allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】30037

【品名】allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

【CA登记号】

【分子式】C₂₀H₃₁NO₅Si

【分子量】393.55538

【元素组成】C 61.04% H 7.94% N 3.56% O 20.33% Si 7.14%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

Azetidinepropanoic acid derivative (I) was converted to the mixed anhydride with isobutyl chloroformate and then coupled with N,O-dimethylhydroxylamine to afford the N-methoxyamide (II). This was treated with 2-thiazolylmagnesium bromide (III) to give thiazolyl ketone (IV). Condensation of (IV) with allyl glyoxylate hydrate (V) produced adduct (VI). Further reaction of (VI) with SOCl2 and then with triphenylphosphine gave the corresponding phosphorane, which cyclized in boiling anisole to generate the carbapenem (VII). After N-methylation at the thiazole ring of (VII) with methyl triflate, the thiazolium salt (VIII) was reduced with NaBH4 and subsequently hydrolyzed to aldehyde (IX) in the presence of HgCl2. Addition of isopropylmagnesium bromide to (IX) at -78 C, followed by desilylation with tetra-butylammonium fluoride yielded diol (X). Then, palladium-catalyzed deprotection of the allyl ester of (X) in the presence of sodium 2-ethylhexanoate provided the sodium carboxylate salt (XI). Finally, reaction of (XI) with 1-iodoethyl isopropyl carbonate (XII) in cold DMF produced the target ester.

参考文献中间体

合成目标

【1】 Pyun, D.K.; Lee, J.S.; Kim, J.H.; Lee, C.H.; KR-21012, a new carbapenem: I. Synthesis and structure-activity relationships of beta-methyl-2-(alpha-functionalized) carbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-46.
【2】 Lee, C.H.; Lee, D.H.; Kim, K.S.; Kim, J.H.; Kim, Y.S.; Jun, Y.S.; Lim, S.S.; Bae, E.M.; Kim, B.J. (Korea Research Institute of Chemical Technology); beta-Methylcarbapenem derivs., process for the preparation thereof and pharmaceutical compsn. comprising same. EP 1019405; JP 1999500750; US 5869477; WO 9720844 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	30029	(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid	C₁₄H₂₇NO₄Si	详情	详情
(II)	30030	(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide	C₁₆H₃₂N₂O₄Si	详情	详情
(III)	30031	bromo(1,3-thiazol-2-yl)magnesium	C₃H₂BrMgNS	详情	详情
(IV)	30032	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-azetidinone	C₁₇H₂₈N₂O₃SSi	详情	详情
(V)	30033	allyl 2,2-dihydroxyacetate	C₅H₈O₄	详情	详情
(VI)	30034	allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxoazetidinyl]-2-hydroxyacetate	C₂₂H₃₄N₂O₆SSi	详情	详情
(VII)	30035	allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-(1,3-thiazol-2-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₂H₃₂N₂O₄SSi	详情	详情
(VIII)	30036	2-[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-3-methyl-1,3-thiazol-3-ium trifluoromethanesulfonate	C₂₄H₃₅F₃N₂O₇S₂Si	详情	详情
(IX)	30037	allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₀H₃₁NO₅Si	详情	详情
(X)	30038	allyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₇H₂₅NO₅	详情	详情
(XI)	30039	sodium (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₄H₂₀NNaO₅	详情	详情
(XII)	15685	1-iodoethyl isopropyl carbonate	C₆H₁₁IO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Azetidinepropanoic acid derivative (I) was converted to the mixed anhydride with isobutyl chloroformate and then coupled with N,O-dimethylhydroxylamine to afford the N-methoxyamide (II). This was treated with 2-thiazolylmagnesium bromide (III) to give thiazolyl ketone (IV). Condensation of (IV) with allyl glyoxylate hydrate (V) produced adduct (VI). Further reaction of (VI) with SOCl2 and then with triphenylphosphine gave the corresponding phosphorane, which cyclized in boiling anisole to generate the carbapenem (VII). After N-methylation at the thiazole ring of (VII) with methyl triflate, the thiazolium salt (VIII) was reduced with NaBH4 and subsequently hydrolyzed to aldehyde (IX) in the presence of HgCl2. Addition of isopropylmagnesium bromide to (IX) at -78 C, followed by desilylation with tetra-butylammonium fluoride yielded diol (X). Finally, palladium-catalyzed deprotection of the allyl ester of (X) in the presence of sodium 2-ethylhexanoate provided the title sodium carboxylate salt.

参考文献中间体

合成目标

【1】 Pyun, D.K.; Lee, J.S.; Kim, J.H.; Lee, C.H.; KR-21012, a new carbapenem: I. Synthesis and structure-activity relationships of beta-methyl-2-(alpha-functionalized) carbapenems. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-46.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	30029	(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid	C₁₄H₂₇NO₄Si	详情	详情
(II)	30030	(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide	C₁₆H₃₂N₂O₄Si	详情	详情
(III)	30031	bromo(1,3-thiazol-2-yl)magnesium	C₃H₂BrMgNS	详情	详情
(IV)	30032	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-azetidinone	C₁₇H₂₈N₂O₃SSi	详情	详情
(V)	30033	allyl 2,2-dihydroxyacetate	C₅H₈O₄	详情	详情
(VI)	30034	allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxoazetidinyl]-2-hydroxyacetate	C₂₂H₃₄N₂O₆SSi	详情	详情
(VII)	30035	allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-3-(1,3-thiazol-2-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₂H₃₂N₂O₄SSi	详情	详情
(VIII)	30036	2-[(4S,5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-3-methyl-1,3-thiazol-3-ium trifluoromethanesulfonate	C₂₄H₃₅F₃N₂O₇S₂Si	详情	详情
(IX)	30037	allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₀H₃₁NO₅Si	详情	详情
(X)	30038	allyl (4S,5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₇H₂₅NO₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The oxidation of the hydroxymethyl carbapenem (I) with MnO2 in refluxing dichloromethane gives the corresponding aldehyde (II), which is treated with isopropylmagnesium chloride in THF yielding, after chromatographic separation, the 1(R)-hydroxy-2-methylpropyl derivative (III). Finally, this compound is deprotected with Pd(PPh3)4 and converted to the sodium salt with sodium 2-ethylhexanoate (SHE).

参考文献中间体

合成目标

【1】 Kim, J.H.; Jeong, H.J.; Kim, B.J.; Kwak, H.J.; Pyun, D.K.; Lee, C.H.; Kim, E.J.; Synthesis and antibacterial activity of 2alpha-functionalized 1beta-methylcarbapenems related to KR-21012. Bioorg Med Chem Lett 2000, 10, 4, 333.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	35497	allyl (4S,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₀H₃₃NO₅Si	详情	详情
(II)	30037	allyl (4S,5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-formyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₀H₃₁NO₅Si	详情	详情
(III)	35498	allyl (4S,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-[(1R)-1-hydroxy-2-methylpropyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₂₃H₃₉NO₅Si	详情	详情

Extended Information