2-Nitrobenzaldehyde Nifedipine

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]. 

Nicardipine Nicardipine, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methyl-phenylmethyl)-amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different )3-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocycUzation reaction is accomplished by reacting, the methyl ester of 8-aminocrotonic acid with the 2-methyl-2-benzyl-aminoethyl ester of acetoacetic acid [24-27]. 

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. ... 

Meyer and co-workers also used the active methylene compound 1,3-cyclohexanone 191 in their synthesis of highly substituted tetracyclic nifedipine derivatives. Reaction of 191 with 3-nitrobenzaldehyde 192 and enamines 189 gave the corresponding tricyclic systems 193 in modest yields ( = 1, 50% yield w = 3, 46% yield). Compound 195 was prepared in a similar manner from enamine 194 in 59% yield. 

In a later report, Meyers used ethyl acetoacetate 8, aromatic aldehydes such as 3-nitrobenzaldehyde 192, and 2,2-methylenediimidazoline hydrochloride 196 to produce the corresponding 1,4-dihydropyridine 197 as a more complex derivative of nifedipine in 65% yield. A series of aromatic aldehydes were employed to generate additional 1,4-dihydropyridines of this nature in 14-74% yield (not shown). Meyers and co-workers also prepared several novel analogs by varying the ketone source to produce compounds such as 198, or by using the Michael addition products of various aldehydes and ketones to produce compounds such as 199. 

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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