合成路线1

A mixture of freshly distilled pyridine (A) and 1-chloro-2,4-dinitrobenzene (I) in dry acetone is allowed to reflux for 15 h. Removal of the solvent in vacuo affords a residue which is washed with ether, recrystallized in absolute ethanol and characterized as N-(2,4-dinitrophenyl)pyridinium chloride (II). To an ice-cooled solution of compound (II) in methanol, a suspension of isonicotinic acid hydrazide in methanol in five aliquots is added with stirring. Triethylamine is then added and the reaction is allowed to stand at room temperature overnight. The solid which precipitates is purified and characterized as compound (III). A suspension of compound (III) in dioxane:water (4:1 v/v) is heated under reflux for 12 h to afford a clear solution. Separation and purification of the products gives a yellowish crystalline solid of N-(4-pyridylcarbonylimino)pyridiniumylide (IV) and 2,4-dinitroaniline (V). A solution of compound (IV) in 95% ethanol is added dropwise to a solution of sodium borohydride in 95% ethanol pre-cooled to 0 C. After stirring for 4 h at 0 C, the reaction mixture is poured onto crushed ice and allowed to come to room temperature. Extraction with chloroform, drying and purification yields N-(4-pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine.

合成路线2

This compound can be obtained by four different ways: 1) By condensation of 5,6,7,8-tetrahydro-2-naphthol (I) with N-(6-methoxy-2-pyridyl)-N-methylthiocarbamoyl chloride (II) by means of K2CO3 in refluxing butanone. 2) By condensation of 2-naphthyloxythiocarbonyl chloride (III) with 6-methoxy-2-(methylamino)pyridine (IV) by means of K2CO3 in acetone. 3) The reaction of pyridine (IV) with CS2 and NaOH in THF gives N-(6-methoxy-2-pyridyl)-N-methyldithiocarbamic acid sodium salt (V), which is then condensed with 2-(2,4-dinitrophenoxy)-5,6,7,8-tetrahydronaphthalene (VI) in DMF. 4) The reaction of the dithiocarbamate (V) with 2,4-dinitrochlorobenzene (VII) in ethanol gives N-(6-methoxy-2-pyridyl)-N-methyldithiocarbamic acid 2,4-dinitrophenyl ester (VIII), which is then treated with naphthol (I) and sodium methoxide in DMF.

合成路线3

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4

Condensation of isonicotinamide (I) with 1-chloro-2,4-dinitrobenzene (II) gave quaternary pyridinium salt (III). This was further converted into pyridinium salt (V) by treatment with 2-methoxyaniline (IV) in MeOH. Catalytic transfer hydrogenation of the pyridine ring of (V) provided piperidine (VI). The amide function of (VI) was then reduced to amine (VII) using either borane-dimethyl sulfide complex or LiAlH4. Condensation of 4-chlorocatechol (VIII) with epichlorohydrin (IX) in aqueous KOH produced a mixture of regioisomeric benzodioxans (X) and (XI), from which the major 7-chloro isomer (X) was isolated by flash chromatography after treatment with tosyl chloride and pyridine yielding tosylate (XII). This compound was finally coupled with amine (VII) in the presence of K2CO3 and KI in boiling acetonitrile.

合成路线5

The condensation of 4-(3-hydroxypropyl)pyridine (I) with 2,4-dinitrochlorobenzene (II) in refluxing acetone gives the pyridinum chloride (III), which is treated with 2-pyridylcarbonyl hydrazide (IV) and triethylamine in methanol yielding the dinitroaniline derivative (V). The cyclization of (V) in refluxing dioxane/water affords the pyridinium ylide (VI), which is finally reduced with NaBH4 in ethanol.

合成路线6