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This compound can be prepared in several ways from the lactone (I), which is obtained by treatment of benzyl cyanide (A) and epichlorhydrin (B) with sodium amide: 1) The opening of lactone (I) with SOBr2-ethanol gives a bromo ester, which is treated successively by ammonia and sodium hydroxide to yield the amino acid (II). The reaction of (II) with SOCl2 and diethylamine in ethanol gives the final product, which is converted to the hydrochloric salt by treatment with HCl ethanol. 2) Lactone (I), opened with 33% HBr-AcOH, gives the bromo acid (III), which is treated by SOCl2 and then diethylamine in ethanol. The bromoamide (IV) reacts with potassium phthalimide and is deprotected by hydrazine or methylamine to yield, after salification, title compound. 3) Lactone (I) is treated by potassium phthalimide and then SOCl2 and diethylamine in EtOH to give compound (V), treated as above. 4) Bromoamide (IV) can be treated by hexamethylenetetramine in butanol and hydrolyzed by refluxing with 15% HCl in ethanol.

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The condensation of ethyl 2-bromo-3-methylbutyrate (IX) with phenylacetonitrile (X) by means of activated Zn in THF gives the ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (XI), which is cyclized with thiourea (XII) by means of sodium ethoxide in refluxing ethanol yielding 6-benzyl-5-isopropyl-2-thioracil (XIII). The desulfurization of (XIII) with a refluxing solution of 10% chloroacetic acid in water affords the corresponding uracil (XIV), which is finally alkylated with chloromethyl ethyl ether (II) and BSA in chloroform.

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Nibentan is obtained as illustrated in Scheme 22645801a: Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II). Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III). Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV), which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V). The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI), which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol. Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII). Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.

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The reaction of 2-phenylacetonitrile (I) with 2-bromo-3-methylbutyric acid ethyl ester (II) by means of Zn in THF gives the ketoester (III), which is cyclized with thiourea (IV) by means of sodium ethoxide in ethanol yielding 6-benzyl-5-isopropyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally, this compound is treated with chloromethyl methyl sulfide (VI) and K2CO3 in DMF.

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The alkylation of (R)-alpha-methylbenzylamine (I) with methyl bromoacetate (II) gave aminoacetate (III). This was coupled with protected histidine (IV) by means of HATU as the coupling agent, yielding the protected dipeptide (V). Subsequent saponification of (V) using LiOH gave acid (VI). beta,beta-Dimethyl-phenethylamine (IX) was prepared by alkylation of phenylacetonitrile (VII) with iodomethane and NaH, followed by hydrogenation of the resulting dimethylated compound (VIII) in the presence of Raney Nickel. Coupling of amine (IX) with dipeptide (VI) provided the corresponding amide (X). The trityl protecting group of (X) was finally removed by treatment with trifluoroacetic acid.

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The precursor mesylate (V) was synthesized as follows. Alkylation of phenylacetonitrile (I) using isopropyl bromide in the presence of KOH provided 2-phenylisovaleronitrile (II). Michael addition of ethyl acrylate to the potassium anion of nitrile (II) afforded cyano ester (III). After ester group reduction with LiAlH4, the resultant alcohol (IV) was treated with methanesulfonyl chloride and triethylamine to yield mesylate (V).

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