CA1216851A - Process for the production of 2-hydroxypyridines from 2-pyridine carboxylic acid-n-oxides - Google Patents
Process for the production of 2-hydroxypyridines from 2-pyridine carboxylic acid-n-oxidesInfo
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- CA1216851A CA1216851A CA000438988A CA438988A CA1216851A CA 1216851 A CA1216851 A CA 1216851A CA 000438988 A CA000438988 A CA 000438988A CA 438988 A CA438988 A CA 438988A CA 1216851 A CA1216851 A CA 1216851A
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Abstract
ABSTRACT OF THE DISCLOSURE
Process for the production of 2-hydroxypyridines having the formula:
from 2-pyridine carboxylic acid-N-oxides having the formula:
wherein R is H, a -COOH group, an alkyl group having 1 to 8 carbon atoms or an aryl group and n designates a number between 1 and 4. The N-oxide is converted using lower aliphatic carboxylic acld anhydrides in the presence of a tertiary amine.
The conversion product is then hydrolyzed.
Process for the production of 2-hydroxypyridines having the formula:
from 2-pyridine carboxylic acid-N-oxides having the formula:
wherein R is H, a -COOH group, an alkyl group having 1 to 8 carbon atoms or an aryl group and n designates a number between 1 and 4. The N-oxide is converted using lower aliphatic carboxylic acld anhydrides in the presence of a tertiary amine.
The conversion product is then hydrolyzed.
Description
3 ~.
The invention relates to a process for the production of 2-hydroxypyridines, especially 2-hydroxypyridine carboxy-lic acid and 2-hydroxyalkyl pyridine.
The invention relates to a process for the production of 2-hydroxypyridines, especially 2-hydroxypyridine carboxy-lic acid and 2-hydroxyalkyl pyridine.
2-hydroxypyridines can be obtained by diazotization of -the corresponding amine pyridines and subsequen-t treatment with alkali lye. 2-hydroxypyridines can also be obtained from pyridine sulfonic acids or halogen pyridines by ex-change with alkali, possibly by means of metal catalysts, such as, copper. The literature describes converting pyridine-N-oxide with acetic acid anhydride to 2-acetoxy-pyridine, which can be converted by hydrolysis into 2-hydroxypyridine or 2-pyridone. On the other hand, the re-action of picolinic acid-N-oxide with acetic acid anhydride only produces 2-hydroxypyridine in small quantities.
Pyridine-N-oxide develops as the main product. (See J. Org.
~. 26, 1961, 428.) Wheneve~ the same reaction is carrled out with isocinchomeronic acid-N-oxide, in an analogous manner only traces of 6-hydroxynicotinic acid are obtained and nicotinic acid-N-oxide is the main product. The reaction of 6-methylpicolinic acid-N-oxide with acetic acid anhydride is an exception, which produces 2-hydroxy-6-methyl pyridine in a good yield. ~See Bull. Chem. Soc. Japan 42, 3350, (196~).) ~ n object of the invention is to produce 2-hydroxypyri-dine carboxylic acids and 2-hydroxy-alkyl pyridines in high yields. Other objects and advantages of the invention are set out herein ` or are obvlous herefrom to one ordinarlly skllled ln the art.
: The obJects and advantages of the inventlon are achleved by the process of the inventlon.
The lnventlon lnvolves a process for the production of a 2-hydroxypyrldlne havlng the formula:
N
from a 2-pyrldlne carboxylic acld-N-oxide havlng the formula:
Rn ~ ~ COOH
N
wherein R is H, -COOH, an alkyl group havlng one to eight carbon atoms or an aryl group and n is a number between 1 and 4. The 2-pyridine carboxylic acid-N-oxide is acylated using a lower allphatic carboxylic acid anhydride ln the presence of a tertiary amlne to form an acyla-ted produc-t, which is hydrolyzed or saponified to produce the 2-hydroxypyridine.
Preferably the carboxylic acid anhydride is acetic anhydride. Also preferably the tertlary amlne is triethyl amlne. The ratlo of tertiary amine to 2-pyridine carboxylic acid-N-oxide preferably lies between 1 to 1 and 20 to 1 and most ~referably between 2 to 1 and 5 to 1. The reaction preferably ls carried out at a temperature Or 0 to 80C- and most preferably between 20 and 60C. Freferably the reactlon is conducted ln the presence of a ~olvent.
....
When 2-pyridine carboxylic acid-N-oxide is ~eacted with lower aliphatic carboxylic acid anhydrides in -the pre-sence of a -tertiary amine, for example, triethyl amine, at a tempera-ture of 20 to 60C. and subsequently the inter-mediate is saponified, the 2-acetoxypyridine is formed.
The invention also involves a composition containing a 2-pyridine carboxylic acid-N-oxide having the formula:
~n ~ ~
- COOH
~0 wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group, a lower aliphatic carboxylic acid anhydride and a tertiary amine. A solvent can also be present in the composition.
The lower aliphatic anhydrides usually have 2 to 8 carbon atoms. The preferred lower aliphatic anhydride is acetic acid anhydride. Examples of useEul lower aliphatic anhydrides are propionic acid anhydride, n-butyric acid anhydride, valeric acid anhydride, caproic acid anhydride, oenanthic acid anhydride, caprylic acid anhydride, iso-butyric acid anhydride, trimethylacetic acid anhydride, iso-caproic acid anhydride, diethyl acetic acid anhydride, dimethylethylacetic acid anhydride, n-nonanoic acid anhydride, 2-ethylhexanoic acid anhydride and lauric acid anhydride.
The carboxylic acid anhydride, in relation to the pyridine carboxylic acid-N-oxide, ~. .
~2~
is used ln 1 to 10 times molar excess and can also serve as the solvent.
Accordin~ to the lnventlon process 2-hydroxypyridine carboxylic aclds are surprlsingly obtalned at hlgh ylelds, wlth the reaction occurrlng at an extremely fast speed at relatl~ely low temperatures.
The process of the invention can also be carrled out in the presence of or~anlc or lnorganic solvents, such as toluene, petroleum ether, CC14, aceti~ acid ethyl ester, acetonitrlle, n-hexane, cyclohexane, xylene, n-heptane, ethyl benzene, isopropylbenzene, n-octane, nltromethane, nitroethane, methyl cellosolve acetate, c~llosolve acetate, methylene chloride, chlorobenzene, chlorotoluene, trichloroethane, methyl acetate, methyl formate, ethyl formate, n-pr~pyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and nltrobenzene. The useful solvents include hydrocarbon solvents, halogenated solvents, ester solvents, ether solvents, nltrohydrocarbon solvents and the like, provided they are llquld in at least part of the temperature range used in the lnventlon process.
~ eside triethylamine, other aliphatic or allphatlc/aromatlc tertiary amlnes, pyridine or DMF can be used as a catalyst ln the process.~ Examples of other useful tertlary amines are tri-n-butylamlne, trimethylaDlne, tributylamlne, dlethylmethyl amine, benzylethylphenylamine, benzylmethylphenylamlne, dibenzylphenylamine, tributylamine, tripropylamlne and diphenylmethylamine. Trialkylamlnes are partlcularly useful catalysts. Preferably triethylamine ls used and is applied in a molar ratio oE tertiary amine to pyridine carboxylic acid-N-oxide of between 1 to 1 and 10 to 1, and preferably of between 2 to 1 and 5 to 1.
Beside 2-pyridine monocarboxylic acid-N-oxide, the corresponding pyridine dicarboxylic acid-N-oxides, such as, pyridine carboxylic acid-(2,3)-N-oxide(quinolinic acid), pyridine carboxylic acid-(2,4)-N-oxide(lutidinic acid), pyridine dicarboxylic acid-(2,5)-N-oxide(isocinchomeronic acid) and pyridine dicarboxylic acid-(2,6)-N-oxide(dipico-linic acid), and the corresponding pyridine tricarboxylicacid-N-oxides, such as, pyridine tricarboxylic acid-(2,3,4)-N-oxide (N-carbocinchomeronic acid), pyridine tricarboxylic acid-(2,4,5)-N-oxide(berberonic acid), pyridine tricarboxylic acid-(2,4,6)-N-oxide(trimesitic acid) and pyridine pentacar-boxylic acid-N-oxide, can be used.
The pyridine carboxylic acid-N-oxides can be ring-substituted 1 to 4 times with an alkyl group having 1 to 8 carbon atoms or an aryl group. Examples of useful alkyl groups are methyl, ethyl, octyl, butyl, propyl, isopropyl, isobutyl, 3-methyl-1-butyl, 2-butyl, 2-pentyl, heptyl, 2-methyl-2-butyl, hexyl, 2-ethyl-1-butyl, 2-methyl-1-butyl,
Pyridine-N-oxide develops as the main product. (See J. Org.
