Certain 6-benzamidomethyl-2(1H)-pyridone derivatives

Certain substituted pyridine compounds are useful synthetic intermediates for preparing compounds of pharmaceutical interest. A synthetic process for using these intermediates is also described.

TECHNICAL FIELD 
This invention relates to substituted pyridine compounds and a synthetic 
process which are useful in the preparation of compounds of pharmaceutical 
interest. 
BACKGROUND OF THE INVENTION 
Esters of benzoic acid which are substituted on the aromatic ring by 
1,1-dihydroperfluoroalkoxy substituents and exhibit anesthetic activity 
are described in U.S. Pat. No. 3,655,728. Amides of benzoic acid which are 
substituted on the aromatic ring by 1,1-dihydroperfluoroalkoxy 
substituents and exhibit antiarrhythmic activity are described in U.S. 
Pat. No. 3,719,687. U.S. Pat. Nos. 3,900,481, 4,071,524 and 4,097,481 
describe antiarrhythmic agents including, inter alia, 
N-(piperidylmethyl)benzamides substituted by one or more 
1,1-dihydroperfluoroalkoxy groups. Above-mentioned U.S. Pat. No. 3,900,481 
discloses the compound 
2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide, a 
particularly useful antiarrhythmic agent also known as flecainide. An 
article appearing in the Journal of Medicinal Chemistry, Vol. 20, pg. 821 
(1977), discloses many of the compounds of the patents, and also discloses 
various additional compounds such as 
2-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamides in which the 
aromatic ring is substituted in the 5-position by a non-functional group, 
i.e., methyl, chloro or fluoro. 
U.S. Pat. No. 4,339,587 discloses 
5-hydroxy-2-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide and 
synthetic intermediates useful in the synthesis thereof. This compound is 
a metabolite of flecainide, and is useful as an intermediate in the 
synthesis of flecainide and as an antiarrhythmic agent itself. 
DETAILED DESCRIPTION OF THE INVENTION 
In one aspect, the present invention relates to compounds of Formula I 
##STR1## 
wherein A is selected from the group consisting of 
##STR2## 
and acid addition salts thereof when A is --CH.sub.2 NH.sub.2. 
In another aspect, the present invention relates to compounds of Formula II 
##STR3## 
wherein Q is selected from the group consisting of --CH.sub.2 NH.sub.2 and 
##STR4## 
and acid addition salts thereof when Q is --CH.sub.2 NH.sub.2. 
The compounds of Formulas I and II are useful as synthetic intermediates in 
the preparation of 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
(a metabolite of flecainide) and 
2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide. 
In still another aspect, the present invention relates to a process for 
preparing 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
and 2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide 
using the above intermediates. 
Synthetic 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
is useful as a standard for monitoring the metabolism of flecainide in 
mammals. As for 
2,5-bis(2,2,2-trifluoroethoxy)-N-(6-oxo-2-piperidylmethyl)benzamide, it is 
believed that this compound could be reduced to provide flecainide and 
that it therefore is a useful synthetic intermediate. 
Acid-addition salts of certain of the compounds of Formulas I and II may be 
prepared by conventional techniques. Typically, such salts are prepared by 
reacting the respective compound with an equimolar amount of a relatively 
strong acid, preferably an inorganic acid such as hydrochloric, sulfuric 
or phosphoric acid in a polar solvent. Isolation of the salt is 
facilitated by the addition of a solvent in which the salt is insoluble, 
an example of such a solvent being diethyl ether. Formation of an 
acid-addition salt may be desirable during purification of the respective 
compounds. 
The following reaction scheme shows the synthetic route by which the 
compounds of Formulas I and II may be obtained and the manner in which 
they may be used. In the reaction scheme, B is --CH.sub.2 .phi. or 
--CH.sub.2 CF.sub.3 ; and Y is --CH.sub.2 CF.sub.3 or hydrogen, with the 
provisos that Y is --CH.sub.2 CF.sub.3 when B is --CH.sub.2 CF.sub.3, and 
Y is hydrogen when B is --CH.sub.2 .phi.. 
##STR5## 
In step (1) the known compound 2-cyano-6-methoxypyridine (Formula III) is 
reductively acetylated to provide the novel 
2-acetamidomethyl-6-methoxypyridine (Formula IV). The reductive 
acetylation is carried out catalytically in the presence of hydrogen gas 
and Raney nickel catalyst. An acetate salt such as sodium acetate is 
required, preferably in 0.1 to 1.0 molar amounts relative to the compound 
of Formula III. A large excess of acetic anhydride is used. The reaction 
occurs readily at moderate (0.degree. to 50.degree. C.) temperatures. 
The compound of Formula IV is deacetylated by conventional acid hydrolysis 
techniques in step (2) to provide novel 2-aminomethyl-6-methoxypyridine 
(Formula V). It has been found that dilute aqueous hydrochloric acid 
accomplishes this reaction readily with simple refluxing. The compound is 
obtained as a hydrochloride addition salt. 
In step (3) the 2-aminomethyl-6-methoxypyridine of Formula V is converted 
to novel 6-aminomethyl-2(1H)-pyridone (Formula VI). This conversion is 
somewhat slower than the deacetylation of step (2), but it occurs readily 
also. Indeed, the reaction conditions of step (2), if carried out for 
several hours, were found to partially achieve the reaction of step (3). 
Step (3) was completed by heating and refluxing compound of Formula V (or 
a mixture of IV and V) in 48% hydrobromic acid. The product is obtained as 
a hydrobromide addition salt. 
Step (4) involves the reaction of 6-aminomethyl-2(1H)-pyridone (Formula VI) 
with 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride, (Formula VIA), 
a compound described in U.S. Pat. No. 4,339,587. This reaction can also be 
carried out between 6-aminomethyl-2(1H)-pyridone and the known compound, 
2,5-bis(2,2,2-trifluoroethoxy)benzoyl chloride. This reaction may be 
carried out in an inert solvent such as acetone with (preferably) or 
without an acid acceptor such as sodium carbonate. 
Compounds of Formula VII wherein B is 2,2,2-trifluoroethyl can be converted 
directly by catalytic reduction to a novel compound of Formula VIII 
wherein Y is trifluoroethyl. This reduction is rapidly accomplished as 
shown in step (5) on a Parr apparatus at about 20.degree. C. using rhodium 
on alumina (Al.sub.2 O.sub.3) as catalyst in the presence of hydrogen gas. 
It is preferred to use a non-reactive solvent such as a lower alkanol, for 
example, ethanol and/or methanol. 
The compound of Formula VII wherein B is benzyl is converted as shown in 
step (6) to a novel compound of Formula IX by catalytic reduction on a 
Parr apparatus at about 20.degree. C. The catalyst used is palladium on 
charcoal. The reduction is carried out in an inert solvent such as a lower 
alkanol, for example, ethanol and/or methanol. 
In step (7), the compound of Formula IX is reduced to provide a compound of 
Formula VIII wherein Y is hydrogen. This reduction is readily accomplished 
as shown in the presence of hydrogen gas using rhodium on alumina as 
catalyst. The reduction occurs rapidly at 20.degree. C. in a nonreactive 
solvent such as a lower alkanol, for example, ethanol and/or methanol. 
The following examples illustrate the preparation of compounds of the 
invention.

