CS262689B2 - Process for the preparation of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyipyridine-3,5-dicarboxylic acid derivatives - Google Patents

Abstract

A process for the preparation of compounds of general formula II, where either Ri and Rz are ethyls or Ri is methyl and R2 is isopropyl, consisting in the reaction of 2,1,3-benzoxadiazole of formula III with an organic lithium base, to form 4-(2,1,3)-benzoxadiazolide salt of formula IV, which is formylated to 2,1,3-benzoxadiazole-4-carbaldehyde of formula I, which is then subjected to reaction with ethyl acetoacetic acid ester and ammonium salt or with isopropyl acetoacetic acid ester and methyl /3-aminocrotonic acid ester. The proposed process is suitable for industrial use.

Description

The present invention relates to a novel process for the preparation of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylic acid derivatives using 2,1,3-benzoxadiazole intermediates, namely, 2,1,3-benzoxadiazole, lithium-4- (2,1,3-benzoxadiazolidide and 2,1,3-benzoxadiazole-4-carbaldehyde).

2,1,3-benzoxa-diazole-4-carbaldehyde is known [see, for example, D. Dal Monte, F. Sandri and W. Cere, Annali di Chimica Roma, 60, pp. 801-814; (1970)] and in due to the presence of the formyl group at the 4-position, it is an intermediate which can be used to prepare 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid diethyl ester (hereinafter referred to as Compound A), 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-3-methoxycarbonyl-2,6-dimethylpyridine-5-carboxylic acid isopropyl ester (hereinafter referred to as Compound) B) and other diesters of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid and their derivatives as described in European Patent Specification No. 150 and DOS Nos. 2,949,491 and 2,949,464.

The above compound has so far been prepared by a multi-step synthesis from 3-methyl-2-nitrophenylamino via 4-methyl-2,1,3-benzoxadiazole. However, this preparation is not suitable for industrial scale production because 3-methyl-2-nitrophenylamine and its precursor, 3-methyl-2-nitrobenzoic acid, are not readily available.

Similarly, diesters of 4- (2,1,3-benzothiadiazol-4-yl) -1,4-dihydro-3,5-dicarboxylic acids and their derivatives are used in the above-cited patent publications for the preparation of which a known starting material is used 2,1,3-henzo-thiadiazole-4-carbaldehyde. This carbaldehyde is described in Chemistry of Heterocyclic Compounds (Chimija Geterocyclic Soyedidenij) 818-820 (1967).

It has now been found that 2,1,3-benzoxazole-4-carbaldehyde can be prepared from 2,1,3-benzoxazole via a 4- (2,1,3'-benzioxazolide anion) to give 2,1,3- beinzoxadiazole-4-carbaldehyde in high yield.

It is surprising that the 2,1,3-benzoxazolidone ring system is not disrupted in the formation of the anion, and that the reaction of the anion with the formulated reagent takes place at most specifically at the 4-position of the ring system.

The present invention provides a process for the preparation of a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid derivative of the formula II

R _Z OQC

CQQR _lf

7 - / -

C Η-λ μ j ¹ · (li) in which

R1 and R2 are either ethyl or R1 is methyl and R2 is isopropyl, characterized in that

2,1,3-benzoxadiazolide of formula III (!!!) is reacted with an organic cast iron base to give the corresponding 4- (2,1,3) benzoxadiazolide salt of formula IV

This salt is formulated. to give 2,1,3-benzoxadiazole-4-carbaldehyde of formula I!

CHO which is then reacted either with ethyl acetate and the ammonium salt or with isopropyl acetate and methyl ester (S-aminocrotonic acid).

The preparation of the 4- (2,1,3-benzoxadiazolidide salt of formula IV) is carried out in a manner known per se, in particular the reaction is carried out under strongly basic conditions and the lithium base is suitably used to prepare the anion. 2,2,6,6-tetramethylpiperidide, lithium isopropylcyclohexylamide or lithium diisopropylamide.

The reaction is preferably carried out in a solvent which behaves aprotic to very strong bases. The solvent is preferably a polar solvent such as tetrahydrofuran or a non-polar solvent such as toluene, benzene or cyclohexane.

A suitable reaction temperature is between about -50 ° C and about -100 ° C.

The reaction is conveniently carried out under anhydrous conditions, preferably under an inert gas atmosphere.

The 4- (2,1,3) benzoxadiazolidone salt is an intermediate that can be used not only to produce 2,1,3-benzoxadiazole-4-carbaldehyde, but also to produce a wide variety of pharmacologically active 4-substituted

2,1,3-benzoxadiazole compounds.

The aforementioned salt can be formyl swept in a conventional manner using the appropriate formylating agent, which can be prepared from an N-disubstituted formamide derivative in which preferably one of the substituents is an alkyl group such as a methyl group. Examples of such formamide derivatives are dimethylformamide or N-methyl-N-phenylformamide. The reaction is preferably carried out in an aprotic solvent, in particular tetrahydrofuran, toluene, benzene or cyclohexane, for example.

Preferably, the anion solution is added to the N-disubstituted formamide.

A suitable temperature is between about -30 ° C and about -100 ° C. The reaction is preferably carried out under anhydrous conditions and under an inert gas atmosphere.

The reaction mixture may be hydrolyzed in a conventional manner, for example by adding water at a temperature preferably between -80 ° C and room temperature. The resulting aldehyde can be isolated and purified in a conventional manner, for example by crystallization, vacuum distillation or conversion to a bisulfite adduct. However, if desired, the aldehyde can be further processed without isolation.

