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.

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.

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.

Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.

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.

Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.