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【结 构 式】

【分子编号】30033

【品名】allyl 2,2-dihydroxyacetate

【CA登记号】

【 分 子 式 】C5H8O4

【 分 子 量 】132.11612

【元素组成】C 45.46% H 6.1% O 48.44%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

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.

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 CAS号 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:(V)

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.

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 CAS号 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
Extended Information