ethyl 2-phenoxyacetate -Drug Synthesis Database

【结构式】

【分子编号】32040

【品名】ethyl 2-phenoxyacetate

【CA登记号】2555-49-9

【分子式】C₁₀H₁₂O₃

【分子量】180.20348

【元素组成】C 66.65% H 6.71% O 26.64%

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：(III)

The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

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
(I)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	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)	32048	4-pentynoic acid	6089-09-4	C₅H₆O₂	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

合成路线2

该中间体在本合成路线中的序号：(III)

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