JPH0610198B2 - Process for producing 4-acylaminopyridines - Google Patents

Description

TECHNICAL FIELD The present invention relates to a synthetic intermediate of 4-amino-2-unsubstituted or halo-substituted pyridines, which is important as a synthetic intermediate of a compound as an active ingredient of medicines, agricultural chemicals and the like. Which is 4-acylamino-2-unsubstituted or halo-substituted pyridines.

Conventional Techniques and Problems The following methods have been conventionally known as methods for synthesizing 4-amino-2-chloropyridine.

Method A [Indian, J. Chem., 4,403 (1966)] Method B [Helv. Chim. Acta., 34, 496 (1951)] Method C [Rec. Trav. Chim., 69, 673 (1950)] Method D [JP-A-59-225163] However, in Method A, fuming nitric acid and concentrated sulfuric acid, which are difficult to handle on an industrial scale, are used to carry out the nitration reaction at high temperature, which is accompanied by the danger of explosion. In Method B and Method D, 2-chloroisonicotinoyl azide and 2-chloroisonicotinamide, which are potentially explosive, are used. Method A,
In method C, the yield is low because the starting material and the intermediate are thermally unstable. In method D, the production of side reaction products is unavoidable in the final step, so that purification is difficult. Therefore, 2-chloro-4-aminopyridine is not easy to produce and obtain in large quantities.

On the other hand, when 2 or 3-pyridyl-methylketone oxime is subjected to Beckmann rearrangement with phosphorus pentachloride in ethyl ether, a rearrangement product is obtained in a yield of 50 to 60%. It has been reported that, even if the reaction is carried out, the starting material is recovered, or only the other reaction product is obtained and the rearrangement product is not obtained [Pharmaceutical Journal, 87,689 (1967)]. Therefore, it was considered that 4-amino-2-chloropyridine could not be produced by the following Step E.

Process E However, when another specific solvent was used instead of ethyl ether, it was found that the Beckmann rearrangement proceeded, and the present invention was derived.

The applications of 4-amino-2-chloropyridine and its analogs are described in, for example, JP-A-54-81275 and 55-62066.

DISCLOSURE OF THE INVENTION The present invention has the formula (II) (In the formula, R represents a lower alkyl group or an unsubstituted or substituted phenyl group, and X represents a hydrogen atom or a halogen atom) [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] carbon disulfide, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether (glyme), bis (2-methoxyethyl) ether (diglyme), acetonitrile, halogenated lower alkane, Formula (I) characterized by reacting an acid in an inert solvent consisting of a benzene solvent or a mixture thereof. (In the formula, R and X are as defined above)
The present invention relates to a method for producing acylaminopyridines.

In the definition of R in the formula (II), the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl and the like. Includes. Further, in the definition of R, the substituent referred to in the substituted phenyl group includes a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl and ethyl, and a halogen atom such as chlorine and bromine. X
In the definition of, halogen atom is chlorine, bromine, fluorine,
Means iodine.

In the compound (II), a compound in which X is a hydrogen atom is a novel compound.

In the inert solvent used in this reaction, a halogenated lower alkane is a linear or branched alkane having 1 to 4 carbon atoms substituted with halogen such as chlorine and bromine, for example, methylene dichloride, chloroform, carbon tetrachloride, ethylene dichloride. Etc. are included. The benzene-based solvent includes benzene, toluene, xylene, chlorobenzene and the like.

The acid used in this reaction is a phosphorus halide, such as phosphoryl chloride, phosphoryl bromide, phosphoryl fluoride, phosphorus trichloride, phosphorus tribromide, phosphorus trifluoride, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, Including phosphorus pentafluoride and concentrated sulfuric acid. These may be used alone or as a mixture.

The concentration of the compound (II) in the reaction solvent is appropriately 1 to 20% (w / v). The amount of acid used for the compound (II) is 1.0 to
A suitable amount is 1.0-fold mole, particularly 1.0-5.0-fold mole. The reaction temperature for this reaction is suitably between 0 ° C. and the boiling point of the solvent, but room temperature is usually sufficient. Under such conditions usually 0.5-1
The reaction is completed in 0 hours.

