JPS6061567A - Manufacture of 2-hydroxypyridine from 2-pyridinecarboxylic acid-n-oxide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-hydroxypyridines, particularly 2-hydroxypyridinecarboxylic acids and 2-hydroxyalkylpyridines.

2-Hydroxypyridine is obtained by diazotization of the corresponding aminopyridine followed by treatment with a caustic alkali and from pyridine sulfonic acid or a halogen pyridine, optionally using a metal catalyst such as copper. By stating the exchange reaction with 1
It is known that it is q. Furthermore, in the literature, 2-
It is described that lysine-N-71 oxide can be converted to ace[-xypyridine with acetic anhydride, which can then be converted to 2-hydroxypyridine or 2-pyridone by hydrolysis. According to another document, picolinic acid-N
The reaction between -71kizide and acetic anhydride has a small amount of 2
- It only gives hydroxypyridine. The main product is pyridine-N-oxide (J, Cbcv,
Soc, 1961.5216). If the same reaction is carried out using isocincomeronic acid, a similar procedure will yield trace amounts of 6-hydroxynicodine Milj and nicodinic acid-11-71 quizide as the main products ().
It is.

The exception is 6-methylbicolinate and acetic anhydride.
which gives 2-hydroxy-6- in good yield.
gives methylpyridine (3ull, Cbem.

Soc, Japan 42, 3350.1969).

The object of the present invention is to produce 2-hydroxypyridinecarboxylic acids and 2-hydroxyalkylpyridines in high yields.

This objective was achieved according to the invention by reacting 2-pyridinecarboxylic acid-N-71 oxide with a lower aliphatic carboxylic acid anhydride in the presence of a tertiary amine such as triethylamine at a temperature of 20 to 30°C to form a 2-7
This is achieved by saponifying setoxypyridine.

As the lower aliphatic carboxylic acid anhydride, acetic anhydride and propionic anhydride, preferably acetic anhydride, are added.

The carboxylic acid anhydride can be used in a 1 to 10 molar excess, based on the 2-pyridinecarboxylic acid N-oxide used, and can serve as a solvent.

According to the process of the invention, it is surprisingly possible to obtain 2-hydroxypyridinecarboxylic acid in high yields, and the reaction proceeds at a high rate at relatively low temperatures 43 .

The process according to the invention can also be carried out in the presence of solvents such as 1 to toluene, petroleum ether, CCQ4, edzirconisder acetate, ^1 acid, arelhenyl-lyl, and the like.

It is possible to use as catalysts other than ethylamine, other aliphatic or aliphatic/aromatic tertiary amines, pyridine or DMF. Interaction of the tertiary amine to the 2-pyridine carbon M-N-71 kylide using IF or triethylamine,
1:1 to 20:1, preferably 5:1 to 2:1
Use as.

In addition to the N-7j oxide, the corresponding pyridinedicarboxylic acids -N-oxy-do(quinolinic acid) as shown below Dicarboxylic acid-(2,4) -N--A kyridide (ludizic acid) 0 pyridine dicarboxylic acid 1l-(2,5)-N-71 quidide (isocincomeronic acid) O pyridine dicarboxylic acid-(2,61 -1'm-Zki)
nide (dipicolinic acid) The corresponding pyridine 1-helicalboxylic acid-N as shown below.
-; loxide 0 pyridine tricarboxylic acid - (2,3,4)-N-oxy(nide (α-carbocincomeronic acid) 0 pyridine) ~
Ricarboxylic acid-(2,4,5)-N-A quinonoid (berberonic acid) 0 Pyridine 1-LinoJ Rubonic acid-(2,4,6)-N-
Oki-1 phyto(trimeditic acid) A3 and pyridine pentacarboxylic acid are obtained.

In addition, the above-mentioned pyridine carbon M-N-Δkylid is
The nucleus may be substituted at 1 to 4 positions with an alkyl group or an aryl group having a chain length of C1-Cs.

The exchange reaction is carried out at a temperature of 0 to 50°C, preferably 20 to 30°C.
It is carried out at a temperature of 0°C.

[E9L Isocincomelon 110-N-oxide (IC8O)
Preparation of 6-hydroxynicotinic acid (6-OHNS) from 200 (+ acetic anhydride <1.96 mol) and 50 (+ triethylamine (0.5 mol)) were placed in a flask, and 3
6 g of IC8O (0,197 mol) were added in small portions at room temperature, ensuring that the reaction temperature did not exceed 30°C.
After the addition was complete, the mixture was stirred at 30° C. for about 1 hour, and no more CO2 evolved. The resulting dark brown solution was transferred to a rotary evaporator (30 Torr, 60
℃) and 81i! The shrunken, sticky residue was reduced to 1/2 at 80°C by addition of 20% KOH (final pH -12).
It was saponified for 4 hours.

For removal of triethylamine, the liquid reaction mixture was extracted with CH2C9,2 and finally tliQ tl C
visibly acidified (pI-11). The precipitate thus generated is separated by filtration and washed with 45
It was dried at 20 Torr.

Yield: 23 (+ (purity determined by titration GJ 96
.

