JPH07206821A - Production of pyridine compound having chlorine atom at alpha-site - Google Patents

Abstract

PURPOSE:To obtain a pyridine compound having chlorine at alpha-site, useful as a synthetic raw material for pharmaceuticals, agrochemicals, etc., in high yield and purity by using phosgene as a chlorination agent and chlorinating a pyridine compound having OH at alpha-site with the chlorination agent in an inexpensive inert solvent in the presence of a specific acid amide derivative. CONSTITUTION:A pyridine compound having Cl at alpha-site and expressed by formula TV is produced by chlorinating a pyridine compound having OH at alpha-site and expressed by formula III (R<1> is H, F, Cl, cyano or a 1-4C alkyl) with phosgene in an inert solvent in the presence of an acid amide derivative of formula I or formula II (R<2> to R<4> each is H, an alkyl or an aryl; R<5> is an alkyl or an aryl; n is 1-5). The acid amide derivative of formula I is preferably dialkylformamides and the acid amide derivative of formula II is preferably N-methylpyrrolidone. The starting compound of formula III is 3-cyano-6- hydroxypyridine. The inert solvent is preferably an aromatic hydrocarbon such as benzene and toluene from the viewpoint of yield. The reaction is preferably carried out by using a reaction assistant such as a dialkylformamide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing pyridines having a chlorine atom at the α-position. Pyridines having a chlorine atom at the α-position produced by the present invention are useful compounds as synthetic raw materials for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Conventionally, phosphorus oxychloride, phosphorus pentachloride or triphenylphosphine dichloride has been well known as a substance for chlorinating a hydroxy group on an aromatic ring, but only a few examples thereof are thionyl chloride and phosgene. It is only known. Particularly, as an example of chlorination of a hydroxy group with phosgene, an example having a large number of electron-withdrawing substituents on an aromatic ring (J. org. Chem., 37, 62).
6 (1972)). Further, as the chlorinating agent for the nucleus-substituted hydroxy group of pyridines, only those using the above phosphorus chloride compound are known (Chemistry of Heter).
cyclic Compounds, Pyridin
end it Derivatives, Part
2, 299 (1961)). As a method for producing pyridines having a chlorine atom at the α-position by chlorinating pyridines having a hydroxy group at the α-position, for example, 2-hydroxy-5-methylpyridine is reacted with phosphorus oxychloride and phosphorus pentachloride. There is known a method for producing 2-chloro-5-methylpyridine (J. org. Chem.
26 (1961) 122-125).

[0003]

However, oxy
The conventional method using phosphorus chloride is PO (OH)₃Is a deputy
When pyridines are washed with water after completion of chlorination reaction,
PO (OH) in the waste liquid of ₃Will be mixed. Present
Currently, phosphorus-containing waste liquid is a cause of environmental pollution.
Has become. More technically, the water phase and organic phase of the washing
There are difficulties such as difficult liquid separation. Therefore, the conventional method
It is not the best method in terms of cost and economy, and
It is difficult to satisfy as an industrial manufacturing method in terms of the degree and yield.
It was.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to improve the prior art, and as a result, by using phosgene as a chlorinating agent, an appropriate reaction auxiliary agent can be prepared in an inexpensive inert solvent. It was discovered that the hydroxy group of the pyridine ring was easily and quantitatively replaced with a chlorine atom by the reaction, and the present invention was completed. That is, the gist of the present invention is the following general formula (I)

[0005]

[Chemical 5][In the above formula, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom,
Cyano group or C₁-C _FourRepresents an alkyl group. ] In the table
Inactive pyridines with hydroxy group at α position
In a solvent, the following general formula (II) or (III)

[0006]

[Chemical 6]

[0007]

[Chemical 7] [In the above formula, R ² , R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group or an aryl group, and R ⁵
Represents an alkyl group or an aryl group, and n represents an integer of 1 to 5. ] The chlorination using phosgene in the presence of the acid amide derivative represented by the following general formula (IV)

[0008]

[Chemical 8] [In the above formula, R ¹ is as defined above. ] It exists in the manufacturing method of the pyridines which have a chlorine atom in the alpha position represented by these. As the inert solvent used in the production method of the present invention, an aliphatic or aromatic hydrocarbon, for example, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, methylchlorohexane, dichloromethane, chloroform,
Carbon tetrachloride and the like can be mentioned. Among these, especially benzene,
Aromatic hydrocarbons such as toluene are preferable in terms of yield.
The amount of the solvent used is preferably 1 to 10 times the weight of the pyridines having a hydroxy group at the α-position.

The reaction aid used in the production method of the present invention includes formamide, for example, N, N-dimethylformamide, N, N-dibutylformamide, N-methylformanilide, distearylformamide, or N.
-Methylpyrrolidone. Of these, dialkylformamide and N-methylpyrrolidone are particularly preferable in terms of yield. The amount of dialkylformamide used is pyridines 1 having a hydroxy group at the α-position.
0.001 to 3 mol per mol, preferably 0.01 to
It is in the range of 2 moles.

