• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】Butorphanol tartrate, levo-BC-2627(free base), Stadol NS, Stadol

【化学名称】(-)-17-(Cyclobutylmethyl)morphinan-3,14-diol D-tartrate

【CA登记号】54965-23-0, 42408-82-2 (free base)

【 分 子 式 】C25H35NO8

【 分 子 量 】477.5596

【开发单位】Bristol-Myers Squibb (Originator), Nastech (Formulation)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics

合成路线1

The condensation of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone (I) with tetramethylene dibromide (A) by means of NaH in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone (II), b.p.(0.05) = 120-3 C, which is treated with acetonitrile and butyllithium in THF yielding 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthaleneacetonitrile (III), m.p. 140-2 C. This compound is reduced with LiAlH4 in THF to afford hydro-2,2-tetramethylene-1-naphthol (IV), m.p 178-80 C, and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene (V), m.p. 187 C. This amine is cyclized by reaction with bromine in CHCl3 giving 3-methoxy-9a-bromonrhasybanan hydrobromide (VI), m.p. 207.0-8.5 C (decomp.), and isomerized with dehydrobromination by treatment with NaHCO3 in DMF affording 3-methoxy-DELTA(8,14)-morphinan (VII), m.p. 180-4 C. The acetylation of (VII) with trifluoroacetic anhydride (B) yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan (VIII), m.p. 94-6 C, which is epoxidized with m-chloroperbenzoic acid in methylene chloride giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphinan (IX), m.p. 102-5 C. The deacetylation of (IX) with NaSH4 in ethanol gives 8,14-epoxy-3-methoxymorphinan (X), oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan (XI) (HCl salt, m.p. 243-4 C (decomp.)). The condensation of (Xl) with cyclobutylcarbonyl chloride (C) by means of pyridine in CH2Cl2 affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan (XII), m.p. 183-5 C, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (XIII) (HCl salt, mp. 248-50 C (decomp.)). Finally, (XIII) is demethylated by treatment with refluxing 48% HBr.

1 Conway, T.T.; Monkovic, I.; J Am Chem Soc 1973, 95, 23, 7910-12.
2 Pachter, I.; et al.; 14-Hydroxymorphinan derivatives. DE 2243961; FR 2154481; GB 1412129; GB 1412130; US 3819635 .
3 Monkovic, I.; Conway, T.T.; Process for the preparation of 14-hydroxymorphinan derivatives. JP 49061169; NL 7306344; US 3775414 .
4 Paton, D.M.; Castaner, J.; Butorphanol. Drugs Fut 1977, 2, 4, 231.
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) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(B) 33862 trifluoroacetic anhydride 407-25-0 C4F6O3 详情 详情
(I) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 33856   C15H18O2 详情 详情
(III) 33857 RCL R15,507-1 C17H21NO2 详情 详情
(IV) 33858   C17H25NO2 详情 详情
(V) 33859 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]ethylamine; 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]-1-ethanamine C17H23NO 详情 详情
(VI) 33860   C17H22BrNO 详情 详情
(VII) 33861 (1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraene; (1S,9R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-4-yl methyl ether C17H21NO 详情 详情
(VIII) 33863 2,2,2-trifluoro-1-[(1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-17-yl]-1-ethanone C19H20F3NO2 详情 详情
(IX) 33864 2,2,2-trifluoro-1-[(1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-18-yl]-1-ethanone C19H20F3NO3 详情 详情
(X) 33865 (1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-triene; methyl (1S,9R,10S,12S)-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-4-yl ether C17H21NO2 详情 详情
(XI) 33866 (1S,9R,10S)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol C17H23NO2 详情 详情
(XII) 33867 cyclobutyl[(1S,9R,10S)-10-hydroxy-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-17-yl]methanone C22H29NO3 详情 详情
(XIII) 33868 (1S,9R,10S)-17-(cyclobutylmethyl)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol C22H31NO2 详情 详情
(C) 18589 cyclobutanecarbonyl chloride 5006-22-4 C5H7ClO 详情 详情
Extended Information