SC-795, -Drug Synthesis Database

【结构式】

【药物名称】SC-795

【化学名称】(+)-1,1,1-Trifluoro-3-[N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amino]propan-2(R)-ol

【CA登记号】263264-30-8

【分子式】C₂₄H₂₀F₇NO₃

【分子量】503.4207

【开发单位】Pfizer (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Cholesteryl Ester Transfer Protein (CETP) Inhibitors

合成路线1 合成路线2

合成路线1

Radical bromination of 3-(1,1,2,2-tetrafluoroethoxy)toluene (I) by means of N-bromosuccinimide in the presence of AIBN provided benzyl bromide (II), which was then condensed with 3-phenoxyaniline (III) in refluxing cyclohexane to afford (IV). Alternatively, (IV) was obtained by reductive condensation of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (A) with 3-phenoxyaniline (III) in the presence of sodium triacetoxyborohydride. The condensation of the secondary amine (IV) with commercially available trifluoromethyloxirane (V) of unspecified enantiomeric composition in the presence of ytterbium triflate furnished a 1:7 mixture of enantiomeric amino alcohols (VI). The title compound was then isolated from (VI) as the minor enantiomer by means of preparative chiral HPLC.

参考文献中间体

【1】 Durley, R.C.; et al.; Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 24, 4575.
【2】 Vernier, W.F.; Wang, L.; Mischke, D.A.; Hamme, A.T.; Promo, M.A.; Sikorski, J.A.; Spangler, D.P.; Grapperhaus, M.L.; Massa, M.A.; Durley, R.C.; Reinhard, E.J.; Fobian, Y.M.; Hickory, B.S.; Tollefson, M.B.; Norton, M.B.; Rueppel, M.L. (Pharmacia Corp.); (R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity. WO 0018721; WO 0018724 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	45688	3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde	35295-35-3	C₉H₆F₄O₂	详情	详情
(Va)	45689	(2R)-2-(trifluoromethyl)oxirane		C₃H₃F₃O	详情	详情
(VIa)	45690	(2R)-1,1,1-trifluoro-3-[3-phenoxy[3-(1,1,2,2-tetrafluoroethoxy)benzyl]anilino]-2-propanol		C₂₄H₂₀F₇NO₃	详情	详情
(Vb)	45691	(2S)-2-(trifluoromethyl)oxirane		C₃H₃F₃O	详情	详情
(VIb)	45692	(2S)-1,1,1-trifluoro-3-[3-phenoxy[3-(1,1,2,2-tetrafluoroethoxy)benzyl]anilino]-2-propanol		C₂₄H₂₀F₇NO₃	详情	详情
(I)	45684	3-methylphenyl 1,1,2,2-tetrafluoroethyl ether; 1-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzene	1737-10-6	C₉H₈F₄O	详情	详情
(II)	45685	3-(bromomethyl)phenyl 1,1,2,2-tetrafluoroethyl ether; 1-(bromomethyl)-3-(1,1,2,2-tetrafluoroethoxy)benzene		C₉H₇BrF₄O	详情	详情
(III)	45686	3-phenoxyphenylamine; 3-phenoxyaniline	3586-12-7	C₁₂H₁₁NO	详情	详情
(IV)	45687	N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline		C₂₁H₁₇F₄NO₂	详情	详情

合成路线2

The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII), followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH. Finally, reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.

参考文献中间体

【1】 Durley, R.C.; et al.; Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2002, 45, 18, 3891.
【2】 Grapperhaus, M.L.; Hickory, B.S.; Sikorski, J.A.; Wang, L.J.; Massa, M.A.; Mischke, D.A.; Honda, D.D.; New simple class of potent cholesteryl ester transfer protein inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 283.
【3】 Durley, R.C.; et al.; Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 24, 4575.
【4】 Vernier, W.F.; Wang, L.; Mischke, D.A.; Hamme, A.T.; Promo, M.A.; Sikorski, J.A.; Spangler, D.P.; Grapperhaus, M.L.; Massa, M.A.; Durley, R.C.; Reinhard, E.J.; Fobian, Y.M.; Hickory, B.S.; Tollefson, M.B.; Norton, M.B.; Rueppel, M.L. (Pharmacia Corp.); (R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity. WO 0018721; WO 0018724 .

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)	45687	N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline		C₂₁H₁₇F₄NO₂	详情	详情
(VII)	39909	3-bromo-1,1,1-trifluoroacetone	431-35-6	C₃H₂BrF₃O	详情	详情
(VIII)	45693	chloro[(1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl][(1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane		C₂₀H₃₄BCl	详情	详情
(IX)	45694	(2S)-3-bromo-1,1,1-trifluoro-2-propanol	88378-50-1	C₃H₄BrF₃O	详情	详情
(X)	45689	(2R)-2-(trifluoromethyl)oxirane		C₃H₃F₃O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)