Alcohol (I) was converted to fluoride (II) by treatment with either diethylaminosulfur trifluoride or the Ishikawa reagent. Subsequent acid cleavage of the Boc protecting group of (III) provided piperidine (VI). Alternatively, alcohol (III) was converted to mesylate (IV), which was displaced with tetrabutylammonium fluoride to afford fluoride (V). The benzamido group of (V) was then hydrolyzed with HCl in aqueous MeOH.
Amine intermediate (XIV) has been obtained as follows: N-(Carbobenzoxy)-L-aspartic acid alpha-benzyl ester (VII) was converted to acid chloride (VIII) and then coupled to 2-aminophenyl disulfide (IX) to afford the bis-amide (X). Reductive cleavage of the disulfide group of (X), followed by basic cyclization, produced the benzothiazole (XI) (2). Hydrolysis of the benzyl ester group of (XI) and subsequent coupling of the resulting carboxylic acid (XII) with piperidine (VI) gave amide (XIII). The carbobenzoxy group of (XII) was then cleaved with HBr in HOAc, yielding intermediate amine (XIV).
2-Aminobenzonitrile (XV) was acylated with 2-bromoisobutyryl bromide (XVI) to afford the cyano amide (XVII). Halogen-metal exchange with ethylmagnesium bromide followed by intramolecular addition to the cyano group of (XVII) gave rise to the quinoline dione (XVIII). This was reduced to the tetrahydroquinoline (XIX) by means of LiAlH4 and AlCl3. Iodination of (XIX) with benzyltrimethylammonium iodine dichloride furnished (XX), which was coupled with ethyl acrylate (XXI) in the presence of palladium acetate, yielding the unsaturated ester (XXII). After catalytic hydrogenation of the olefin (XXII) to propionyl ester (XXIII), sulfonation and treatment with POCl3, intermediate sulfonyl chloride (XXIV) was obtained.
An alternative procedure for the preparation of tetrahydroquinoline (XXIII) consisted in the acylation of ethyl 4-aminocinnamate (XXV) with the in situ prepared dimethylmalonyl chloride (to give (XXVI)), followed by cyclization to the quinoline dione (XXVII) by means of phosphorus pentoxide and methanesulfonic acid. The hydrogenation of the double bond of (XXVII) and simultaneous reduction of the keto group produced quinolinone (XXVIII). Further reduction of the lactam carbonyl group of (XXVIII) to provide (XXIII) was carried out via conversion to thiolactam (XXIX), which was alkylated with iodomethane to the S-methyl thioimidate (XXX) and then reduced with NaBH3CN.
Quinolinone (XXVIII) was also obtained by reduction of quinoline dione (XXXI) to alcohol (XXXII), followed by esterification to acetate (XXXIII) and hydrogenolysis of the acetoxy group in the presence of palladium oxide.
Coupling between sulfonyl chloride (XXIV) and amine (XIV) provided sulfonamide (XXXIV). The ethyl ester group of (XXXIV) was then hydrolyzed to carboxylic acid (XXXV), which was finally coupled with N-(2-morpholin-4-yl-2-oxoethyl)piperazine (XXXVI) to furnish the title amide.