【结 构 式】 |
【分子编号】34230 【品名】methyl 5-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate 【CA登记号】 |
【 分 子 式 】C21H32O5 【 分 子 量 】364.48208 【元素组成】C 69.2% H 8.85% O 21.95% |
合成路线1
该中间体在本合成路线中的序号:(XII)The esterification of 4alpha-carboxymethyl-5beta-benzyloxymethyl-cyclopent-2-en-1alpha-ol (I) with methyl iodide and K2CO3 in acetone gives the corresponding methyl ester (II), which by reaction with triethyl - orthoacetate (III) at 145 C is converted into 3-ethoxycarbonylmethyl-4-methoxycarbonylmethyl-5-benzyloxymethyl-1-cyclopentene (IV). The cyclization of (IV) with potassium tert-butoxide in benzene yields 6-benzyloxymethyl-cis-bicyclo[3.3.0]oct-7-ene-3-one (V), which by reaction with N-bromosuccinimide in DMSO - water affords 6-benzyloxymethyl-7-hydroxy-8-bromo-cis-bicyclo[3.3.0]octan-3-one (VI). Debromination of (VI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light gives 6-benzyloxymethyl-7-hydroxy-cis-bicyclo[3.3.0]octan-3-one (VII), which is treated with dihydropyran and p-toluenesulfonic acid in methylene chloride yielding the corresponding protected compound (VIII). Elimination of the benzyl group of (VIII) with H2 over Pd/C in acetic acid affords 6-hydroxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (IX), which is submitted to a Wittig condensation with (4-carboxybutyl) triphenylphosphonium bromide (X) and the sodium salt of DMSO in this solvent, followed by a methylation with diazomethane, affording 3-(4-methoxycarbonylbutylidene)-6-hydroxymethyl-7-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XI). Oxidation of (XI) with CrO3 in methylene chloride gives the corresponding 6-formyl derivative (XII), which is submitted to a new Wittig condensation with dimethyl 2-oxo-2-cyclopentylethylphosphonate (XIII) and NaH in THF yielding methyl 6,9-methano-11-(tetrahydropyranyloxy)-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-3,5-dienoate (XIV). Deprotection of (XIV) with acetic acid in THF - water gives the corresponding 11-hydroxy compound (XVI), which is reduced with NaBH4 in methanol affording the 11,15-dihydroxy ester (XVI). Finally, this compound is hydrolyzed with NaOH in methanol - water.
【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 . |
【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833. |
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) | 34221 | 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetic acid | C15H18O4 | 详情 | 详情 | |
(II) | 34222 | methyl 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetate | C16H20O4 | 详情 | 详情 | |
(III) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
(IV) | 34223 | methyl 2-[(1S,2R,5S)-2-[(benzyloxy)methyl]-5-(2-ethoxy-2-oxoethyl)-3-cyclopenten-1-yl]acetate | C20H26O5 | 详情 | 详情 | |
(V) | 34224 | (3aS,4R,6aS)-4-[(benzyloxy)methyl]-3,3a,4,6a-tetrahydro-2(1H)-pentalenone | C16H18O2 | 详情 | 详情 | |
(VI) | 34225 | (3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone | C16H19BrO3 | 详情 | 详情 | |
(VII) | 34226 | (3aS,4S,5R,6aR)-4-[(benzyloxy)methyl]-5-hydroxyhexahydro-2(1H)-pentalenone | C16H20O3 | 详情 | 详情 | |
(VIII) | 34227 | (3aS,4R,5R,6aR)-4-[(benzyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C22H30O4 | 详情 | 详情 | |
(IX) | 34228 | (3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C15H24O4 | 详情 | 详情 | |
(X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
(XI) | 34229 | methyl 5-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H34O5 | 详情 | 详情 | |
(XII) | 34230 | methyl 5-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H32O5 | 详情 | 详情 | |
(XIII) | 34231 | dimethyl 2-cyclopentyl-2-oxoethylphosphonate | C9H17O4P | 详情 | 详情 | |
(XIV) | 34232 | methyl 5-[(3aS,4S,5R,6aR)-4-[(E)-3-cyclopentyl-3-oxo-1-propenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C28H42O5 | 详情 | 详情 | |
(XV) | 32433 | (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one | C34H65NO4Si2 | 详情 | 详情 | |
(XVI) | 34234 | methyl 5-[(3aS,4S,5R,6aS)-4-[(E,3S)-3-cyclopentyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]pentanoate | C22H34O4 | 详情 | 详情 |