5%), corresponding to 81% of the theoretical amount.Preparation of 2-hydroxynicotinic acid (2-OHNS) from quinoline M-N-oxide (CSO) 100 g of anhydrous vinegar 12 (0.98 mol) and 25°C of triethylamine (0.25 mol) and heated to 40°C.
8 g C8O (0,098 mol) was added in small portions during which vigorous gas evolution continued.

The subsequent treatment of the reaction mixture was carried out analogously to Example 1.

Yield: 5 as pure 2-0HNS according to NMR
．． 69 (approximately 41% of theory) Preparation of 2-hydroxypyridine from 1 tl-N-oxide (picoline fill-N-oxide: PSO) 200 g of anhydrous vinegar 111 (1,96 mol) and 40° triethylamine (0.4 mol) into a flask,
6o of PSO (0,26'El) was added and the reaction temperature was kept between 20 and 30°C during the addition of PSO.

After the reaction was completed, the liquid was evaporated on a rotary evaporator and the residue was dissolved in water.

Slowly add 30% NaOH to this aqueous solution,
This was done until the sediment no longer changed. The Na salt of 2-hydroxypyridine thus obtained was filtered off, washed with 30% NaOH, recrystallized from 95% alcohol and dried at 45° C. and 20 torr.

Yield: Pure 2-hydroxypyridine-Na-130,5(1) by NMR. Ta.

Preparation of 6-hydroxynicotinic acid 20.4 (+ acetic anhydride (0.2 mol), 20°20 Et 3N (0.2 mol) and 50 all CCf
L4 was placed in the flask. 18.30 of Isocincomelon fill-N-7j quizide (0.1 mol) was added in small portions to this solution. The temperature reached 50°C. After the reaction was completed, the solvent was distilled off. Approximately 100 #Iil of KO+-1 (20%) was added dropwise to the sticky liquid residue to saponify the acetate at 80° C. for 15 minutes. After removing the Et 3N by extraction, the aqueous solution was acidified with II II CU. The precipitate was filtered off, washed with water and dried under vacuum.

11. 1% OQ of 6-hydrooxynicotinic acid.

According to NMR, it is pure and has a crude ICo content of 79%.

1"[[Production of 6-hydroxynicotinic acid"J: Sea urchin, but using "C" propionic anhydride instead of acetic anhydride, the yield of 6-hydroxynicotinic acid was 78. I got %.

Example 6 Production of 0-hydroxynicotinic acid Ft3N
JFl, lr: was carried out using l~libdelamine in place of JFl, lr:.75% yield of 6-hydroxynicotinic acid.

and 1 lL 6-Hydoxynicotinic Acid 'JA'r Collection of 6-hydroxynicotinic acid was carried out as in Example 4, but using petroleum ether in place of CCQ 4'. Obtained 67%.

Example 8 6-hydro [manufactured by Jxypicolinic acid]
<0°15 mol) was placed in the flask. Dipicolinic acid-N-J oxide was added to the solution in small portions and the temperature reached 35°C. After the addition was complete, the solution was evaporated on a rotary evaporator. 80d KO against Residue
H (20%) was added and kept at 80°C for 15 minutes. E
After extraction with t3N CH2Ct2, the aqueous phase was acidified to pl-12 with 1 (l). The crystals were filtered off, washed with water and dried.

4.2 g of 6-hydroxypicoline was obtained.

According to NMR, it was pure. The casual clothes rate is 60%.

Example 9 81 of 6-methylpyridone-2! I-formed acetic anhydride (0.5 mol) and Et 3N (0.15 mol) were placed in a flask. Then, divide it into small parts,
9.1 (+ (0,59 mol) of 6-methylbicholic acid-N-Δoxide was added. Temperature (during the addition, 45
℃-H. After the evolution of CO2 ceased, the black solution was evaporated on a rotary evaporator. Carefully remove the residue
Hydrolyze with AHc (115m) to obtain 90% acetate-h.
It was saponified at ℃ for 5 hours. After evaporation of the aqueous solution, the residue was made basic with K01' and 6-methylpyridone-
2 was extracted with Ct-120Q 2.

3.7 g of product was isolated, which was pure according to NMR. Yield is approximately 57%.

Patent applicant Long Limited Agent: Patent Attorney Souo Suga

Claims (5)

[Claims] (1) 2-human of the general formula (in the formula, R = H, -COOH group, C: L-Ca alkyl group, or aryl group, and is a number between 111 and 1 and 4) 1] A method for producing xypyridine from 2-pyridinecarboxylic acid of the general formula 1ll-N-; A method characterized by carrying out the reaction in the presence of an amine and hydrolyzing the reaction product. (2) The method according to claim 1, characterized in that acetic anhydride is used as the carboxylic anhydride. (3) Claim 1 or 2, characterized in that 1-liezylamine is used as the tertiary amine.
Either way. (4) Tertiary amine 2-pyridinecarboxylic acid-N-
A method according to any one of claims 11 to 3, characterized in that the ratio to 73 oxide is between 1:1 and 20:1, preferably between 5:1 and 2=1. (5) The method according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of a solvent.