4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】22686

【品名】4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate

【CA登记号】

【分子式】C₁₆H₁₆N₂O₇

【分子量】348.31232

【元素组成】C 55.17% H 4.63% N 8.04% O 32.15%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.

参考文献中间体

合成目标

【1】 Kumar, Y.; Tewari, N.; Rai, B.P. (Ranbaxy Laboratories Ltd.); Process for the preparation of imipenem. WO 0294828 .

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)	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
(II)	16074	Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate	2524-64-3	C₁₂H₁₀ClO₃P	详情	详情
(III)	57095	4-nitrobenzyl (5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₈H₂₅N₂O₁₀P	详情	详情
(IV)	13186	2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine	60-23-1	C₂H₇NS	详情	详情
(V)	57096	4-nitrobenzyl (5R,6S)-3-[(2-aminoethyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₈H₂₁N₃O₆S	详情	详情
(VI)	57097	benzyl iminoformate		C₈H₉NO	详情	详情
(VII)	57098	4-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-({2-[(iminomethyl)amino]ethyl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₉H₂₂N₄O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

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

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(XI)

The bromination of 6-bromo-2-methylfluoren-9-one (I) with NBS and AIBN in refluxing CCl4 gives the 2-bromomethyl compound (II), which is treated with potassium acetate in DMF to afford the acetoxymethyl derivative (III). The hydrolysis of (III) with NaOMe in methanol provides the hydroxymethyl compound (IV), which is treated with hexamethyldistannane and Pd(PPh3)4 in refluxing toluene to give the trimethylstannyl derivative (V). The condensation of (V) with the carbapenem triflate (VI) by means of a Pd catalyst in THF yields the adduct (VII), which is condensed with 1-methylimidazole by means of Tf2O in dichloromethane affording the imidazolium derivative (IX). The desilylation of (IX) with TBAF in THF gives the 1-hydroxyethyl derivative (X), which is finally treated with H2 over Pd/C in THF/ethanol/water to obtain the target compound as an inner salt. The intermediate carbapenem triflate (VI) has been obtained by reaction of 2-oxocarbapenam (XI) with Tf2O, followed by silylation with Tes-OTf.

参考文献中间体

合成目标

【1】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem antibacterial agents. EP 0472306; JP 1993105679; US 5034384 .
【2】 Greenlee, M.L.; Dininno, F.P.; Cama, L.D.; Heck, J.V. (Merck & Co., Inc.); 2-(9-Fluorenonyl)-carbapenem intermediates. US 5356889 .

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)	38623	6-bromo-2-methyl-9H-fluoren-9-one		C₁₄H₉BrO	详情	详情
(II)	38624	6-bromo-2-(bromomethyl)-9H-fluoren-9-one		C₁₄H₈Br₂O	详情	详情
(III)	38625	(6-bromo-9-oxo-9H-fluoren-2-yl)methyl acetate		C₁₆H₁₁BrO₃	详情	详情
(IV)	38626	6-bromo-2-(hydroxymethyl)-9H-fluoren-9-one		C₁₄H₉BrO₂	详情	详情
(V)	38627	2-(hydroxymethyl)-6-(trimethylstannyl)-9H-fluoren-9-one		C₁₇H₁₈O₂Sn	详情	详情
(VI)	38628	4-nitrobenzyl (5R,6S)-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-3-[[(trifluoromethyl)sulfonyl]oxy]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₃H₂₉F₃N₂O₉SSi	详情	详情
(VII)	38629	4-nitrobenzyl (5R,6S)-3-[7-(hydroxymethyl)-9-oxo-9H-fluoren-3-yl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₆H₃₈N₂O₈Si	详情	详情
(VIII)	38630	1-methyl-1H-imidazole	616-47-7	C₄H₆N₂	详情	详情
(IX)	38631	1-methyl-3-[[6-((5R,6S)-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-6-[(1R)-1-[(triethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1H-imidazol-3-ium chloride		C₄₀H₄₃ClN₄O₇Si	详情	详情
(X)	38632	3-[[6-((5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[[(4-nitrobenzyl)oxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl)-9-oxo-9H-fluoren-2-yl]methyl]-1-methyl-1H-imidazol-3-ium chloride		C₃₄H₂₉ClN₄O₇	详情	详情
(XI)	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

合成路线4

该中间体在本合成路线中的序号：(VII)

1-Formyl-3-bromodibenzofuran (I) was converted to oxime (II) by reaction with hydroxylamine.HCl in pyridine-ethanol. Dehydration of oxime (II) to nitrile (III) was accomplished by treatment with trifluoromethanesulfonic anhydride and triethylamine. Subsequent reaction of (III) with hexamethylditin in the presence of palladium catalyst produced the trimethylstannane (IV). Addition of methyl-chloroaluminum amide (V) to the cyano group of (IV) then furnished the amidinium chloride (VI). The known 2-oxocarbapenam (VII) was converted to enol triflate by treatment with trifluoromethanesulfonic anhydride and diisopropyl ethylamine and subsequently protected as the trimethylsilyl ether (VIII) with trimethylsilyl triflate. Coupling of vinyl triflate (VIII) with stannane (VI) employing Pd2(dba)3.CHCl3 as the catalyst produced the dibenzofuranyl carbapenem (IX). Then, acid hydrolysis of the silyl group of (IX), followed by hydrogenolysis of the p-nitrobenzyl ester gave the title compound.

参考文献中间体

合成目标

【1】 DiNinno, F.; Grrenlee, M.L.; Sundelof, J.G.; Laub, J.B.; Huber, J.L.; The synthesis and anti-MRSA activity of amidinium-substituted 2-dibenzofuranylcarbapenems. Bioorg Med Chem Lett 1999, 9, 20, 2973.
【2】 Greenlee, M.L.; Laub, J.B. (Merck & Co., Inc.); 2-(Dibenzofuranyl)- and 2-(dibenzothienyl)-carbapenems, compsns. containing such cpds. and methods of use. GB 2301820 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	40656	2-bromodibenzo[b,d]furan-4-carbaldehyde	C₁₃H₇BrO₂	详情	详情
(II)	40657	2-bromodibenzo[b,d]furan-4-carbaldehyde oxime	C₁₃H₈BrNO₂	详情	详情
(III)	40658	2-bromodibenzo[b,d]furan-4-carbonitrile	C₁₃H₆BrNO	详情	详情
(IV)	40659	2-(trimethylstannyl)dibenzo[b,d]furan-4-carbonitrile	C₁₆H₁₅NOSn	详情	详情
(V)	40660		CH₅AlClN	详情	详情
(VI)	40661	2-(trimethylstannyl)dibenzo[b,d]furan-4-carboximidamide	C₁₆H₁₈N₂OSn	详情	详情
(VII)	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
(VIII)	40662	4-nitrobenzyl (5R,6S)-7-oxo-3-[[(trifluoromethyl)sulfonyl]oxy]-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₀H₂₃F₃N₂O₉SSi	详情	详情
(IX)	40663	4-nitrobenzyl (5R,6S)-3-[4-[amino(imino)methyl]dibenzo[b,d]furan-2-yl]-7-oxo-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₂H₃₂N₄O₇Si	详情	详情

Extended Information