Improvements in the reduction of 6-acetamido-2-picoline to produce 6-ethylamino-2-picoline, the improvements being in the use of diborane as the reducing agent and in the use of a low boiling petroleum solvent to separate the soluble 6-ethylamino-2-picoline from the insoluble starting material 6-acetamido-2-picoline. The 6-ethylamino-2-picoline final product is useful as an intermediate in a known method of preparing nalidixic acid, an antibacterial agent.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a process for preparing and purifying 
6-ethylamino-2-picoline, an intermediate for a method of synthesizing 
nalidixic acid. 
2. Description of the Prior Art 
The various known methods of preparing 6-ethylamino-2-picoline usually 
result in the production of the desired compound together with some 
starting material, e.g., 6-amino-2-picoline or 6-acetamido-2-picoline, 
and/or one or more by-products, e.g., 6-diethylamino-2-picoline, 
ring-hydrogenated by-products using certain reducing agents such as 
lithium aluminum hydride and sodium borohydride. Separation of the desired 
6-ethylamino-2-picoline from the starting material and/or by-product(s) is 
effected by various means, e.g., vacuum distillation, selective 
recrystallization, selective reaction of the starting material or 
by-product with an appropriate reagent and separation of the resulting 
derivative, and the like. 
The Koei Japanese Patent Publication No. 15269/74, published Apr. 13, 1974, 
which was based on Application No. 16282/71, filed Mar. 20, 1971, 
describes a process for producing 6-ethylamino-2-picoline, characterized 
by catalytically hydrogenating 6-amino-2-picoline in liquid phase in the 
presence of an excess of acetaldehyde. By-product 
6-diethylamino-2-picoline is removed by fractional distillation under high 
vacuum. 
The Mitsubischi Chemical Industries, Ltd. provisional Japanese Patent 
Publication No. SHO49-108080, published Oct. 14, 1974 and based on 
Application No. SHO48-21945, filed Feb. 23, 1973, describes a process for 
the purification of 6-ethylamino-2-picoline by heating 
6-ethylamino-2-picoline containing starting material 6-amino-2-picoline 
with an orthoformate in the presence of a weak acidic catalyst and 
separating by distillation the unreacted 6-ethylamino-2-picoline from the 
reaction products of 6-amino-2-picoline and an orthoformate, namely, 
N,N'-bis(6-methyl-2-pyridine)formamidine or alkyl 
(6-methyl-2-pyridyl)-formimidate. 
The Kohjin Co., Ltd., Japanese Provisional Patent Publication No. 
50-100064/75, published Aug. 8, 1975 and based on Application No. 
49-6071/74, filed Jan. 11, 1974, discloses that the starting material, 
6-ethylamino-2-picoline, used for the invention described therein can be 
prepared by reducing 6-acetamido-2-picoline with lithium aluminum hydride. 
No experimental details are given in this Kohjin patent publication for 
preparing 6-ethylamino-2-picoline, but it appears that the reduction of 
6-acetamido-2-picoline with lithium aluminum hydride most likely would 
produce a mixture of the final product, some starting material, and 
probably one or more ring-hydrogenated by-product(s). 
The Koei Chemical Co., Ltd., British patent specification No. 1,338,023, 
published Nov. 21, 1973, shows in Example 2 the use of 
"6-methyl-2-ethylaminopyridine" (same as 6-ethylamino-2-picoline) as an 
intermediate in preparation of nalidixic acid. 
SUMMARY OF THE INVENTION 
The invention relates to improvements in the reduction of 
6-acetamido-2-picoline to produce 6-ethylamino-2-picoline, the 
improvements being in the use of diborane as the reducing agent and the 
use of a low boiling petroleum solvent to separate the soluble 
6-ethylamino-2-picoline from the insoluble starting 6-acetamido-2-picoline 
.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
In a process for producing 6-ethylamino-2-picoline by reduction of 
6-acetamido-2-picoline, the invention resides in the improvement 
comprising carrying out the reduction using diborane as the reducing 
agent. In a preferred embodiment, the reduction is carried out using 
tetrahydrofuran as a solvent. 
In a process for producing 6-ethylamino-2-picoline by reduction of 
6-acetamido-2-picoline, the invention also resides in the improvement 
comprising using a low boiling petroleum solvent to separate the soluble 
6-ethylamino-2-picoline from the insoluble 6-acetamido-2-picoline. In a 
preferred embodiment, the low boiling petroleum solvent is n-hexane. 
The invention in an another process aspect comprises the combination of 
said improvements comprising carrying out the reduction using diborane as 
a reducing agent and using a low boiling petroleum solvent to separate the 
soluble 6-ethylamino-2-picoline from the insoluble 6-acetamido-2-picoline. 
