Process for the synthesis of the nicotinyl ester of 6-aminonicotinic acid

6-Aminonicotinic acid is reacted with an alkali carbonate selected from the group consisting of sodium carbonate and potassium carbonate. The reaction is carried out at elevated temperature and in dimethylformamide. The 6-aminonicotinic acid alkali salt so produced is reacted with 3-chloromethylpyridine hydrochloride. The reaction is carried out at elevated temperature and in dimethylformamide. The desired nicotinyl ester is thus produced.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a method of producing the nicotinyl ester of 
6-aminonicotinic acid. More particularly, the invention relates to a 
method of producing such ester in high yield. 
2. Description of the Prior Art 
U.S. Pat. No. 4,141,977, issued Feb. 2, 1979 to Eugene Van Scott and Ruey 
J. Yu, discloses 6-substituted nicotinic acid and its esters when 
topically applied are useful in alleviating the symptoms of psoriasis. The 
6-aminonicotinic acid methyl ester, the ethyl ester, the tert. butyl ester 
and the nicotinyl ester are specifically disclosed. In col. 5, lines 59 et 
seq. of the patent, a method of synthesis of the ethyl ester is set forth. 
The method results in the production of an amount of 6-aminonicotinic acid 
ethyl ester corresponding to a yield of 82% based on the weight of the 
starting materials. One skilled in the art would appreciate that if this 
method were utilized to produce the nicotinyl ester, a substantially 
lower, unacceptable, yield would result. 
U.S. Pat. No. 2,199,839, issued May 7, 1940 to Raemer R. Renshaw and Paul 
F. Dreisbach, also discloses the synthesis of a variety of lower alkyl 
esters of 6-aminonicotinic acid by the method of Fischer esterification. 
Again, one skilled in the art would appreciate that a substantial yield of 
the nicotinyl ester of 6-aminonicotinic acid could not be obtained through 
use of this method. The hydrogen chloride gas would react with the 
nicotinyl alcohol to form an intractable mass. U.S. Pat. No. 2,199,839 
further discloses reaction of the potassium salt of 6-aminonicotinic acid 
with 2-chloroethyldiethyl amine by heating both components on a steam bath 
in the absence of solvent. The present inventors similarly reacted the 
potassium salt of 6-aminonicotinic acid with 3-chloromethylpyridine. No 
yield whatsoever of nicotinyl ester of 6-aminonicotinic acid resulted. 
Only a tar was obtained. 
Thus, there is need for development of a synthetic method for producing the 
nicotinyl ester of 6-aminonicotinic acid in high yield. 
DISCLOSURE OF INVENTION 
According to the method of the present invention 6-aminonicotinic acid is 
reacted with an alkali carbonate selected from the group consisting of 
sodium carbonate and potassium carbonate. The reaction is carried out at 
elevated temperature and in dimethylformamide. The 6-aminonicotinic acid 
alkali salt so produced is reacted with 3-chloromethylpyridine 
hydrochloride. The reaction is carried out at elevated temperature and in 
dimethylformamide. The nicotinyl ester of 6-aminonicotinic acid is thus 
produced. 
Various solvents have been evaluated as reaction solvents in the 
above-described synthesis of the present invention. Water, 
dimethoxyethane, acetone/water mixture, dioxane, dimethylsulfoxide, 
ethanol and acetonitrile when used as the reaction solvent resulted in the 
production of the nicotinyl ester in unacceptably low yields. 
Surprisingly, of the numerous solvents tested, only dimethylformamide 
enabled attainment of the desired high yield of the nicotinyl ester. 
As alkali carbonate, one can employ sodium carbonate or potassium 
carbonate. The highest yield is attainable with sodium carbonate. 
Potassium carbonate results in a substantially lower yield. We have 
determined that, at a reaction temperature of 100.degree. C., with use of 
sodium carbonate as a reactant, there is an almost two-fold increase in 
yield of the nicotinyl ester as compared with use of an equimolar amount 
of potassium carbonate reaction product. This is indeed surprising and 
unexpected. 
The reaction is desirably carried out at elevated temperature. Preferably, 
the temperature ranges from about 80.degree. C. to reflux temperature. 
More preferably, the temperature is from about 100.degree. C. to reflux 
temperature. Most preferably the temperature is reflux temperature. 
The present inventors have found that surprisingly, as the reaction 
temperature is increased from 80.degree. C. to 100.degree. C., the yield 
rises and peaks at 100.degree. C. The yield then falls between 100.degree. 
C. to 140.degree. C. Then, surprisingly, and unexpectedly, there is a 
sharp increase in yield as the temperature is increased from 140.degree. 
C. to reflux temperature. In point of fact, over this very short 
temperature span, the yield dramatically and unexpectedly increases 
approximately 25%. 
In the step of reacting the alkali salt of 6-aminonicotinic acid, 
3-chloromethylpyridine hydrochloride or other suitable salt thereof may be 
employed as co-reactant. Preferably, 3-chloromethylpyridine hydrochloride 
is utilized.

The invention will now be illustrated and described in greater detail with 
reference to the examples which follow: 
EXAMPLE 1 
414.4 g (3.0 moles) 6-aminonicotinic acid and 414.6 g (3.0 moles) potassium 
carbonate are added to 5.5 liters N,N-dimethylformamide ("DMF") in a 12 
liter three-necked round bottom reaction flask equipped with a stirrer. 
