Dihydropyridines hydrolysis

The product (15-2) from aldol condensation of meto-nitrobenzaldehyde with the dimethyl acetal from ethyl 4-formylacetoacetate (15-1) provides the starting material for a dihydropyridine in which one of the methyl groups is replaced by a nitrile. Reaction of (15-2) with the eneamine from isopropyl acetoacetate gives the corresponding dihydropyridine hydrolysis of the acetal function with aqueous acid affords the aldehyde (15-3). That function is then converted to its oxime (15-4) by reaction with hydroxylamine. Treatment of that intermediate with hot acetic acid leads the oxime to dehydrate to a nitrile. There is this obtained nilvadipine (15-5) [16]. 

The Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Scheme 1.4 Asymmetric hydrolysis of dihydropyridine diesters influence of solvent on lipase stereochemical preference.

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

The oxidation of dihydropyridine-based chemical delivery systems (CDSs) pioneered by Bodor and co-workers [176] has been discussed in a previous book (Chapt. 13 in [81]). There, we examined the principles by which such compounds function to deliver drugs to the brain. Here, we focus our attention to the last step in the activation of these double prodrugs, namely hydrolysis to release the drug. 

Fig. 8.15. Resonance forms that show why the dihydropyridine pro-pro-moiety (A) is less susceptible to alkaline and enzymatic hydrolysis than the pyridinium pro-moiety (B). Electron donation from the ring to decrease the electrophilicity of the carbonyl C-atom is possible for A but not for the pyridinium compound B. 

A further condition for good brain delivery, one that is particularly relevant in the present context, is that e) direct hydrolysis of the dihydropyridine pro-prodrug (Fig. 8.14, Reaction c) does not compete with oxidation, especially in the periphery, since this would decrease the amount of CDS available for brain delivery. In fact, the pyridinium metabolite is more susceptible than the dihydropyridine pro-prodrug to alkaline and enzymatic hydrolysis, since the carbonyl C-atom of the pyridinium compound (B, Fig. 8.15) is much more electrophilic than that of the dihydropyridine (A, Fig. 8.15). 

Brain delivery of steroid hormones is also of interest to medicinal chemists. Again, most data available on CDSs of steroids pertain to rates of oxidation of the dihydropyridine carrier, to blood and brain concentrations, and to pharmacological activities. The latter can then be taken as proof of efficient cerebral hydrolysis of the pyridinium metabolite. Thus, the dihydrotrigonelline carrier allowed good brain delivery of estradiol and some other estrogens [181][182],... 

The resonance mechanism shown in Fig. 8.15 accounts for the greater stability of dihydropyridine pro-prodrugs vs. their pyridinium metabolites in base-catalyzed and enzymatic reactions of hydrolysis, but it also suggests a decreased stability of the former in acid-catalyzed hydrolysis. Indeed, the carbonyl O-atom is deduced from Fig. 8.15 to be more nucleophilic in dihydropyridine (A) than in pyridinium derivatives (B). The stability of dihydropyridine pro-prodrugs under the acidic conditions of the stomach and small intestine should, therefore, be examined further. 

There are now a reasonable number of reactions in which derivatives of pyrimidine are converted into pyridines. The tetrahydropyrimidine (792) is converted into a dihydropyridine by heating with silica and alumina (48HCA612). It was assumed that hydrolysis gave a ketoimine (also obtained directly from acetone and ammonia), which recydized. Pyrimidine itself is converted by hot (190 °C) aqueous ammonia or methylamine into 2-methyl-5-ethylpyridine (793) (71RTC1246), while 2-methoxy-5-arylpyrimidines (794) with... 

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

Pyridines are more susceptible to reduction than benzenes. Sodium in ethanol or in liquid ammonia evidently reduces pyridine to 1,4-dihydropyridine (or a tautomer) because hydrolysis of the reaction mixture affords glutaric dialdehyde (318 — 317 — 316). Reduction of pyridines with sodium and ethanol can proceed past the dihydro stages to A3-tetrahydropyridines and piperidines (318 — 319 and 320). 

Oxidation of the dihydropyridine derivative is most conveniently carried out with an aqueous nitric-sulphuric acid mixture. Removal of the ethoxycarbonyl groups may be achieved by a stepwise hydrolysis and decarboxylation sequence, but the one-step reaction described in Expt 8.29 using soda-lime is convenient. 

Among other antidiabetic drugs, tolbutamide was determined in formulations and in biological fluids by acid hydrolysis, reaction of the resulting amine with acetylacetone and formaldehyde, and fluorimetric determination of the resulting substituted dihydropyridine at 600 nm, with excitation at 480 nm (8). 

Acyl-2-fluoro-l,4-dihydropyridines 149, easily synthesized by alkylation of 2-fluoropyridinium salts, undergo hydrolysis to form dihydro-2-pyridones 150 in which only the more stable 3,4-/ra t-isomer is formed. 1,4-Dihydropyridines 149 can also be oxidized with DDQ to form 2-pyridones 151 (Scheme 40) <2002JOC7465, 2000CC2459>. 

The reduction of pyridine with trimethylsilane and hydrolysis of the resulting 1-trimethylsilyl intermediate has been reported as a route to unsubstituted 1,4-dihydropyridine.156 The reduction has been shown to be reversible at higher temperatures leading to an equilibrium mixture of dihydropyridines.157... 

Hydrolysis of dimethyl 6-methyl-8-(3-nitrophenyl)-3-oxo-l,3,4,8-tetrahy-dropyrido[2,l-c][l,4]oxazine-7,9-dicarboxylate in MeOH in the presence of KOH at room temperature afforded 2-[2-hydroxymethyl-6-methyl-4-(3-ni-trophenyl)-3,5-bis(methoxycarbonyl)-l,4-dihydropyridin-l-yl]acetic acid (95PHA681). Hydrolysis of 7,8,9,10-tetrafluoro-l,2,4,6-tetrahydro[l,4]ox-... 

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