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【结 构 式】 
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【药物名称】R-59274, CS-570 【化学名称】17(R)-Methyl-20-isopropylidenecarbacyclin sodium salt 【CA登记号】71806-48-9 【 分 子 式 】C25H39NaO4 【 分 子 量 】426.57698 |
【开发单位】Sankyo (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Prostaglandins |
合成路线1
The decarboxylative hydrolysis ot 2beta,4alpha-di(methoxycarbonyl)-3alpha-(3-phenylpropyl)cyclopentanone (I) with HCl in refluxing acetic acid gives 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-carboxylic acid methyl ester (II), which by successive reactions with oxalyl chloride in refluxing benzene, with diazomethane in ether, and with silver benzoate and triethylamine in methanol, is converted to 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-acetic acid methyl ester (III). The dehydrogenation of (III) by reaction with N-bromosuccinimide and sodium selenobenzene in benzene and THF affords 3alpha-(3-phenyl-2-propenyl)cyclopentanone-4alpha-acetic acid methyl ester (IV), which is oxidized with sodium methaperiodate and Jones reagent, and methylated with diazomethane to give cyclopentanone 3alpha,4alpha-di(acetic acid) dimethyl ester (V). The reaction of (V) with ethyl eneglycol and p-toluenesulfonic acid yields the corresponding ketal (VI), which is submitted to a cyclization with sodium methoxide in hot methanol - DMSO to afford 7,7-ethylenedioxybicyclo[3.3.0] octan-3-one-4beta-carboxylic acid methyl ester (VII). The reduction of (VII) with NaBH4 in methanol gives the corresponding hydroxyester (VIII), which is protected with dihydropyran and p-toluenesulfonic acid to the corresponding tetrahydropyranyloxy compound (IX). The reduction of (IX) with LiAlH4 in ether affords the methanol derivative (X), which is oxidized with CrO3 - pyridine to the aldehyde (XI). The Wittig condensation of (XI) with dimethyl 2-oxo-4R,8-dimethyl-7-nonenylphosphonate (XII) by means of NaH in THF affords the dienic ketone (XIII).
| 【1】 Kojima, K.; Sakai, K.; Kobayashi, S. (Sankyo Co., Ltd.); Protacyclin compounds. DE 2900352; FR 2414039; GB 2012265; JP 54095552 . |
| 【2】 Prous, J.; Castaner, J.; CS-570. Drugs Fut 1986, 11, 11, 918. |
| 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) | 24516 | methyl (1R,2S,3R)-3-acetyl-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate | C18H22O4 | 详情 | 详情 | |
| (II) | 24517 | methyl (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylate | C16H20O3 | 详情 | 详情 | |
| (III) | 24518 | methyl 2-[(1S,2S)-4-oxo-2-(3-phenylpropyl)cyclopentyl]acetate | C17H22O3 | 详情 | 详情 | |
| (IV) | 24519 | methyl 2-[(1S,2S)-4-oxo-2-[(E)-3-phenyl-2-propenyl]cyclopentyl]acetate | C17H20O3 | 详情 | 详情 | |
| (V) | 24520 | methyl 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetate | C11H16O5 | 详情 | 详情 | |
| (VI) | 24521 | methyl 2-[(7R,8S)-8-(2-methoxy-2-oxoethyl)-1,4-dioxaspiro[4.4]non-7-yl]acetate | C13H20O6 | 详情 | 详情 | |
| (VII) | 11312 | (3'aS,4'R,6'aS)-5'-Oxoperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester | C12H16O5 | 详情 | 详情 | |
| (VIII) | 11313 | (3'aS,4'R,5'R,6'aR)-5'-Hydroxyperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester | C12H18O5 | 详情 | 详情 | |
| (IX) | 24524 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-carboxylic acid | C17H26O6 | 详情 | 详情 | |
| (X) | 24525 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-methanol | C16H26O5 | 详情 | 详情 | |
| (XI) | 24526 | (1'R,2'R,3'aR,6'aS)-2'-(Tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalene]-1'-carbaldehyde | C12H18O3 | 详情 | 详情 | |
| (XII) | 63310 | dimethyl (4R)-4,8-dimethyl-2-oxo-7-nonenylphosphonate | C13H25O4P | 详情 | 详情 | |
| (XIII) | 24527 | 5(R),9-Dimethyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]deca-1(E),8-dien-3-one | C27H42O5 | 详情 | 详情 |
合成路线2
Ketone (XIII) is reduced with NaBH4 to the dienic alcohol (XIV). The hydrolysis of (XIV) with HCl in aqueous acetone gives the dihydroxyketone (XV), which is treated with dihydropyran and p-toluenesulfonic acid to afford the bistetrahydropyranyloxy derivative (XVI). The Wittig condensation of ketone (XVI) with 4-(methoxycarbonylbutyl)triphenylphosphonium bromide (XVII) by means of NaH in DMSO affords the protected carbacyclin (XVIII), which is deprotected with acetic acid in THF water yielding 17R-methyl-20-isopropylidenecarbacyclin methyl ester (XIX). Finally, this compound is saponified with KOH in aqueous methanol.
| 【1】 Kojima, K.; Sakai, K.; Kobayashi, S. (Sankyo Co., Ltd.); Protacyclin compounds. DE 2900352; FR 2414039; GB 2012265; JP 54095552 . |
| 【2】 Prous, J.; Castaner, J.; CS-570. Drugs Fut 1986, 11, 11, 918. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 24527 | 5(R),9-Dimethyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]deca-1(E),8-dien-3-one | C27H42O5 | 详情 | 详情 | |
| (XIV) | 24537 | 5(R),9-Dimethyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]deca-1(E),8-dien-3(S)-ol | C27H44O5 | 详情 | 详情 | |
| (XV) | 24528 | (3aS,4S,5R,6aR)-5-hydroxy-4-[(1E,3S,5R)-3-hydroxy-5,9-dimethyl-1,8-decadienyl]hexahydro-2(1H)-pentalenone | C20H32O3 | 详情 | 详情 | |
| (XVI) | 24529 | (3aS,4S,5R,6aR)-4-[5(R),9-dimethyl-3(S)-(tetrahydropyranyloxy)deca-1(E),8-dien-1-yl]-5-(tetrahydropyranyloxy)perhydropentalen-2-one | C26H42O3 | 详情 | 详情 | |
| (XVII) | 24530 | methyl 5-(triphenylphosphoranyl)pentanoate | C24H27O2P | 详情 | 详情 | |
| (XVIII) | 24531 | methyl 4-[(3aS,4S,5R,6aS)-4-[(1E,3S,5R)-5,9-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,8-decadienyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2(1H)-pentalenylidene]butanoate | C35H56O6 | 详情 | 详情 | |
| (XIX) | 24532 | methyl 4-[(3aS,4S,5R,6aS)-5-hydroxy-4-[(1E,3S,5R)-3-hydroxy-5,9-dimethyl-1,8-decadienyl]hexahydro-2(1H)-pentalenylidene]butanoate | C25H40O4 | 详情 | 详情 |