The reaction mixture is stirred mechanically, refluxed for about 60 hours, 
then cooled to 100.degree. C. Then, while maintaining the reaction mixture 
at a temperature of 100.degree. C., 492.2 g (3.0 moles) 
3-chloromethylpyridine hydrochloride are incrementally added thereto over 
a period of one hour. The reaction temperature of 100.degree. C. is 
maintained for an additional hour. Then, the DMF is removed by 
concentrating the reaction mixture to about 1 liter by distillation in 
vacuo and 3 liters of ice are added to the cooled reaction mixture. The 
suspension which results is diluted to 3.5 liters with water and the 
resultant product collected and washed repeatedly with water until the 
washings are nearly colorless. The product is dried and then 
recrystallized from toluene (12.5 liters) whereby 236.6 g (representing a 
yield of 34.4%) of the nicotinyl ester of 6-aminonicotinic acid (C.sub.12 
H.sub.11 N.sub.3 O.sub.2, M.W.=229.24, m.p. 142.degree.-143.5.degree. C.) 
are obtained. The reaction scheme is depicted as follows: 
##STR1## 
EXAMPLE 2 
414.4 g (3.0 moles) 6-aminonicotinic acid and 318 g (3.0 moles) sodium 
carbonate are added to 5.5 liters of N,N-dimethylformamide ("DMF") in a 12 
liter three-necked round bottomed flask equipped with a stirrer. The 
reaction mixture is stirred mechanically and refluxed vigorously for at 
least 1 to 11/2 hours. During this time, the contents of the reaction 
flask thicken considerably. The reaction mixture is cooled to 140.degree. 
C. and while this temperature is maintained, 492.2 g (3.0 moles) 
3-chloromethylpyridine hydrochloride are added over a period of one hour 
and at a rate of approximately 8.2 g/min. After the addition of the 
3-chloromethylpyridine hydrochloride is complete, the reaction mixture is 
heated to reflux and maintained at reflux temperature for one hour. 
Thereafter, the reaction mixture is concentrated in vacuo to about 1 
liter. Then, 3 liters of ice are added to the concentrate. The mixture so 
produced is stirred and diluted with water to a total volume of 3.5 
liters. The brown solid which results is collected, washed with water, 
resuspended in 2.5 liters of an ice/water mixture and then once again 
collected. This procedure is repeated until the washings are nearly 
colorless, at which point the product is collected and dried completely in 
vacuo whereby 572.7 g of crude nicotinyl ester of 6-aminonicotinic acid 
are obtained. Recrystallization of this product from toluene (15 liters) 
affords 527.3 g (representing a yield of 76.76%) of pure nicotinyl ester 
of 6-aminonicotinic acid (C.sub.12 H.sub.11 N.sub.3 O.sub.2, M.W.=229.24, 
m.p. 142.degree.-143.5.degree. C.). The reaction scheme is depicted as 
follows: 
##STR2## 
EXAMPLE 3 
Example 2 is repeated, except the reaction of 6-aminonicotinic acid with 
sodium carbonate and the subsequent reaction with 3-chloromethylpyridine 
hydrochloride are carried out at a temperature of 80.degree. C. 330.5 g 
(representing a yield of 48.09%) of the nicotinyl ester of 
6-aminonicotinic acid are obtained. 
EXAMPLE 4 
Example 2 is repeated, except the reaction of 6-aminonicotinic acid with 
sodium carbonate and the subsequent reaction with 3-chloromethylpyridine 
hydrochloride are carried out at a temperature of 100.degree. C. 470.6 g 
(representing a yield of 68.43%) of the nicotinyl ester of 
6-aminonicotinic acid are obtained. 
EXAMPLE 5 
Example 2 is repeated, except the reaction of 6-aminonicotinic acid with 
sodium carbonate and the subsequent reaction with 3-chloromethylpyridine 
hydrochloride are carried out at a temperature of 120.degree. C. 445 g 
(representing a yield of 64.75%) of the nicotinyl ester of 
6-aminonicotinic acid are obtained. 
EXAMPLE 6 
Example 2 is repeated, except the reaction of 6-aminonicotinic acid with 
sodium carbonate and the subsequent reaction with 3-chloromethypyridine 
hydrochloride are carried out at a temperature of 140.degree. C. 423.6 g 
(representing a yield of 61.64%) of the nicotinyl ester of 
6-aminonicotinic acid are obtained. 
The results of examples 1-6 clearly demonstrate that sodium carbonate is 
most preferred; potassium carbonate is next preferred. 
A comparison of the results of Examples 3 and 4 shows that all conditions 
being equal, use of potassium carbonate as a reactant results in a yield 
of 34.4% of the desired nicotinyl ester. In contrast thereto, when sodium 
carbonate is employed as a reactant, the nicotinyl ester is produced in a 
yield of 68.43%. This two-fold increase is indeed surprising and 
unexpected. 
The examples further demonstrate that although the process is operative at 
elevated temperature, a range of about 80.degree. C. to reflux temperature 
is preferred, a range of about 100.degree. C. to reflux temperature is 
more preferred, and reflux temperature is most preferred. 
Examples 3 and 4 demonstrate that as the reaction temperature is raised 
from 80.degree. C. to 100.degree. C., the yield rises rapidly. The 
reaction temperature peaks at 100.degree. C., then starts to fall from 
100.degree.-140.degree. C., then, surprisingly and unexpectedly, there is 
a sharp increase in yield as the temperature rises from 140.degree. C. to 
reflux temperature. 
Over this very short temperature span, the yield increases from 61.64% to 
76.76%. This represents a dramatic and unexpected increase in yield of 
about 24.5%.