For the isolation and purification of compound (I) from the reaction solution, a method commonly used in organic synthesis is applied. For example, the reaction solution is poured into ice water to decompose the unreacted phosphorus pentachloride differential acid, and then 10 ° C.
The following is basic (pH 9
10 is suitable) to give compound (I) as an acid addition salt as a free oil. Then, the oily substance is extracted with an organic solvent such as ethyl acetate, chloroform and ethyl ether, dried and the solvent is distilled off to obtain the compound (I) as white crystals.

Compound (I) is prepared by adding an aqueous solution of a base such as sodium hydroxide or potassium hydroxide in methanol to 1 to 5 of compound (I).
4-amino-2 is obtained by adding twice the mole and hydrolyzing.
-Can be led to unsubstituted or halo-substituted pyridines (Reference Example 3). Further, as described above, the compound (II) which is the starting compound is a novel compound in which X is not a hydrogen atom, and this novel compound can be synthesized as follows. That is, referring to Ger.Offen.1,811,833, 2
-Haloisonicotinonitrile and a compound represented by the formula (III) RMgHal (III) (wherein R is as defined above and Hal represents a halogen atom, for example, chlorine, bromine or iodine) in tetrahydrofuran, The reaction is carried out according to the usual Grignard reaction to obtain the compound of formula (IV) (Wherein R has the same meaning as described above and X ₁ represents a halogen atom) to obtain a compound (Reference Example 1). Then, this compound is subjected to a method commonly used for oximation of ketones, for example, compound (IV) is dissolved in hydrous alcohol (hydrous methanol, hydrous ethanol, etc.), sodium carbonate,
Hydroxylamine hydrochloride was added in the presence of a base such as sodium hydroxide to carry out the reaction at room temperature to give the compound (I
I) can be obtained (Reference Example 2). Compound (IV),
Isolation and purification of (II) and the like can be performed in the same manner as for compound (I).

Next, examples and reference examples of the present invention will be shown.

Example 1. 4-Viridyl-methylketone oxime (1.60 g) was dissolved in tetrahydrofuran (20 ml) and phosphorus pentachloride 4.2 was added under ice cooling.
g was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, stirred for 30 minutes, and then adjusted to pH 10 with a 10N sodium hydroxide aqueous solution. It was extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated liquid was allowed to cool, and the precipitated crystals were separated to obtain 1.47 g of white crystals (yield 90.2). %).

IR ▲ ν ^heat _{C = 0} ▼ 1685 cm ^{-1 1} H-NMR (in CDCl ₃ ): δ (ppm) 2.1 (s, 3H), 7.56 (d, 2H), 8.43 (d, 2H), 10.35 (s, 1H) It was confirmed to be 4-acetylaminopyridine by comparison with a standard product synthesized from 4-aminopyridine and acetic anhydride.

Example 2. 4- (2-chloropyridyl) -methylketone oxime 6.
0 g was dissolved in 60 ml of tetrahydrofuran, 13.0 g of phosphorus pentachloride was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, adjusted to pH 10 with a 10N sodium hydroxide aqueous solution, and then extracted twice with 200 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5.7 g of 2-chloro-4-acetaminopyridine as a colorless oil (yield 95%).

IR ▲ ν ^heat _{C = 0} ▼ 1690 cm ^{-1 1} H-NMR (in CDCl ₃ ): δ (ppm) 2.20 (s, 3H), 7.46 (t, 2H), 8.16 (d, 1H), 8.04 (dr, 1H) Example 3. 4- (2-chloropyridyl) -methylketone oxime 6.
0 g was dissolved in a mixed solvent of 30 ml of tetrahydrofuran and 30 ml of benzene, and under ice cooling, 13.0 g of phosphorus pentachloride and concentrated sulfuric acid.
0.38 g was added and the mixture was stirred at room temperature for 5 hours. Thereafter, the same treatment as in Example 2 was carried out to obtain the desired product, 2-chloro-4-
5.58 g of acetaminopyridine was obtained (yield 93.0
%).

