JPS6210065A - Production of 4-acylaminopyridine - Google Patents

Abstract

PURPOSE:To obtain a 4-acylaminopyridine useful as an intermediate for medicines, agricultural chemicals, etc., in high yield, by reacting a 4-pyridyl- methyl ketoxime which is novel except part thereof with an acid in a specific solvent, e.g. tetrahydrofuran. CONSTITUTION:A compound expressed by formula I (R is lower alkyl, unsubstituted or substituted phenyl; X is H or halogen; the compound in which X is other than H is novel) which is novel except part thereof is reacted with an acid, e.g. phosphorus halide such as phosphorus pentachloride or concd. sulfuric acid, in an inert solvent consisting of carbon disulfide, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether bis(2-methoxyethyl) ether, acetonitrile, halogenated lower alkanes, benzene based solvents or a mixture thereof to afford advantageously the aimed compound expressed by formula II. According to this method, a compound expressed by formula III, etc., useful as an intermediate for medicines, agricultural chemicals, etc., is obtained from a compound expressed by formula IV in four steps in high yield without problems, e.g. danger of explosion, as in the well-known method.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to intermediates for the synthesis of 4-amino-2-unsubstituted or halo-substituted pyridines, which are important as intermediates for the synthesis of compounds that are used as active ingredients in medicines, agricultural chemicals, etc. The present invention relates to a method for producing 4-acylamino-2-unsubstituted or halo-substituted pyridines.

BACKGROUND ART AND PROBLEMS The following methods are conventionally known as methods for synthesizing 4-amino-2-chloropyridine.

Method A [: Indian, J, Chem,, 4.40
3 (1966)) Method () Ielv, Chim, A
cta, 34.496 (1951)) C method [R
ec, Trav, Chim, 69.673 (1
950) ) Method D [JP-A-59-2251631 ↓ However, in Method A, on an industrial scale, using fuming nitric acid and concentrated sulfuric acid, which are difficult to handle, the nitration reaction is carried out at high temperatures with the risk of explosion. Methods B and D use 2-chloroisonicotinoyl azide and 2-chloroisonicotinamide, respectively, which have a risk of explosion. A method,
In Method C, the yield is low because the starting materials and intermediates are unstable to heat. In method D, purification is difficult because the production of side reaction products is unavoidable in the final step. Therefore, it is not easy to produce 2-chloro-4-aminopyridine or to obtain it in large quantities.

On the other hand, when 2- or 3-pyridyl-methylketoxime is subjected to Beckmann rearrangement with phosphorus pentachloride in ethyl ether, the rearranged product is obtained in a yield of 50-60%.
It has been reported that even if 4-pyridyl-methylketone oxime is subjected to a similar reaction, only the raw material is recovered or other reaction products are obtained, but no rearrangement products are obtained. , 87.689 (1967)).

Therefore, it was thought that 4-amino-2-chloropyridine could not be produced by the following Step E.

C.I.

(2) However, when another specific solvent was used in place of ethyl ether, it was found that the Beckmann rearrangement proceeded, leading to the present invention.

For the use of 4-amino-2-chloropyridine and its analogues, see, for example, JP-A-54-81275.55.
-62066 etc.

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by formula (n) (wherein 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 with other formula numbers] carbon disulfide, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether (glyme), bis(2-methoxyethyl) ether (diglyme), acetonitrile, halogenated lower alkanes, 4- represented by formula (I) (wherein R and
This invention relates to a method for producing acylaminopyridines.

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

Among compounds (n), compounds in which X is other than hydrogen are new compounds.

In the inert solvent used in this reaction, the halogenated lower alkane is a straight or branched alkane having 1 to 4 carbon atoms substituted with a halogen such as chlorine or bromine, such as methylene dichloride, chloroform, carbon tetrachloride ethylene dichloride, etc. includes. In addition, benzene-based solvents include benzene, toluene,
Includes xylene, chlorobenzene, etc.