~. 26, 1961, 428.) Wheneve~ the same reaction is carrled out with isocinchomeronic acid-N-oxide, in an analogous manner only traces of 6-hydroxynicotinic acid are obtained and nicotinic acid-N-oxide is the main product. The reaction of 6-methylpicolinic acid-N-oxide with acetic acid anhydride is an exception, which produces 2-hydroxy-6-methyl pyridine in a good yield. ~See Bull. Chem. Soc. Japan 42, 3350, (196~).) ~ n object of the invention is to produce 2-hydroxypyri-dine carboxylic acids and 2-hydroxy-alkyl pyridines in high yields. Other objects and advantages of the invention are set out herein ` or are obvlous herefrom to one ordinarlly skllled ln the art.
: The obJects and advantages of the inventlon are achleved by the process of the inventlon.
The lnventlon lnvolves a process for the production of a 2-hydroxypyrldlne havlng the formula:
N
from a 2-pyrldlne carboxylic acld-N-oxide havlng the formula:
Rn ~ ~ COOH
N
wherein R is H, -COOH, an alkyl group havlng one to eight carbon atoms or an aryl group and n is a number between 1 and 4. The 2-pyridine carboxylic acid-N-oxide is acylated using a lower allphatic carboxylic acid anhydride ln the presence of a tertiary amlne to form an acyla-ted produc-t, which is hydrolyzed or saponified to produce the 2-hydroxypyridine.
Preferably the carboxylic acid anhydride is acetic anhydride. Also preferably the tertlary amlne is triethyl amlne. The ratlo of tertiary amine to 2-pyridine carboxylic acid-N-oxide preferably lies between 1 to 1 and 20 to 1 and most ~referably between 2 to 1 and 5 to 1. The reaction preferably ls carried out at a temperature Or 0 to 80C- and most preferably between 20 and 60C. Freferably the reactlon is conducted ln the presence of a ~olvent.
....
When 2-pyridine carboxylic acid-N-oxide is ~eacted with lower aliphatic carboxylic acid anhydrides in -the pre-sence of a -tertiary amine, for example, triethyl amine, at a tempera-ture of 20 to 60C. and subsequently the inter-mediate is saponified, the 2-acetoxypyridine is formed.
The invention also involves a composition containing a 2-pyridine carboxylic acid-N-oxide having the formula:
~n ~ ~
- COOH
~0 wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group, a lower aliphatic carboxylic acid anhydride and a tertiary amine. A solvent can also be present in the composition.
The lower aliphatic anhydrides usually have 2 to 8 carbon atoms. The preferred lower aliphatic anhydride is acetic acid anhydride. Examples of useEul lower aliphatic anhydrides are propionic acid anhydride, n-butyric acid anhydride, valeric acid anhydride, caproic acid anhydride, oenanthic acid anhydride, caprylic acid anhydride, iso-butyric acid anhydride, trimethylacetic acid anhydride, iso-caproic acid anhydride, diethyl acetic acid anhydride, dimethylethylacetic acid anhydride, n-nonanoic acid anhydride, 2-ethylhexanoic acid anhydride and lauric acid anhydride.
The carboxylic acid anhydride, in relation to the pyridine carboxylic acid-N-oxide, ~. .
~2~
is used ln 1 to 10 times molar excess and can also serve as the solvent.
Accordin~ to the lnventlon process 2-hydroxypyridine carboxylic aclds are surprlsingly obtalned at hlgh ylelds, wlth the reaction occurrlng at an extremely fast speed at relatl~ely low temperatures.
The process of the invention can also be carrled out in the presence of or~anlc or lnorganic solvents, such as toluene, petroleum ether, CC14, aceti~ acid ethyl ester, acetonitrlle, n-hexane, cyclohexane, xylene, n-heptane, ethyl benzene, isopropylbenzene, n-octane, nltromethane, nitroethane, methyl cellosolve acetate, c~llosolve acetate, methylene chloride, chlorobenzene, chlorotoluene, trichloroethane, methyl acetate, methyl formate, ethyl formate, n-pr~pyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and nltrobenzene. The useful solvents include hydrocarbon solvents, halogenated solvents, ester solvents, ether solvents, nltrohydrocarbon solvents and the like, provided they are llquld in at least part of the temperature range used in the lnventlon process.
