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【结 构 式】 
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【药物名称】LY-193239 【化学名称】7(S)-[2-(2-Aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-(methylsulfonyl)-8-oxo-1,5-diazabicyclo[3.3.0]oct-2-ene-2-carboxylic acid 【CA登记号】122620-17-1 【 分 子 式 】C14H16N6O7S2 【 分 子 量 】444.44762 |
【开发单位】Lilly (Originator) 【药理作用】Pyrazolidinones |
合成路线1
The reaction of N-(tert-butoxycarbonyl)-L-serine methyl ester (I) with hydrazine gives the corresponding hydrazide (II), which is acylated with trifluorothioacetic acid S-ethyl ester (III), yielding the diacylated hydrazine (IV). The cyclization of (IV) by means of DEAD and PPh3 affords the pyrazolidinone (V), which is deacylated with NaOH to furnish 4(S)-(tert-butoxycarbonyl)pyrazolidin-3-one (VI). The condensation of (VI) with vinylphosphonate (VII) gives the adduct (VIII), which is cyclized with the oxalyl monoester chloride (IX) by means of DIEA, yielding the pyrazolopyrazole (X). Finally, this compound is deprotected in acid medium and acylated with thiazole derivative (XI) by means of a Pd(0) catalyst to furnish the target compound.
| 【1】 Ternansky, R.J.; Draheim, S.E.; The synthesis of bicyclic pyrazolidinone antibacterial agents. 30th Nat Org Symp (Vancouver) 1987. |
| 【2】 Jungheim, L.N.; Holmes, R.E. (Eli Lilly and Company); Substd. diazolidinones. US 4826993 . |
| 【3】 Jungheim, L.N.; Ternansky, R.J.; Holmes, R.E.; BICYCLIC PYRAZOLIDINONE ANTIBACTERIAL AGENTS. Drugs Fut 1990, 15, 2, 149. |
| 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) | 43221 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate | 2766-43-0 | C9H17NO5 | 详情 | 详情 |
| (II) | 43222 | tert-butyl (1S)-2-hydrazino-1-(hydroxymethyl)-2-oxoethylcarbamate | C8H17N3O4 | 详情 | 详情 | |
| (III) | 43223 | S-ethyl 2,2,2-trifluoroethanethioate | 383-64-2 | C4H5F3OS | 详情 | 详情 |
| (IV) | 43224 | tert-butyl (1S)-1-(hydroxymethyl)-2-oxo-2-[2-(2,2,2-trifluoroacetyl)hydrazino]ethylcarbamate | C10H16F3N3O5 | 详情 | 详情 | |
| (V) | 43225 | tert-butyl (4S)-3-oxo-1-(2,2,2-trifluoroacetyl)pyrazolidinylcarbamate | C10H14F3N3O4 | 详情 | 详情 | |
| (VI) | 43226 | tert-butyl (4S)-3-oxopyrazolidinylcarbamate | C8H15N3O3 | 详情 | 详情 | |
| (VII) | 43230 | diethyl 1-(methylsulfonyl)vinylphosphonate | C7H15O5PS | 详情 | 详情 | |
| (VIII) | 43231 | diethyl 2-[(4S)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-(methylsulfonyl)ethylphosphonate | C15H30N3O8PS | 详情 | 详情 | |
| (IX) | 15585 | allyl 2-chloro-2-oxoacetate | C5H5ClO3 | 详情 | 详情 | |
| (X) | 43232 | allyl (6S)-6-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-3-carboxylate | C16H23N3O7S | 详情 | 详情 | |
| (XI) | 24316 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride | C6H6ClN3O2S | 详情 | 详情 |