KR880001054B1 - Process for preparing 1,2-dihydro-6-methyl-20x0-5-(pyridinyl) nicotino-nitriles - Google Patents

Abstract

The title compd. is prepd. by reacting pyridinylmethyl methyl ketone with ethoxymethylene malononitrile in low alkanol. The reaction performs at 75-100 deg.C. The novel compd. is useful as cardiotonic drug. Pyridinyl is 4- or 3- pyridinyl, or 4- or 3-pyridinyl having low alkyl sustituents.

Description

Method for preparing 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile

The present invention relates to a process for the preparation of 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile useful as a cardiac agent.

U.S. Patent No. 4,276,293 discloses 1- (pyridinyl) -2- (dimethylamino) ethenyl lower alkyl ketones by reacting pyridinylmethyl lower alkyl ketones with dimethylformamide di- (lower alkyl) acetals to obtain 1- (pyridinyl) -2- (dimethylamino) ethenyl lower alkyl ketones. The process for preparing 1,2-dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) nicotinonitrile is described by reacting a back with α-cyanoacetamide. U.S. Patent No. 4,223,149 also discloses the reaction of α- (pyridinyl) -β- [di- (lower alkyl) amino] -acrolein with malononitrile in lower alkanols to 1,2-dihydro-2-oxo- A method for preparing 5- (pyridinyl) nicotinonitrile is described.

The process of the present invention reacts pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile in lower alkanols to yield 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile. Wherein the pyridinyl is 4- or 3-pyridinyl, or 4- or 3-pyridinyl with one or two lower alkyl substituents.

In a preferred embodiment of the invention, 4 (or 3) -pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are heated in ethanol to 1,2-dihydro-6-methyl-2-oxo-5- [4 (Or 3) -pyridinyl] nicotinonitrile is prepared. In a particularly preferred embodiment of the invention, 4-pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are heated in reflux ethanol to produce 1,2-dihydro-6-methyl-2-oxo-5- (4- Pyridinyl) nicotinonitrile is prepared.

The term "lower alkyl" as used herein as a substituent to pyridinyl, for example, refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, iso Propyl, n-butyl, 2-butyl or isobutyl.

As used herein, the term "lower alkanol" refers to an alkanol having from 1 to 4 carbon atoms, for example methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like. .

The term " pyridinyl " as used, for example, in the reactant pyridinylmethyl methyl ketone and as the 5-substituted product of the nicotinonitrile product according to the invention is 4- or 3-pyridinyl, or one or two lower Means 4- or 3-pyridinyl with alkyl substituents, for example 2-methyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 2,6-dimethyl -4-pyridinyl, 6-methyl-3-pyridinyl (alternatively may be referred to as 2-methyl-5-pyridinyl), 2,3-dimethyl-4-pyridinyl, 2-ethyl-4- Pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diisopropyl-4-pyridinyl and the like have.

The molecular structure of the product prepared according to the method of the present invention is determined by infrared spectra, nuclear magnetic resonance spectra and mass spectra, also by chromatographic flow, and between calculated and measured values in the elemental analysis for a representative example. The data presented by the correspondence of

The process of the invention generally involves heating the reactants, ie pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile, at lower temperatures of about 60 ° C.-120 ° C. in lower alkanols (especially reflux ethanol). Preferably by heating at a temperature of about 75 ° C-100 ° C.

The method of the present invention has many advantages over conventional methods as described in US Pat. No. 4,276,293. The ethoxymethylenemalononitrile used as reactant in the present invention is more suitable for commercial mass production because it is cheaper and easier to purchase in large quantities than the dimethylformamide dimethyl acetal used as reactant in the above-described US patent. In addition, in the process of the present invention, since the reaction step is much reduced, the production cost required for the process is reduced by reducing the use of drugs and shortening the reaction time. In other words, since the above-mentioned conventional method using α-cyanoacetamide must be carried out under alkaline conditions, the step of acidifying the alkaline reaction mixture must be accompanied in order to obtain the required product. In contrast, no alkali or acid is required in carrying out the process of the present invention.

Hereinafter, although an Example further demonstrates this invention, this invention is not limited to these Examples.

Example 1

A mixture of 13.5 g of 4-pyridinylmethyl methyl ketone, 12.2 g of ethoxymethylenemalononitrile and 100 ml of ethanol was refluxed for 5 hours with stirring and then cooled to room temperature. The isolated crystalline product was collected, washed with cold ethanol and dried in a vacuum oven at 60 ° C. to 14.2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotino Nitrile was obtained (melting point: 300 degreeC or more). The results of nuclear magnetic resonance spectra and infrared spectra for this compound were determined by other methods, namely by reacting 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone with α-cyanoacetamide. It is consistent with the above spectral result of the same compound obtained. Also, the melting point did not drop at all when the product obtained by the present invention was mixed with the product obtained by the above-mentioned other method.

Example 2-5

The procedure of Example 1 was repeated except that an equivalent molar amount of appropriate pyridinylmethyl ketone was used in place of 4-pyridinylmethyl methyl ketone as described below, thereby providing the corresponding 1,2-dihydro-6-methyl- 2-oxo-5- (pyridinyl) nicotinonitrile was prepared in Example 2-5.

Example 2; 1,2-Dihydro-6-methyl-2-oxo-5- (2-methyl-4-pyridinyl) -2-oxonicotinonitrile was prepared using 3-pyridinylmethyl methyl ketone.

Example 4; 5- (2-ethyl-4-pyridinyl) -1,2-dihydro-6-methyl-2-oxonicotinonitrile was prepared using (2-ethyl-4-pyridinyl) methyl methyl ketone.

Example 5: 1,2-dihydro-6-methyl-5- (2,6-dimethyl-4-pyridinyl) -2- using (2,6-dimethyl-4-pyridinyl) methyl methyl ketone Preparation of oxonicotinonitrile.

Claims (3)

Reacting pyridinylmethyl methyl ketone with ethoxyketylenemalononitrile in lower alkanols where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two lower alkyl substituents Method for producing 1,2-dihydro-6-methyl-2-oxo-5- (pyridinyl) nicotinonitrile characterized by the above. The method of claim 1, wherein 4 (or 3) -pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are heated in ethanol to produce 1,2-dihydro-6-methyl-2-oxo-5- [4 ( Or 3) -pyridinyl] nicotinonitrile. 4. The 2-pyridinylmethyl methyl ketone and ethoxyketylenemalononitrile are refluxed in ethanol to allow 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl). Method for Making Nicotinonitrile.