JPS62240661A - 2-halo-4-pyridyl ketone oxime and derivative thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R1 is lower alkyl or (substituted) phenyl; R2 is H, lower alkanoyl, arylcarbonyl, sulfo, alkylsulfonyl or arylsulfonyl; X is halogen) and its derivative. USE:A synthetic intermediate for pharmaceuticals and agricultural chemicals. PREPARATION:The compound of formula I can be produced by reacting 1 equivalent of a compound of formula II with 1-2 equivalent of the compound of formula III or its acid addition salt in water or a water-containing inert solvent (e.g. ethanol containing 1-50% water) under refluxing for 1-20hr.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel intermediate derived from 2-halo-4-aminopyridines, which is an important intermediate for the synthesis of compounds that are used as active ingredients in medicines, agricultural chemicals, etc. .

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

A method [:1ndian, J, Chern,,
4. 403 (1966)]↓ Mouth B method [1lv, Chim, ^cta,, 34
．． 496 (1951)] C method [: Rec, Trav
, Chim, 69.673 (1950)] D method [
JP-A-59-225163] However, in Method A, on an industrial scale, fuming nitric acid and concentrated sulfuric acid, which are difficult to handle, are used, and the nitration reaction is carried out at high temperatures with the risk of explosion. Methods B and D use 2-chloroinicotinoyl azide and 2-chloroinicotinamide, 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 and obtain large quantities of 2-chloro-4-aminopyridine.

On the other hand, when 2- or 3-pyridyl-methylketone oxime is subjected to Beckmann rearrangement with phosphorous pentachloride in ethyl ether, the rearranged product is obtained in a yield of 50-60%, but when 4-pyridyl-methylketone oxime is subjected to a similar It has been reported that even when subjected to a reaction, only the raw materials are recovered or other reaction products are obtained, but no rearrangement products are obtained [Yakugaku Zasshi, Noki, 689 (1967)].

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

Process E 5t+・ C1(.

(2) However, when another specific solvent was used in place of ethyl ether, it was found that the Beckmann rearrangement proceeded, and further studies led 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. are described.

Means for Solving the Problems The present invention is based on the formula (1) (wherein R1 is lower alkyl, or unsubstituted or substituted phenyl, and R2 is a hydrogen atom, lower alkanoyl,
2-halo 4-pyridyl ketone oxime and derivatives thereof [hereinafter referred to as compound (I)] represented by arylcarbonyl, sulfo, lower alkylsulfonyl or arylsulfonyl, and X is a halogen atom. The same applies to compounds with other formula numbers.

In the definition of R1 in formula (I), lower alkyl is straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isolofuropyl, n-butyl, isobutyl, n-pentyl, Includes isopentyl and the like. In the definition of R1, the substituent for monosubstituted phenyl is a linear or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.

n-butyl, isobutyl, etc., halogen atoms, i.e.
Includes chlorine, bromine, iodine, fluorine, etc.

In the definition of R2, lower alkanoyl has 1 to 4 carbon atoms.
alkanoyl, such as formyl, acetyl, propionyl, arylcarbonyl includes phenylcarbonyl, lower alkylsulfonyl includes 1 to 4 carbon atoms.
arylsulfonyl includes benzenesulfonyl, p-toluenesulfonyl and the like.

In the definition of X, halogen atoms are chlorine and bromine.

Meaning fluorine and iodine.

Compound (I) has the formula (If) (wherein R and X have the same meanings as in formula (1))
The compound represented by formula (III) HzN-○Rt
It can be obtained by reacting a compound represented by (III) [wherein R3 has the same meaning as in formula (1)] or an acid addition salt thereof in water or a water-containing inert solvent.

Compound (III) or its acid addition salt is preferably used in an amount of 1 to 10 equivalents, particularly 1 to 2 equivalents, relative to compound (II). Here, the acid addition salt includes hydrochloride and the like.

As the water-containing inert solvent, lower aliphatic alcohols containing 1 to 50% water, such as methanol, ethanol, propatool, and isopropanol, are preferably used. When using an acid addition salt of compound (III), such as a hydrochloride, the reaction is carried out in the presence of a base necessary for neutralization. As a base, sodium carbonate.

Potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc. are used. The amount of base used is
The amount is preferably 1 to 5 equivalents based on the acid addition salt of compound (III).

The reaction is suitably carried out under reflux and is usually completed in 1 to 20 hours.