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, and phosphorus pentafluoride. Includes phosphorus chloride, concentrated sulfuric acid, etc. These may be used alone or in combination.

The concentration of compound (■) in the reaction solvent is 1-20% (w/v
) is appropriate. The amount of acid to be used is suitably 1.0 to 10.0 times, particularly 1.0 to 5.0 times, by mole relative to compound (II). 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 these conditions, the reaction is usually completed in 0.5 to 10 hours.

For isolation and purification of compound (1) from the reaction solution, methods commonly used in organic synthesis are applied. For example, after pouring the reaction solution into ice water to decompose unreacted acids such as phosphorus pentachloride,
Below, the alkali metal hydroxide is made basic (
pH 9 to 10 is suitable) to convert Compound (I), which is an acid addition salt, into a free oil. Then, the oil was extracted with an organic solvent such as ethyl acetate, chloroform, or ethyl ether, and after drying, the solvent was distilled off to obtain compound (I).
can be obtained as white crystals.

Compound (1) is prepared by preparing compound (I) in methanol using an aqueous solution of a base such as sodium hydroxide or potassium hydroxide as a base.
) by adding 1 to 5 times the mole of 4-
This can lead to amino-2-unsubstituted or halo-substituted pyridines (Reference Example 3). Furthermore, as mentioned above, among the starting compounds ([r), compounds in which X is other than a hydrogen atom are new compounds, and these new compounds can be synthesized as follows. That is, Ger, 0ffen, 1
, 811.833, 2-haloysonicotinonitrile and the formula (III) RMgHa I (III) (wherein R has the same meaning as above, and Hat represents a halogen atom, such as chlorine, bromine, or iodine). ) in tetrahydrofuran according to the usual Grignard reaction to obtain a compound represented by the formula (rV) (wherein R has the same meaning as above and x1 represents a halogen atom). is obtained (Reference Example 1).

Next, this compound is subjected to a method commonly used for the oxime formation of ketones, for example, by dissolving compound (IV) in hydrous alcohol (hydrous methanol, hydrous ethanol, etc.), and removing the presence of a base such as sodium carbonate or sodium hydroxide. Compound (II) can be obtained by adding hydroxylamine hydrochloride and carrying out the reaction at room temperature (Reference Example 2). Compound (■).

Isolation and purification of (II) etc. can be performed in the same manner as for compound (1).

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

Example 1 1.60 g of 4-pyridyl-methylketone oxime was dissolved in 2 Qml of tetrahydrofuran, 4.2 g of phosphorus pentachloride was added under water cooling, 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 aqueous sodium hydroxide solution. Extraction was carried out with 12 times of 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. Leave the concentrate to cool,
The precipitated crystals were separated one by one to obtain 1.47 g of white crystals (yield: 90.2%).

'H-NMR (in CDC13): δ (ppm) 2.1 (
s, 3H), 7.56 (6,28), 8.4
3(d, 2H).

10.35 (s, E) In addition, it was confirmed that it was 4-acetylaminopyridine by comparison with a standard product synthesized from 4-aminopyridine and acetic anhydride.

Example 2゜4-(2-chloropyridyl)-methylketone oxime 6
, Og was dissolved in 601 Tll of tetrahydrofuran, 13.0 g of phosphorus pentachloride was added under water cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, adjusted to pH 10 with 1ON sodium hydroxide solution, and then added with ethyl acetate 2
Extracted twice with 0 Qml. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-4
5.7 g of -acetaminopyridine was obtained as a colorless oil (yield 95%).

'H-NMR (in CDC13): δ (ppm) 2.20
(s, 3H), 7.46 (t, 2H), 8
．． 16(d, IH).

8.04 (br, E) Example 3゜4-(2-chloropyridyl)-methylketone oxime 6
, Og in tetrahydrofuran 3Qml, benzene 3Qm
13.0 g of phosphorus pentachloride dissolved in 100 g of mixed solvent and cooled with water.
, 0.38 g of concentrated sulfuric acid was added, and the mixture was stirred at room temperature for 5 hours.

