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【结 构 式】 
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【分子编号】39646 【品名】allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C19H22N2O5S 【 分 子 量 】390.46016 【元素组成】C 58.45% H 5.68% N 7.17% O 20.49% S 8.21% |
合成路线1
该中间体在本合成路线中的序号：(V)MK-0826 can be synthesized as follows: The cyclization of 2-diazo-4-[3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-3-oxopentanoic acid allyl ester (I) by means of rhodium octanoate gives the 2-oxocarbapenam derivative (II), which by reaction with chlorophosphoric acid diphenyl ester (III) and DIEA in acetonitrile yields the enol phosphate (IV). Condensation of (IV) with the sulfanylpyrrolidine (V) by means of DIEA in acetonitrile affords the corresponding addition compound MK-0826 diallyl ester (VI), which is finally deprotected by means of Meldrum's acid and Pd(PPh3)4 in DMF/THF and converted to the sodium salt.
| 【1】 Betts, M.J.; Davies, G.M.; Swain, M.L. (AstraZeneca plc); Carbapenems containing a carboxy substd. phenyl group, processes for their preparation, intermediates and use as antibiotics. EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078 . |
| 【2】 Leeson, P.A.; Rabasseda, X.; Castañer, J.; Sorbera, L.A.; MK-0826. Drugs Fut 2000, 25, 8, 795. |
| 【3】 Houghton, P.; Williams, J.M.; Skerlj, R.; Brands, K.M.J. (Merck & Co., Inc.); Process for synthesizing carbapenem antibiotics. WO 9945010 . |
| 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) | 39645 | allyl (4R)-2-diazo-4-[(2R,3S)-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-3-oxopentanoate | C13H17N3O5 | 详情 | 详情 | |
| (II) | 32616 | allyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate | C13H17NO5 | 详情 | 详情 | |
| (III) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (IV) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (V) | 39646 | allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C19H22N2O5S | 详情 | 详情 | |
| (VI) | 39647 | allyl (4R,5S,6S)-3-[[(3S,5S)-1-[(allyloxy)carbonyl]-5-([3-[(allyloxy)carbonyl]anilino]carbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C32H37N3O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The sulfanylpyrrolidine (V) can be obtained as follows: Esterification of 3-nitrobenzoic acid (VII) with allyl bromide and K2CO3 in DMF gives the corresponding allyl ester (VIII), which is reduced with SnCl2 in refluxing ethyl acetate to yield the 3-aminobenzoate (IX). The condensation of (IX) with the pyrrolidinecarbonyl chloride (X), obtained from the corresponding carboxylic acid (XI) and oxalyl chloride, by means of NMM in dichloro-methane affords the expected amide (XII), which is finally deacetylated with NaOH in allyl alcohol.
| 【1】 Betts, M.J.; Davies, G.M.; Swain, M.L. (AstraZeneca plc); Carbapenems containing a carboxy substd. phenyl group, processes for their preparation, intermediates and use as antibiotics. EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078 . |
| 【2】 Leeson, P.A.; Rabasseda, X.; Castañer, J.; Sorbera, L.A.; MK-0826. Drugs Fut 2000, 25, 8, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 39646 | allyl (2S,4S)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C19H22N2O5S | 详情 | 详情 | |
| (VII) | 39648 | 1-Carboxy-3-Nitrobenzene; m-Nitrobenzoic acid; 3-Nitrobenzoic acid; 3-Nitrodracylic acid | 121-92-6 | C7H5NO4 | 详情 | 详情 |
| (VIII) | 39649 | allyl 3-nitrobenzoate | C10H9NO4 | 详情 | 详情 | |
| (IX) | 39650 | allyl 3-aminobenzoate | C10H11NO2 | 详情 | 详情 | |
| (X) | 39651 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(chlorocarbonyl)-1-pyrrolidinecarboxylate | C11H14ClNO4S | 详情 | 详情 | |
| (XI) | 39652 | (2S,4S)-4-(acetylsulfanyl)-1-[(allyloxy)carbonyl]-2-pyrrolidinecarboxylic acid | C11H15NO5S | 详情 | 详情 | |
| (XII) | 39653 | allyl (2S,4S)-4-(acetylsulfanyl)-2-([3-[(allyloxy)carbonyl]anilino]carbonyl)-1-pyrrolidinecarboxylate | C21H24N2O6S | 详情 | 详情 |