkylated with 2-butenyl bromide (III) yielding the N-alkyl carbamate (IV). The cleavage of (IV) with hydrazine and KOH affords the secondary amine (V), which is condensed with dimethyl malonate to give the malonamic ester (VI). The radical cyclization of (VI) by means of manganese triacetate dihydrate/copper acetate hydrate affords the pyrrolidinone (VII), which is treated with P2S5 in THF to give the thione (VIII). The cyclization of (VIII) with guanidine (IX) yields the pyrrolopyrimidinone (X), which is condensed with N-(4-iodobenzoyl)-L-glutamic acid diethyl ester (XI) by means of palladium diacetate to afford the ethano-bridged pyrrolopyrimidine (XII). Elimination of the dimethoxybenzyl-protecting group of (XII) with TFA/H2SO4 gives the diethyl ester of pemetrexed (XIII), which is finally saponified with NaOH in THF/water.
| 【1】 Taylor, E.C.; Liu, B.; A novel synthetic route to 7-substituted derivatives of the antitumor agent LY231514 (MTA). Tetrahedron Lett 1999, 40, 29, 5291. |
| 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) | 13920 | (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine | 5763-61-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 35244 | methyl 3,4-dimethoxybenzylcarbamate | C11H15NO4 | 详情 | 详情 | |
| (III) | 35252 | (E)-1-bromo-2-butene | 29576-14-5 | C4H7Br | 详情 | 详情 |
| (IV) | 35245 | methyl (E)-2-butenyl(3,4-dimethoxybenzyl)carbamate | C15H21NO4 | 详情 | 详情 | |
| (V) | 35246 | N-[(E)-2-butenyl]-N-(3,4-dimethoxybenzyl)amine; (E)-N-(3,4-dimethoxybenzyl)-2-buten-1-amine | C13H19NO2 | 详情 | 详情 | |
| (VI) | 35247 | methyl 3-[(E)-2-butenyl(3,4-dimethoxybenzyl)amino]-3-oxopropanoate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 35248 | methyl 1-(3,4-dimethoxybenzyl)-2-oxo-4-vinyl-3-pyrrolidinecarboxylate | C17H21NO5 | 详情 | 详情 | |
| (VIII) | 35249 | methyl 1-(3,4-dimethoxybenzyl)-2-thioxo-4-vinyl-3-pyrrolidinecarboxylate | C17H21NO4S | 详情 | 详情 | |
| (IX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (X) | 35250 | 2-amino-7-(3,4-dimethoxybenzyl)-5-vinyl-3,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | C17H20N4O3 | 详情 | 详情 | |
| (XI) | 14283 | diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate | C16H20INO5 | 详情 | 详情 | |
| (XII) | 35251 | diethyl (2S)-2-[(4-[2-[2-amino-7-(3,4-dimethoxybenzyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl)amino]pentanedioate | C33H39N5O8 | 详情 | 详情 | |
| (XIII) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)In an alternative route, 2-N-acetyl-4,6-O-isopropylidene-D-glucosamine benzyl pyranoside (XVII) was alkylated with 1-bromo-2-butene (XVIII) in the presence of barium oxide and barium hydroxide to produce the 3-O-crotyl ether (XIX). After acidic hydrolysis of the isopropylidene ketal (XIX), the resultant diol (XX) was selectively mono-acylated at the primary hydroxyl with benzoyl chloride (XXI) to afford the 6-benzoate ester (XXII). Protection of the 3-hydroxyl group of (XXII) by means of dihydropyran (DHP) and p-toluenesulfonic acid gave rise to the tetrahydropyranyl ether (XXIII). After methanolysis of the benzoate ester of (XXIII) in the presence of NaOMe, the resultant primary alcohol (XXIV) was protected as the benzyl ether (XXV). Subsequent hydrolysis of the tetrahydropyranyl group of (XXV) in aqueous HOAc furnished the protected glucosamine intermediate (XXVI).
| 【1】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8. |
| 【2】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 56337 | N-[(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide | C18H25NO6 | 详情 | 详情 | |
| (XVIII) | 35252 | (E)-1-bromo-2-butene | 29576-14-5 | C4H7Br | 详情 | 详情 |
| (XIX) | 56338 | N-{(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-[(E)-2-butenyloxy]-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl}acetamide | C22H31NO6 | 详情 | 详情 | |
| (XX) | 56339 | N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | C19H27NO6 | 详情 | 详情 | |
| (XXI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XXII) | 56340 | {(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-hydroxytetrahydro-2H-pyran-2-yl}methyl benzoate | C26H31NO7 | 详情 | 详情 | |
| (XXIII) | 56341 | [(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]methyl benzoate | C31H39NO8 | 详情 | 详情 | |
| (XXIV) | 56342 | N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-6-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide | C24H35NO7 | 详情 | 详情 | |
| (XXV) | 56343 | N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide | C31H41NO7 | 详情 | 详情 | |
| (XXVI) | 56344 | N-{(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-hydroxytetrahydro-2H-pyran-3-yl}acetamide | C26H33NO6 | 详情 | 详情 |