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【结 构 式】 
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【分子编号】49426 【品名】(2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C10H19NO3Si 【 分 子 量 】229.3513 【元素组成】C 52.37% H 8.35% N 6.11% O 20.93% Si 12.25% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of N-(tert-butyldimethylsilyl)-4-oxoazetidine-2(S)-carboxylic acid (I) with 1-chloro-3-iodopropane (II) by means of BuLi and triisopropylamine (TIA) in THF, followed by treatment with HCl, gives the 3(R)-(3-chloropropyl) derivative (III), which is treated with tetrabutylammonium azide and tetrabutylammonium iodide in DMF to yield the 3-azidopropyl derivative (IV). The reduction of (IV) with H2 over Pd/C in DMF affords the 3-aminopropyl compound (V), which is treated with 1-[N,N'-bis(benzyloxycarbonyl)-1H-pyrazole] (VI) in the same solvent to provide the protected 3-guanidinopropyl compound (VII). The esterification of (VII) with NaHCO3, tetrabutylammonium iodide and Bn-Br in DMF gives the benzyl ester (VIII), which is condensed with N-tert-butylpiperazine-1-carboxamide (IX) and phosgene by means of TEA in toluene to yield the protected precursor (X). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in dioxane to give the target azetidine-carboxylic acid.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 49416 | 1-Chloro-3-iodopropane | 6940-76-7 | C3H6ClI | 详情 | 详情 |
| (III) | 49417 | (2S,3R)-3-(3-chloropropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10ClNO3 | 详情 | 详情 | |
| (IV) | 49418 | (2S,3R)-3-(3-azidopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10N4O3 | 详情 | 详情 | |
| (V) | 49419 | (2S,3R)-3-(3-aminopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H12N2O3 | 详情 | 详情 | |
| (VI) | 49420 | benzyl (E)-[[(benzyloxy)carbonyl]amino](1H-pyrazol-1-yl)methylidenecarbamate | C20H18N4O4 | 详情 | 详情 | |
| (VII) | 49421 | (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylic acid | C24H26N4O7 | 详情 | 详情 | |
| (VIII) | 49422 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylate | C31H32N4O7 | 详情 | 详情 | |
| (IX) | 49423 | N-(tert-butyl)-1-piperazinecarboxamide | C9H19N3O | 详情 | 详情 | |
| (X) | 49424 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-1-([4-[(tert-butylamino)carbonyl]-1-piperazinyl]carbonyl)-4-oxo-2-azetidinecarboxylate | C41H49N7O9 | 详情 | 详情 | |
| (XI) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (XIII) | 49425 | tert-butyl 4-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C14H27N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Ethyl nipecotate (I) was protected as the N-Boc derivative (II) and subsequently reduced to alcohol (III) by means of LiAlH4. Conversion of alcohol (III) into iodide (IV) was achieved by treatment with iodine and triphenylphosphine. The dianion of the chiral azetidinecarboxylic acid (V) was alkylated with iodide (IV) to furnish adduct (VI) as a diastereomeric mixture that was desilylated to (VII) using tetrabutylammonium fluoride. Benzyl ester (VIII) was then obtained by reaction of carboxylic acid (VII) with benzyl bromide and NaHCO3.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 51124 | tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 51120 | tert-butyl 3-(iodomethyl)-1-piperidinecarboxylate | C11H20INO2 | 详情 | 详情 | |
| (V) | 51121 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C21H38N2O5Si | 详情 | 详情 | |
| (VI) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (VII) | 51122 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-4-oxo-2-azetidinecarboxylic acid | C15H24N2O5 | 详情 | 详情 | |
| (VIII) | 51123 | tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate | C22H30N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The homochiral azetidinone (IX) was prepared from the known beta-lactam (VIII) by N-silylation with tert-butyldimethylsilyl chloride followed by catalytic hydrogenolysis of the benzyl ester. The 3-silylated azetidinone intermediate (X) was obtained by treatment of the lithium enolate of (IX) with trimethylsilyl chloride. Subsequent Peterson reaction of (X) with the 4-silyloxybenzaldehyde (XI) and LDA furnished olefin (XII) as a mixture of geometric isomers. After esterification of the carboxylate group of (XII) with benzyl alcohol in the presence of EDC to yield (XIII), the catalytic hydrogenation of the olefin double bond of (XIII) gave rise to the cis-azetidinone (XIV). The N-tert-butyldimethylsilyl group of (XIV) was selectively removed by treatment with HF in acetonitrile to afford (XV). Acylation of the lactam N of (XV) with acid chloride (VII) in the presence of sodium hexamethyldisilazide provided (XVI). The remaining silyl group of (XVI) was finally removed by treatment with ammonium hydrogen difluoride in NMP-DMF.