~ eside triethylamine, other aliphatic or allphatlc/aromatlc tertiary amlnes, pyridine or DMF can be used as a catalyst ln the process.~ Examples of other useful tertlary amines are tri-n-butylamlne, trimethylaDlne, tributylamlne, dlethylmethyl amine, benzylethylphenylamine, benzylmethylphenylamlne, dibenzylphenylamine, tributylamine, tripropylamlne and diphenylmethylamine. Trialkylamlnes are partlcularly useful catalysts. Preferably triethylamine ls used and is applied in a molar ratio oE tertiary amine to pyridine carboxylic acid-N-oxide of between 1 to 1 and 10 to 1, and preferably of between 2 to 1 and 5 to 1.
Beside 2-pyridine monocarboxylic acid-N-oxide, the corresponding pyridine dicarboxylic acid-N-oxides, such as, pyridine carboxylic acid-(2,3)-N-oxide(quinolinic acid), pyridine carboxylic acid-(2,4)-N-oxide(lutidinic acid), pyridine dicarboxylic acid-(2,5)-N-oxide(isocinchomeronic acid) and pyridine dicarboxylic acid-(2,6)-N-oxide(dipico-linic acid), and the corresponding pyridine tricarboxylicacid-N-oxides, such as, pyridine tricarboxylic acid-(2,3,4)-N-oxide (N-carbocinchomeronic acid), pyridine tricarboxylic acid-(2,4,5)-N-oxide(berberonic acid), pyridine tricarboxylic acid-(2,4,6)-N-oxide(trimesitic acid) and pyridine pentacar-boxylic acid-N-oxide, can be used.
The pyridine carboxylic acid-N-oxides can be ring-substituted 1 to 4 times with an alkyl group having 1 to 8 carbon atoms or an aryl group. Examples of useful alkyl groups are methyl, ethyl, octyl, butyl, propyl, isopropyl, isobutyl, 3-methyl-1-butyl, 2-butyl, 2-pentyl, heptyl, 2-methyl-2-butyl, hexyl, 2-ethyl-1-butyl, 2-methyl-1-butyl,
3-methyl-1-pentyl, l-pentyl, isohexyl, 2-hexyl and 3-methyl-2-pentyl. Examples of useful aryl groups are phenyl and naphthyl. An example of a useful alkaryl group is benzyl.
The CGnverSion reaction is advantageously carried out at a temperature of 0 to 80 C., preferably at 20C to 60C.
By way of summary, 2-hydroxypyridines are produced from 2-pyridine carboxylic acid-N-oxides by reaction with acetic acid anhydride and tertiary amine.
The following Examples illustra-te the invention:
EXAMPI,E 1 Production of 6-hydroxynicotinic acid (6-OHNS) from iso-cinchomeronic acid-N-oxide (ICSO).
200 g of acetic acid anhydride (1.96 mole) and 50 g of triethylamine (0.5 mole) were mixed, and 36 g of ICSO (0.197 mole) was added portionwise at ambient temperature in such a way that the reaction temperature did not exceed 30C. After completion of the addition, the mixture was allowed to react again for about 1 hour at 30C. until CO2 no longer escaped.
The resultant brownish-black solu-tion was concentrated on a rotavapor (30 torr, 60C.), and the viscous residue was saponified by the addition of 20 percent KOH (end pH ~ 12) at 80C. for 1/4 hour. To remove the triethyl amine, the liquid reaction mixture was extracted with CH2C12 and subse-quently acidified with concentrated HCl (pH 1). The preci-pitate obtained thereby was sucked off, washed with H2O and dried at 45C. and 20 torr. The yield of 23 g (titrimeri-cally determined content 96.5 percent) corresponded to 81 percent of theoretical.
EXA~IPLE 2 Production of 2-hydroxynicotinic acid (2-DHNS) from quino-linic acid-N-oxide (CSO).
100 g of acetic acid anhydride (Q.98 mole~ and 25 g of triethylamine (0.25 mole) were mixed and heated to 40C. in order to ensure a lively development of gas during the addition in portions of 18 g of CSO (0.098 mole). The re-processing of the reaction mixture took place analogously to Example 1. The yield was 5.6 g of pure 2-OHNS according to NMR (about 41 percent of theoretical).
