The synthesis of the precursor (XII) has been reported by two related procedures. Ethyl nipecotate (I) was protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Benzylic bromination of 4-methylthiazole (III) with NBS and AIBN provided bromide (IV). Then, alkylation of protected nipecotate (II) with bromide (IV) in the presence of potassium hexamethyldisilazide gave the thiazolylmethyl derivative (V). Subsequent acid deprotection of the Boc group of (V) yielded racemic piperidine (VI). Resolution was achieved by coupling with (R)-O-acetylmandelic acid, followed by chromatographic separation of the diastereomeric amides (VII), and hydrolytic removal of the chiral auxiliary. The required (S)-nipecotate (VIII) was condensed with N-Boc-D-tryptophan (IX) to provide amide (X). Deprotection of the Boc group and further coupling of (X) with N-Boc-2-aminoisobutyric acid (XI) then furnished intermediate (XII).
Alternatively, N-Boc-D-tryptophan (IX) was esterified with benzyl alcohol in the presence of EDC and DMAP to give benzyl ester (XIII). Deprotection of the Boc group of (XIII) with TFA, followed by coupling of the resulting amino ester (XIV) with N-Boc-2-aminoisobutyric acid (XI) provided protected dipeptide (XV). Hydrogenolytic removal of the benzyl ester of (XV) gave carboxylic acid (XVI), which was coupled to the (S)-nipecotate (VIII) to afford the precursor (XII). Finally, removal of the Boc protecting group by treatment with HCl in EtOAc yielded the title compound.
Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 4-(bromomethyl)thiazole (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 2-(chloromethyl)pyridine chloride (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.