合成路线1

Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .