Process for the preparation of nicotinic acids

The present invention relates to an improved process for the preparation of nicotinic acids represented by the following structural formula (I): ##STR1## which are prepared by reacting a nicotinic amide compound having the formula: ##STR2## under acidic conditions with a nitrite salt. In the process of the invention have the groups R.sup.1, R.sup.2, and R.sup.3, in the compounds are independently selected from the group consisting of hydrogen, and halogen atoms and R.sup.4 is selected from the group consisting of hydrogen, lower alkyl and aryl. The process provides the nicotinic acid compounds in improved yields.

TECHNICAL FIELD 
The present invention relates to an improved process for the preparation of 
nicotinic acids and derivatives of nicotinic acid. The process uses 
nitrite salts to convert nicotinic amides to acids or esters. 
BACKGROUND OF THE INVENTION 
Substituted pyridines are useful as intermediates for the synthesis of 
naphthyridine antibacterial agents. 2,6-Dichloro-5-fluoronicotinic acid is 
of particular interest because it is a key intermediate in the synthesis 
of naphthyridine antibacterial agents. (See for example, European 
Published Patent Applications 132,845, 160,578, 153,580 and U.S. Pat. Nos. 
4,840,954, 4,649,144, 4,616,019, and Chu, D. T. W., et al., J. Med. Chem., 
29, 2363-2369 (1986)). Several of these references disclose a process for 
preparing nicotinic acid. However, many of the processes provide the 
product in low overall yield, about 50-60%. 
European Patent Application 333 020 discloses a process for preparing 2,6- 
dichloro-5-fluoronicotinic acid starting from inexpensive starting 
materials, ethyl formate, ethyl fluoro acetate, and cyanoacetamide. 
However, in this process purification procedures are required to remove 
byproducts. Another drawback is the low overall yield (40%-45%) in 
converting 2,6-dihydroxy-3-cyano-5-fluoropyridine to 
2,6-dichloro-5-fluoronicotinic acid. 
U.S. Pat. No. 5,204,478 discloses the preparation of 
2,6-dichloro-5-fluoronicotinic acid and 2,6-dichloro-5-fluoronicotinoyl 
chloride. The process described converts a 2,6-dihydroxy-5-fluoronicotinic 
acid ester into 2,6-dichloro-5-fluoronicotinoyl chloride. The ester is 
converted using phosphorus oxychloride and a lithium reagent to 
2,6-dichloro-5-fluoronicotinoyl chloride in one step. This is followed by 
conversion, by basic hydrolysis, to afford 2,6-dichloro-5-fluoronicotinic 
acid. 
It would be advantageous to have a method for the preparation of nicotinic 
acid derivatives which provides nicotinic acid derivatives in high yields 
and high purity. 
It would be advantageous to have a method for the preparation of nicotinic 
acid derivatives which eliminated the need for purification of 
intermediate compounds. 
SUMMARY OF THE INVENTION 
The present invention relates to a process for preparing compounds 
represented by the following structural formula (I): 
##STR3## 
which are prepared by reacting a compound having the formula: 
##STR4## 
under acidic conditions with a nitrite salt. The R.sup.1, R.sup.2, and 
R.sup.3, groups are independently selected from the group consisting of 
hydrogen, and halogen atoms and the R.sup.4, is selected from the group 
consisting of hydrogen, lower alkyl and aryl. 
DETAILED DESCRIPTION OF THE INVENTION 
It has surprisingly been found that nicotinamides can be converted, in high 
yield and purity, to nicotinic acids with nitrite salts in the presence of 
an acid. The process described provides an efficient method for the 
preparation of nicotinic acids which eliminates the need for additional 
purification of the intermediate or final products. This process utilizes 
a new method for the preparation, inexpensive starting materials, and a 
more efficient solvent for extraction of the product, without the need for 
methylene chloride solvent. This method affords higher yields than the 
previous methods. 
The process for preparing compounds represented by formula (I): 
##STR5## 
comprises the step of reacting a compound having the formula: 
##STR6## 
with a nitrite salt, under acidic conditions. The groups, R.sup.1, 
R.sup.2, and R.sup.3, are independently selected from the group consisting 
of hydrogen, and halogen atoms and the R.sup.4 group is selected from the 
group consisting of hydrogen, lower alkyl and aryl. 
The nitrite salts which are useful in practicing the present invention are 
alkali metal salts having the formula MNO.sub.2 where M is an alkali 
metal. Non-limiting examples of alkali metal salts useful in the present 
invention include salts such as, sodium nitrite, lithium nitrite, 
potassium nitrite and the like. As used herein, the term "alkyl" means a 
straight or branched hydrocarbon radical having from one to six carbon 
atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, 
n-butyl, secondary butyl, isobutyl, tertiary butyl, n-pentyl, n-hexyl, and 
the like. Preferably the R.sup.4, groups are hydrogen, methyl, or ethyl. 
