methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate -Drug Synthesis Database

【结构式】

【分子编号】63472

【品名】methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate

【CA登记号】

【分子式】C₂₂H₂₇NO₄

【分子量】369.46072

【元素组成】C 71.52% H 7.37% N 3.79% O 17.32%

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：

A new synthesis for L-659989 has been reported: The alkylation of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (I) with propyl bromide in hot DMF gives 3-iodo-5-methoxy-4-propoxybenzaldehyde (II), which is condensed with tert-butyl acrylate (III) by means of NaCN in DMF to yield 3-(3-iodo-5-methoxy-4-propoxybenzoyl)propionic acid tert-butyl ester (IV). The stereoselective reduction of (IV) with chlorodiisopinocampheylborane (V) in THF affords 4(S)-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid tert-butyl ester (VI), which is hydrolyzed with KOH in methanol-water to the corresponding free acid (VII). The cyclization of (VII) with pyridinium p-toluenesulfonate in toluene gives 5(S)-(3-iodo-5-methoxy-4-propoxyphenyl)tetrahydrofuran-2-one (VIII), which is treated with dimethyl disulfide and copper in refluxing pyridine to yield 5(S)-[3-methoxy-5-(methylthio)-4-propoxyphenyl]tetrahydrofuran-2-one (IX). The oxidation of (IX) with magnesium monoperoxyphthalate in acetonitrile-water affords the corresponding sulfone (X), which is reduced with diisobutylaluminum hydride in toluene giving 5(S)-[3-methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydrofuran-2-ol (XI). Finally, this compound is treated first with bromotrimethylsilane and then with 3,4,5-trimethoxyphenylmagnesium bromide, yielding the final product with a trans/cis ratio of 15/1 and a yield of 55%.

参考文献中间体

合成目标

【1】 Tschaen, D.M.; Russ, W.; Thompson, A.S.; Simpson, P.; McSwine, D.; Conversion of a silylated hemiacetal into an alpha-bromoether using trimethylsilylbromide - Synthesis of platelet activating factor antagonist. Tetrahedron Lett 1990, 31, 48, 6953.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	32378	bromo(3,4,5-trimethoxyphenyl)magnesium		C₉H₁₁BrMgO₃	详情	详情
	63472	methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate		C₂₂H₂₇NO₄	详情	详情
(I)	12758	4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin	5438-36-8	C₈H₇IO₃	详情	详情
(II)	12759	3-Iodo-5-methoxy-4-propoxybenzaldehyde		C₁₁H₁₃IO₃	详情	详情
(III)	12760	tert-butyl acrylate	1663-39-4	C₇H₁₂O₂	详情	详情
(IV)	12761	tert-butyl 4-(3-iodo-5-methoxy-4-propoxyphenyl)-4-oxobutanoate		C₁₈H₂₅IO₅	详情	详情
(V)	12762	Chlorodiisopinocampheylborane		C₂₂H₄₀	详情	详情
(VI)	12763	tert-butyl (4S)-4-hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butanoate		C₁₈H₂₇IO₅	详情	详情
(VII)	12764	(4S)-4-Hydroxy-4-(3-iodo-5-methoxy-4-propoxyphenyl)butyric acid		C₁₄H₁₉IO₅	详情	详情
(VIII)	12765	(5S)-5-(3-Iodo-5-methoxy-4-propoxyphenyl)dihydro-2(3H)-furanone		C₁₄H₁₇IO₄	详情	详情
(IX)	12766	(5S)-5-[3-Methoxy-5-(methylsulfanyl)-4-propoxyphenyl]dihydro-2(3H)-furanone		C₁₅H₂₀O₄S	详情	详情
(X)	12767	(5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]dihydro-2(3H)-furanone		C₁₅H₂₀O₆S	详情	详情
(XI)	12768	(5S)-5-[3-Methoxy-5-(methylsulfonyl)-4-propoxyphenyl]tetrahydro-2-furanol		C₁₅H₂₂O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

3-(Benzyloxy)aniline (I) is acylated by suberic acid mono-methyl ester (II) either employing EDC as the coupling reagent or via activation with oxalyl chloride to produce the suberoyl anilide (III). Further displacement of the methyl ester group of (III) with hydroxylamine in the presence of NaOMe leads to the target hydroxamic acid

参考文献中间体

合成目标

【1】 Belvedere, S.; Zhou, W.; Witter, D.; Yan, J.; Chen, W.; Secrist, J.P.; Richon, V.; Miller, T.; SAHA derived inhibitors of histone deacetylase (HDAC). 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 102.

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)	63471	3-[(phenylmethyl)oxy]aniline; 3-[(phenylmethyl)oxy]phenylamine		C₁₃H₁₃NO	详情	详情
(II)	56374	Methyl hydrogen octane-1,8-dioate; Monomethyl suberate; Octanedioic acid monomethyl ester; Suberic acid monomethyl ester	3946-32-5	C₉H₁₆O₄	详情	详情
(III)	63472	methyl 8-oxo-8-({3-[(phenylmethyl)oxy]phenyl}amino)octanoate		C₂₂H₂₇NO₄	详情	详情

Extended Information