In a preferred embodiment, the reduction is carried out using 
tetrahydrofuran as a solvent and the low boiling petroleum solvent is 
n-hexane. 
The term, "a low boiling petroleum solvent" as used herein, preferably 
means an alkane having 5, 6 or 7 carbon atoms or mixtures thereof having a 
boiling point of about 28.degree. through 100.degree. C., a preferred low 
boiling petroleum or alkane solvent being n-hexane having a boiling point 
of 65.degree.-69.4.degree. C. 
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 reduction of 6-acetamido-2-picoline with diborane to produce 
6-ethylamino-2-picoline is conveniently carried out by mixing the 
reactants, preferably in a solution in an inert non-polar solvent at about 
0.degree. to 70.degree. C. until the reaction is completed. In practicing 
the invention I found it convenient to use tetrahydrofuran as the solvent 
and to mix the reactants at about 0.degree. C., preferably under an inert 
atmosphere, e.g., nitrogen, and then to allow the reaction mixture, 
preferably with stirring, to warm up to room temperature (about 
25.degree.-30.degree. C.) and then slowly bringing the reaction mixture to 
reflux and holding it at reflux until completion of the reaction. Other 
inert non-polar solvents can be used, e.g., ethylene glycol dimethyl 
ether, and the like. Preferably the reaction mixture was then first made 
strongly acidic with an aqueous mineral acid, e.g., hydrochloric acid, and 
then the resulting acidic solution was made basic by addition of aqueous 
alkali hydroxide solution, potassium or sodium hydroxide, followed by 
filtering the alkaline mixture and concentrating the filtrate in vacuo. 
The remaining residue containing the desired 6-ethylamino-2-picoline 
together with some starting material, 6-acetamido-2-picoline, was shaken 
well with a low boiling petroleum or alkane solvent, preferably n-hexane, 
b.p. 65.degree.-69.4.degree. C., and the insoluble 6-acetamido-2-picoline 
was filtered off. The alkane filtrate was first optionally washed with 
aqueous alkali hydroxide solution and once with brine, and then it was 
concentrated in vacuo to remove the alkane and to produce the desired 
6-ethylamino-2-picoline. The remaining 6-ethylamino-2-picoline after 
removal of alkane can be further purified by distillation under vacuum to 
yield a highly purified 6-ethylamino-2-picoline. 
The best mode contemplated for carrying out the invention is now set forth 
as follows. 
The intermediate 6-acetamido-2-picoline [known: Meyer, Rec. trav. chim. 44, 
323 (1925)] was prepared as follows: a mixture containing 420 g. of 
6-amino-2-picoline and one liter of acetic anhydride was heated on a steam 
bath for one hour and then evaporated in vacuo on a steam bath to remove 
the excess acetic anhydride and the acetic acid formed by the reaction. 
The hot residue was then poured into ice and an excess of ammonium 
hydroxide was added. The separated precipitate was collected, washed well 
with water and then recrystallized from benzene to yield 530 g. of 
6-acetamido-2-picoline. A solution containing 300 g. of 
6-acetamido-2-picoline in about 400 ml. of tetrahydrofuran was added to 
1300 ml. of one molar diborane (B.sub.2 H.sub.6) solution in 
tetrahydrofuran under nitrogen at 0.degree. C. The reaction mixture was 
stirred for thirty minutes at 0.degree. C., allowed to rise to room 
temperature and stirred at room temperature for another thirty minutes. 
The reaction mixture was then slowly brought to reflux and held at reflux 
for three hours. The reaction mixture was chilled and to it was slowly 
added a solution containing 150 ml. of water and 150 ml. of concentrated 
hydrochloric acid. To the resulting acidic solution was slowly added 
potassium hydroxide pellets until the mixture was strongly basic. The 
alkaline mixture was filtered and the filtrate was concentrated in vacuo. 
The remaining residue, which contained 6-ethylamino-2-picoline along with 
some starting material, namely, 6-acetamido-2-picoline, was shaken well 
with 2,000 ml. of n-hexane. The insoluble 6-acetamido-2-picoline was 
filtered off and the n-hexane filtrate was washed once with dilute aqueous 
sodium hydroxide solution and once with brine and then concentrated in 
vacuo to remove the n-hexane. The remaining residue, consisting primarily 
of 6-ethylamino-2-picoline, was distilled to yield 90 g. of 
6-ethylamino-2-picoline, b.p. 103.degree. C. at 8 mm. The nuclear magnetic 
resonance spectrum of this compound was determined and found to be 
consistent with the assigned chemical structure.