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【结 构 式】 
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【分子编号】30030 【品名】(2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-N-methoxy-N-methylpropanamide 【CA登记号】 |
【 分 子 式 】C16H32N2O4Si 【 分 子 量 】344.52666 【元素组成】C 55.78% H 9.36% N 8.13% O 18.58% Si 8.15% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(XXXII)Azetidinepropanoic acid (XXXI) was converted to methoxyamide (XXXII) and then treated with trimethylsilylmethyllithium to give silyl ketone (XXXIII). After conversion of (XXXIII) to bromoketone (XXXIV), displacement by an acetate group afforded acetoxymethyl ketone (XXXV). A similar route as above produced phosphorane (XXXVI), which was then cyclized to the carbapenem (XXXVII).
| 【1】 Yasuda, N.; et al.; Preparation of anti-MRS carbapenem L-786,392. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-31. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 30029 | (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXII) | 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 | |
| (XXXIII) | 30145 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-3-(trimethylsilyl)propyl]-2-azetidinone | C18H37NO3Si2 | 详情 | 详情 | |
| (XXXIV) | 30146 | (3S,4R)-4-[(1R)-3-bromo-1-methyl-2-oxopropyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-azetidinone | C15H28BrNO3Si | 详情 | 详情 | |
| (XXXV) | 30147 | (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxobutyl acetate | C17H31NO5Si | 详情 | 详情 | |
| (XXXVI) | 30148 | (3R)-3-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1-[3-(4-nitrobenzyloxy)-2-oxo-1-(triphenylphosphoranylidene)propyl]-4-oxoazetidinyl]-2-oxobutyl acetate | C44H51N2O9PSi | 详情 | 详情 | |
| (XXXVII) | 30149 | 4-nitrobenzyl (4S,5R,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 | C24H34N2O7Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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 |