The condensation of 4-benzyloxyphenacyl chloride (XV) with the amine (IV) in refluxing CH2Cl2 gives N-(3,4-dimethoxyphenylethyl)-4-benzyloxyphenacylamine (XVI), which is reduced with NaSH4 in ethanol, also affording the protected product (VI).
The benzylation of 4-hydroxymandelic acid (I) with benzyl alcohol (II) and K2CO3 in methanol gives 4-benzyloxymandelic acid (III), which is condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of (C2H5O)2PON3 in THF to afford N-(3,4-dimethoxyphenylethyl)-4-benzyloxymandelamide (V). The reduction of (V) with diborane in THF yields the final product protected at the phenolic hydroxyl (VI) This compound is finally deprotected by hydrogenolysis with H2 over Pd/C.
The condensation of 4-benzyloxybenzaldehyde (VII) with N-(3,4-dimethoxyphenylethyl)glycine (VIII) in refluxing pyridine also gives the protected product (VI).
The formylation of 2-(4-hydroxyphenyl)glycine (IX) as usual gives N-formyl-2-(4-hydroxyphenyl)glycine (X), which by treatment with benzyl alcohol as before yields N-formyl-2-(4-benzyloxyphenyl)glycine (XI). The condensation of (XI) with the amine (IV) by means of butyl chloroformate affords the corresponding amide (XII), which is deformylated by treatment with HCl in methanol to give the glycinamide (XIII). The diazotation of (XIII) with NaNO2 in acetic acid affords N-(3,4-dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide (XIV), which is finally reduced and deacetylated with LiAlH4 in THF yielding the protected product (VI).
The oxidation of 4-benzyloxyphenacyl chloride (XV) with KI and DMSO gives 4-benzyloxy-alpha-oxophenylacetaldehyde (XVII), which is condensed with the amine (IV) to afford the corresponding Schiff base (XVIII). Finally, this compound is reduced with NaBH4 yielding the protected product (VI), already obtained.
By reduction of benzyl (4-benzyloxy)phenacyl-(3,4-dimethoxyphenethyl)carbamate (XIX) with sodium prolinate-borane complex (XX) and hydrogenation over 10% palladium on a carbon catalyst.
A new enantioselective synthesis of R-(-)-denopamine has been published: The silylation of 4-hydroxyphenacyl chloride (I) with tert-butyldimethylchlorosilane (II) and imidazole in THF gives the silylated compound (III), which is enantioselectively reduced with borane, using the (R)-oxaazaborilidine (IV) as optically active catalyst in THF, yielding (R)-2-chloro-1-[4-(tert-butyldimethylsilyloxy)phenyl]ethanol (V). The reaction of (V) with NaI in refluxing acetone affords the corresponding iodo-alcohol (VI), which is protected with triethylchlorosilane and imidazole in DMF to give the fully silylated compound (VIII). The condensation of (VIII) with 2-(3,4-dimethoxyphenyl)ethylamine (IX) by means of triethylamine in THF at 100 C in a sealed tube yields the fully silylated denopamine (X), which is finally deprotected by a treatment with KF and HCl in methanol.
A new enantioselective synthesis for denopamine has been reported: The acylation of 1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanone (I) with benzyloxycarbonyl chloride (II) by means of NaHCO3 in dichloromethane gives the protected aminoketone (III), which is submitted to an asymmetric reduction with (R)-(+)-2-amino-3-methyl-1,1-diphenyl-1-butanol-borane complex in THF yielding the (R)-(-)-protected alcohol (V). Finally, the debenzylation of (V) by hydrogenolysis with H2 over Pd/C in methanol affords denopamine with 96% optical purity.
The enantioselective condensation of 4-(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in ethanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with carboxylic acid (VI) by means of 2,2-dimethylpropanoyl chloride and DIEA in THF affords the corresponding amide (VII), which is reduced with LiAlH4 in Et2O to yield the protected hydroxyamine (VIII). Finally, this compound is desilylated by means of HCl and KF in MeOH to furnish the target tetrahydroxyamine derivative.
The enantioselective condensation of 3,4-bis(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in methanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with 4-[4-(tert-butyldimethylsilyloxy)phenyl]butyric acid (VI) by means of diphenyl chlorophosphate and DIEA in dichloromethane affords the corresponding amide (VII), which is reduced by conventional methods to the protected hydroxyamine (VIII). Finally, this compound is desilylated as usual to furnish the target tetrahydroxyamine derivative.
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of HCl in water to provide the target Denopamine.
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 6-(4-phenylbutoxy)hexylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the precursor (V), which is finally deprotected by means of HCl in water to provide the target (R)-salmeterol.
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 6-(4-phenylbutoxy)hexylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of H2,Pd/C in water to provide the target (R)-salmeterol.