After that, the same treatment as in Example 2 was carried out to obtain the desired product, 2-
5.58 g of chloro-4-acetaminopyridine was obtained (yield 93.0%).

Reference Example 1 10.0 g of 2-chloroisonicotinonitrile was dissolved in 10 Qml of tetrahydrofuran, and 53 ml of a tetrahydrofuran solution of a Grignard reagent synthesized from 12.4 g of methyl bromide and 4.0 g of metallic magnesium was added to the solution under cooling. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and under reflux for 2 hours. After cooling, IQml of 2N hydrochloric acid was added and the mixture was separated. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 8.5 g of 2-chloro-4-acetylpyridine as a colorless oil, yield 76%.
). In addition, it can also be crystallized from petroleum ether.

Melting point = 35-37°C (petroleum ether) IR c-
o 1695cl''H-NMR (CDCf, medium): δ (ppm) 2.62
(s, 3tl), 7.62(t, 21(),
8.52(d, 11().

Reference Example 2 6.0 g of 2-chloro-4-acetylpyridine was dissolved in 2 Oml of ethanol, and 6.0 g of sodium carbonate was added.

2.7 g of hydroxylamine hydrochloride, 15 g of water, and 0 ml of water were sequentially added and stirred at room temperature for 5 hours to precipitate white crystals. After crystallization under water cooling, it is suitable for p. After washing with cold water, it was dried under reduced pressure to obtain 5.6 g of crystals having the following physical properties.

Melting point: 136-137°C IR (KBr): 3400.2700.1590
．． 1360.1130°1030, 1015.815c
r' NMR (in DMSO) δ (ppm): 2.16 (
s, 3tl).

7.58 (t, 2H), 8.36 (d, L
H), 11.84 (s, 1) 1) Elemental analysis value (
%) Actual value C: 49.25. H:4.20. N:
16.40C, H, ON, f: Calculated value C: 49.28. H:4.14. N: 16.4
2 From the results of these physical properties, thin layer chromatography, mixed melting test, gas chromatography, etc., 4-
It was confirmed to be (2-chloro,pyridyl)-methylketone oxime (yield: 84.8%).

Reference Example 3 10 Qml of ethanol and 2Qml of 5% aqueous potassium hydroxide solution were added to 4.0 g of 2-chloro-4-acetylaminopyridine, and the mixture was stirred under reflux for 2 hours.

The reaction solution 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 concentrated under reduced pressure to give 2-chloro-4-
2.9 g of aminopyridine was obtained as white crystals. Yield: 9
6.6%) Melting point: 80-90℃ (recrystallized from water-methanol)'H
-NMR (in CDCj23): δ (ppm) 4.46 (
br, 2H), 6.40 (t, 211),
7.88 (d, IM) Effects of the Invention According to the present invention, 4-acylaminopyridines can be obtained in high yield from the corresponding oxime.

As a result, a four-step reaction (step E) using 2-chloroinnicotinonitrile as a starting compound and including the steps of the method of the present invention
To obtain 4-amino-2-unsubstituted or halo-substituted pyridines, which are important intermediates for the synthesis of compounds that are used as active ingredients in medicines, agricultural chemicals, etc., without the problems of conventional methods and with a good overall yield. I can do it.

Procedural amendment September 2, 1985

Claims (1)

[Claims] Formula (II) ▲Mathematical formulas, chemical formulas, tables, etc.▼(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. ), carbon disulfide, tetrahydrofuran, dioxane, dimethoxyethane, 2-methoxyethyl ether, bis(2-methoxyethyl) ether, acetonitrile, halogenated lower alkanes, benzene solvents, or mixtures thereof. Formula (I) characterized by the action of an acid in an active solvent ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R and X have the same meanings as above) 4-
A method for producing acylaminopyridines.