Production oE 2-hydroxypyridine from 2-pyridine carboxylic acid-N-oxide(picolinic acid-N-oxide; PSO).
200 g of acetic acid anhydride (1.96 mole) and 40 g of triethylamine (0.4 mole) were placed in a flask and 36 g of PSO (0.26 mole) was added in doses. The reaction temperature during the addition of the PSO was kept between 20 and 30 C.
After completion of the reaction, the fluid was evaporated on a rotavapor and the residue was absorbed with water. To this aqueous solution, 30 percent NaOH was added slowly until no further precipitate developed. The Na salt of the 2-hydroxy pyridine thus obtained was sucked off, was washed with 30 percent NaOH, was recrystallized from 95 percent alcohol and was dried at 45C. and 20 torr. The yield was 30.5 g of pure hydroxypyridine-Na-salt according -to H-NMR.
Since the 2-hydroxypyridine-Na-salt still contained about 3 percent H2O, this resulted in about 35 percent of theoretical.
Production of 6-hydroxynicotinic acid.
20.4 g of acetic acid anhydride (0.2 mole), 20.2 g of Et3N (0.2 mole) and 50 ml of CC14 were placed in a flask.
18.3 g of isocinchomeronic acid-N-oxide (0.1 mole) was added by portions to this solution. The temperature rose to 50 C.
After completion of the reaction the solvents were distilled off. About 100 ml of 20 percent KOH was added drop by drop to the viscous residue and the acetate was saponified over a 15 minute period at 80C. After removal of the ~t3N by ~.' extraction, the aqueous solution was acidified wi-th concen--trated HCl. The precipitate was sucked off, washed with water and dried under a vacuum. 11.0 g of 6-hydroxy nicoti-nic acid was ob-tained, which was pure according -to NMR. The crude yield was about 79 percen-t.
EX~MPLE 5 Production of 6-hydroxynicotinic acid.
Example 1 was repeated, except that propionic acid anhydride was used instead of acetic acid anhydride. The yield of 6-hydroxynicotinic acid was 78 percent.
Production of 6-hydroxynico-tinic acid.
Example 1 was repeated, except that tributylamine was used instead of Et3N. The yield of 6-hydroxynicotinic acid was 75 percent.
Production of 6-hydroxynicotinic acid.
Example 4 was repeated, excep-t that petrolether was used instead of CC14. The yield of 6-hydroxynicotinic acid was 67 percent.
Production of 6-hydroxy picolinic acid.
Acetic acid anhydride (O;S mole) and Et3N (0.15 mole) were placed in a flask. Dipicolinic acid-N-oxide (0.05 mole) was put into this solution in portions; the temperature amounted to 35C. After completion of the addition, the solution was concentrated by evaporation on a ro-tavapor.
80 ml. of 20 percent KOH was added to the residue and was kept for 15 minutes at 80C. After extraction of the Et3N
with CH2Cl2, the aqueous phase was acidified with HCl concentrated to pH 2. The crystals were sucked off, washed with water and dried. 4.2 g of 6-hydroxypicolinic acid was obtained and was pure according to NMR. The crude yield was about 60 percent.
Production of 6-methylpyridone-2.
Acetic acid anhydride t0.5 mole) and Et3N (0.15 mole) were placed in a flask. To this was added by portions 9.1 g (0.59 mole) of 6-methylpicolinic acid-N-oxide. During the addition the temperature rose up to 45C. After completion of the CO2-development, the black solution was evaporated on a rotavapor. The residue was carefully hydrolyzed with concentrated HCl (115 ml) and the acetate was saponified for 5 hours at 90C. After dis~illing off the aqueous solu-tion, the residue was adjusted basically tpH 7-8) with KOH
20 and the 6-methylpyridone-2 was extracted with CH2C12. 3.7 g of this product were isolated and was pure according to NMR.
The yield was about 57 percent.
:.,
The CGnverSion reaction is advantageously carried out at a temperature of 0 to 80 C., preferably at 20C to 60C.
By way of summary, 2-hydroxypyridines are produced from 2-pyridine carboxylic acid-N-oxides by reaction with acetic acid anhydride and tertiary amine.
The following Examples illustra-te the invention:
EXAMPI,E 1 Production of 6-hydroxynicotinic acid (6-OHNS) from iso-cinchomeronic acid-N-oxide (ICSO).
