2-(3-hydroxyphenyl)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】58561

【品名】2-(3-hydroxyphenyl)acetic acid

【CA登记号】

【分子式】C₈H₈O₃

【分子量】152.14972

【元素组成】C 63.15% H 5.3% O 31.55%

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 title compound was prepared by solid-phase synthesis on a Sasrin resin. The silylated m-hydroxyphenylacetic acid (I) was attached to the resin using DCC and DMAP to yield the acid-bound resin (II). The silyl group of (II) was then removed by treatment of resin (II) with tetrabutylammonium fluoride in THF. The resultant phenol (III) was coupled to 3-bromo-1-propanol (IV) under Mitsunobu conditions to afford the bromide functionalized resin (V). Displacement of the bromide ion of (V) with 2,2-diphenylethylamine (VI) furnished the secondary amine (VII), which was subjected to reductive alkylation with aldehyde (VIII) in the presence of NaBH(OAc)3 to produce the resin-bound product (IX). Cleavage from the solid support employing trifluoroacetic acid in CH2Cl2 provided the target carboxylic acid.

参考文献中间体

合成目标

【1】 Collins, J.L.; et al.; Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 2002, 45, 10, 1963.
【2】 Willson, T.M.; Collins, J.L.; Maloney, P.R.; Fivush, A.M.; Stewart, E.L. (GlaxoSmithKline plc); Chemical cpds.. WO 0224632 .

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),(II)	58560	2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetic acid		C₁₄H₂₂O₃Si	详情	详情
(III)	58561	2-(3-hydroxyphenyl)acetic acid		C₈H₈O₃	详情	详情
(IV)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(V)	58562	2-[3-(3-bromopropoxy)phenyl]acetic acid		C₁₁H₁₃BrO₃	详情	详情
(VI)	38962	2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine	3963-62-0	C₁₄H₁₅N	详情	详情
(VII)	58563	2-(3-{3-[(2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid		C₂₅H₂₇NO₃	详情	详情
(VIII)	58564	2-chloro-3-trifluoromethyl benzaldehyde	93118-03-7	C₈H₄ClF₃O	详情	详情
(IX)	58565	2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid		C₃₃H₃₁ClF₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Claisen rearrangement of allyl ether (I) in refluxing o-dichlorobenzene affords (II). The allyl group of (II) is subsequently hydrogenated over Pd/C to provide the propyl derivative (III). Benzophenone (III) is converted into the corresponding oxime (IV) by means of hydroxylamine hydrochloride and NaOAc. Acetylation of oxime (IV), followed by refluxing in pyridine gives rise to the benzisoxazole (V). The phenolic hydroxyl group of (V) is then alkylated by 1,4-dibromobutane (VI) producing the bromobutyl ether (VII). 3-Hydroxyphenylacetic acid (VIII) is esterified with MeOH/H2SO4 to give the methyl ester (IX). This is then condensed with bromide (VII) in the presence of K2CO3 to furnish diether (X). Finally, saponification of the methyl ester group of (X) employing LiOH yields the target carboxylic acid (1,2)

参考文献中间体

合成目标

【1】 Adams, A.D.; Yuen, W.; Hu, Z.; Santini, C.; Jones, A.B.; MacNaul, K.L.; Berger, J.P.; Doebber, T.W.; Moller, D.E.; Amphipathic 3-phenyl-7-propylbenzisoxazoles; human PPAR gamma, delta and alpha agonists. Bioorg Med Chem Lett 2003, 13, 5, 931.
【2】 Adams, A.D.; Berger, J.P.; Berger, G.D.; Fitch, K.J.; Graham, D.W.; Jones, A.B.; Von Langen, D.; Leibowitz, M.D.; Moller, D.E.; Patchett, A.A.; Santini, C.; Sahoo, S.P.; Tolman, R.L.; Toupence, R.B.; Walsh, T.F. (Merck & Co., Inc.); Heterocyclic derivs. as antidiabetic and antiobesity agents. EP 0882029; JP 2002503203; US 6090836; WO 9728137 .

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)	63548	[4-(allyloxy)-2-hydroxyphenyl](phenyl)methanone		C₁₆H₁₄O₃	详情	详情
(II)	63549	(3-allyl-2,4-dihydroxyphenyl)(phenyl)methanone		C₁₆H₁₄O₃	详情	详情
(III)	63550	(2,4-dihydroxy-3-propylphenyl)(phenyl)methanone		C₁₆H₁₆O₃	详情	详情
(IV)	63551	(2,4-dihydroxy-3-propylphenyl)(phenyl)methanone oxime		C₁₆H₁₇NO₃	详情	详情
(V)	63552	3-phenyl-7-propyl-1,2-benzisoxazol-6-ol		C₁₆H₁₅NO₂	详情	详情
(VI)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(VII)	63553	6-(4-bromobutoxy)-3-phenyl-7-propyl-1,2-benzisoxazole; 4-bromobutyl 3-phenyl-7-propyl-1,2-benzisoxazol-6-yl ether		C₂₀H₂₂BrNO₂	详情	详情
(VIII)	58561	2-(3-hydroxyphenyl)acetic acid		C₈H₈O₃	详情	详情
(IX)	58567	methyl 2-(3-hydroxyphenyl)acetate		C₉H₁₀O₃	详情	详情
(X)	63554	methyl 2-(3-{4-[(3-phenyl-7-propyl-1,2-benzisoxazol-6-yl)oxy]butoxy}phenyl)acetate		C₂₉H₃₁NO₅	详情	详情

Extended Information