iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】32271

【品名】iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

【CA登记号】

【分子式】C₉H₁₂INO₅S

【分子量】373.16849

【元素组成】C 28.97% H 3.24% I 34.01% N 3.75% O 21.44% S 8.59%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

The esterification of penicillanic acid (I) with chloromethyl chlorosulfate by means of KHCO3 and tetrabutylammonium hydrogen sulfate in CH2Cl2 - water gives chloromethyl penicillanate (II), which is oxidized to chloromethyl penicillanate 1,1-dioxide (III) by means of H2O2 and sodium tungstate in isopropanol. The reaction of (III) with Na in acetone affords iodomethyl penicillanate 1,1-dioxide (IV), which is condensed with potassium 6-[N-(1-methoxycarbonylpropen-2-yl)-D-alpha-amino-alpha-phenylacetamido]penicillanate (V) in DMF yielding 1,1-dioxopenicillanoyloxymethyl-6-[N-1-methoxycarbonylpropen-2-yl)-D-alpha-amino-alpha-phenylacetamido penicillanate (VI). Finally, this compound is deprotected by treatment with 4N HCl. Compound (III) can also be obtained by direct esterification of penicillanic acid 1,1-dioxide (VII) with chloromethyl chlorosulfate as before. Compound (V) is obtained bv reaction of ampicillin (VIII) with methyl acetoacetate (IX) by means of K2CO3 in DMF.

参考文献中间体

合成目标

【1】 Baltzer, B.; et al.; Mutual pro-drugs of beta-lactam antibiotics and beta-lactamase inhibitors. J Antibiot 1980, 33, 10, 1183-92.
【2】 Von Daehne, W.; Godtfresen, W.O. (Leo Pharmaceutical Products Ltd. A/S); beta-Lactam compounds, antibacterial compositions thereof and method of use. DE 3005164; FR 2449089; GB 2044255; GB 2108107; US 4342772; US 4840944 .
【3】 Castaner, J.; Serradell, M.N.; Sweetman, A.J.; Blancafort, P.; VD-1825 and VD-1827. Drugs Fut 1981, 6, 8, 496.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40923	chloromethanesulfonyl chloride	3518-65-8	CH₂Cl₂O₂S	详情	详情
(I)	32276	Penicillanic acid; (5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid		C₈H₁₁NO₃S	详情	详情
(II)	32269	chloromethyl (5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₉H₁₂ClNO₃S	详情	详情
(III)	32270	chloromethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₉H₁₂ClNO₅S	详情	详情
(IV)	32271	iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₉H₁₂INO₅S	详情	详情
(V)	32275	potassium (2S,5R,6R)-6-[((2R)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₂₁H₂₄KN₃O₆S	详情	详情
(VI)	32272	[([(2S,5R,6R)-6-[((2R)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl]carbonyl)oxy]methyl (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane		C₃₀H₃₆N₄O₁₁S₂	详情	详情
(VII)	32273	(5R)-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid		C₆H₇NO₅S	详情	详情
(VIII)	32274	potassium (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₁₆H₁₈KN₃O₄S	详情	详情
(IX)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The condensation of 2-nitrophenyl isocyanate (V) with endo-8-methyl-8-azabicyclo[3,2,1]octan-3-amine (IV) in THF/cyclohexane gives the corresponding 2-nitrophenylurea (VI), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminophenylurea (VII). The acylation of (VII) with phenyl chloroformate (VIII) in toluene affords the carbamate (IX), which is finally cyclized by means of NaOH in ethanol.

参考文献中间体

合成目标

【1】 Turconi, M.; et al.; Azabicycloalkyl benzimidazolone derivatives: A novel class of 5-HT3 receptor antagonists. 199th ACS Natl Meet (April 22 1990, Boston) 1990, Abst MEDI 103.
【2】 Turconi, M.; et al.; Synthesis of a new class of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent 5-HT3 receptor antagonists. J Med Chem 1990, 33, 8, 2101.
【3】 Turconi, M.; Schiantarelli, P.; Borsini, F.; Rizzi, C.A.; Ladinsky, H.; Donetti, A.; Azabicycloalkyl benzimidazolones: Interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications. Drugs Fut 1991, 16, 11, 1011.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	19105	(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine		C₈H₁₆N₂	详情	详情
(V)	32271	iodomethyl (5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₉H₁₂INO₅S	详情	详情
(VI)	42927	N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N'-(2-nitrophenyl)urea		C₁₅H₂₀N₄O₃	详情	详情
(VII)	42928	N-(2-aminophenyl)-N'-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]urea		C₁₅H₂₂N₄O	详情	详情
(VIII)	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(IX)	42929	phenyl 2-[([[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino]carbonyl)amino]phenylcarbamate		C₂₂H₂₆N₄O₃	详情	详情

Extended Information