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【结 构 式】 
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【分子编号】13220 【品名】4-Methoxybenzylhydrosulfide; (4-Methoxyphenyl)methanethiol; 4-Methoxy-alpha-toluenethiol 【CA登记号】6258-60-2 |
【 分 子 式 】C8H10OS 【 分 子 量 】154.2328 【元素组成】C 62.3% H 6.54% O 10.37% S 20.79% |
合成路线1
该中间体在本合成路线中的序号：(VIII)2) The acylation of hydrazine (I) with di-tert-butyl dicarbonate (II) gives 1,2-di(tert-butyloxycarbonyl)hydrazine (III), which is cyclized with 1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane (IV) by means of NaH in DMF yielding the pyrazolidine (V). The desilylation of (V) with tetrabutylammonium fluoride in THF affords 1,2-di(tert-butoxycarbonyl)-4-hydroxypyrazolidine (VI). Acylation of (VI) with methanesulfonyl chloride in dichloromethane gives the corresponding mesylate (VII), which is condensed with 4-methoxybenzyl mercaptane (VIII) by means of butyllithium in hexane to yield the benzyl ether (IX). The cyclization of (IX) with methyl formimidate hydrochloride in methanol-water affords 6-(4-methoxybenzylthio)-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (X), which is deprotected with trifluoroacetic acid giving 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (XI). Finally, this compound is condensed with (1R,5R,6S)-2-(diphenylphosphonooxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XII) by means of diisopropylethylamine in DMF followed by hydrogenolysis with H2 over Pd/C in butanol-EtOAc-potassium phosphate buffer.
| 【1】 Ratcliffe, R.W.; Wildonger, K.J.; Heteroaryliumthio substituted carbapenem derivatives: Synthesis and in vitro activity of 1beta-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems. J Antibiot 1993, 46, 12, 1866-82. |
| 【2】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (III) | 13215 | di(tert-butyl) 1,2-hydrazinedicarboxylate; Di-tert-butyl hydrazodicarboxylate | 16466-61-8 | C10H20N2O4 | 详情 | 详情 |
| (IV) | 13216 | [2-Bromo-1-(bromomethyl)ethoxy](tert-butyl)dimethylsilane; 2-Bromo-1-(bromomethyl)ethyl tert-butyl(dimethyl)silyl ether | C9H20Br2OSi | 详情 | 详情 | |
| (V) | 13217 | di(tert-butyl) 4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrazolidinedicarboxylate | C19H38N2O5Si | 详情 | 详情 | |
| (VI) | 13218 | di(tert-butyl) 4-hydroxy-1,2-pyrazolidinedicarboxylate | C13H24N2O5 | 详情 | 详情 | |
| (VII) | 13219 | di(tert-butyl) 4-[(methylsulfonyl)oxy]-1,2-pyrazolidinedicarboxylate | C14H26N2O7S | 详情 | 详情 | |
| (VIII) | 13220 | 4-Methoxybenzylhydrosulfide; (4-Methoxyphenyl)methanethiol; 4-Methoxy-alpha-toluenethiol | 6258-60-2 | C8H10OS | 详情 | 详情 |
| (IX) | 13221 | di(tert-butyl) 4-[(4-methoxybenzyl)sulfanyl]-1,2-pyrazolidinedicarboxylate | C21H32N2O5S | 详情 | 详情 | |
| (X) | 13222 | 6-[(4-Methoxybenzyl)sulfanyl]-5H,6H,7H-pyrazolo[1,2-a][1,2,4]triazol-4-ium chloride | C13H16ClN3OS | 详情 | 详情 | |
| (XI) | 13223 | 6-Sulfanyl-5H,6H,7H-pyrazolo[1,2-a][1,2,4]triazol-4-ium chloride | 153851-71-9 | C5H8ClN3S | 详情 | 详情 |
| (XII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Condensation of methyl 3-(3-hydroxyphenyl)propanoate (I) with an excess of methyl magnesium bromide in THF at low temperature afforded tertiary alcohol (II), which was brominated with N-bromosuccinimide (NBS) in DMF at 0 C to give (III). Then, a double Mannich reaction with pyrrolidine (IV) and formaldehyde provided diamine (V). To hydrogenolyze the benzylic amine groups an indirect route was required. Thus, reaction with an excess of 4-methoxybenzylmercaptan (VI) at 180 C displaced both amino groups with concomitant debromination to give thioether (VII), which was desulfurized on treatment with Raney Nickel to the dimethylphenol (VIII). The Ritter reaction with NaCN in sulfuric acid-acetic acid yielded directly the cyclized imine (IX), generated from the intermediate nitrilium ion. Reduction to amine (X) was effected by catalytic hydrogenation in the presence of Raney Nickel, and this compound was finally oxidized to N-oxide the nitrone with H2O2 and a catalytic amount of sodium tungstate.
| 【1】 Fevig, T.L.; et al.; Design, synthesis, and in vitro evaluation of cyclic nitrones as free radical traps for the treatment of stroke. J Med Chem 1996, 39, 25, 4988. |
| 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) | 18437 | methyl 3-(3-hydroxyphenyl)propanoate | C10H12O3 | 详情 | 详情 | |
| (II) | 18438 | 3-(3-hydroxy-3-methylbutyl)phenol | C11H16O2 | 详情 | 详情 | |
| (III) | 18439 | 4-bromo-3-(3-hydroxy-3-methylbutyl)phenol | C11H15BrO2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 18441 | 4-bromo-3-(3-hydroxy-3-methylbutyl)-2,6-bis(1-pyrrolidinylmethyl)phenol | C21H33BrN2O2 | 详情 | 详情 | |
| (VI) | 13220 | 4-Methoxybenzylhydrosulfide; (4-Methoxyphenyl)methanethiol; 4-Methoxy-alpha-toluenethiol | 6258-60-2 | C8H10OS | 详情 | 详情 |
| (VII) | 18443 | 3-(3-hydroxy-3-methylbutyl)-2,6-bis[[(4-methoxybenzyl)sulfanyl]methyl]phenol | C29H36O4S2 | 详情 | 详情 | |
| (VIII) | 18444 | 3-(3-hydroxy-3-methylbutyl)-2,6-dimethylphenol | C13H20O2 | 详情 | 详情 | |
| (IX) | 18445 | 3,3,6,8-tetramethyl-4,5-dihydro-3H-2-benzazepin-7-ol | C14H19NO | 详情 | 详情 | |
| (X) | 18446 | 3,3,6,8-tetramethyl-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol | C14H21NO | 详情 | 详情 |