Usually, as the reaction progresses, crystals of compound (1) precipitate, so by dividing the crystals, compound (1) can be easily formed.
can be isolated.

Compounds of formula (I) in which R2 is a group other than a hydrogen atom also include:
Also by reacting the compound (1) in which R2 is a hydrogen atom with a carboxylic acid or sulfonic acid corresponding to the definition of R2 or a reactive derivative thereof using the latter as a solvent or in an inert solvent in the presence of a base. Obtainable.

Reactive derivatives include acid chloride, jil! Bromides, acid iodides, acid anhydrides, etc. are used. As the inert solvent, halogenated lower alkanes such as methylene chloride, chloroform, 1,2-dichloroethane, benzene solvents such as benzene, toluene, and esters such as ethyl acetate are used. The above carboxylic acid or sulfonic acid or a reactive derivative thereof is used in an amount of 1 to 50 equivalents, especially 1 equivalent to the compound (1) in which R2 is a hydrogen atom.
It is preferable to use ~10 equivalents. As the base, inorganic basic compounds such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, tertiary amines such as pyridine, triethylamine, dimethylaniline are used. These bases are usually used in an equimolar amount to the above-mentioned reactive derivative.

The reaction is carried out at room temperature to the boiling point of the solvent and is usually completed in 1 to 10 hours.

For isolation and purification of compound (1) in which R2 is a group other than a hydrogen atom from the reaction-completed solution, techniques commonly used in general organic synthesis are applied. For example, pour the reaction completed solution into ice water and
After making it basic (appropriately pH 9-10) with an aqueous solution of an alkali metal hydroxide, such as sodium hydroxide, at a temperature below 0.0°C, an organic solvent that is immiscible with water, such as ethyl ether or benzene.

Compound (1) in which R1 is other than a hydrogen atom can be obtained by extracting with chloroform, ethyl acetate, etc., drying the extract, and then distilling off the solvent.

Compound (T1), which is a starting compound, is a compound containing a known compound, and is a compound containing 2-haloysonicotinonitrile and the formula (I
V) R+ M g Ha l (IV) [wherein,
R1 has the same meaning as in formula (I), and Hal is a . Reference example 1).

That is, the first half of the reaction is carried out at room temperature to the boiling point of the solvent, and is usually completed in 30 minutes to 10 hours. The hydrolysis reaction can be carried out by mixing the reaction mixture of the first half reaction with an aqueous hydrochloric acid solution under water cooling.

Compound (II) can be separated and purified by a method commonly used in organic synthesis. For example, the hydrolysis reaction solution is separated to obtain an organic layer. After drying this organic layer, the solvent is distilled off to obtain compound (II). It can also be easily crystallized from a suitable organic solvent such as petroleum ether, n-hexane, etc.

Compound (II) can also be prepared by treating a compound represented by formula (V) (wherein R1 has the same meaning as in formula (I)) with a peracid to form an N-oxide of compound (V), It can also be obtained by the action of phosphorus halides (Reference Examples 2 and 3).

That is, the first half, N-oxide, is usually synthesized using water.

The reaction is carried out using 1 to 10 times the molar amount of hydrogen peroxide relative to compound (V) in a single or mixed solvent such as acetic acid.

The reaction is suitably carried out between 0°C and the boiling point of the solvent, and is usually completed in 0.5 to 10 hours.

To isolate the N-oxide of compound (V), crystals of the target substance will precipitate as the reaction progresses, so either crystallization is performed as it is, or crystallization is performed after part of the solvent is distilled off under reduced pressure. Then, it can be obtained as white crystals.

The second half of the reaction with the phosphorus halide is carried out in a solvent such as carbon tetrachloride using 1 to 10 times the molar amount of the phosphorus halide relative to the N-oxide of compound (V). Phosphoryl chloride is a phosphorus halide.

Phosphoryl bromide, phosphoryl fluoride, phosphorus trichloride.

Examples include phosphorus tribromide, phosphorus trifluoride, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, and phosphorus pentafluoride, which may be used alone or in combination.

This reaction can also be carried out using the phosphorus halide as a solvent. The reaction is usually carried out at a temperature ranging from room temperature to 200°C, and is usually completed in 1 to 10 hours.

Compound (II) can be isolated and purified by methods commonly used in organic synthesis. For example, by pouring the reaction solution into ice water to decompose unreacted phosphorus halide, extracting with an organic solvent such as ethyl acetate, chloroform, or ethyl ether, drying, and then distilling off the solvent. Compound (n) can be obtained.

