Process for preparing 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles

A process for preparing cardiotonically active 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles which comprises reacting a pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile, where pyridinyl is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
This invention relates to a process for preparing cardiotonically active 
1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles. 
(b) Description of the Prior Art 
Lesher, Opalka and Page U.S. Pat. No. 4,276,293, issued June 30, 1981 and 
based on application Ser. No. 135,211, filed Mar. 28, 1980, discloses the 
process for preparing a 
1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitrile by first 
reacting a pyridinylmethyl lower-alkyl ketone with dimethylformamide 
di-(lower-alkyl) acetal to produce a 
1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and then 
reacting said ketone with alpha-cyanoacetamide. 
Opalka and Lesher U.S. Pat. No. 4,223,149, issued September 16, 1980, 
discloses and claims the process for preparing a 
1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitrile by reacting 
alpha-(pyridinyl)-beta-[di-(lower-alkyl)amino]acrolein with malononitrile 
in a lower-alkanol. 
SUMMARY OF THE INVENTION 
The present invention resides in the process for preparing 
1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles by reacting a 
pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile. 
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
The invention resides in the process which comprises reacting 
pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile in a 
lower-alkanol to produce 
1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitrile, where pyridinyl 
is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl 
substituents. In a preferred embodiment 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. In a 
particularly preferred embodiment 4-pyridinylmethyl methyl ketone and 
ethoxymethylenemalononitrile are heated in refluxing ethanol to produce 
1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile. 
The term "lower-alkyl" as used herein, e.g., as a substituent for 
"pyridinyl", means alkyl radicals having from one to four carbon atoms 
which can be arranged as straight or branched chains, illustrated by 
methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl or isobutyl. 
The term "lower-alkanol" as used herein means an alkanol having from one to 
four carbon atoms, illustrated by methanol, ethanol, n-propanol, isopropyl 
alcohol, n-butanol, and the like. 
The term "pyridinyl" as used herein, e.g., in the intermediate 
pyridinylmethyl methyl ketone and as the 5-substituent of the 
nicotinonitrile product of the process of the invention, means 4- or 
3-pyridinyl or 4- or 3-pyridinyl having one or two "lower-alkyl" 
substituents, illustrated by 2-methyl-4-pyridinyl, 3-methyl-4-pyridinyl, 
2-methyl-3-pyridinyl, 2,6-dimethyl-4-pyridinyl, 6-methyl-3-pyridinyl 
(alternatively named 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. 
The molecular structures of the products produced by the process of the 
invention were assigned on the basis of evidence provided by infrared, 
nuclear magnetic resonance and mass spectra, by chromatographic 
mobilities, and by the correspondence of calculated and found values for 
the elementary analyses for representative examples. 
The manner of making and using the instant invention will now be generally 
described so as to enable a person skilled in the art of chemistry to make 
and use the same, as follows: 
The process of the invention is carried out by heating the reactants, that 
is, a pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile, in a 
lower-alkanol at about 60.degree. C. to 120.degree. C., preferably about 
75.degree. to 100.degree. C., particularly preferably in refluxing ethanol 
.

The following examples will further illustrate the invention without, 
however, limiting it thereto. 
EXAMPLE 1 
A mixture containing 13.5 g. of 4-pyridinylmethyl methyl ketone, 12.2 g. of 
ethoxymethylenemalononitrile and 100 ml. of ethanol was refluxed with 
stirring for five hours and then allowed to cool to room temperature. The 
separated crystalline product was collected, washed with cold ethanol and 
dried in a vacuum oven at 60.degree. C. to yield 14.2 g. of 
1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p. 
&gt;300.degree. C. The nuclear magnetic resonance and infrared spectra of 
this product were identical with the corresponding respective spectra of 
the same compound prepared by a different method, that is, by reacting 
1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone with 
alpha-cyanoacetamide. Also, a mixed melting point with the same compound 
prepared by said different method showed no depression. 
Following the procedure described in Example 1 but using in place of 
4-pyridinylmethyl methyl ketone a molar equivalent quantity of the 
appropriate pyridinylmethyl ketone, it is contemplated that there can be 
obtained the corresponding 
1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles of Examples 2 
through 5. 
2. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinyl)nicotinonitrile, using 
3-pyridinylmethyl methyl ketone. 
3. 1,2-Dihydro-6-methyl-5-(2-methyl-4-pyridinyl)-2-oxonicotinonitrile, 
using (2-methyl-4-pyridinyl)methyl methyl ketone. 
4. 5-(2-Ethyl-4-pyridinyl)-1,2-dihydro-6-methyl-2-oxonicotinonitrile, using 
(2-ethyl-4-pyridinyl)methyl methyl ketone. 
5. 1,2-Dihydro-6-methyl-5-(2,6-dimethyl-4-pyridinyl)-2-oxonicotinonitrile, 
using (2,6-dimethyl-4-pyridinyl)methyl methyl ketone.