合成路线1

Reaction of alpha-tetralone (I) with formadehyde (II) and tyramine hydrochloride (III) in alcohol.

合成路线2

The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (II), which is regioselectively demethylated with conc. H2SO4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (III). The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 in ethanol affords the secondary amine (V), which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (VI). The oxidative cyclization of (VI) by means of potassium ferricyanide and K2CO3 in toluene/water gives the (+/-)-bromoformylnarwedine (VII), which is protected with propyleneglycol (VIII) and TsOH in hot toluene yielding the ketal (IX). The reduction of the formyl group of (IX) with LiAlH4 in THF affords racemic narwedine (X), which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing TEA, an 80% of (-)-narwedine (XI) is obtained. Finally, this compound is stereoselectively reduced to the target compound by means of L-selectride in THF.

合成路线3

1) The N-acylation of DL-serine (I) with 3,5-di-tert-butyl-4-hydroxybenzoic acid by means of carbonyldiimidazole (CDI) in THF gives the acylated serine (III), which is cyclized by means of CBr4/triphenylphosphine/imidazole in acetonitrile to yields the oxazoline (IV). The dehydrogenation of (IV) with activated MnO2 in acetone affords 2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole-4-carboxylic acid methyl ester (V), which is reduced with LiBH4 in THF/methanol giving the oxazolylmethnaol (VI). The reaction of (VI) with Br2/triphenylphosphine in acetonitrile yields the bromomethyl derivtive (VII), which is condensed with N-ethyl-N-[2-(4-hydroxyphenyl)ethyl]formamide (VIII) by means of NaH in THF to afford the formylated precursor (IX). Finally, this compound is converted into LY-382924 by reduction of the formyl group with AlH3 (LiAlH4/H2SO4) in THF and treatmnt with HCl gas in CHCl3. 2) The intermediate N-ethyl-N-[2-(4-hydroxyphenyl)ethyl]formamide (VIII) has been obtained as follows: The acylation of 2-(4-hydroxyphenyl)ethylamine (X) with acetic anhydride gives the acetamide (XI), which is reduced with LiAlH4 to the secondary amine (XII). Finally, this amine is formylated with formic acid and carbonyldiimidazole (CDI) in THF.

合成路线4

The N-protection of 4-(2-aminoethyl)phenol (I) with benzyl chloroformate gives the N-benzyloxycarbonyl derivative (II), which is condensed with 1-methyl-1-(trichloromethyl)ethanol (III) by means of NaOH in acetone yielding the phenoxyisobutyric acid (IV). The deprotection of the amino group of (IV) by hydrogenation over Pd/C affords the ethylamino derivative (V), which is reprotected with 9-fluorenylmethoxycarbonyl protecting group to provide carbamate (VI). The acid group of (VI) is then coupled to a Sasrin polystyrene resin giving the N-protected resin (VII), which is deprotected with piperidine affording resin (VIII) with a free amino group, which is condensed with heptanoic acid (A) by means of DIC and HOBT to give the amide (IX). The reduction of the carbonyl group amide (IX) with BH3/THF yields the heptylamine (X), which is condensed with 4-fluorophenyl isocyanate (XI) to afford the urea (XII). Finally, this compound is treated with trifluoroacetic acid to eliminate the polystyrene resin and isolate the target compound. Alternatively, the heptylamine (X) can also be obtained directly by reductocondensation of the free amino group of the resin (VIII) with heptanal (B) by means of NaBH3CN.

合成路线5

The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in acetic acid gives 2-bromo-4,5-dimethoxybenzaldehyde (II), which is selectively demethylated with H2SO4 yielding 2-bromo-5-hydroxy-4-methoxybenzaldehyde (III). The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 affords the secondary amine (V), which is formylated with ethyl formate in dioxane/DMF giving the formamide (VI). The cyclization of (VI) by means of potassium hexacyanoferrate (III) and K2CO3 in hot toluene yields racemic N-formylbromonarwedine (+/-)(VII), which is reduced with lithium tri-tert-butoxyaluminum hydride furnishing a mixture of N-demethylbromogalanhamine (+/-)(VIII) and N-demethylepibromogalanthamine (+/-)(IX). After chromatographic separation of the two racemic epimers, resolution of racemic (+/-)(VIII) is carried out employing di-p-toluoyl tartaric acid to afford the required levo isomer. Alkylation of (-)(VIII) with 1-(3-chloropropyl)piperidine (X) gives (XI), which is finally converted to the title compound by reductive debromination in the presence of Zn and CaCl2.

合成路线6

The benzoylation of tyramine (2-(p-hydroxyphenyl)ethylamine) (I) with 4-chlorobenzoyl chloride (II) in pyridine gives 4-(4-chlorobenzoylaminoethyl)phenol (III), which by condensation with ethyl alpha-bromoisobutyrate (IV) by means of K2CO3 in refluxing butanone affords ethyl alpha-[4-(4-chlorobenzoylaminoethyl)phenoxy]isobutyrate (V). Finally, this compound is hydrolyzed with KOH in dioxane - water.

合成路线7

Coupling of tyramine (I) with p-nitrophenyl isocyanate (II) affords urea (III). Subsequent nitro group reduction with H2 and Pd/C gives amine (IV). Condensation of amine (IV) with ethylene oxide (V) leads to the bis-hydroxyethyl amine (VI). This is finally chlorinated employing SOCl2 in pyridine. Alternatively, amine (IV) is subjected to reductive alkylation with chloroacetaldehyde and NaBH3CN to furnish the target bis-chloroethyl amine. (1,2)

合成路线8

Reaction of tyramine (VIII) with p-nitrophenyl chloroformate (IX) gives rise to the nitrophenyl carbamate (X). Finally, coupling of (X) with aniline (VII) provides the title urea.

合成路线9