methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate -Drug Synthesis Database

【结构式】

【分子编号】32051

【品名】methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate

【CA登记号】

【分子式】C₃₇H₅₂O₉

【分子量】640.81448

【元素组成】C 69.35% H 8.18% O 22.47%

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：(XV)

The acetylation of (XIII) with acetic anhydride and triethylamine in methylene chloride yields the diacetoxy-bistetra-hydropyranyloxy acetylenic compound (XlV), which by a treatment with Cu2Br2-LiCH3 in ether is converted into 16-phenoxy-9alpha-acetoxy-11alpha,15alpha-bistetrahydropyranyloxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XV). Elimination of the tetrahydropyranyl groups with acetic acid in water gives the corresponding dihydroxy compound (XVI), which is fully deprotected with K2CO3 in methanol yielding 9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). The methylation of (XVII) with diazomethane affords the corresponding methyl ester (XVIII), which by treatment with tert-butyldimethylsilyl chloride (XIX) in DMF is converted into the corresponding 11,15-bis(silyloxy) compound (XX). The oxidation of (XX) with CrO3 - pyridine in CH2Cl2 affords 9-oxo-16-phenoxy-11alpha,15alpha-bis(tert-butyldimethylsilyloxy)-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid methyl ester (XXI), which is deprotected with aqueous acetic acid giving the free keto ester (XXII). Finally, this ester is hydrolyzed by treatment with pancreatic lipase.

参考文献中间体

合成目标

【1】 Van Horn, A.R.; Garay, G.; Edwards, J.A. (Syntex (USA), Inc.); (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof. DE 2927715; EP 0008003; ES 482330; FR 2430939; GB 2025413; US 4178457 .
【2】 Muchowski, J.M.; Fried, J.H. (Syntex (USA), Inc.); 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives. DE 2627910; ES 449162; FR 2315263; US 3985791 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hillier, K.; RS-84,135. Drugs Fut 1982, 7, 11, 812.

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)	32049	methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate		C₃₅H₅₀O₉	详情	详情
(XIV)	32050	methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate		C₃₉H₅₄O₁₁	详情	详情
(XV)	32051	methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate		C₃₇H₅₂O₉	详情	详情
(XVI)	32052	methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate		C₂₅H₃₂O₇	详情	详情
(XVII)	32053	7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid		C₂₂H₂₈O₆	详情	详情
(XVIII)	32054	methyl 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate		C₂₃H₃₀O₆	详情	详情
(XIX)	32057	tert-butyl(chloro)dimethylsilane	18162-48-6	C₆H₁₅ClSi	详情	详情
(XX)	32055	methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-phenoxy-1-butenyl)-5-hydroxycyclopentyl]-4,5-heptadienoate		C₃₅H₅₈O₆Si₂	详情	详情
(XXI)	32056	methyl 7-[(1R,2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-phenoxy-1-butenyl)-5-oxocyclopentyl]-4,5-heptadienoate		C₃₅H₅₆O₆Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The condensation of phenol (I) with ethyl bromoacetate (II) by means of NaH in refluxing dimethoxyethane gives phenoxyacetate (III), which by condensation with dimethyl methylphosphonate (IV) by means of butyllithium in THF is converted into dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy)-5'beta-formylcyclopent-1’alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in methoxyethane affords the phenoxylactone (VII), which is reduced witl aluminium isopropoxide in refluxing toluene to yield the hydroxylactone (VIII). The hydrolysis of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with dihydropyran and p-toluenesulfonic acid in methylene chloride giving the bis-tetrahydropyranyloxylactone (X). The reduction of (X) with diisobutylaluminium hydride in toluene yields [2'alpha-hydroxy-4'alpha-tetrahydropyranyloxy-5'beta-(3''alpha-tetrapyranyloxy-4''-phenoxybut-1''-trans-en-1''-yl)cyclopent-1'alpha-yl]acetaldehyde 1,2-hemiacetal (XI), which is condensed with 4-pentynoate (XII) by means of methyllithium and diisopropylamine in ether to afford the acetylenic prostaglandin derivative (XIII). The acetylation of (XIII) with acetic anhydride - triethylamine and dimethylaminopyridine in methylene chloride gives the diacetoxy compound (XIV), which by treatment with Cu2I2 and methyllithium in ether is converted into the cumulenic prostaglandin (XV). The elimination of the tetrahydropyran groups with acetic acid yields the dihydroxy-acetoxy ester (XVI), which is fully hydrolyzed with K2ClO3 in MeOH affording 8R-9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). Finally this compound is methylated with diazomethane in ether

参考文献中间体

合成目标

【1】 Serradell, M.N.; Castaner, J.; Adaikan, P.G.; Kottegoda, S.R.; Fenprostalene. Drugs Fut 1984, 9, 11, 817.
【2】 Muchowski, J.M.; et al. (Syntex (USA) Inc.); US 3985791 .

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)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(II)	10640	(1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate		C₄₁H₅₈O₈SSi	详情	详情
(III)	32040	ethyl 2-phenoxyacetate	2555-49-9	C₁₀H₁₂O₃	详情	详情
(IV)	13607	dimethyl methylphosphonate	756-79-6	C₃H₉O₃P	详情	详情
(V)	32041	dimethyl 2-oxo-3-phenoxypropylphosphonate	40665-68-7	C₁₁H₁₅O₅P	详情	详情
(VI)	32042	(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₂₁H₁₈O₅	详情	详情
(VII)	32043	(3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₃₀H₂₆O₆	详情	详情
(VIII)	32044	(3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₃₀H₂₈O₆	详情	详情
(IX)	32045	(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one		C₁₇H₂₀O₅	详情	详情
(X)	32046	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one		C₂₉H₄₀O₇	详情	详情
(XI)	32047	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₉H₄₂O₇	详情	详情
(XII)	51633	methyl 4-pentynoate		C₆H₈O₂	详情	详情
(XIII)	32049	methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate		C₃₅H₅₀O₉	详情	详情
(XIV)	32050	methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate		C₃₉H₅₄O₁₁	详情	详情
(XV)	32051	methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate		C₃₇H₅₂O₉	详情	详情
(XVI)	32052	methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate		C₂₅H₃₂O₇	详情	详情
(XVII)	32053	7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid		C₂₂H₂₈O₆	详情	详情

Extended Information