Compound (I) can be easily converted into the formula (Vl
) [In the formula, X and R1 have the same meanings as in formula (1)]
(Reference Example 4). That is, compound (1) contains carbon disulfide.

Tetrahydrofuran, dioxane, dimethoxyethane,
2-methoxyethyl ether (glyme).

Bis(2-methoxyethyl)ether (diglyme),
Acetonitrile, halogenated lower alkanes.

Compound (Vl) can be obtained by reacting with an acid in an inert solvent consisting of a benzene-based solvent or a mixture thereof.

In the inert solvent used in this reaction, the halogenated lower alkane is a linear 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, or ethylene dichloride. etc. Also, benzene-based solvents include benzene, toluene, and xylene.

Includes chlorobenzene, etc.

The acid used in this reaction is a phosphorus halide, such as phosphoryl chloride, phosphoryl bromide, phosphoryl fluoride, phosphorus trichloride, phosphorus tribromide, and phosphorus trifluoride.

Includes phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, phosphorus pentafluoride, concentrated sulfuric acid, etc. These may be used alone or in combination.

The concentration of compound (I) in the reaction solvent is 1 to 20% (11/
V) is appropriate. The amount of acid to be used is suitably 1.0 to 1000 times, particularly 1.0 to 5.0 times, by mole relative to compound (I). 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 (Vl) from the reaction solution, methods commonly used in organic synthesis are applied. For example, after pouring the reaction solution into ice water and decomposing unreacted acids such as phosphorus pentachloride,
℃ or below with an aqueous solution of alkali metal hydroxide (pH
9 to 10) to convert compound (VI), which is an acid addition salt, into a free oil. Next, the oily substance is extracted with an organic solvent such as ethyl acetate, chloroform, or ethyl ether, and after drying, the solvent is distilled off to obtain compound (Vl).
can be obtained as white crystals.

Compound (VI) is prepared by adding an aqueous solution of a base such as sodium hydroxide or potassium hydroxide to 1 of compound (Vl) in ethanol.
By adding ~5 times the mole and hydrolyzing it, 4-amino-2-halopyridine can be obtained (Reference Example 5).

After the reaction, the ethanol in the reaction solution is distilled off under reduced pressure, and then extracted with an organic solvent such as ethyl ether, benzene, chloroform, or ethyl acetate. After drying the resulting organic layer, the solvent is distilled off to obtain 2-halo-4-aminopyridine as white crystals. This product can also be easily recrystallized from aqueous methanol.

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

Example 1 6.0 g of 2-chloro-4-acetylpyridine was dissolved in 20 ml of ethanol, and 6.0 g of sodium carbonate was added.

Hydroxylamine hydrochloride 2.7 g, water 15. Qml
were sequentially added and stirred at room temperature for 5 hours to precipitate white crystals. After crystallization under water cooling, it was filtered. 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''H-NMR (in DMSO) δ (ppm): 2.1
6 (t, 3H).

7.58 (t, 2H), 8.36 (d, IH
).

11.84 (s,, IH) Elemental analysis value (%) Actual value C: 49.25. H:4.20. N:
Calculated value C as 16.40CJJN2CI: 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., 2-
It was confirmed that it was chloro-4-pyridylmethylketone oxime (yield: 84.8%).

Example 2 Dissolve 6.1 g of 2-chloro-4-pyridylphenyl ketone in 14.5 ml of ethanol, and dissolve 4.4 g of sodium carbonate.
5g, hydroxylamine hydrochloride'1.95g.

11 ml of water was successively added, and the reaction and post-treatment were carried out in the same manner as in Example 1 to obtain 5.72 g of 2-chloro-4-pyridylphenylketone oxime.

Melting point + 154.7°C IR (KBr): 3130.2g50. 15
90. 1535.1372°1015, 945.
800cr''H-NMR (in CDIJ3) δ (ppm) Near, 2
6 (t, 21(), 7.29 (s, 511
).

8.40 (d, 18), 11.70 (s, I
H) Elemental analysis value (%) Actual value C: 62.12. H: 3,7 skin N: 11
．． Calculated value C as 98C, 2H, 0N2C1: 61.95. H: 3,90. N:12.0
4 Example 3 8.7 g of 2-chloro-4-pyridyl n-propyl ketone
Dissolved in ethanol 251+11, sodium carbonate 7
, 5 g, hydroxylamine hydrochloride 3.3 g, water 35
ml was added one after another, and the reaction and post-treatment were carried out in the same manner as in Example 1 to obtain 7.2 g of 2-chloro-4-pyridyl n-propyl ketone oxime.