The amount of phosgene used in the present invention is 1.0 per mol of pyridines having a hydroxy group at the α-position.
It is in the range of -10 mol, preferably 1.0-2 mol.
Hereinafter, the present invention will be described in detail. The reaction temperature of the present invention is
The temperature is in the range of 20 to 200 ° C., but the range of 60 to 150 ° C. is preferable in terms of reaction rate and yield. The reaction conditions according to the present invention are not particularly limited except the reaction temperature, but are generally carried out under normal pressure. However, 0.
It can also be carried out under pressure of 1 to 10 atm or under reduced pressure.

In the present invention, pyridines having a hydroxy group at the α-position of the raw material, an inert organic solvent, and a reaction aid are charged into a reactor to raise the temperature, and phosgene is continuously supplied under normal pressure while maintaining the reaction temperature. The method of making is common. During the reaction, hydrogen chloride and carbon dioxide gas are by-produced and discharged to the outside of the system, but in addition to this, phosgene used in excess is also discharged to the outside of the system. Under the reaction conditions, these are generally discharged as a gas out of the system. Therefore, the impurities accumulated in the reaction system are extremely small. In addition, the reaction aid dimethylformamides used as a catalyst are highly water-soluble, and very easily migrate to the water phase by washing with water after the completion of the reaction.
Since the amount of catalyst used is small, it is unlikely to pollute the environment when it is discarded.

The desired product can be purified by a general method. For example, the reaction mixture can be washed with water, the organic phase can be separated, and then the organic solvent can be removed by distillation, or can be purified by a crystallization method using a temperature difference in solubility. The residual is essentially of formula (IV)
Of the product, which can be further purified by conventional methods such as vacuum distillation.

[0013]

EXAMPLES The present invention will be described more specifically by way of examples, but the present invention is not limited to the examples. Example 1 In 300 ml of toluene, 0.91 g (0.0125 mol) of N, N-dimethylformamide was added to 30 g (0.250 mol) of 3-cyano-6-hydroxypyridine,
The mixture was heated to 100 ° C. 15 g (0.3 mol) of phosgene was passed slowly (about 3 hours) until no starting material was detected. For treatment, excess phosgene was removed by purging with nitrogen at 100 ° C., then the mixture was cooled to 50 ° C., after which 75 ml of water was added and stirred, the organic phase was separated, and the solvent was removed under reduced pressure. . Melting point 116
3-cyano-6-chloropyridine 33.5 at ~ 117 ° C
g (purity 98%; yield 95%) was obtained.

Example 2 When N-methylpyrrolidone was used in place of N, N-dimethylformamide, the same procedure as in Example 1 was carried out.
33.1 g of cyano-6-chloropyridine (purity 98%;
Yield 94%) was obtained. Comparative Example 3-Cyano-6-chloropyridine 30 g (0.250 mol) of 3-cyano-6-hydroxypyridine to 76.7 g (0.50 mol) of phosphorus oxychloride.
Was added and the mixture was heated to 90 ° C. The mixture was then heated under reflux for 1 hour, cooled to 80 ° C. and then slowly added dropwise to 450 ml of ice-cooled water. Next, the precipitate was filtered by suction, washed with 90 ml of water and then dried. 3-cyano-
6-chloropyridine 33.1 g (purity 91%; yield 87)
%) Was obtained.

[0015]

EFFECTS OF THE INVENTION According to the present invention, a drug substance, an agricultural chemical, etc.
Pyridines having a chlorine atom at the α-position, which are useful as intermediates, can be produced with higher purity and higher yields than the conventional method without the problem of treating phosphorus-containing waste liquid.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07B 61/00 300

Claims (4)

[Claims] 1. The following general formula (I):[In the above formula, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom,
Cyano group or C₁-C _FourRepresents an alkyl group. ] In the table
Inactive pyridines with hydroxy group at α position
In a solvent, the following general formula (II) or (III)[Chemical 3][In the above formula, R², R³And R^FourAre each independent
Represents a hydrogen atom, an alkyl group or an aryl group, and R^Five
Represents an alkyl group or an aryl group, n is an integer of 1 to 5
Represents a number. ] In the presence of an acid amide derivative represented by
The following general formula characterized by chlorination using gen
(IV) [Chemical 4][In the above formula, R¹Is as previously defined. ]so
Method for producing pyridines having chlorine atom at α position
Law. 2. The method according to claim 1, wherein the acid amide derivative represented by formula (II) is a dialkylformamide. 3. The acid amide derivative represented by the general formula (III) is
The method according to claim 1, which is N-methylpyrrolidone. 4. The method according to claim 1, wherein the pyridine compound having a hydroxy group at the α-position of the general formula (I) is 3-cyano-6-hydroxypyridine.