The condensation of 3-acetyl-4-hydroxyaniline (I) with N,N-diethylcarbamoyl chloride (II) in pyridine gives the urea (II), which is treated with epichlorohydrin (IV) and NaOH to yield N-[3-acetyl-4-(2,3-epoxypropoxy)phenyl]-N',N'-diethylurea (V). Finally, the epoxy ring of (V) is opened with tert-butylamine (VI).
The reaction of 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy)aniline (VII) with phenyl carbamate (VIII) in pyridine gives the N-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamic acid phenyl ester (IX), which is tretated with diethylamine (X) in ethanol/water. By reaction of N-[3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl]-N',N'-diethylurea (XI) with tert-butylamine (VI).
The reaction of 4-nitrophenol (I) with acetic anhydride in aqueous NaOH gives the corresponding acetate (II), which is submitted to a Fries migration with AlCl3 in nitrobenzene at 140 C to yield the acetophenone (III). The condensation of (III) with epichlorohydrin (IV) by means of K2CO3 affords the adduct (V), which is treated with tert-butylamine (VI) in water to obtain the aminoisopropanol derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the corresponding amino derivative (VIII), which is finally condensed with N,N-diethylcarbamoyl chloride (IX) by means of TEA in THF to yield the target urea.
The reaction of D-mannitol (I) with acetone and ZnCl2 gives the diacetonide (II), which is oxidized with Pb(OAc)4 to yield the acetonide of (R)-glyceraldehyde (III). The reduction of (III) with H2 over Pd/C affords the (S)-glycerin acetonide (IV), which is treated with TsCl in pyridine to provide the corresponding tosylate (V). The condensation of (V) with the urea derivative (VI) by means of KOH in DMSO gives the adduct (VII), which is deprotected with HCl in acetone to yield the diol (VIII). Monotosylation of (VIII) with TsCl in pyridine affords the primary tosylate (IX), which is treated with Na in methanol to provide the epoxide (X). Finally this compound is treated with tert-butylamine to furnish the target (R)-enantiomer.
The condensation of 4-ethoxyaniline (II) with N,N-diethylcarbamoyl chloride (II) by means of KHCO3 gives the urea (III), which is acylated with acetyl chloride and AlCl3 to yield N-(3-acetyl-4-hydroxyphenyl)-N',N'-diethylurea (IV). The alkylation of (IV) with epichlorohydrin (V) affords the adduct (VI), which is treated with HBr providing the bromoalcohol (VII). Finally this compound is treated with tert-butylamine to furnish the target urea.
There are several pathways for the preparation of the title compound according to the patent literature.