Reaction of the methyl benzylideneacetoacetate (Ia) with the ethyl acetoacetate (II) gives nitrendipine (IIIc) as the main product, together with the symmetrical esters (IIIa) and (IIIb).
In the synthesis of nitrendipine (4ab) according to methods A and B the Konkurrierende Reaktionen bei der Synthese von Nitrendipin corresponding symmetrical diesters 4aa and 4bb have been found as byproducts. The formation of the substituted I .2,3.4-tetrahydropyrimidines 6a and b via retrograde Krioeivnagel leacrion has teen proved in method 8. The preparation of 6a.b was achieved by reaction of 3-nitrobenzylideneacetoace-Utes 5a,b with ammonia.Bei der Synthese von Nitrendipin (4ab) nach den Methoden A und B wurden die entspr. symmeuischen Diester 4aa und 4bb als Nebenproduhe gefunden. Die Bildung substituierter 1.2,3,4-Tetrahydmpyrimidine 6a,b durch eine Retr~Knoevenogel-Reaktion wurde bei der Methode B nachgewiesen. Die praparative Darstellung von 6a,b wurde durch Umsetzung der 3-Nitrobenzylidenacetessigester 5a,b mit Ammoniak erzielt. Nitrendipine (4ab) is a 1 ,J-dihydropyridine calcium antagonist with nonidentical ester groups at C-3 and C-5. Its synthesis has been accomplished by Meyer et in three ways (methods A, B and C, scheme 1). The authors reported') that in method A the corresponding symmetrical 3.5diestereither 4aa or 4bbcan be isolated as byproduct in a few cases. This is due to the reaction of 3-nitrobenzaldehyde (2) with 2 mol of the enaminoester 3a (or 3b). Method B has been only briefly mentioned in a pateni3' (without experimental details) and no other data for in applicahility are available in the literature. Pharm. (Weinheim) 322,253-256 (1989) OVCH Verlagsgesellschafi mbH. D-6940 Weinheim, 1989 0365-6233/89x)505-0253 $ M.mm Arch.
The adductsIn a previous communication'' we described the addition of some enamino esters to coumarins with electron-withdrawing 3-substituents. The present paper deals with the application of the adducts thus formed for the synthesis of new heterocyclic compounds containing a pyridine ring.We found that the adduet 4b of 3-cyanocoumarin (1 b) and ethyl 3,3-diamino-2-propenoate (2) failed to be isolated because of rapid cyclization to the benzopyrano[3,4-~]pyridine 5 (Scheme 1). The reaction was carried out by refluxing of the reactants in ethanol to afford 5 in 53% yield. By the way, compound 5 is of interest as an analog of the 1,4-dihydropyridine calcium antagonists'). The adduct 4a, initially formed from coumarin-3-carboxylic acid (I a) and 2 under reflux in ethanol, decarboxylated spontaneously to give the dihydroeoumarin 3 which is also directly obtainable from 2 and eoumarin'). Compound 3 underwent thermal changes upon heating above its melting point (198'C): (a) for 10 min at 210-220°C a mixture of the benzopyrano[3,4-~]pyridines 7 and 8 in ca. 60% yield and (b) for 60 min at 2 5 0 T the product 8 in 39% yield were obtained. We assume that this thermal rearrangement includes an initial lactone opening and closure of the 2-pyrimidinone ring, followed by relactonization with the ethoxycarbonyl group under elimination of ethanol. Compound 8 is obviously a result of air oxidation of 7 to give a fully conjugated system. This multistep sequence could be interrupted by treatment of 3 with acetic anhydride in glacial acetic acid at room temperature to afford an acetylated 2-pyridinone intermediate 6 in 78% yield.Since the thermal rearrangement of 3 was accompanied by undesirable decomposition or side processes, we undertook numerous attempts in order to elaborate a convenient preparative procedure for this reaction. We expected that a basic catalyst would favour the first transformation step, i.e. the opening of the lactone ring in 3. And indeed, treatment of 3 with sodium ethoxide in ethanol under reflux for 1 h led to almost pure 7 in 85% yield. The phenol acetate 6 could also be quantitatively converted into 7 (partially oxidized to 8) in the presence of sodium ethoxide at room temperature. A more convenient oxidation of 7 to 8 was achieved by using chromium trioxide in pyridine (yield 53%).The addition of ethyl 3-amino-2-butenoate (9) occurred by an attack of its C-4 on the conjugated double bond of the coumarin 1 a, as observed earlier') by the reaction of 9 with ethyl eoumarin-3-carboxylate. But in this ease, the initial adduet 10 undergoes spontaneous decarboxylation to provide a mixture of products 11, 12. and 13 (Scheme 2), successfully separated by column chromatography on silica gel. The main component 12 (yield 40%) is obviously a rearrangement product of the deearboxylated dihydro-
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