Melting point near 2.8℃ IR (Br): 315G, 2860.1590
．． 1535.1470°1365, 1050.980.
825 cm-''H-NMR (in CDCL) δ (pp
m): 0.93 (t, 3H), 1.47 (m
, 2H).

2.48 (t, 2H), 7.20 (t, 2H
).

8.37 (d, LH), 9.48 (s, LH
) Elemental analysis value (%) Actual value C: 54.38. H:5.60. N:
14.06CsH+ Calculated value C as 1ON2c l
:54.41. H: 5.5g, N: 14.10
Example 4゜10g of 2-chloro-4-pyridylmethylketone oxime
, 5Qml of acetic anhydride and 10g of IJum (acetic acid)
were mixed and refluxed for 2 hours under stirring. Ice water 10 Qml
After pouring the reaction solution into the solution and adjusting the pH to 10.0 with 10N aqueous sodium hydroxide solution, 5Qm of chloroform was added.
Extracted twice with l. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0-acetyl-2-chloro-4-pyridylmethylketone oxime9.
3 g were obtained as a colorless oil.

820cI11-''H-NMR (in CDCj!2) δ (ppm): 2.
19 (s, 3H), 2.31 (s, 3H).

7.47 (t, 2)1), 8.31 (d, 2
H) Elemental analysis value (%) Actual value C: 50.80. H:4.31. N:
13.16 Calculated value C as C, H, mouth, N, C1:
50.83. H:4.27. N: 13.18 Example 5 15.5 g of 2-chloro-4-acetylpyridine was dissolved in 109 ml of ethanol, and under water cooling, 13.6 g of hydroxylamine-〇-sulfonic acid and 1 portion of sodium acetate were added.
0g was added and stirred at 50°C for 2 hours.

Pour the reaction solution into 100 ml of ice water and add 53 ml of chloroform.
Extracted twice with m1. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 24.8 g of 2-chloro-4-pyridylmethylketone oxime-〇-sulfonic acid.

Melting point: 108.8°C IR: 2g50.1590.1530.
1365.995°820cr''HNMR (in CDCjis) δ (ppm): 2.2
2 (s, 3H), 7.44 (t, 2)1).

8.31 (d, LH), 9.12 (s, IH
) Elemental analysis value (%) Actual value C: 33.61. H:2.77, N:
11.20CJtOaNzSC (calculated value C as l:
33.54. H:2.81. N: 11.18 Reference Example 1 2-chloroisonicotinonitrile lO,Og was dissolved in tetrahydro7ran 1001111, and a Grignard reagent synthesized from 12.4 g of methyl bromide and 4.0 g of metallic magnesium was added to the solution. Tetrahydrofuran solution 5Qml
was added dropwise under cooling, and then at room temperature for 1 hour and under reflux for 2 hours.
Stir for hours. After cooling, IQml of 2N hydrochloric acid was added and the mixture was separated. The 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℃ (petroleum ether) IRV"
”': l 695 cm-''H-NMR (CDC
Il, medium) δ (ppm): 2.68 (s, 3
H), 7.62 (t, 2N).

8.52 (d, IH) Reference example 2゜36.6 g of 4-benzoylpyridine and 184 ml of acetic acid
, add 35% hydrogen peroxide 32.11111, 70-7
The mixture was stirred at 5°C for 4 hours. After the reaction, the reaction mixture was cooled and concentrated under reduced pressure to about half the volume, and white crystals were immediately precipitated. After crystallization, the crystals were collected and 4-benzoylpyridine-N
-26.6 g of oxide were obtained.

IR (Or): 1650.1600.1435
．． 1250.1140c+a-''H-NMR (CDI
J3) δ (ppm):'7.4~7.8 (n
+, 7H), 8.28 (d, 2H) obtained 4
-Pyridylphenylketone-N-oxide 9.96 g
Phosphoryl chloride 20111 which had been cooled on ice in advance
1 was added. After that, slowly heat it to 95℃ for 3
Stir for hours. The reaction solution was cooled and added to 50 Qml of ice water. After stirring for 30 minutes, the mixture was extracted with ethyl acetate. After drying the extract, the solvent was distilled off to obtain oily 2-chloro-4
-11.1 g of pyridylphenyl ketone was obtained.