EXAMPLE 1 
Preparation of 2-Acetamidomethyl-6-methoxypyridine 
A mixture of 1.0 g (7.46 mmole) of 2-cyano-6-methoxypyridine, 0.37 g (4.48 
mmole) of sodium acetate, 25 ml of acetic anhydride and about 1.0 g of 
Raney nickel was hydrogenated on a Parr apparatus for about 5.5 hours. The 
mixture was filtered, and then evaporated with warming in vacuo to provide 
2-acetamidomethyl-6-methoxypyridine. The structural assignment was 
supported by infrared spectral analysis. 
EXAMPLE 2 
Preparation of 2-Aminomethyl-6-methoxypyridine 
The crude product, 2-acetamidomethyl-6-methoxypyridine from Example 1, was 
combined with 10 ml of 6N hydrochloric acid, and the resulting mixture was 
heated at its reflux temperature for about 16 hours. The mixture was 
evaporated to provide a tan solid residue. The product was determined by 
infrared and nuclear magnetic resonance spectral analyses to be a mixture 
of 2-aminomethyl-6-methoxypyridine hydrochloride and 
6-aminomethyl-2(1H)-pyridone hydrochloride. 
EXAMPLE 3 
Preparation of 6-Aminomethyl-2(1H)-pyridone 
The crude product from Example 2 was combined with 10 ml of 48% hydrobromic 
acid, and the resulting mixture was heated at its reflux temperature for 
one hour. Evaporation to dryness provided 6-aminomethyl-2(1H)-pyridone 
hydrobromide as a water-soluble solid. The structural assignment was 
supported by infrared and nuclear magnetic resonance spectral analyses. 
EXAMPLE 4 
Preparation of 
6-[5-Benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone 
To a stirred mixture of the crude product from Example 3, 20 ml of acetone 
and 4.7 g of sodium carbonate was added dropwise 2.8 g (8.21 mmole) of 
5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 10 ml of acetone. 
The mixture was stirred at about 20.degree. C. for about 16 hours. To the 
mixture was added 50 ml of acetone, and the resulting inorganic residue 
was separated by filtration and washed with acetone. The filtrate and 
washings were combined and evaporated. This residue was dissolved in 
benzene, and the solution was washed sequentially with 10% aqueous sodium 
carbonate solution, 2% acetic acid, water, saturated aqueous sodium 
bicarbonate solution and saturated aqueous sodium chloride solution. The 
organic solution was dried over magnesium sulfate, and then filtered and 
evaporated. The residue was boiled in carbon tetrachloride, and the 
mixture was cooled and the solid was separated by filtration. The solid 
was purified by chromatography on 30 g of silica gel. The column was 
eluted sequentially with 5% ethyl acetate in dichloromethane and 2% 
methanol in dichloromethane. The product was obtained as a white solid, 
6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. 
The structural assignment was supported by infrared and nuclear magnetic 
resonance spectral analyses. 
EXAMPLE 5 
Preparation of 
6-[5-Hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone 
A mixture of 0.5 g of 
6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 
60 ml of ethanol, 40 ml of methanol and 0.043 g of 10% palladium on 
charcoal was hydrogenated on a Parr apparatus at about 20.degree. C. for 
about 16 hours. Filtration followed by evaporation of the filtrate 
provided a residue which was triturated with acetonitrile. The solid was 
separated by filtration and washed with acetonitrile to provide 
6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. The 
structural assignment was supported by infrared and nuclear magnetic 
resonance spectral analyses. 
EXAMPLE 6 
Preparation of 
5-Hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide 
A mixture of 0.16 g (0.468 mmole) of 
6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 
0.05 g of 5% rhodium on alumina and 50 ml of methanol was hydrogenated on 
a Parr apparatus for 50 minutes. The mixture was filtered, the filtrate 
was evaporated, and the residue was dried to provide 
5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide. 
The structural assignment was confirmed by comparison of infrared and 
nuclear magnetic resonance spectra to those of the same compound prepared 
by an alternative synthetic procedure.