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【结 构 式】 
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【分子编号】24482 【品名】dimethyl 3-methyl-2-oxo-5-heptynylphosphonate 【CA登记号】 |
【 分 子 式 】C10H17O4P 【 分 子 量 】232.216342 【元素组成】C 51.72% H 7.38% O 27.56% P 13.34% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of 7-bromo-3a,8b-cis-3a,8b dihydro-3H-5-cyclopenta[b]benzofurancarboxylic acid (I) with trioxane and H2SO4, followed by methylation with diazomethane and debromination with H2 over Pd/C, gives the hydroxymethyl compound (II), which is protected with 1,1-diethoxyethane and p-toluenesulfonic acid to give the protected ester (III). Reduction of the ester (III) with LiAlH4 in THF affords the corresponding hydroxymethyl compound (IV), which by reaction with SOCl2 in DMF is converted to the chlorometnyl derivative (VI). The condensation of (V) with beta-propiolactone (VI) by means of Mg in TFH gives the phenylbutyric acid (VII), which by methylation with diazomethane and deprotection with HCl in metnanol yields the dihydroxyester (VIII). Selective acetylation of (VIII) by reaction with trimethyl-tert-butylchlorosilane, then with acetic anhydride and final desilylation with acetic acid affords methyl 4-(2alpha-acetoxy-1-hydroxymethyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuranyl)butyrate (IX), which is oxidized with DMSO. dicyclohexylcarbodiimide (DCC) and trifluoroacetic acid to the corresponding aldehyde (X). The Wittig condensation of (X) with dimethyl 3-methyl-2-oxohept-5-yn-1-yl phosphonate (XI) by means of NaH in DMF affords 11,15-dideoxy-11-acetoxy-16-methyl-15-oxo-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene-prostaglandin I2 methyl ester (XII), vvhich is reduced with cerium chloride and NaBH4 in methanol to the corresponding 15-hydroxy compound (XIII). Finally, this compound is deacetylated and saponified as usual.
| 【1】 Matsumoto, K.; Nagase, H.; Ohno, K. (Toray Industries, Inc.); Preparation of 5,6,7-trinor-4,8-inter-m-phenylene pgi2derivative. JP 1984134787 . |
| 【2】 Ohno, K.; Nagase, H.; Matsumoto, K.; Nishio, S. (Toray Industries, Inc.); 5,6,7-Trinor-4,8-inter-m-phenylene protaglandin I2 derivatives useful in anti-ulcer, hypotensive and platelet aggregation inhibiting compositions. EP 0084856; JP 58124778; US 4474802 . |
| 【3】 Castaner, J.; Prous, J.; TRK-100. Drugs Fut 1986, 11, 11, 956. |
| 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) | 24472 | (3aS,8bS)-7-bromo-3a,8b-dihydro-3H-cyclopenta[b][1]benzofuran-5-carboxylic acid | C12H9BrO3 | 详情 | 详情 | |
| (II) | 24473 | methyl (3aS,8bS)-2-hydroxy-1-(hydroxymethyl)-3a,8b-dihydro-3H-cyclopenta[b][1]benzofuran-5-carboxylate | C14H14O5 | 详情 | 详情 | |
| (III) | 24474 | methyl (4aR,5aS,10bS,10cS)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5',4':3,4]cyclopenta[1,2-b][1]benzofuran-7-carboxylate | C16H18O5 | 详情 | 详情 | |
| (IV) | 24475 | [(4aR,5aS,10bS,10cS)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5',4':3,4]cyclopenta[1,2-b][1]benzofuran-7-yl]methanol | C15H18O4 | 详情 | 详情 | |
| (V) | 24476 | (4aR,5aS,10bS,10cS)-7-(chloromethyl)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5',4':3,4]cyclopenta[1,2-b][1]benzofuran | C15H17ClO3 | 详情 | 详情 | |
| (VI) | 24477 | 2-oxetanone | 57-57-8 | C3H4O2 | 详情 | 详情 |
| (VII) | 24478 | 4-[(4aR,5aS,10bS,10cS)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5',4':3,4]cyclopenta[1,2-b][1]benzofuran-7-yl]butyric acid | C18H22O5 | 详情 | 详情 | |
| (VIII) | 24479 | methyl 4-[(2R,3aS,8bS)-2-hydroxy-1-(hydroxymethyl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoate | C17H22O5 | 详情 | 详情 | |
| (IX) | 63079 | methyl 4-[(2R,3aS,8bS)-2-(acetyloxy)-1-(hydroxymethyl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoate | C19H24O6 | 详情 | 详情 | |