As used herein, the term "aryl", refers to carbocyclic aromatic radicals, 
such as, phenyl, benzyl, naphthyl, and the like. 
As used herein the term "alkali metal" is a metal in Group IA of the 
periodic table and includes metals such as, lithium, sodium, potassium, 
and the like. 
Abbreviations 
Abbreviations which have been used in the descriptions of the scheme and 
the examples that follow are, DMSO for dimethyl sulfoxide, DCE for 
1,2-dichloroethane; HPLC for high performance liquid chromatography, MeOH 
for methanol, MTBE for Methyl tert-butyl ether; PCl.sub.5 for phosphorus 
pentachloride; and POCl.sub.3 for phosphorus oxychloride. 
Synthetic Methods 
The compounds and processes of the present invention will be better 
understood in connection with the following synthetic schemes which 
illustrate the methods by which the compounds of the invention may be 
prepared. The groups R.sup.1, R.sup.2, R.sup.3, and R.sup.4, are as 
defined above unless otherwise noted below. 
The nicotinic acids, I are prepared starting from a nitrile having formula 
II and hydrolyzing it to an amide, formula III. The amide is reacted with 
a nitrite salt under acidic conditions to provide the nicotinic acid, I. 
The use of nitrite salts allows the reaction to be performed without the 
need for purification of the nicotinamide, III or the product acid, I 
saving time and improving the yield. This is illustrated in Scheme I, 
below. 
##STR7## 
A preferred embodiment for preparing the nicotinic acids is illustrated in 
Scheme II. The 2,6-dihydroxy-3-cyano-5-fluoropyridine (1) is prepared 
according to the method described in European Patent Application 333 020 
(EP 020), incorporated herein by reference. This document describes the 
preparation of 2,6-dihydroxy-3-cyano-5-fluoropyridine starting with ethyl 
formate, ethyl fluoro acetate, and cyanoacetamide. The ethyl formate and 
ethyl fluoro acetate, are initially reacted in the presence of sodium 
methoxide, followed by addition of cyanoacetamide to provide the dihydroxy 
cyanopyridine (1). The 2,6-dihydroxy-3-cyano-5-fluoropyridine is converted 
to 2,6-dichloro-3-cyano-5-fluoropyridine (2) with phosphorus oxychloride 
(POCl.sub.3) and phosphorus pentachloride (PCl.sub.5). The 
2,6-dichloro-5-fluoro-3-cyanopyridine is hydrolyzed to 
2,6-dichloro-5-fluoronicotinamide (3) by heating the cyano compound in the 
presence of concentrated sulfuric acid. The 2,6-dichloro-5-fluoronicotinic 
acid (4) was prepared by reaction of the amide (3) with sodium nitrite 
under aqueous acidic conditions. 
##STR8## 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The compounds and processes of the present invention will be better 
understood in connection with the following examples, which are intended 
as an illustration of and not a limitation upon the scope of the 
invention. 
The reagents required for the synthesis of the compounds of the invention 
are readily available from a number of commercial sources such as Aldrich 
Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., 
USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); Alfa Aesar (Ward 
Hill, Mass. 01835-9953); Eastman Chemical Company (Rochester, N.Y. 
14652-3512); Lancaster Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum 
Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 
08901); Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not 
commercially available can be prepared by employing known methods from the 
chemical literature. 
The compounds prepared in Examples 1b and 1c were analyzed by HPLC. The 
analyses were performed on a Shimadzu HPLC instrument, using a variable 
wavelength UV detector at 284 nm and a 30 cm.times.3.9 mm Waters 
.mu.-Bondpack C-18 column. The mobile phase was 64% by volume 0.5M citric 
acid solution (9.6 g/L, HPLC grade water) and 36% by volume acetonitrile 
(HPLC grade). The flow rate was 2 mL/minute and the injection volumes were 
about 10-20 .mu.L.

EXAMPLE 1 
Preparation of 2,6-Dichloro-5-fluoronicotinamide (3) 
1a. Preparation of 2,6-Dihydroxy -5-fluoro-3-cyanopyridine (1) 
A 300 gallon reaction vessel was charged with 300 L of toluene, blanketed 
with nitrogen and 30.6 kg of sodium methoxide was added. This was followed 
by 62.6 kg of ethyl formate. The temperature was maintained below 
30.degree. C. Ethyl fluoroacetate, 30 kg, was added to the mixture. 
