Ammonia Nifedipine

Another important reaction of diketene derivatives is the Hant2sch 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-alkyhdene 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). 

Nifedipin Nifedipine, dimethyl ether l,4-dihydro-2,6-dimethyl-4-(2 -nitrophenyl)-3,5-piridindicarboxylic acid (19.3.16), is synthesized by a Hantsch synthesis from two molecules of a j3-dicarbonyl compound—methyl acetoacetate, using as the aldehyde component—2-nitrobenzaldehyde and ammonia. The sequence of the intermediate stages of synthesis has not been completely established [20-23]. 

Step, aldol condensation to form the benzylidene derivative (12-3). Conjugate addition of a second mole of acetoacetate would then afford the 1,5-diketone (12-4). Reaction of the carbonyl groups with ammonia will lead to the formation of the dihydropyridine ring. Alternatively, acetoacetate may go on to form the imine (12-5) reaction of this with the aldol product (13-3) will give the same dihydropyridine. The product, nifedipine (12-6) [13], has been used extensively for the treatment of angina and hypertension. 

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-... 

Nitrobenzaldehyde 181 (1 equiv), methyl acetoacetate 180 (1.6 equiv), methanol (75 mL per equiv 2-nitrobenzaldehyde), and ammonia (32 mL per 290 mmol 2-nitrobenzaldehyde) were refluxed for several hours until the reaction was complete. The reaction was cooled to room temperature, and the resulting crystals were collected by vacuum filtration to produce nifedipine in 72% yield. 

Nifedipine (Procardia and Adalat) belongs to a class of drugs called calcium channel blockers and is effective in the treatment of various types of angina, including that induced by exercise. Show how nifedipine can be synthesized from 2-nitrobenzaldehyde, methyl acetoacetate, and ammonia. Hint Review the chemistry of your answers to Problems 19.43 and 19.54 and then combine that chemistry to solve this problem.)... 

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