| (X) | 24481 | methyl 4-[(2R,3aS,8bS)-2-(acetoxy)-1-formyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoate | C19H22O6 | 详情 | 详情 | |
| (XI) | 24482 | dimethyl 3-methyl-2-oxo-5-heptynylphosphonate | C10H17O4P | 详情 | 详情 | |
| (XII) | 24483 | (2R,3aS,8bS)-4-[2-Acetoxy-1-(4-methyl-3-oxooct-1(E)-en-6-ynyl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl]butyric acid methyl ester; (2R,3aS,8bS)-4-[2-Acetoxy-1-(4-methyl-3-oxooct-1(E)-en-6-ynyl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl]butyric acid methyl ester | C26H32O4 | 详情 | 详情 | |
| (XIII) | 24484 | methyl 4-[(2R,3aS,8bS)-2-(acetoxy)-1-[(E,3S)-3-hydroxy-4-methyl-1-octen-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl]butanoate | C27H34O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Reaction of the lactone (I) with lithium ethyl acetate followed by acid catalyzed dehydration and hydrolysis of the ester group with K2CO3 in methanol affords the hydroxy compound (II), which gives after Collins oxidation, treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and reduction with NaBH4, the ketoester (III). Dealkoxy carbonylation with DABCO in toluene, benzoylation and removal of the silyl group with acetic acid in THF-water yield the ketone (IV). Ketalization of the ketone (IV) with ethylene glycol, Collins oxidation and condensation of the resulting aldehyde with the sodium salt of the phosphonate (V) afford the enone (VI). Reduction of (VI) with NaBH4 in methanol, cleavage of the ketal function with acetic acid-H2O and subsequent tetrahydropyranylation lead to the ketone (VII). Wittig condensation of the ketone (VII) with (VIII) and NaH in DMSO affords after chromatographic separation the acid (IX), which is finally deprotected to (X) (ZK-36374) by treatment with acetic acid in THF-water mixture.
| 【1】 Skuballa, W.; Raduechel, B.; Vorbrueggen, H.; Mannesmann, G.; Losert, W.; Casals, J. (Schering AG); Novel prostacyclin derivatives and a process for the preparation thereof.. DE 2845770; ES 485199; US 4692464 . |
| 【2】 Vorbruggen, H.; Schillinger, E.; Ciloprost. Drugs Fut 1981, 6, 11, 676. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (IIIa) | 32254 | ethyl (1R,3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-2-oxooctahydro-1-pentalenecarboxylate | C18H32O5Si | 详情 | 详情 | |
| (IIIb) | 32255 | (3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1-methylhexahydro-2(1H)-pentalenone | C18H32O5Si | 详情 | 详情 | |
| (VIa) | 32257 | Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(S)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester | C26H30O5 | 详情 | 详情 | |
| (VIb) | 32258 | Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(R)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester | C26H30O5 | 详情 | 详情 | |
| (VIIa) | 32259 | (3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H44O5 | 详情 | 详情 | |
| (VIIb) | 32260 | (3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H44O5 | 详情 | 详情 | |
| (IXa) | 32261 | 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H52O6 | 详情 | 详情 | |
| (IXb) | 32262 | 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C34H52O6 | 详情 | 详情 | |
| (I) | 32252 | (3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C21H30O5Si | 详情 | 详情 | |
| (II) | 32253 | ethyl 2-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-ylidene]acetate | C18H32O5Si | 详情 | 详情 | |
| (IV) | 32256 | (1S,2R,3aR,6aS)-1-(hydroxymethyl)-5-oxooctahydro-2-pentalenyl benzoate | C16H18O4 | 详情 | 详情 | |
| (V) | 24482 | dimethyl 3-methyl-2-oxo-5-heptynylphosphonate | C10H17O4P | 详情 | 详情 | |
| (VIII) | 29762 | sodium 5-(triphenylphosphoranylidene)pentanoate | C23H22NaO2P | 详情 | 详情 |