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【结 构 式】

【药物名称】BMY-25174

【化学名称】[5R-[5alpha,6alpha(R*)]]-2-[2-Carboxy-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-ylsulfanylmethyl]-1-methylpyridinium hydroxide,inner salt
      (5R,6S)-6-[1(R)-Hydroxyethyl]-3-(1-methylpyridinium-2-ylmethylsulfanyl)-1-carba-2-penem-3-carboxylate

【CA登记号】91615-54-2

【 分 子 式 】C16H18N2O4S

【 分 子 量 】334.39686

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Carbapenems

合成路线1

1) The trans-esterification of methyl acetoacetate (I) with allyl alcohol (II) gives the allyl ester (III), which is treated with p-toluenesulfonyl azide (IV) and triethylamine in acetonitrile to yield the diazo derivative (V). The reaction of (V) with tert-butyl-dimethylsilyl triflate (VI) and triethyl amine in dichloromethane affords the enol silyl ether (VII), which is condensed with 3-[1-(tert-butyldimethyl-silyloxy)ethyl-4 acetoxyazetidin-2-one (VIII) by means of ZnCl2 in dichloromethane giving 3-[l-(tertbutyldimethylsilyloxy)ethyl]-4-(4-allyloxy-3-diazo-2,4-dioxobutyl)azetidin-2-one (IX). The cyclization of (IX) by means of rhodium acetate in refluxing benzene yields allyl 6alpha-[l(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate (X), which is condensed with 2-(mercaptomethyl)pyridine (XI) by means of diphenyl chlorophosphate and diisopropylamine in acetonitrile affording allyl 6alpha-[l(R)-hydroxy-ethyl]-2-(2-pyridylmethylthio)carbapen-2-em-3-carboxylate (XII). The hydrolysis of (XII) with tetrakis-triphenylphosphine-palladium, triphenylphosphine and potassium 2-ethylhexanoate in dichloromethane gives the potassium salt (XIII), which is finally quaternized with methyl triflate and p-toluenesulfonic acid in acetone.

1 Kim, C.U. (Bristol-Myers Squibb Co.); Carbapenem antibiotics. DE 3334937; GB 2128187; US 4644061 .
2 Prous, J.; Castaner, J.; BMY-25174. Drugs Fut 1988, 13, 6, 511.
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) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(III) 22675 allyl 3-oxobutanoate 1118-84-9 C7H10O3 详情 详情
(IV) 22676 p-Toluenesulfonyloxy azide C7H7N3O3S 详情 详情
(V) 22677 2-Diazo-3-oxobutyric acid allyl ester C7H8N2O3 详情 详情
(VI) 22678 tert-butyl(dimethyl)silyl trifluoromethanesulfonate 69739-34-0 C7H15F3O3SSi 详情 详情
(VII) 22679 2-Diazo-3-(tert-butyldimethylsilyloxy)-3-butenoic acid allyl ester C13H22N2O3Si 详情 详情
(VIII) 22680 (3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl acetate C13H25NO4Si 详情 详情
(IX) 22681 4-[3(S)-[1(R)-(Tert-butyldimethylsilyloxy)ethyl]-4-oxoazetidin-2(R)-yl]-2-diazo-3-oxobutyric acid allyl ester C18H29N3O5Si 详情 详情
(X) 22682 allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C12H15NO5 详情 详情
(XI) 22683 2-pyridinylmethylhydrosulfide; 2-pyridinylmethanethiol C6H7NS 详情 详情
(XII) 22684 allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2-pyridinylmethyl)sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C18H20N2O4S 详情 详情
(XIII) 22685 (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2-pyridinylmethyl)sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C15H15KN2O4S 详情 详情

合成路线2

2) The condensation of 4-nitrobenzyl 6-[1(R)-hydroxyethyl]-2-oxocarbapenam-3-carboxylate (XIV) with diphenyl chlorophosphate as before gives 4-nitrobenzyl 6-[1(R)-hydroxyethyl]-2-(2 pyridyl-methylthio)carbapen-2-em-3-carboxylate (XV), which is quaternized with methyl iodide in acetone to afford the quaternized ester (XVI). Finally, this compound is deprotected by hydrogenolysis with H2 over Pd/C in basic THF.

1 Kim, C.U.; Misco, P.F.; Luh, B.Y.; Hitchcock, M.J.M.; Synthesis and in vitro activity of C-2 quaternary heterocyclic alkylthio carbapenems. J Antibiot 1987, 40, 12, 1707.
2 Kim, C.U. (Bristol-Myers Squibb Co.); Carbapenem antibiotics. DE 3334937; GB 2128187; US 4644061 .
3 Prous, J.; Castaner, J.; BMY-25174. Drugs Fut 1988, 13, 6, 511.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 22683 2-pyridinylmethylhydrosulfide; 2-pyridinylmethanethiol C6H7NS 详情 详情
(XIV) 22686 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate C16H16N2O7 详情 详情
(XV) 22687 4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2-pyridinylmethyl)sulfanyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C22H21N3O6S 详情 详情
(XVI) 22688 2-[[((5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)sulfanyl]methyl]-1-methylpyridinium iodide C23H24IN3O6S 详情 详情
Extended Information