合成路线1

Nitration of 1,8-naphthalic anhydride (I) in sulfuric acid at 60 C for 1 h gives 3,6-dinitro-1,8-naphthalic anhydride (II) in 80% yield (m.p. 209-211 C from toluene; NMR: in CDCl3 a 9.22, 9.27, 2 singlet aromatic H), which, on treatment with unsym-N,N-dimethylethylenediamine at room temperature for 30 min, followed by azeotropical removal of water at 140 C for 2 h in refluxing toluene solution and salt conversion with HCl, yields the monohydrochloride salt of dinimide in 62% yield.

合成路线2

The reaction of 1,8-naphthoic anhydride (I) with hydroxylamine and NaOAc in water gives the N-hydroxynaphthalimide (II), which is condensed with 2,4-dinitrochlorobenzene (III) by means of Na2CO3 in hot water yielding the expected naphthalimide derivative (IV). The rearrangement of (IV) induced by NaOH in ethanol/water affords 8-amino-1-naphthoic acid (V), which is cyclized by means of sulfuric acid to the benz[cd]indolin-2-one (VI). The nitration of (VI) with HNO3 in acetic aid gives the expected 6-nitro derivative (VII), which is reduced with H2 over Pd/C in THF to the corresponding amino derivative (VIII). The condensation of (VIII) with the benzyl bromide (IX) by means of DIEA in hot DMF affords the secondary amine (X), which is methylated with methyl iodide and DIEA in hot DMF to provide the tertiary amine (XI). The reaction of the carbonyl group of (XI) with Lawesson's reagent gives the thione (XII), which is methylated with methyl iodide and NaOH to give the methylsulfanyl derivative (XIII). Finally, this compound is treated with ammonia in methanol.

合成路线3

By condensation of 1,8-naphthalic anhydride (I) wih N,N’-bis(2-aminoethyl)propane-1,2-diamine (II) in refluxing dioxane, or in hot NMM.

合成路线4

RS-25259-197 can be obtained by several related ways: 1) The condensation of naphthalene-1,8-dicarboxylic anhydride (I) or the corresponding imide (II) with quinuclidin-3(S)-amine (III) in refluxing isopropanol gives 2-[3(S)-quinuclidinyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (IV), which by hydrogenation with H2 over PtO2 in ethanol yields 3-hydroxy-2-[3(S)-quinuclidinyl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquionlin-1-one (V). The dehydration of (V) with HCl in refluxing isopropanol affords the 2,4,5,6-tetrahydro compound (VI) (1), which is finally hydrogenated with H2 over Pd/C in acetic acid to yield a mixture of (S,S)- and (R,S)-diastereomers that is resolved by crystallization and chromatography. 2) The partial hydrogenation of anhydride (I) with H2 over Pd/C in hot acetic acid gives 3-acetoxy-5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (VIII), which is deacetylated by hydrogenation with H2 over Pd/C in ethyl acetate, yielding 5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (IX). Finally, this compound is condensed with the quinuclidine (III) by heating at 140 C and digestion with methanol to afford the hydroxy compound (V), already obtained. 3) The cyclization of N-[3(S)-quinuclidinyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide (X) by means of butyllithium and DMF gives the 2,4,5,6-tetrahydro compound (VI), already obtained.

合成路线5

The reaction of 5-aminoisophthalic acid (I) with 1,8-naphthalic anhydride (II) in DMSO/pyridine gives the expected naphthalimide (III), which is condensed with diethylenetriamine (IV) by means of CDI in DMA to yield the isophthalamide (V). Finally, the free amino groups of (V) are condensed with 4-chloronaphthalic anhydride (VI) in pyridine/DMSO to afford the target tris naphthalimide.

合成路线6

Condensation of 1,8-naphthalic anhydride (I) with ethylenediamine (II) provides the N-aminoethyl naphthalimide (III). Amine (III) is subsequently condensed with 2-chloroethyl isocyanate (IV) to afford urea (V). Finally, nitrosation of (V) by means of NaNO2 and formic acid leads to the title N-nitrosourea.

合成路线7

合成路线8