(Extreme caution must be used when working with ethyl fluoroacetate. Ethyl 
fluoroacetate is highly toxic). The ethyl formate and ethyl fluoroacetate 
were metered to maintain the temperature at about 30.degree. C. The 
reaction mixture was allowed to stir for 3 to 5 hours and formed a 
suspension. The suspension was allowed to cool to 5.degree.-10.degree. C. 
and cyanoacetamide, 71.4 kg, was added. This formed a thick suspension 
which was diluted with about 300 L of methanol, allowed to warm to room 
temperature (about 20.degree. C.) and stirred for an additional 12-16 
hours. Glacial acetic acid, 35.6 L, and water, 200 L, were added to the 
suspension. The suspension was centrifuged to separate the product. The 
product was collected and dried. The title compound, M. W. 154.10, had a 
purity of 95%, by HPLC, and m.p. 135.degree.-140.degree. C. 
1b. Preparation of 2,6-Dichloro-5-fluoro-3-cyanopyridine (2) 
A 12 liter (L) reaction vessel equipped with a mechanical stirrer, 
thermometer, condenser and nitrogen inlet was added 2000 mL of phosphorus 
oxychloride (POCl.sub.3). The vessel was cooled to 5.degree.-10.degree. 
C., and 500 g of dry 2,6-Dihydroxy-5-fluoro-3-cyanopyridine (2. 1% 
moisture: dried at 115.degree. C. under vacuum overnight) was added in 
portions, keeping temperature below 30.degree. C. The mixture was heated 
at 80.degree.-85.degree. C. for 60 minutes and allowed to cool to room 
temperature. Phosphorus pentachloride (PCl.sub.5), 2200 g, was added, in 
portions, to the mixture. After the addition was complete the mixture was 
heated to 100.degree.-104.degree. C. and monitored by HPLC, at 24 hours, 
93% product and 30 hours, 95% product. The reaction was stopped after 
about 30 hours. The mixture was cooled down to room temperature and 
POCl.sub.3 was removed under reduced pressure (temperature 
30.degree.-60.degree. C.). 1,2-Dichloroethane (DCE), 2.0 L, was added to 
the residue and the mixture was cooled to 5.degree.-10.degree. C. in an 
ice bath. Distilled water, 5000 mL, was added slowly to the mixture, 
maintaining the temperature below 40.degree. C. After the water addition 
the mixture was stirred at room temperature for an hour. The 
1,2-dichloroethane (DCE) layer was separated and the aqueous layer was 
extracted with DCE (2.times.1000 ml). The DCE extracts were combined. The 
DCE was removed by vacuum distillation. The residual 
2,6-dichloro-5-fluoro-3-cyanopyridine product is used in situ for next 
step. 
1c. Preparation of 2,6-Dichloro-5-fluoronicotinamide (3) 
The amide was prepared from the 2,6-dichloro-5-fluoro-3-cyanopyridine 
described in Example 1b. The cyanopyridine was placed in 12 L flask, 
cooled to 5.degree.-10.degree. C. in an ice bath, and 2300 mL of 
concentrated sulfuric acid was added. The residual DCE was then removed 
under vacuum at room temperature. After removal of the DCE the mixture was 
heated at 65.degree.-70.degree. C. for 1-2 hours and monitored by HPLC. 
After about 2 hours the mixture was cooled to about 10.degree. C. in an 
ice bath. The amide product (3) formed was used directly for the next step 
without isolation or purification. 
EXAMPLE 2 
Preparation of 2,6-Dichloro-5-fluoronicotinic acid (4) 
An aqueous sodium nitrite (NaNO.sub.2) solution, prepared from 400 g of 
sodium nitrite in 500 m/of distilled water, was added dropwise, under the 
surface of the acidic amide reaction mixture from Example 1c, maintaining 
temperature between 35.degree.-40.degree. C. An exotherm up to 50.degree. 
C. was observed towards the end of addition of sodium nitrite solution. 
(The exotherm may be avoided by increasing the amount of sulfuric acid). 
The reaction mixture became thick and required thorough mixing. After the 
addition of the sodium nitrite solution, the reaction mixture was stirred 
for about 15 minutes, warmed to 45.degree.-50.degree. C., and monitored by 
HPLC. After about 3 hours the reaction mixture was cooled to 
0.degree.-5.degree. C., and 5000 mL of distilled water was added slowly, 
maintaining the temperature below about 30.degree. C. The mixture was 
stirred at room temperature for 60 minutes. Methyl tert-butyl ether 
(MTBE), 2000 mL, was added and the mixture was stirred at room temperature 
for an additional 30 minutes. The MTBE layer was separated and the aqueous 
layer was extracted with MTBE (2.times.1000 mL). The combined MTBE layers 
were washed with distilled water (1.times.500 ml). The combined MTBE layer 
was mixed with 10% aqueous sodium carbonate solution (2 L). The mixture 
was stirred at room temperature for about 30 minutes to extract the acid 
product into the aqueous layer. The aqueous layer was separated, and the 
MTBE layer was discarded. The aqueous layer was cooled to 
10.degree.-15.degree. C. and acidified to pH&lt;2 with concentrated HCl, 
about 310 mL, to precipitate the solid product. The product was filtered 
and washed with water (2.times.500 mL). This solid was dried at 65.degree. 