Reference Example 1. 2-Chloroisonicotinonitrile (10.0 g) was dissolved in tetrahydrofuran (100 ml), and methyl bromide (12.4 g) was added thereto.
Then, 50 ml of a tetrahydrofuran solution of a Grignard reagent synthesized from 4.0 g of magnesium metal was added dropwise under cooling, and then the mixture was stirred at room temperature for 1 hour and under reflux for 2 hours. After cooling, 10 ml of 2N hydrochloric acid was added and the layers were separated. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 8.5 g of 2-chloro-4-acetylpyridine as a colorless oil (yield 76%). It is also possible to crystallize from petroleum ether.

Melting point: 35 to 37 ° C (petroleum ether) IR ▲ ν ^heat _{C = 0} ▼ 1695 cm ^{-1 1} H-NMR (in CDCl ₃ ): δ (ppm) 2.62 (s, 3H), 7.62 (t, 2H), 8.52 (d, 1H), Reference Example 2. 2-Chloro-4-acetylpyridine (6.0 g) was dissolved in ethanol (20 ml), sodium carbonate (6.0 g), hydroxylamine hydrochloride (2.7 g) and water (15.0 ml) were sequentially added, and the mixture was allowed to stand at room temperature. In 5
White crystals precipitate when stirred for hours. After crystallization under ice cooling, pass. After washing with cold water and drying under reduced pressure, 5.6 g of crystals having the following physical properties were obtained.

Melting point: 136-137 ° C IR (KBr): 3400, 2700, 1590, 1360, 1130, 1030, 1015, 815 cm ^{-1 1} H-NMR (in DMSO) δ (ppm): 2.16 (s, 3H), 7.58 ( t, 2H), 8.36 (d, 1H), 11.84 (s, 1H) Elemental analysis value (%) Actual value C: 49.25, H: 4.20, N: 16.40 C ₇ H ₇ Calculated as ON ₂ Cl C: 49.28 , H: 4.14, N: 16.42 Based on these physical property values, thin layer chromatography, blending test, gas chromatography, etc., 4-
It was confirmed to be (2-chloropyridyl) -methylketone oxime (yield 84.8%).

Reference Example 3. 2-chloro-4-acetylaminopyridine (4.0 g), ethanol (100 ml) and 5% potassium hydroxide aqueous solution (20 ml).
Was added, and the mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and then extracted twice with 50 ml of chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 2.9 g of 2-chloro-4-aminopyridine.
Was obtained as white crystals (yield 96.6%) Melting point: 89-90 ° C. (recrystallized from water-methanol) ¹ H-NMR (in CDCl ₃ ): δ (ppm) 4.46 (br, 2H), 6.40 (t, 2H), 7.88 (d, 1M) Effect of the Invention According to the present invention, 4-acylaminopyridines can be obtained in high yield from the corresponding oxime. As a result, 2
4-amino-2, which is important as a synthetic intermediate for a compound that is used as an active ingredient of medicines, agricultural chemicals, etc. in a four-step reaction (step E) including chloroisonicotinonitrile as a starting compound and the steps of the method of the present invention -Unsubstituted or halo-substituted pyridines can be obtained in good yield without problems as in the conventional method.

Claims (1)

[Claims] 1. A formula (II) (Wherein R represents a lower alkyl group or an unsubstituted or substituted phenyl group, and X represents a hydrogen atom or a halogen atom), and carbon disulfide, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether, Formula (I) characterized by reacting an acid in an inert solvent consisting of bis (2-methoxyethyl) ether, acetonitrile, a halogenated lower alkane, a benzene solvent, or a mixture thereof. (In the formula, R and X are as defined above)
Process for producing acylaminopyridines.