As mentioned above, 2,1,3-benzoxadiazole-4-carbaldehyde is a derivative which can be used to prepare a wide variety of other compounds, such as compounds A and B above. These compounds A and B can be prepared by replacing the oxo group in the formyl group. a suitable amino-bivinylene group.

In accordance with the invention, 2,1,3-benzoxa-6-diazole-4-carbaldehyde is converted to the compound of formula II above.

This process is described in detail in European Patent Specification No. 150 and in DOS Nos. 2,949,491 and 2,949,464. For Compound A, the 1,4-dihydropyridinium residue is conveniently prepared from ethyl acetate and the ammonium salt. For compound B, the 1,4-dihydropyridine residue is conveniently synthesized from acetopropyl acetic acid isopropyl ester and (3-aminocrotonic acid methyl ester) The reaction is normally carried out in solution, e.g. acetic.

A suitable reaction temperature is from about 20 ° C to 160 ° C, preferably from about 60 ° C to 120 ° C.

The compounds of formula II can be used to treat cardiac insufficiency.

2,1,3-Benzoxadiazole can be readily prepared, for example, by oxidation of o-nitrophenylamine (see Org. Syn. Coll. Vol. IV, p. 74) followed by reduction of the formed benzofuroxane [see J. H. Boyer and S. E. Ellzey, J. Org. Chem. 26, 4,684 (1961)].

The invention is illustrated by the following non-limiting examples. The temperatures indicated are not corrected.

Example 1

Preparation of 2,1,3-benzoxadiazole-4-carbaldehyde

To a mixture of 7.9 kg of diisopropylamine and 35 liters of tetrahydrofuran at -20 ° C was added 23.1 kg of a 20% solution of butyllithium in cyclohexane. The solution was cooled to -75 ° C and 8.5 kg of 2,1,3-benzoxadiazole in 35 liters of tetrahydrofuran was added at this temperature. The reaction mixture was stirred for 35 minutes to give 4- (2,1,3) benzoxadiazolidide salt.

The resulting mixture was added to 8.4 kg of dimethylformamide and 30 liters of tetrahydrofuran at -75 ° C to form an adduct. 62 L of water / acetic acid (3: 1) was added and the reaction was worked up by adding 45 L of toluene at room temperature and separating the organic phase.

Crude 2,1,3-benzoxadiazole-4-carbaldehyde is isolated as follows:

The organic phase is evaporated to about half its original volume, 90 liters of hexane are added to the residue and the brown crystalline crude product is filtered off. This material melts at 100-104 ° C.

Pure 2,1,3-benzoxadiazole-4-carbaldehyde is isolated as follows:

The organic phase was stirred with 20.5 liters of a 40% aqueous sodium bisulfite solution for 0.5 hour to form the bisulfite adduct. The aqueous phase was separated. After addition of 140 liters of ethyl acetate and liters of a 40% aqueous formaldehyde solution, the mixture is stirred for 0.5 hours, then the organic phase is separated and concentrated by washing with water. Hexane (21 L) was added and pure crystalline 2,1,3-benzoxadiazole-4-, carbaldehyde was filtered off. The product melts at 107-109 ° C.

Example 2

Preparation of dihydropyridine compounds

(a) 59 g of crude 2,1,3-benzoxadiazole-4-carbaldehyde, prepared as described in Example 1, 130 g of ethyl acetate, 40 g of ammonium acetate and 240 ml of ethanol are reacted for 3 hours at reflux, then 370 ml of water are added and the mixture is cooled to room temperature. The crude crystalline diethyl ester, melting at 151-154 ° C, was filtered off. Recrystallization from toluene and ethanol gave the pure product, m.p. 154-155 ° C.

b) A mixture of 74 g of pure 2,1,3-benzoxadiazole-4-carbaldehyde prepared according to Example 1, 83 g of acetopropyl acetic acid isopropyl ester, 750 ml of toluene, 3 g of acetic acid and 2 g of piperidine was refluxed for 2 hours. water separator. After addition of 63 g of β-aminocrotonic acid methyl ester, the mixture is allowed to react for a further 6 hours, then concentrated to half its original volume and 1000 ml of cyclohexane and the resulting crude crystalline isopropyl ester of 4- (2,1,3-benzoxadiazoh4-yl) are added. -1,4-Dihydro-3-methoxycarbonyl-2,6-dimethylpyridine-5-carboxylic acid, melting at 160-162 ^° C, was filtered off.

Recrystallization from ethanol gave the pure product, m.p. 167-168 ° C.

Claims (2)

A process for the preparation of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid derivatives of the general formula II ynAlez in which: Ri and R? either being ethyl or R 1 is methyl and R 5 is isopropyl, characterized in that: The 2,1,3-benzoxadiazole of formula III is reacted with an organic lithium base to give the corresponding 4- (2,1,3) benzoxadiazolidide salt of formula IV, which salt is formulated to give the 2,1,3-benzoxacliazole-4-carbaldehyde of formula I which is then reacted either with ethyl acetate or with an ammonium salt or with isopropyl acetate and / S-aminocrotonic acid methyl ester. 2. The process of claim 1 wherein the lithium base is butyllithium, lithium dicyclohexylamide, lithium-2,2,6,6-tetramethylpiperidide, lithium isopropylcyclohexylamide or lithium dilsopropylamide.