GW-3965, -Drug Synthesis Database

【结构式】

【药物名称】GW-3965

【化学名称】2-[3-[3-[N-[2-Chloro-3-(trifluoromethyl)benzyl]-N-(2,2-diphenylethyl)amino]propoxy]phenyl]acetic acid

【CA登记号】405911-09-3, 405911-17-3 (hydrochloride)

【分子式】C₃₃H₃₁ClF₃NO₃

【分子量】582.06812

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ABCA1 Expression Enhancers, Liver X Receptor (LXR) Agonists

合成路线1 合成路线2

合成路线1

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

【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

In a solution-phase synthesis, 2,2-diphenylethylamine (VI) was reductively condensed with 2-chloro-3-(trifluoromethyl)benzaldehyde (VIII) using a polymer-supported borohydride resin to give the secondary amine (X). Mitsunobu coupling of methyl 3-hydroxyphenylacetate (XI) with 3-bromo-1-propanol (IV) afforded the bromopropyl ether (XII). Condensation of bromide (XII) with amine (X) in refluxing acetonitrile furnished amino ester (XIII). This was finally hydrolyzed with LiOH to the title carboxylic acid.

参考文献中间体

【1】 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
(IV)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(VI)	38962	2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine	3963-62-0	C₁₄H₁₅N	详情	详情
(VIII)	58564	2-chloro-3-trifluoromethyl benzaldehyde	93118-03-7	C₈H₄ClF₃O	详情	详情
(X)	58566	N-[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenyl-1-ethanamine; N-[2-chloro-3-(trifluoromethyl)benzyl]-N-(2,2-diphenylethyl)amine		C₂₂H₁₉ClF₃N	详情	详情
(XI)	58567	methyl 2-(3-hydroxyphenyl)acetate		C₉H₁₀O₃	详情	详情
(XII)	58568	methyl 2-[3-(3-bromopropoxy)phenyl]acetate		C₁₂H₁₅BrO₃	详情	详情
(XIII)	58569	methyl 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate		C₃₄H₃₃ClF₃NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)