Nafetolol, K-5407, -Drug Synthesis Database

【结构式】

【药物名称】Nafetolol, K-5407

【化学名称】8-[3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-5-ol

【CA登记号】42050-23-7, 42050-24-8 (hydrochloride)

【分子式】C₁₉H₂₉NO₃

【分子量】319.44788

【开发单位】

【药理作用】　

合成路线1 合成路线2

合成路线1

The selective methylation of 5,6,7,8-tetrahydro-5,8-ethanonaphthalene-1,4-diol (I) with dimethylsulfate in a two phase system gives 4-methoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (II), which is condensed with epichlorohydrin (III) by means of piperidine at 100 C yielding 1-methoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (IV). The reaction of (IV) with tert-butylamine (V) at 100 C affords 1-methoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VI), which is finally demethylated by treatment with pyridine hydrochloride at 160 C

参考文献中间体

【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; McGillion, F.B.; Nafetolol. Drugs Fut 1981, 6, 2, 92.
【2】 Momiyama, N.; Ichikawa, Y.; Hasegawa, S.; Ishikawa, T.; Matsuyama, R.; Miazaki, K.; Shimada, H.; Targeting MMP-7 via antisense oligonucleotide shows anti-metastatic effects in a colon cancer murine model. Eur J Med Chem 1974, 9, 5, 501.

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)	61070	tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-triene-3,6-diol		C₁₂H₁₄O₂	详情	详情
(II)	61071	6-methoxytricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-ol		C₁₃H₁₆O₂	详情	详情
(III)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(IV)	60172	4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione		C₁₇H₁₂N₂O₂	详情	详情
(V)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(VI)	60173	10-bromo-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione		C₁₇H₁₁BrN₂O₂	详情	详情

合成路线2

The selective hydrolysis of 1,4-diacetoxy-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII) with diethylamine in methanol gives 4-acetoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (VIII), which is condensed with epichlorohydrin (III) by means of piperidine at 90 C to afford 1-acetoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII). The reaction of (IX) with tert-butylamine (V) in refluxing toluene gives 1-acetoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (X), which is finally hydrolyzed with dry HCl in refluxing methanol

参考文献中间体

【1】 Lauria, F.; et al. (Carlo Erba, S.p.A.); BE 790188; CA 992983; CH 565741; DE 2251095; FR 2157897; GB 1351557; JP 7349750; NL 7214106; ZA 7207459 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; McGillion, F.B.; Nafetolol. Drugs Fut 1981, 6, 2, 92.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(V)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(VII)	61074	6-(acetyloxy)tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate		C₁₆H₁₈O₄	详情	详情
(VIII)	61075	6-hydroxytricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate		C₁₄H₁₆O₃	详情	详情
(IX)	61076	6-(2-oxiranylmethoxy)tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate		C₁₇H₂₀O₄	详情	详情
(X)	61077	6-[3-(tert-butylamino)-2-hydroxypropoxy]tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate		C₂₁H₃₁NO₄	详情	详情

Extended Information