BMY-25174, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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	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