Sultamicillin tosylate, VD-1827, CP-49952(free base), Unacim, Bacimex, Unasyn, -Drug Synthesis Database

【结构式】

【药物名称】Sultamicillin tosylate, VD-1827, CP-49952(free base), Unacim, Bacimex, Unasyn

【化学名称】Hydroxymethyl (2S,5R,6R)-6-[(R)-(2-amino-2-phenylacetamido)]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate,(2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate(ester) S,S-dioxide tosylate
　　　　　　6beta-[2(R)-Amino-2-phenylacetamido]penicillanic acid 1,1-dioxopenicillanoyloxymethyl ester tosylate

【CA登记号】76497-13-7 (free base)

【分子式】C₃₂H₃₈N₄O₁₂S₃

【分子量】766.87126

【开发单位】Pfizer (Originator), Jouveinal (Licensee)

【药理作用】beta-Lactamase Inhibitors, Penicillins

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

The condensation of 6-[2-(benzyloxycarbonylamino)-2-phenylacetamido]penicillanic acid potassium salt (I) with chloromethyl penicillanate 1,1-dioxide (II) by means of NaI in DMSO gives the target bisester.

参考文献中间体

【1】 Bigham, E.C. (Pfizer Inc.); Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide. US 4244951 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	48603	potassium (2S,5R,6R)-6-[((2R)-2-[[(benzyloxy)carbonyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate	C₂₄H₂₄KN₃O₆S	详情	详情
(II)	48604	chloromethyl (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate	C₉H₁₂ClNO₅S	详情	详情
(III)	48605	[([(2S,5R,6R)-6-[((2R)-2-[[(benzyloxy)carbonyl]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-2-carboxylate	C₃₃H₃₆N₄O₁₁S₂	详情	详情

合成路线3

The condensation of 6-(2-amino-2-phenylacetamido)penicillanic acid sodium salt (I) with benzaldehyde (II) in DMF gives the corresponding imine (III), which is then condensed with iodomethyl penicillanate 1,1-dioxide (IV) in DMF to yield the bisester (V). Finally, this compound is deprotected by means of Girard P reagent and TsOH in methanol to afford the target bis-penicillanate.

参考文献中间体

【1】 del Pozo, C.; et al.; Synthesis of 1,1-dioxopenicillanoyloxymethyl 6-[D-alpha-(benzylideneaminophenylacetamido)]penicillanate and analogs. New intermediates in the preparation of sultamicillin. Tetrahedron 2001, 57, 29, 6209.

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)	48606	sodium (2S,5R,6R)-6-[((2R)-2-[[(benzyloxy)carbonyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₂₄H₂₄N₃NaO₆S	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	48607	sodium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[((2R)-2-phenyl-2-[[(E)-benzylidene]amino]ethanoyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate		C₂₃H₂₂N₃NaO₄S	详情	详情
(IV)	48608	iodomethyl (2S,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)	48609	[([(2S,5R,6R)-3,3-dimethyl-7-oxo-6-[((2R)-2-phenyl-2-[[(E)-benzylidene]amino]ethanoyl)amino]-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-2-carboxylate		C₃₂H₃₄N₄O₉S₂	详情	详情

Extended Information