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【结 构 式】 
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【药物名称】TMA-230 【化学名称】(+)-(5R,6S)-6-[1(R)-Hydroxyethyl]-2-(3-pyridyl)-2-penem-3-carboxylic acid acetoxymethyl ester 【CA登记号】113141-80-3 【 分 子 式 】C16H16N2O6S 【 分 子 量 】364.37972 |
【开发单位】Novartis (Originator), Takeda (Licensee) 【药理作用】Penems |
合成路线1
1) The reaction of 3-pyridylcarbonyl chloride (I) with (3S,4R)-2-[3-[1(R)-hyroxyethyl]-2-oxo-4-sulfanylazetidin-1-yl]-2-(triphenylphosphoranylidene)acetic acid allyl ester silver salt (II) in dichloromethane containing pyridine gives the substituted phosphorane (III), which is cyclized in refluxing benzene to afford (5R,6S)-6-[1(R)-hydroxyethyl]-2-(3-pyridyl)-2-penem-3-carboxylic acid allyl ester (IV). The deprotection of (IV) by means of triphenylphosphine, tetrakis(triphenylphosphine)palladium and acetic acid yields the free acid (V), which is finally esterified with bromomethyl acetate (VI) in DMF.
| 【1】 Mealy, M.; Castaner, J.; TMA-230. Drugs Fut 1996, 21, 5, 493. |
| 【2】 Bedeschi, A.; Visentin, G.; Perrone, E.; et al.; Synthesis and structure-activity relations in the class 2-(pyridyl)penems. J Antibiot 1990, 43, 3, 306-13. |
| 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) | 10753 | Nicotinoyl chloride | C6H4ClNO | 详情 | 详情 | |
| (II) | 12676 | (3S,4R)-2-[3-(1(R)-Hydroxyethyl)-2-oxo-4-sulfanylazetidin-1-yl]-2-(triphenylphosphanylidene)acetic acid allyl ester S-silver salt | C28H27AgNO4PS | 详情 | 详情 | |
| (III) | 12677 | allyl 2-[(3S,4R)-3-[(1R)-1-hydroxyethyl]-2-oxo-4-[(3-pyridinylcarbonyl)sulfanyl]azetidinyl]-2-(triphenylphosphoranylidene)acetate | C34H31N2O5PS | 详情 | 详情 | |
| (IV) | 12678 | allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(3-pyridinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C16H16N2O4S | 详情 | 详情 | |
| (V) | 12679 | (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-(3-pyridinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C13H12N2O4S | 详情 | 详情 | |
| (VI) | 12680 | bromomethyl acetate | 590-97-6 | C3H5BrO2 | 详情 | 详情 |
合成路线2
2) The reaction of 3-pyridylcarbonyl chloride (I) with (3S,4R)-2-[3-[1(R)-(allyloxycarbonyloxy)ethyl]-2-oxo-4-sulfanylazetidin-1-yl]-2-(triphenylphosphoranylidene)acetic acid allyl ester silver salt (VII) in dichloromethane containing pyridine gives the substituted phosphorane (VIII), which is cyclized in refluxing toluene to afford (5R,6S)-6-[1(R)-(allyloxycarbonyloxy)ethyl]-2-(3-pyridyl)-2-penem-3-carboxylic acid allyl ester (IX). The deprotection of (IX) with tetrakis(triphenylphosphine)palladium, tributyltin hydride and NaHCO3 in THF gives the free acid (X) as the sodium salt, which is finally esterified with bromomethyl acetate.
| 【1】 Mealy, M.; Castaner, J.; TMA-230. Drugs Fut 1996, 21, 5, 493. |
| 【2】 Lang, M. (Novartis AG); 2-Pyridyl-penem cpds. EP 0246187; JP 1987263183; US 4826832 . |
| 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) | 10753 | Nicotinoyl chloride | C6H4ClNO | 详情 | 详情 | |
| (VI) | 12680 | bromomethyl acetate | 590-97-6 | C3H5BrO2 | 详情 | 详情 |
| (VII) | 12681 | (3S,4R)-2-[3-[1(R)-(Allyloxycarbonyloxy)ethyl]-2-oxo-4-sulfanylazetidin-1-yl]-2-(triphenylphosphanylidene)acetic acid allyl ester S-silver salt | C32H31AgNO6PS | 详情 | 详情 | |
| (VIII) | 12682 | allyl 2-[(3S,4R)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-oxo-4-[(3-pyridinylcarbonyl)sulfanyl]azetidinyl]-2-(triphenylphosphoranylidene)acetate | C38H35N2O7PS | 详情 | 详情 | |
| (IX) | 12683 | allyl (5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-7-oxo-3-(3-pyridinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C20H20N2O6S | 详情 | 详情 | |
| (X) | 12684 | sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(3-pyridinyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C13H11N2NaO4S | 详情 | 详情 |