'H-NMR (in CDCj!3) δ (ppm) Near,
4-7.8 (m, 6H), 8.54 (d, I
H) Reference Example 3 10.4 g of isonicotinonitrile was dissolved in 14 Qml of tetrahydrofuran, and a solution of 115 g of Grignard reagent synthesized from 22.26 g of n-propyl bromide and 5.5 g of metallic magnesium in tetrahydrofuran was added to the solution.
After ffl+ was added dropwise under cooling, the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled, and 15 ml of 2N hydrochloric acid was added to separate the layers. The organic layer was washed with water, dried, and the solvent was distilled off to obtain 13.4 g of 4-pyridyl n-propyl ketone as a yellow oil.

IRν"°"': 1690cm-"'H-NMR (CDCj!, middle) δ (ppm): 1.
00 (t, 3H), 1.72 (m, 2H).

2.76 (t, 2H), 7.72 (d, 2H
).

8.12 (d, 2H) 4.22 g of 4-pyridyl n-propyl ketone and 2 acetic acid
61111.35% hydrogen peroxide4. Add Qml, 70
Stirred at ~75°C for 8 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain 4-pyridyl n-propyl ketone-N-oxide as pale yellow crystals. This is n-hexane 1
Recrystallization from a mixed solvent of 0ml and ether IQ+nl gave 4.2g of white crystals.

IR(KBr): 1680.1610.144
0.1270.1160c+a-''H-NMR (CD
IJ, medium) δ (ppm): 0.95 (t, 3H)
, 1.72 (m, 2H).

2.76 (t, 2H), 7.72 (d, 2H
).

8.12 (6,2H) 4-pyridyl n-propyl ketone-N-oxide 2.0
4.7 m of phosphoryl chloride that had been previously ice-cooled
1. After that, slowly heat it to an internal temperature of 100℃.
The mixture was stirred for 3 hours. Cool the reaction solution and add ice water 20+111
I poured it inside. After stirring for 30 minutes, the mixture was extracted with ethyl acetate. After drying the extract with anhydrous magnesium sulfate,
The solvent was distilled off to obtain 2.6 g of black oil. This was subjected to silica gel chromatography (Silica gel G manufactured by Merck & Co., West Germany, Art 7734.Developing solvent: chloroform), and 1.74 g of 2-chloro-
4-pyridyl n-propyl ketone was obtained.

'H-NMR (in COCj!s) δ (ppm): 0.
94 (t, 3)1), 1.64 (m, 2H)
.

3.04 (t, 2B), 7.18 (t, 2H
).

9.04 (d, 1ll) Reference example 4゜2-chloro-4-pyridylmethylketone oxime 6.0
g was dissolved in 5 Qml 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 and 1ON-hydroxylated) After adjusting the pH to 10 with an aqueous IJ solution, 20 Q of ethyl acetate was added.
Extracted twice with ml. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.7 g of 2-chloro-4-acetaminopyridine as a colorless oil (yield 95%).

'H-NMR (CDC1!, medium) δ (ppm): 2.
20 (s, 3)1), 7.46 (t, 2H)
.

8.16 (d, IH), 8.04 (br, I
H) Reference Example 5 10 Qml of ethanol and 2Qml of a 5% aqueous potassium hydroxide solution were added to 4.0 g of 2-chloro-4-acetylaminopyridine, and the mixture was refluxed for 2 hours with stirring.

The reaction solution was concentrated under reduced pressure to remove ethanol, and then extracted twice with 5 Qml of chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
2.9 g of -chloro-4-aminopyridine was obtained as white crystals (yield: 96.6%).

Melting point: 89-90℃ (recrystallized from water-methanol)'
H-NMR (in CDCl s) δ (ppm):
4゜46 (br, 2)1), 6.40 (t,
28).

7.88 (d, 1) 1) Effects of the Invention According to the present invention, 4-acylaminopyridines can be obtained from compound (1) in high yield.

As a result, in a four-step reaction process using 2-haloisonicotinonitrile as a starting compound and compound (1) as a synthetic intermediate, 4-haloysonicotinonitrile is an important synthetic intermediate for compounds used as active ingredients in medicines, agricultural chemicals, etc. -Amino-2-halo-substituted pyridines can be obtained in good yields without the problems of conventional methods.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is lower alkyl, or unsubstituted or substituted phenyl, and R_2 is a hydrogen atom, lower alkanoyl, arylcarbonyl, sulfo, lower alkyl 2-halo-4-pyridylketone oxime and derivatives thereof, which are sulfonyl or arylsulfonyl, and X is a halogen atom.