| 【1】 Adlington, R.M.; Baldwin, J.E.; Becker, G.W.; et al.; Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen. J Med Chem 2001, 44, 10, 1491. |
| 【2】 Chen, B.; Adlington, R.M.; Baldwin, J.E.; et al.; Design and synthesis of novel monocyclic beta-lactam inhibitors of prostate specific antigen. Bioorg Med Chem Lett 1997, 7, 13, 1689. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 50935 | (2S)-1-[tert-butyl(dimethyl)silyl]-3-[(Z)-(4-[[tert-butyl(diphenyl)silyl]oxy]phenyl)methylidene]-4-oxo-2-azetidinecarboxylic acid | C33H41NO4Si2 | 详情 | 详情 | |
| (XIIb) | 50936 | (2S)-1-[tert-butyl(dimethyl)silyl]-3-[(E)-(4-[[tert-butyl(diphenyl)silyl]oxy]phenyl)methylidene]-4-oxo-2-azetidinecarboxylic acid | C33H41NO4Si2 | 详情 | 详情 | |
| (XIIIa) | 50937 | benzyl (2S)-1-[tert-butyl(dimethyl)silyl]-3-[(Z)-(4-[[tert-butyl(diphenyl)silyl]oxy]phenyl)methylidene]-4-oxo-2-azetidinecarboxylate | C40H47NO4Si2 | 详情 | 详情 | |
| (XIIIb) | 50938 | benzyl (2S)-1-[tert-butyl(dimethyl)silyl]-3-[(E)-(4-[[tert-butyl(diphenyl)silyl]oxy]phenyl)methylidene]-4-oxo-2-azetidinecarboxylate | C40H47NO4Si2 | 详情 | 详情 | |
| (VII) | 50932 | benzyl 3-(2-chloro-2-oxoethyl)benzoate | C16H13ClO3 | 详情 | 详情 | |
| (VIII) | 50942 | (S)-Benzyl 2-azetidinone-4-carboxylate; Benzyl (S)-4-oxo-2-azetidinecarboxylate | 72776-05-7 | C11H11NO3 | 详情 | 详情 |
| (IX) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (X) | 50933 | lithium (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-3-(trimethylsilyl)-2-azetidinecarboxylate | C13H26LiNO3Si2 | 详情 | 详情 | |
| (XI) | 50934 | 4-[[tert-butyl(diphenyl)silyl]oxy]benzaldehyde | C23H24O2Si | 详情 | 详情 | |
| (XIV) | 50939 | benzyl (2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-(4-[[tert-butyl(diphenyl)silyl]oxy]benzyl)-4-oxo-2-azetidinecarboxylate | C40H49NO4Si2 | 详情 | 详情 | |
| (XV) | 50940 | benzyl (2S,3S)-3-(4-[[tert-butyl(diphenyl)silyl]oxy]benzyl)-4-oxo-2-azetidinecarboxylate | C34H35NO4Si | 详情 | 详情 | |
| (XVI) | 50941 | benzyl (2S,3S)-1-(2-[3-[(benzyloxy)carbonyl]phenyl]acetyl)-3-(4-[[tert-butyl(diphenyl)silyl]oxy]benzyl)-4-oxo-2-azetidinecarboxylate | C50H47NO7Si | 详情 | 详情 |