JPS58210065A - Preparation of 2-hydroxynicotinic acid-based compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for drugs, dye, agricultural chemicals, etc. by an easy reaction in a short reaction time in high yield in high purity, by hydrolyzing a 2-chloro-3-trichloromethylpyridine-based compound with sulfuric acid. CONSTITUTION:A 2-chloro-3-trifluoromethylpyridine-based compound shown by the formula I (X is H or Cl) is reacted with AlCl3 preferably in the presence of an inorganic compound such as KCl, Na2SO4, etc. as a retarding agent at 0-180 deg.C for 0.5-3hr to give a 2-chloro-3-trichloromethylpyridine-based compound (TCP for short) shown by the formula II, which is hydrolyzed in the presence of sulfuric acid at 50-130 deg.C for 1-3hr, to give the desired compound shown by the formula III existing as a tautomerism. The amount of sulfuric acid used is 0.1- 100mol based on 1mol TCP, and the concentration of sulfuric acid is 0.5-96wt%.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2-hydroxynicotinic acid compounds (hereinafter abbreviated as HNA) useful as intermediates for medicines, dyes, agricultural chemicals, and the like.

Conventionally, various methods for producing HNA have been proposed. For example, 2-hydroxynicotinic acid production method-2= Toshihide Journal of Organic Chemistry (Journal of Organic CI+
volume 19, pages 1633-1639, 1
In 954, the following method was proposed.

(1) Nicotinic acid and hydrogen peroxide are reacted in glacial acetic acid to obtain nicotinic acid-1-oxide, which is then reacted with a mixture of phosphorus oxychloride and phosphorus pentachloride to hydrolyze 2-chloronicotine. The acid is obtained and further reacted with hydrogen peroxide in glacial acetic acid to obtain 2-hydroxynicotinic acid.

(2) 2-chloronicotine nitrile and concentrated hydrochloric acid are reacted under reflux, and after cooling, the mixture is made alkaline with concentrated aqueous ammonia, and again with hydrochloric acid (111 is adjusted to obtain 2-hydroxynicotinic acid. However, Method (1) requires the use of a chlorinating agent that is difficult to handle, the process is long, and [1]
The yield of the target product is low, the separation operation is complicated, and (
In the method 2), the raw material is expensive, the separation operation of the target product is complicated, and both methods have difficulties in industrial implementation.

The present inventors studied a method for producing HNA and found that when a 2-chloro-3-trifluoromethylpyrinone compound (hereinafter abbreviated as 'rFP) and aluminum chloride are reacted, the The trifluoromethyl group changes to a trichloromethyl group and the corresponding 2-chloro-3-trichloromethylbilinone compound (hereinafter abbreviated as TCP) is produced. When this TCP is hydrolyzed in the presence of sulfuric acid, the desired HMA is produced. The present invention was completed based on the knowledge that

That is, the present invention provides (1) a reaction between a 2-chloro-;)-trifluoromethylpyrinone compound represented by the general formula (T) (where x is a hydrogen atom or a chlorine atom) and aluminum chloride. Then, the general formula (If
) (where x is as described above) was obtained, and then the 2-chloro-3-trichloromethylbilinone compound was dissolved in sulfuric acid. Hydrolysis in the presence of general formula (III
) 4- A method for producing a 2-hydroxynicotinic acid compound, characterized by producing a 2-hydroxynicotinic acid group compound represented by (in the formula or as described above), 4p
and (2) mJ. A method for producing a 2-hydroxynicotinic acid compound, characterized in that the 2-hydroxynicotinic acid group compound is produced from the 2-chloro-3-trichloromethylpyridine compound by the hydrolysis reaction described above. It is.

The compound represented by the general formula (m) can have the following tautomerism.

(In the formula, X is five as described above) According to method-2 of the present invention, the following advantages can be obtained.

(1) T represented by the general formula (1) as a raw material
FP is already manufactured industrially,
It is available commercially.

(2) In this method, side reactions do not occur much and the intermediate TCP is also stable, so the target product can be obtained in high yield and with high purity.

5- (3) The reaction is simple and the reaction time is short.

Chlorination step: According to the method of the present invention, TFP and aluminum chloride are usually mixed and reacted, but if TFP is solid at room temperature, it is gradually heated to melt it and then reacted to form T'CP. obtain.

TFPs include 2-chloro-3-trifluoromethylpyridine (melting point 39.1°C) and 2.5-E>chloro-3-)trifluoromethylpyridine (boiling point 119-12°C).
1°C/9 ('1mlmm1).The amount of aluminum chloride used is usually 0.1°C/9 ('1mlmm1).
The amount is 5 to 5 mol, preferably 1 to 1.5 mol, and the reaction temperature cannot be absolutely specified, but is usually 0 to 180°C, preferably room temperature to 70°C. Reaction time is generally 0.5~
It is 3 hours.

