(3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone -Drug Synthesis Database

【结构式】

【分子编号】34225

【品名】(3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone

【CA登记号】

【分子式】C₁₆H₁₉BrO₃

【分子量】339.22906

【元素组成】C 56.65% H 5.65% Br 23.55% O 14.15%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(VI)

The protection of bromoketol (VI) with dihydropyran and p-toluene sulfonic acid in methylene chloride gives the corresponding tetrahydropyranyl derivative (XVII), which is debrominated with tributyltin hydride as usual yielding (VIII), already obtained.

参考文献中间体

合成目标

【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	分子式	供应商	用于合成
(VI)	34225	(3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone	C₁₆H₁₉BrO₃	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
(XVII)	34235	(3aR,4R,5R,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone	C₂₂H₂₉BrO₄	详情	详情

Extended Information