【结 构 式】 |
【药物名称】KR-21012 【化学名称】(1S,5R,6S)-6-[1(R)-Hydroxyethyl]-2-[1(R)-hydroxy-2-methylpropyl]-1-methyl-1-carba-2-penem-3-carboxylic acid sodium salt 【CA登记号】191920-71-5, 191920-48-6 (monoK salt) 【 分 子 式 】C14H20NNaO5 【 分 子 量 】305.309 |
【开发单位】Korea Res. Inst. Chem. Technol. (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
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 |
合成路线2
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).
【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 | CAS号 | 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 |