Since this reaction is a rapid exothermic reaction, it is desirable to have an inorganic compound that is chemically stable and suppresses the rapid reaction in the reaction system, since this improves the yield of TCP.

Examples of the inorganic compound include hydrochlorides, sulfates, or nitrates of metals such as potassium, calcium, sodium, copper, zinc, iron, nickel, and cobalt; or mineral silicon compounds containing silicon oxide. Specifically, potassium chloride, sodium chloride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, calcium chloride,
Calcium sulfate; Examples include silica powder, silica sand, kaolin, clay, sericite, bentonite, and diatomaceous earth. In particular, neutral salts or mineral silicon compounds obtained by neutralization with a strong acid and strong salt removal, such as potassium chloride, sodium chloride, potassium sulfate, sodium sulfate, silica powder, and silica sand, are preferred. When adding the inorganic compound, the reaction temperature is preferably 70 to 120°C, and the amount used is usually 1 to 20 parts by weight, preferably 1 to 20 parts by weight, per 1 part of aluminum chloride. It is 0.2 to 2 parts by weight.

In the reaction, when a solvent is used, separation of the reaction product can be simplified. Examples of solvents include methylene chloride, chloroform, and
Cρ2), halogen hydrocarbons such as ethylene chloride,
Examples include aromatic hydrocarbons having an electron-withdrawing group such as monochlorobenzene and nitrobenzene.

+'+ij After the completion of the reaction, the reaction product is cooled, placed in ice water, and subjected to operations such as solvent extraction and distillation (thus, the desired intermediate TCP can be extracted or the reaction product can be 7- may be directly used in the next reaction without purification.

Hydrolysis step: TCP obtained in the engraving step is hydrolyzed in the presence of sulfuric acid to obtain HMA. I (NA) includes 2-hydroxynicotinic acid (melting point 248-251°C) and 5-chloro-2-hydroxynicotinic acid (melting point 208-212°C).
°C).

Although the reaction conditions vary depending on various conditions and cannot be generally specified, the amount of sulfuric acid used is generally 0.1 to 1 mol, preferably 2 to 1 mol, based on 1 mol of TCP.
0 mol, and the concentration of sulfuric acid is usually (), 5-96%
, preferably 1() to 3()%. The reaction temperature is usually 5°C to 130°C, preferably 90 to 120°C, and the reaction time is generally 1 to 3 hours.

After the completion of the reaction described in Mj, highly pure I-INA can be obtained by cooling, filtering, washing, etc. the reaction product.

The method of the present invention will be specifically explained by the following examples.

Example chlorination step: 2-chloro-3-trifluoromethylpyridine and aluminum chloride were mixed, and in some cases an inorganic compound was further added, and they were mixed and reacted. After the reaction was completed, the reaction product was cooled, poured into ice water, and extracted with methylene chloride. In the case of Examples 1 and 2, the raw material (2-chloro-3-trifluoromethylpyrinone) and the desired intermediate (2-chloro-3-trichloromethylpyrinone) are separated using heated 0-hexane. did. These results are shown in Table 1 below.

Table 1 Hydrolysis step: Target intermediate (2-chloro-
Add mineral acid to 3-trichloromethylpyrinone), react with sufficient stirring to produce the target product (2-hydroxynicotinic acid), and after the reaction process, pour the reactant into ice water.
After filtration and washing, the results shown in Table 2 below were obtained. Furthermore, comparison 1
and 2, hydrochloric acid and nitric acid were used as mineral acids.

9- Table 2 In Table 2, in Comparison 1, a mixture of 2-chloronicotinic acid and 2-hydroxynicotinic acid was obtained, and in Comparison 2, a main product of 2-chloronicotinic acid was obtained.

Patent applicant: Ishihara Sangyo Co., Ltd. 110 complete

Claims (1)

[Scope of Claims] A 2-9oa-3-)lichloromethylbilinone compound represented by (in the formula, or a hydrogen atom or a chlorine atom) is hydrolyzed in the presence of sulfuric acid, and the general formula ( A method for producing a 2-hydroxynicotinic acid compound, the method comprising producing a 2-hydroxynicotinic acid compound represented by the formula (wherein X is as described above). A 2-chloro-3-F trifluoromethylpyridine compound represented by the formula 1- (wherein, X is a hydrogen atom or a chlorine atom) and aluminum chloride are reacted to form a compound represented by the general formula (wherein,
2-chloro-3- represented by
A trichloromethylpyridine compound was obtained, and then i1+
Producing a 2-hydroxynicotinic acid compound represented by the general formula (wherein X is as described above) by hydrolyzing the 2-chloro-3-trichloromethylpyridine compound in item i in the presence of sulfuric acid A method for producing a 2-hydroxynicotinic acid compound, the method comprising: