An Efficient and Facile Synthesis of Novel 3-Benzoyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidines

Abstract

The condensation of 1-aryl-2-dimethylaminomethylprop-2-en-1-ones 4 with 2-aminopyridines 5 gives rise to the 3-benzoyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidines 3. The reaction is initiated by addition of the pyridine amino group to the enone double bond, followed by deamination and ring closure to give the anellated pyrimidine ring system, which is an excellent precursor for the synthesis of pharmacological active compounds.A number of biologically active compounds including antiallergic, 1,2 analgetic, 3,4 antihyperlipidemic, 5 neuroleptic, 6,7 antihistaminic, 8 and antihypertensic 9 agents are 3-substituted pyrido[1,2-a]pyrimidines, some of them hydrogenated at the pyridine nucleus ( Figure 1). The most common method for their preparation is either the condensation of 2-aminopyridines with ethoxymethylene malonic acid derivatives or the ring closure reaction of N-(2-pyridyl)-aminomethylenemalonic acid derivatives obtained in good yields by heating 2-aminopyridines with active methylene compounds in the presence of orthoformates. 10-16 Thus, a typical procedure is the condensation of 2-amino-6-methylpyridine with ethoxymethylene malonic acid ester (EMME) to the respective hetarylaminoacrylic acid ester followed by cyclization using a mixture of phosphoryl chloride and polyphosphoric acid. 4,17 Reagents such as EMME possess three electrophilic centers, whose condensation with ambifunctional nucleophilic compounds in one or two steps generally gives rise to the formation of 3-substituted aromatic heterocycles 3, unsubstituted in 2-position. Figure 1We found a simple procedure for preparing 3-substituted pyrido[1,2-a]pyrimidines by condensation of 2-aminopyridines 5 with enone Mannich bases 4, which are easily accessible through heating of aryl methyl ketones, paraformaldehyde, and N,N-dimethylamine hydrochloride in DMF. 18 Like EMME, these enone Mannich bases 4 are characterized by three electrophilic centers. After addition of the nucleophile the dimethylamino group is eliminated and therefore renders possible ring closure reaction to form anellated heterocycles 3. We performed the cyclizations of 4 with 2-aminopyridines 5 in a refluxing ethanol/water mixture (1: 1) in order to study the influence of the polyfunctional character of both reactants. 19 Scheme 1Isolation of the resulting products as hydroperchlorates showed that -as anticipated -an addition-elimination mechanism had taken place. In the first step, the 2-aminopyridine 5 adds to the double bond affording the saturated intermediates 6. 20 Next, the third electrophilic center is generated by elimination of Me 2 NH 2 Cl to form the enone 7 followed by a second addition reaction to the ring closed heterocycle 3, partly hydrogenated in the pyrimidine moiety. The intermediates 6 and 7 could not be isolated. Obviously, attack at the keto carbonyl group of the enone Mannich base 4 by the 2-aminopyridine 5 with formation of the corresponding azomethine derivatives does not occur, the conceivable follow-up products 8 or 9 were not found ( Figure 2). When perform...

Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases

“…The precipitate was filtered, dried and recrystallised from methanol. The yields ranged from 10 to 30% [38,39].…”

“…After the addition of the nucleophile to the enone structure, the dimethylamino group was eliminated followed by ring closure to form anellated heterocycles [39]. Isolating the resulting products as hydroperchlorates or as hydrochlorides showed that an addition-elimination mechanism had taken place.…”

“…20a) were prepared following the general procedure and their physico-chemical properties have been previously reported[39].3-Benzoyl-3,4-dihydro-8-methyl-2H-pyrido[1,2-a]pyrimidine perchlorate (8c) was prepared from 2-(dimethylaminomethyl)-1-phenylprop-2-en-1-one hydrochloride and 2-amino-4-methylpyridine 7c according to the general method. Mp.…”

1H, 13C and 15N NMR spectral analysis of substituted 1,2,3,4‐tetrahydro‐pyrido[1,2‐a]pyrimidines

“…For the methyl-substituted pyridopyrimidines 5, 6 and 7, the 3 J coupling constants were found to be in the same range. For structures 5, 7 and 8, the 4 J coupling constants were unresolved; for 6, this 4 J coupling constant value was about 1.5-1.8 Hz.…”

“…We have shown before that the exchangeable proton is bound to N-1; there is no evidence for tautomeric isomers. [4] The signal of this NH proton is usually rather broad with line widths of several Hz up to 50 Hz (the broadening originating presumably on impurities like traces of excess of acid or water or exchange processes); in some cases, a triplet structure can be anticipated, in those cases the corresponding couplings of this NH proton can be observed in the 4 J(H-7,H-9)] are found. An unresolved 5 J coupling of H-6 with H-9 is observed in the H, H-COSY spectrum of 4, too.…”