C. under vacuum and nitrogen bleeding for 20 hours. The dry weight was 
518.3 g and was 99.9% pure by HPLC, w/w. The overall yield of 
2,6-dichloro-5-fluoronicotinic acid (4) was 76%, based on 
2,6-dihydroxy-5-fluoro-3-cyanopyridine. 
The 2,6-dichloro-5-fluoronicotinic acid product (4) was analyzed by HPLC, 
and compared to an authentic sample using an Alltech Hypersil BDS C-18, 
150.times.4.6 mm column. The mobile phase was 25% by volume Methanol (HPLC 
grade) and 75% by volume 0.05M KH.sub.2 PO.sub.4 buffer. (The buffer was 
prepared from 6.8 g of KH.sub.2 PO.sub.4 in 1 L of D.I. water and 5.0 mL 
of triethylamine. The buffer was acidified to pH 2.5 with phosphoric 
acid.) The flow rate was 1.0 ml/minute and the detector wavelength was 284 
nm. 
COMATIVE EXAMPLE 2 
Preparation of 2,6-Dichloro-5-fluoronicotinic acid (4) 
2b. Preparation of 2,6-Dichloro-5-fluoro-3-cyanopyridine (2) 
A 300 gallon reaction vessel was charged with 300 kg of phosphorous 
oxychloride (POCl.sub.3), cooled and blanketed with nitrogen. To the 
cooled POCl.sub.3 was added phosphorus pentachloride (PCl.sub.5), 182 kg, 
and 30 kg of the dried 2,6-Dihydroxy-5-fluoro-3-cyanopyridine (prepared in 
Example 1a). The mixture was heated at reflux for 20-24 hours and allowed 
to cool to room temperature. The POCl.sub.3 was removed under reduced 
pressure. Methylene chloride, about 473 L, was added and the mixture was 
cooled to 5.degree.-10.degree. C. in an ice bath. The methylene 
chloride/reaction mixture was slowly added to ice water, about 360 kg, 
maintaining the temperature at 0.degree. C. with external cooling. After 
addition to the water the mixture was stirred to decompose the PCl.sub.5. 
The methylene chloride layer was separated, dried and filtered. The 
methylene chloride was removed by distillation. The residual 
2,6-dichloro-5-fluoro-3-cyanopyridine product is used in situ for next 
step. 
2c. 2,6-Dichloro-5-fluoronicotinamide (3) 
The amide was prepared by addition of concentrated sulfuric acid, 185 kg, 
to the 2,6-dichloro-3-cyano-5-fluoropyridine (2) residue prepared in 
Example 2b. The mixture was heated at about 75.degree. C. for 1 hour. The 
solution was cooled and added to 360 kg of ice water. The suspension 
formed was extracted with isopropyl alcohol/chloroform (30:70). The 
organic layer was removed and dried. The solvent was evaporated to provide 
the title compound. 
2d. Preparation of 2,6-Dichloro-5-fluoronicotinic acid (4) 
The acid was prepared directly from the 2,6-dichloro-5-fluoronicotinamide 
(3), described in Example 2c, without purification. The nicotinamide (3), 
was placed in a flask, and concentrated hydrochloric acid, 327 kg, was 
added. The mixture was heated at reflux for about 2 hours. The reaction 
mixture was cooled in an ice bath to provide a solid product. The overall 
yield of 2,6-dichloro-5-fluoronicotinic acid (4) was 55%, based on 
2,6-dihydroxy-5-fluoro-3-cyanopyridine. 
2e. Alternative Preparation of 2,6-Dichloro-5-fluoronicotinic acid (4) 
Alternatively, a one step hydrolysis of 
2,6-dichloro-5-fluoro-3-cyanopyridine (2) can be accomplished as follows: 
The cyanopyridine (2), 28 g, was added to a flask containing concentrated 
sulfuric acid, 26 mL. The mixture was heated at about 75.degree. C. for 
about 45 minutes. The solution was cooled in an ice bath and concentrated 
hydrochloric acid, 130 mL was added dropwise. The mixture was heated at 
reflux for about 1 hour. The mixture was allowed to cool to room 
temperature and then cooled in an ice bath. The precipitate was filtered 
to provide 6 g of 2,6-dichloro-5-fluoronicotinic acid. 
It will be understood that the specification and the examples are 
illustrative and not limitative of the present invention and that other 
embodiments within the spirit and scope of the invention will suggest 
themselves to those skilled in the art.