5-phenylpentanal -Drug Synthesis Database

【结构式】

【分子编号】25636

【品名】5-phenylpentanal

【CA登记号】

【分子式】C₁₁H₁₄O

【分子量】162.23156

【元素组成】C 81.44% H 8.7% O 9.86%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Horner-Emmons condensation of 5-phenylpentanal (I) with phosphonate (II) in the presence of NaH yielded tert-butyl 7-phenyl-2-heptenoate (III). Subsequent Michael addition of 4-methoxythiophenol (IV) to (III) using a catalytic amount of BuLi provided thioether (V). After acid deprotection of the tert-butyl ester of (V) with TFA, the resulting carboxylic acid (VI) was converted to acid chloride (VII) and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target beta-sulfonylhydroxamic acid. Alternatively tet-butyl ester (III) can be hydrolyzed first to the free acid (IX) with TFA, and then condensed with thiophenol (IV) by means of piperidine to afford the previously described carboxylic acid (VI).

参考文献中间体

合成目标

【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	26091	O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane	22737-36-6	C₃H₁₁NOSi	详情	详情
(I)	25636	5-phenylpentanal		C₁₁H₁₄O	详情	详情
(II)	25637	tert-butyl 2-(diethoxyphosphoryl)acetate	6273-47-8	C₁₀H₂₁O₅P	详情	详情
(III)	25638	tert-butyl (E)-7-phenyl-2-heptenoate		C₁₇H₂₄O₂	详情	详情
(IV)	25639	4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol	34320-82-6	C₇H₈OS	详情	详情
(V)	25640	tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoate		C₂₄H₃₂O₃S	详情	详情
(VI)	25641	3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoic acid		C₂₀H₂₄O₃S	详情	详情
(VII)	25642	3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoyl chloride		C₂₀H₂₃ClO₂S	详情	详情
(VIII)	25643	N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanamide		C₂₀H₂₅NO₃S	详情	详情
(IX)	25644	(E)-7-phenyl-2-heptenoic acid		C₁₃H₁₆O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 5-phenylpentanal (I) with triethyl 2-phosphonopropionate (II) by means of NaOEt in THF gives ethyl 2-methyl-7-phenyl-2(E)-heptenoate (III), which is hydrolyzed with NaOH in methanol/water to the corresponding free acid (IV). The reaction of (IV) with 4-methoxythiophenol (V) in hot piperidine affords 3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (VI), which by reaction first with oxalyl chloride, then with O-trimethylsilylhydroxylamine (VII) in dichloromethane, and finally with HCl is converted into the hydroxamic acid (VIII). Finally, this compound is oxidized with oxone in methanol/water to provide the target compound as mixture of diastereomeric racemates that is separated by reversed phase HPLC.

参考文献中间体

合成目标

【1】 Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. (Aventis Pharma SA); Substd. (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid cpds.. EP 0871439; JP 2000503012; WO 9724117 .

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)	25636	5-phenylpentanal		C₁₁H₁₄O	详情	详情
(II)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(III)	26081	ethyl (E)-2-methyl-7-phenyl-2-heptenoate		C₁₆H₂₂O₂	详情	详情
(IV)	26082	(E)-2-methyl-7-phenyl-2-heptenoic acid		C₁₄H₁₈O₂	详情	详情
(V)	25639	4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol	34320-82-6	C₇H₈OS	详情	详情
(VI)	26083	3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid		C₂₁H₂₆O₃S	详情	详情
(VII)	26091	O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane	22737-36-6	C₃H₁₁NOSi	详情	详情
(VIII)	26084	N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide		C₂₁H₂₇NO₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Hydroxyacid (III) was prepared by condensation of 5-phenylpentanal (I) with the dilithium anion of propionic acid (II). Cyclization of (III) upon treatment with dipyridyl disulfide and PPh3, and then with mercuric mesylate yielded an equimolar mixture of beta-lactones (IV) and (V), from which the desired cis isomer (IV) was isolated by flash chromatography. Subsequent ring opening of (IV) with the sodium salt of 4-methoxythiophenol (VI) provided carboxylic acid (VII). This was converted to acid the corresponding chloride by means of oxalyl chloride and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target sulfonylhydroxamic acid.

参考文献中间体

合成目标

【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541.

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)	25636	5-phenylpentanal		C₁₁H₁₄O	详情	详情
(II)	26085	2-Lithiopropionic acid lithium salt		C₃H₄Li₂O₂	详情	详情
(III)	26086	3-hydroxy-2-methyl-7-phenylheptanoic acid		C₁₄H₂₀O₃	详情	详情
(IV)	26087	(3S,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone		C₁₄H₁₈O₂	详情	详情
(V)	26088	(3R,4R)-3-methyl-4-(4-phenylbutyl)-2-oxetanone		C₁₄H₁₈O₂	详情	详情
(VI)	25639	4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol	34320-82-6	C₇H₈OS	详情	详情
(VII)	26089	(2S,3R)-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid		C₂₁H₂₆O₃S	详情	详情
(VIII)	26090	(2S,3R)-N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide		C₂₁H₂₇NO₃S	详情	详情

Extended Information