Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

A new synthesis of sabcomeline hydrochloride has been described: The hydrolysis of quinuclidine-3-carboxylic acid ethyl ester (I) with refluxing aqueous HCl gives the corresponding acid (II), which by reaction with thionyl chloride in refluxing dichloromethane yields the expected acyl chloride (III). The reaction of (III) with O-methylhydroxylamine in chloroform/pyridine affords N-methoxyquinuclidine-3-carboxamide (IV), which by reaction with triphenylphosphine/CCl4 in refluxing acetonirile is converted into the imidoyl chloride (V). The reaction of (V) with NaCN in hot DMSO gives 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (VI) as a mixture of the (E)- and (Z)-isomers that is resolved by column chromatography yielding the (Z)-isomer (VII). Finally, this compound (VII) is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP].