Hantzsch synthesis nifedipine

Extensive stmcture activity relationship (SAR) studies in this series revealed that unsymmetrical substitution on the heterocyclic ring and hence the introduction of chirality on the central carbon atom led to increased potency. Such asymmetrical dihydro-pyridines can be prepared by stepwise variation of the Hantzsch synthesis, based on the hypothetical alternate route to nifedipine. Thus, aldol condensation of methyl acetoacetate with 2,3-dichlorobenzaldehyde (13-1) gives the cinnamyl ketone (13-2). Reaction of that with the enamine (13-3) from ethyl acetoacetate gives the calcium channel blocker felodipine (13-4) [14]. 

Extending the Hantzsch synthesis and in the course of producing new 4-aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino-l,4-dihydropyridine-3-carboxylic esters 20 and 2217 (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-l,3-oxazolinone-5.18... 

Nifedipine 218 and other related 1,4-dihydropyridines are important as antihypertensive agents (Ca antagonists). They are prepared by a classical Hantzsch synthesis from acetoacetic ester, arylaldehyde and NH3 [72]. Sulfapyridine 219 was one of the first sulfonamide antibacterial agents to be used. Cerivastatin (Lipobay) 220, a powerful HMG-CoA reductase inhibitor, is applied for treatment of primary hypercholesteremia types Ila and b. 

Old as it may be, the Hantzsch process still finds use in drug synthesis. Nifedipine, which is used to relieve the chest pain of angina pectoris, is a dihydropyridine derivative prepared by the procedure outlined in Scheme 9.45 from ethyl acetoacetate and ortho-nitrobenzaldehyde, rather than benzaldehyde, and without the step of oxidation to the pyridine. ... 

Bossert and co-workers original three-component Hantzsch synthesis of nifedipine used 1 equiv of 2-ntirobenzaldehyde 181, 2 equiv of methyl acetoacetate 180, and ammonia to give nifedipine in 72% yield. Since their report, a number of variations on the Hantzsch 1,4-dihydropyridine synthesis have been reported. Many of the initial reports on the synthesis of 1,4-dihydropyridine derivatives were aimed at studying the structure activity relationships of these compounds with the goal of developing more potent and specific analogs of nifedipine. 

Ley and co-workers recently used magnesium nitride as a source of ammonia for the Hantzsch synthesis of 1,4-dihydropyridines in high yield. Optimized conditions involved the reaction of 4.5 equiv ethyl acetoacetate 180 and 2 equiv of 2-nitrobenzaldehyde 181 with 1 equiv of magnesium nitride (0.9 M NH3 concentration) in a refluxing solution of ethanol and water (6.5 equiv) for 16 h. The corresponding 1,4-dihydropyridine, in this case nifedipine, was produced in 84%. A number of other 1,4-... 

Nifedipine can be made by a Hantzsch synthesis in a one-step convergent synthesis. However, the product purity is problematic and it is better to synthesize nifedipine in a series of steps [31]. 

A 1,4-dihydropyridine having coronary vasodilatory activity and, therefore, intended for relief of the intense chest pains of angina pectoris is nifedipine (34). Using a portion of the classical Hantzsch pyridine synthesis, condensation of two moles of... 

Application of part of the classical Hantzsch pyridine synthesis leads to nifedipine (87) (81 AG(E)762, 68SAP6801482), a calcium antagonist useful in the treatment of angina. The pharmacology of a chemically related drug, nisoldipine (88), has recently been studied (80AF2144). Both compounds inhibit the transmembrane movement of calcium into activated smooth and cardiac muscle. Nisoldipine, however, is characterized by a high potency and uniqueness of action and may well prove to be of considerable therapeutic value. 

Another important reaction of diketene derivatives is the Hantzsch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkylidene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4], and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

Khadilkar and Madyar have developed a large scale continuous synthesis of Hantzsch l,4-dihydropyridine-3,5-dicarboxylates in aqueous hydrotope solution, using a modified domestic microwave oven [81]. The authors used novel reusable aqueous hydrotope solution as a safe alternative to inflammable organic solutions, in a microwave cavity, for synthesis of commercially important calcium blockers such as nifedipine, nitrendipine, and a variety of other 1,4-dihydropyridines (DHP) (Scheme 10.38). Nitrendipine (R = 3-N02, R = Me) has been obtained in 94% yield (50 g) after 24 min by microwave irradiation of the reaction mixture (final temperature 86 °C) at a flow rate of 100 mL min. The reaction mixture was circulated through the microwave cavity in four cycles of 6 min each a 2-min gap between each cycle was imposed to avoid excessive heating. 

Although the Hantzsch 1,4-dihydropyridine synthesis was originally reported in the late 1800s, interest in this reaction developed only in the past 50 years with Bossert and co-workers synthesis of nifedipine, a potent calcium channel antagonist. The elucidation of the structure of NADH, which contains a dihydropyridine moiety, in the 1980s led to a second surge of research in this area. ... 

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