合成路线1

By a Wittig reaction at naltrexone (I) with triphenylmethylphosphonium bromide (II) in DMSO by means of NaH as base.

合成路线2

The reductocondensation of naltrexone (I) with N-methylbenzylamine (II) by means of sodium cyanoborohydride in THF gives the N-benzyl-N-methylaminomorphinan derivative (III), which is debenzylated by hydrogenation with H2 over Pd/C in methanol yielding the methylaminomorphinan (IV). Finally, this compound is acylated with 3(E)-(3-furyl)acryloyl chloride and NaOH, Na2CO3 or triethylamine in methanol, THF or chloroform. Alternatively, methylaminomorphinan (IV) can also be obtained by direct reductocondensation of naltrexone (I) with methylamine by means of H2 over PtO2 in methanol.

合成路线3

Synthesis of [18F]FEtNTI: The intermediate 2-(N1-phenylhydrazino)acetic acid ethyl ester (II) has been obtained by two different ways: 1.- By nitrosation of N-phenylglycine ethyl ester (I) with NaNO2 followed by readuction with Zn/acetic acid (low yields). 2.- By condensation of phenylhydrazine (III) with ethyl bromoacetate (IV) by means of an excess of triethylamine. The cyclization of intermediate (II) with naltrexone (V) by mans of HCl in methanol gives the indolomorphinanylacetic ester (VI), which is benzyl protected at the OH group by means of benzyl bromide and K2CO3 in DMF yielding the benzyl ether (VII). The reduction of the ester group of (VII) with LiAlH4 in THF/toluene afords the indolomorphinanylethanol (VIII), which is treated with tosyl chloride and potassium trimethylsilanolate in toluene to provide the corresponding tosylate (IX). The reaction of (IX) with potassium [18F]fluoride, K2CO3 and Kryptpfix [2.2.2] in hot DMF gives the 18F labeled intermediate (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in DMF/triethylamine.

合成路线4

Fischer indole cyclization of naltrexone (I) with 4-nitrophenylhydrazine (II) provided 5'-nitronaltrindole (III). Subsequent reduction of the nitro group of (III) by means of hydrazine hydrate and Raney Nickel gave the 5'-amino derivative (IV). Mercury-assisted condensation of (IV) with di(tert-butoxy-carbonyl)thiourea (V) afforded the protected guanidine (VI). Finally, the Boc groups of (VI) were cleaved by treatment with trifluoroacetic acid to furnish the title compound.

合成路线5

The title compound was prepared by condensation of naltrexone hydrochloride (I) with 2-(4-chlorophenyl)malondialdehyde (II) in the presence of ammonium acetate in refluxing AcOH.

合成路线6

The title polycyclic compound was synthesized by Fisher indolization of naltrexone (I) with 1-amino-6-fluoro-1,2,3,4-tetrahydroquinoline (II) in the presence of methanesulfonic acid in refluxing EtOH.

合成路线7

Condensation of naltrexone (I) with benzylamine produces the intermediate imine (II) which is subsequently cyclized with trans-beta-nitrostyrene (III) to produce the required pyrrolomorphinan.

合成路线8

Fischer indole cyclization of naltrexone (I) with 4-(cyanomethyl)phenylhydrazine (II) produces the indolomorphinan derivative (III). Subsequent reduction of the cyano group of (III) by catalytic hydrogenation over Raney-nickel produces amine (IV). This is then condensed with methyl acetimidate (V) to furnish the corresponding amidine.

合成路线9