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【结 构 式】 
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【药物名称】DHET-PGE2 【化学名称】(5Z,11alpha,,13E,15S)-15-Hydroxy-11-(2-hydroxyethylsulfanyl)-9-oxoprosta-5,13-dien-1-oic acid methyl ester 【CA登记号】74412-44-5 【 分 子 式 】C23H38O5S 【 分 子 量 】426.62031 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Prostaglandins |
合成路线1
The hydrogenation of ethyl 3-(2-furyl)acrylate (I) with H2 over Raney-Ni in ethanol gives ethyl 3-(2-furyl)propionate (II), which oxidative methoxylation with Br2 in methanol affords ethyl 3-(2,5-dimethoxy-2,5-dihydro-2-furyl)propionate (III). The partial reduction of (III) with diisobutylaluminum hydride in toluene yields the substituted propionaldehyde (IV), which by a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide by means of NaH in DMSO gives 8-(2,5-dimethoxy-2,5-dihydro-2-furyl)-5-octenoic acid (VI). The hydrolytic ring opening of (VI), followed by an aldol cyclization in refluxing dioxane - water by means of sodium acetate - NaH2PO4 - hydroquinone affords 7-(2-oxo-5-hydroxycyclopent-3-en-1-yl)-5-heptenoic acid (VII), which is isomerized by treatment with H2SO4 yielding 7-(5-oxo-3-hydroxycyclopenten-1-yl)-5-heptenoic acid (VIII). Methylation and esterification of (VIII) with H2SO4/refluxing methanol gives the methoxy methyl ester (IX), which by reaction with 2-mercaptoethanol (A) and sodium methoxide in methanol is converted into methyl 7-[5-oxo-3-(2-hydroxyethylthio)cyclopenten-1-yl]-5-heptenoate (X). The methylation of acid (VI) with NaH and methyl iodide gives the corresponding methyl ester (XIV), which is submitted to a hydrolytic ring opening and aldol cyclization as before to afford methyl 7-(2-oxo-5-hydroxycyclopent-3-en-1-yl)-5-heptenoate (XV). The silylation of (XV) with trimethylchlorosilane and hexamethyldisilazane as usual yields the corresponding trimethylsilyloxy derivative (XVI), which is treated with 2-mercaptoethanol (A) and sodium methoxide to give the isomerized compound (X).
| 【1】 Floyd, M.B.; Prostaglandins and congeners. 18. Synthesis of cyclopentenolone precursors to prostaglandins from 2,5-dihydro-2,5-dimethoxyfurans. J Org Chem 1978, 43, 9, 1641-43. |
| 【2】 Floyd, M.; et al.; Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators. J Med Chem 1980, 23, 8, 903-913. |
| 【3】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castañer, J.; DHET-PGE2. Drugs Fut 1982, 7, 4, 241. |
| 【4】 Weiss, M.J.; Siuta, G.J. (American Cyanamid Co.); 11-(2-Hydroxyethylthio)prostenoic acid E{HD 2 {B series derivatives. US 4085272 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 36375 | 2-Sulfanyl-1-ethanol; 2-Mercaptoethanol | 60-24-2 | C2H6OS | 详情 | 详情 |
| (I) | 36362 | ethyl (E)-3-(2-furyl)-2-propenoate | 623-20-1 | C9H10O3 | 详情 | 详情 |
| (II) | 36363 | ethyl 3-(2-furyl)propanoate | 10031-90-0 | C9H12O3 | 详情 | 详情 |
| (III) | 36364 | ethyl 3-(2,5-dimethoxy-2,5-dihydro-2-furanyl)propanoate | C11H18O5 | 详情 | 详情 | |