200 g of acetic acid anhydride (1.96 mole) and 50 g of triethylamine (0.5 mole) were mixed, and 36 g of ICSO (0.197 mole) was added portionwise at ambient temperature in such a way that the reaction temperature did not exceed 30C. After completion of the addition, the mixture was allowed to react again for about 1 hour at 30C. until CO2 no longer escaped.
The resultant brownish-black solu-tion was concentrated on a rotavapor (30 torr, 60C.), and the viscous residue was saponified by the addition of 20 percent KOH (end pH ~ 12) at 80C. for 1/4 hour. To remove the triethyl amine, the liquid reaction mixture was extracted with CH2C12 and subse-quently acidified with concentrated HCl (pH 1). The preci-pitate obtained thereby was sucked off, washed with H2O and dried at 45C. and 20 torr. The yield of 23 g (titrimeri-cally determined content 96.5 percent) corresponded to 81 percent of theoretical.
EXA~IPLE 2 Production of 2-hydroxynicotinic acid (2-DHNS) from quino-linic acid-N-oxide (CSO).
100 g of acetic acid anhydride (Q.98 mole~ and 25 g of triethylamine (0.25 mole) were mixed and heated to 40C. in order to ensure a lively development of gas during the addition in portions of 18 g of CSO (0.098 mole). The re-processing of the reaction mixture took place analogously to Example 1. The yield was 5.6 g of pure 2-OHNS according to NMR (about 41 percent of theoretical).
Production oE 2-hydroxypyridine from 2-pyridine carboxylic acid-N-oxide(picolinic acid-N-oxide; PSO).
200 g of acetic acid anhydride (1.96 mole) and 40 g of triethylamine (0.4 mole) were placed in a flask and 36 g of PSO (0.26 mole) was added in doses. The reaction temperature during the addition of the PSO was kept between 20 and 30 C.
After completion of the reaction, the fluid was evaporated on a rotavapor and the residue was absorbed with water. To this aqueous solution, 30 percent NaOH was added slowly until no further precipitate developed. The Na salt of the 2-hydroxy pyridine thus obtained was sucked off, was washed with 30 percent NaOH, was recrystallized from 95 percent alcohol and was dried at 45C. and 20 torr. The yield was 30.5 g of pure hydroxypyridine-Na-salt according -to H-NMR.
Since the 2-hydroxypyridine-Na-salt still contained about 3 percent H2O, this resulted in about 35 percent of theoretical.
Production of 6-hydroxynicotinic acid.
20.4 g of acetic acid anhydride (0.2 mole), 20.2 g of Et3N (0.2 mole) and 50 ml of CC14 were placed in a flask.
18.3 g of isocinchomeronic acid-N-oxide (0.1 mole) was added by portions to this solution. The temperature rose to 50 C.
After completion of the reaction the solvents were distilled off. About 100 ml of 20 percent KOH was added drop by drop to the viscous residue and the acetate was saponified over a 15 minute period at 80C. After removal of the ~t3N by ~.' extraction, the aqueous solution was acidified wi-th concen--trated HCl. The precipitate was sucked off, washed with water and dried under a vacuum. 11.0 g of 6-hydroxy nicoti-nic acid was ob-tained, which was pure according -to NMR. The crude yield was about 79 percen-t.
EX~MPLE 5 Production of 6-hydroxynicotinic acid.
Example 1 was repeated, except that propionic acid anhydride was used instead of acetic acid anhydride. The yield of 6-hydroxynicotinic acid was 78 percent.
Production of 6-hydroxynico-tinic acid.
Example 1 was repeated, except that tributylamine was used instead of Et3N. The yield of 6-hydroxynicotinic acid was 75 percent.
Production of 6-hydroxynicotinic acid.
Example 4 was repeated, excep-t that petrolether was used instead of CC14. The yield of 6-hydroxynicotinic acid was 67 percent.
Production of 6-hydroxy picolinic acid.
Acetic acid anhydride (O;S mole) and Et3N (0.15 mole) were placed in a flask. Dipicolinic acid-N-oxide (0.05 mole) was put into this solution in portions; the temperature amounted to 35C. After completion of the addition, the solution was concentrated by evaporation on a ro-tavapor.
80 ml. of 20 percent KOH was added to the residue and was kept for 15 minutes at 80C. After extraction of the Et3N
with CH2Cl2, the aqueous phase was acidified with HCl concentrated to pH 2. The crystals were sucked off, washed with water and dried. 4.2 g of 6-hydroxypicolinic acid was obtained and was pure according to NMR. The crude yield was about 60 percent.
