Hantzsch's Pyridine Synthesis

1,4‐Dihydropyridines—a basis for developing new drugs

“…38 When using higher aliphatic alkylamines, benzylamine, and aromatic amines generally as components I11 of the Hantzsch synthesis (Figure 2), however, aldol condensation with the formation of cyclohexanone derivatives ( 20)28 was preferred in most cases. * These compounds (20) generally reacted further *One exception is compound 25. with the unconverted amine to form practically inactive Schiff bases or enamines (23).39 To produce N-1-substituted 1,4-dihydropyridines, the synthesis procedure previously used was the only option, despite its greater An additional possibility, of forming corresponding cyclohexene derivatives by dehydration of 20 and 23, makes obvious the reason for the lack of clarity that previously existed in attempts to produce N-1-substituted 1,Pdihydropyridines using the Hantzsch procedure.39 A general list of results of pharmacological investigations is given for Nmethyl-l,4-dihydropyridines in Table IX, for N-aryl-1,4-dihydropyridines in Table X, and for N-1-substituted 4-pyridyl-1,4-dihydropyridines in Table XI.…”

“…With the pharmacologically unremarkable 4-alkyl-l,4-dihydropyridines, interest was aroused by the restoration of activity by additional aryl groups on the alkyl residue (Table VII); a surprising occurrence, on the other hand, even though observed only at high doses, was the continuing action of pyran derivatives 1 927 corresponding to the 1,4-dihydropyridines, and of isomeric cyclohexanone derivatives (20) (Table VIII), which can be formed by aldol condensation in a side reaction of the Hantzsch synthesis.28 The pharmacological results obtained with compounds 19 and 20 showed that the action is not limited to 1,4-dihydropyridines, but can also be exerted by other classes of compounds. Further research was intended to produce a double action in the same molecule, namely to combine the coronary vasodilatory action with an additional effect similar to the lipid-reducing action of clofibrate (Table VI; 61) or, parallel to the work done elsewhere on khellin,'" with a P-blocking action similar to that of propranolol (compound 27u).…”

“…It was necessary to determine in further studies whether this hypertensive effect (which deviated from the previous picture) was induced by peripheral vasoconstriction or was a sign of increased cardiac performance. These new findings, which were of great interest to us, were the basis on which compounds with a positive inotropic action were later developed.45 On the other hand, it was noticeable that with the corresponding intermediate products (Table IX, 8,10,11,[15][16][17][18][19][20] there was no hint of a change in action, at least in the i.v. studies.…”

PEG-Promoted One-Pot Synthesis of 1,4-Dihydropyridine Derivatives Via Hantzsch Reaction in H2O

“…2 However, this method involves long reaction time, harsh reaction conditions, the use of a large quantity of volatile organic solvents and generally gives low yields. Therefore, it is necessary to develop an efficient and versatile method for the preparation of 1,4-DHPs and there were several efficient methods developed for the synthesis of 1,4-dihydropyridines, comprising the use of microwave, 3 ionic liquid, 4 solvent-free, 5 TMSClNaI, 6 solar energy, 7 and so on.…”

Synthesis of [13C2]nifedipine

“…2 Since the 13 C-labeled drug would be useful in 13 C-NMR studies of its interactions with other drugs or biological molecules, we synthesized 13 C-labeled nifedipine ð % 3Þ. …”