| (IV) | 36365 | 3-(2,5-dimethoxy-2,5-dihydro-2-furanyl)propanal | C9H14O4 | 详情 | 详情 | |
| (V) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (VI) | 36367 | (Z)-8-(2,5-dimethoxy-2,5-dihydro-2-furanyl)-5-octenoic acid | C14H22O5 | 详情 | 详情 | |
| (VII) | 36368 | (Z)-7-(2-hydroxy-5-oxo-3-cyclopenten-1-yl)-5-heptenoic acid | C12H16O4 | 详情 | 详情 | |
| (VIII) | 36369 | (Z)-7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-5-heptenoic acid | C12H16O4 | 详情 | 详情 | |
| (IX) | 36370 | methyl (Z)-7-(3-methoxy-5-oxo-1-cyclopenten-1-yl)-5-heptenoate | C14H20O4 | 详情 | 详情 | |
| (X) | 36371 | methyl (Z)-7-[3-[(2-hydroxyethyl)sulfanyl]-5-oxo-1-cyclopenten-1-yl]-5-heptenoate | C15H22O4S | 详情 | 详情 | |
| (XIV) | 36372 | methyl (Z)-8-(2,5-dimethoxy-2,5-dihydro-2-furanyl)-5-octenoate | C15H24O5 | 详情 | 详情 | |
| (XV) | 36373 | methyl (Z)-7-(2-hydroxy-5-oxo-3-cyclopenten-1-yl)-5-heptenoate | C13H18O4 | 详情 | 详情 | |
| (XVI) | 36374 | methyl (Z)-7-[2-oxo-5-[(trimethylsilyl)oxy]-3-cyclopenten-1-yl]-5-heptenoate | C16H26O4Si | 详情 | 详情 |
合成路线2
The protection of the free hydroxy group of (X) with trimethylchlorosilane and hexamethyldisilazane in pyridine gives the trimethylsilyl derivative (XI), which is condensed with [3-(triphenylmethoxy)-1-octenyl](pentenyl)lithiocuprate (XII) in HMPT-ether to afford 11-deoxy-11alpha-(2-trimethyl-silyloxyethylthio)-15-triphenylmethoxy-PGE2 methyl ester (XIII). Finally, this compound is deprotected by treatment with acetic acid in THF. The lithium cuprate (XII) is prepared as follows: Hydrogen iodide addition to 3-triphenylmethoxy-1-octyne (XVII) gives 1-iodo-3-triphenylmethoxy-1-octene (XVIII), which is condensed with copper 1-pentyne (B) and butyllithium in ether.
| 【1】 Floyd, M.; et al.; Prostaglandins and congeners. 22. Synthesis of 11-substituted derivatives of 11-deoxyprostaglandins E1 and E2. Potential bronchodilators. J Med Chem 1980, 23, 8, 903-913. |
| 【2】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castañer, J.; DHET-PGE2. Drugs Fut 1982, 7, 4, 241. |
| 【3】 Weiss, M.J.; Siuta, G.J. (American Cyanamid Co.); 11-(2-Hydroxyethylthio)prostenoic acid E{HD 2 {B series derivatives. US 4085272 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 29069 | 1-pentynylcopper | C5H7Cu | 详情 | 详情 | |
| (X) | 36371 | methyl (Z)-7-[3-[(2-hydroxyethyl)sulfanyl]-5-oxo-1-cyclopenten-1-yl]-5-heptenoate | C15H22O4S | 详情 | 详情 | |
| (XI) | 36378 | methyl (Z)-7-[5-oxo-3-([2-[(trimethylsilyl)oxy]ethyl]sulfanyl)-1-cyclopenten-1-yl]-5-heptenoate | C18H30O4SSi | 详情 | 详情 | |
| (XII) | 36379 | C32H37IO | 详情 | 详情 | ||
| (XIII) | 36380 | methyl (Z)-7-[(1R,2R,3R)-5-oxo-3-([2-[(trimethylsilyl)oxy]ethyl]sulfanyl)-2-[(E,3S)-3-(trityloxy)-1-octenyl]cyclopentyl]-5-heptenoate | C45H60O5SSi | 详情 | 详情 | |
| (XVII) | 36376 | 1-pentyl-2-propynyl trityl ether; 1-[[(1-pentyl-2-propynyl)oxy](diphenyl)methyl]benzene | C27H28O | 详情 | 详情 | |
| (XVIII) | 36377 | 1-[[[(E)-3-iodo-1-pentyl-2-propenyl]oxy](diphenyl)methyl]benzene; (E)-3-iodo-1-pentyl-2-propenyl trityl ether | C27H29IO | 详情 | 详情 |