Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction

Rizatriptan (Maxalt®): A 5‐HT1D Receptor Agonist

“…The diethyl 4 -( N,N -dimethylamino)butanal ( 11 ) was readily prepared from chloroacetal 8 via S N 2 displacement using 40% aqueous dimethyl amine; later 11 became commercially available. This more convergent Fisher indole synthesis using the functionalized acetal 11 was previously developed for another 5HT 1D receptor agonist L -695,894 ( 13 ) and was extended to a wide variety of tryptamines, as shown in Scheme 4.2 [5] . For example, condensation of cyanobenzohydrazine 12 with acetal 11 in 4% H 2 SO 4 afforded the desired tryptamine 14 in 81% yield.…”

“…This material, however, contained two major impurities: dimer 69 (7A%) and trimer 70 (2A%). Both of which were presumably formed through 68 [5] and were extremely diffi cult to remove from 2 by silica gel chromatography or traditional crystallization techniques. NuFor the large scale synthesis, the sodium salt of 2 formed in the NaCN -NaOH reaction could be purifi ed by brominated polystyrene resin SP -207 chromatography to avoid acidic work -up which generates HCN.…”

“…Indeed, we were gratifi ed to fi nd that direct condensation of o -iodoaniline 24 ( 77 , R 1 = H) with cyclohexanone (in the presence of 5 mol% Pd(OAc) 2 and 3 equiv DABCO as a base at 0.3 M and 105 ° C afforded the tetrahydrocarbazole 81a in 77% yield with no other major impurities (Figure 4.4 ) [5] . The use of DMF as a solvent is crucial to the success of this reaction; other solvents such as acetonitrile and toluene were ineffective.…”

Regioselective alkylation of 1,2,4-triazole using ionic liquids under microwave conditions

“…Two different methods are reported for the synthesis of anti-migraine drug rizatriptan, and the most obvious synthetic step for the introduction of 1,2,4-triazole is through alkylation reaction [6]. The triazole nucleus exists in two tautomeric forms, namely, 4H-1,2,4-triazoles and 1H-1,2,4-triazoles, and in general, the alkylation reaction results in the formation of an isomeric mixture of 1-substituted 1,2,4-triazole and 4-substituted 1,2,4-triazole.…”

Intermolecular Heck Reaction: Palladium-Catalyzed Coupling Reactions for Industrial Fine Chemicals Syntheses

“…Under these conditions, 80% of the (partially de-O-protected) substituted indole is formed in DMF at 100 °C. [57] IV.2. …”