合成路线1

Alkylation of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene (I) with benzyl bromide provided the corresponding dibenzyl amine (II). The methyl ether of (II) was then cleaved to phenol (III) employing boron tribromide in cold CH2Cl2. Conversion of phenol (III) into amine (VII) was carried out by the sequence involving O-alkylation of (III) with 2-bromoisobutyramide (IV), followed by rearrangement of the resulting ester (V) to the N-substituted amide (VI) upon heating in the presence of NaH and DMPU, and acidic hydrolysis of the amide function of (VI). Acylation of amine (VII) with N-methyl iminodiacetic acid (VIII), via activation with CDI, furnished the cyclic imide (IX), which was further reduced to piperazine (X) using LiAlH4. Bromination of the aromatic amine (X) with Br2 in the presence of NaOAc and HOAc gave bromide (XI). Metalation of (XI) with t-BuLi, followed by addition of methyl chloroformate, produced the carboxylate ester (XII). Subsequent reduction of (XII) by means of LiAlH4 gave rise to the benzylic alcohol (XIII). Removal of the N-benzyl groups of (XIII) and simultaneous alcohol reduction to the methyl derivative (XIV) was achieved by using transfer hydrogenolysis in the presence of ammonium formate and Pd/C. Amine (XIV) was finally coupled with 4-morpholinobenzoic acid (XV) via activation with CDI.