Production of 6-methylpyridone-2.
Acetic acid anhydride t0.5 mole) and Et3N (0.15 mole) were placed in a flask. To this was added by portions 9.1 g (0.59 mole) of 6-methylpicolinic acid-N-oxide. During the addition the temperature rose up to 45C. After completion of the CO2-development, the black solution was evaporated on a rotavapor. The residue was carefully hydrolyzed with concentrated HCl (115 ml) and the acetate was saponified for 5 hours at 90C. After dis~illing off the aqueous solu-tion, the residue was adjusted basically tpH 7-8) with KOH
20 and the 6-methylpyridone-2 was extracted with CH2C12. 3.7 g of this product were isolated and was pure according to NMR.
The yield was about 57 percent.
:.,
Claims (14)
1. Process for the production of a 2-hydroxypyri-dine having the formula:
wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group and n is a number from 1 to 4, which comprises acylating a 2-pyridine carboxylic acid-N-oxide having the formula:
wherein R and n are as defined above, with a lower aliphatic carboxylic acid anhydride in the presence of a tertiary amine and hydrolyzing the acylated product to produce the 2-hydroxypyridine.
wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group and n is a number from 1 to 4, which comprises acylating a 2-pyridine carboxylic acid-N-oxide having the formula:
wherein R and n are as defined above, with a lower aliphatic carboxylic acid anhydride in the presence of a tertiary amine and hydrolyzing the acylated product to produce the 2-hydroxypyridine.
2. Process as claimed in Claim 1 wherein the carboxy-lic acid anhydride is acetic anhydride.
3. Process as claimed in Claim 2 wherein the tertiary amine is -triethylamine.
4. Process as claimed in Claim 3 wherein the molar ratio of the tertiary amine to the 2-pyridine carboxylic acid-N-oxide is between 1 to 1 and 20 to 1.
5. Process as claimed in Claim 4 wherein the reaction is carried out at a temperature of 0° to 80°C.
6. Process as claimed in Claim 5 wherein the reaction carried out in the presence of a solvent.
7. Process as claimed in Claim 1 wherein the tertiary amine is triethylamine.
8. Process as claimed in Claim 1 wherein the molar ratio of the tertiary amine to the 2-pyridine carboxylic acid-N-oxide is between 1 to 1 and 20 to 1.
9. Process as claimed in Claim 1 wherein the molar ratio of the tertiary amine to the 2-pyridine carboxylic acid-N-oxide is from 2 to 1 to 5 to 1.
10. Process as claimed in Claim 1 wherein the reaction is carried out at a temperature of 0° to 80°C.
11. process as claimed in Claim 1 wherein the reaction is carried out at a temperature of 20° to 60°C.
12. Process as claimed in Claim 1 wherein the reaction is carried out in the presence of a solvent.
13. Composition comprised of a 2-pyridine carboxylic acid-N-oxide having the formula:
wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group, a lower aliphatic carboxylic acid anhydride and a tertiary amine.
wherein R is H, -COOH, an alkyl group having 1 to 8 carbon atoms or an aryl group, a lower aliphatic carboxylic acid anhydride and a tertiary amine.
14. Composition as claimed in Claim 13 wherein a solvent is also present.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000438988A CA1216851A (en) | 1980-10-16 | 1983-10-14 | Process for the production of 2-hydroxypyridines from 2-pyridine carboxylic acid-n-oxides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH773180A CH644847A5 (en) | 1980-10-16 | 1980-10-16 | Process for the preparation of 2-hydroxypyridines from 2-pyridinecarboxylic acid N-oxides |
| CA000438988A CA1216851A (en) | 1980-10-16 | 1983-10-14 | Process for the production of 2-hydroxypyridines from 2-pyridine carboxylic acid-n-oxides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1216851A true CA1216851A (en) | 1987-01-20 |
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ID=25670180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000438988A Expired CA1216851A (en) | 1980-10-16 | 1983-10-14 | Process for the production of 2-hydroxypyridines from 2-pyridine carboxylic acid-n-oxides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1216851A (en) |
-
1983
- 1983-10-14 CA CA000438988A patent/CA1216851A/en not_active Expired
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| MKEX | Expiry |