JPS5826341B2 - 5-(Halobutyl) Picolin Sanamide Noseiho - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 5-()-butyl)picolinic acid amide.

The present inventors have previously discovered that 5-(...butyl)picolinic acid and its derivatives significantly inhibit dopamine-β-hydroxylase and have good antihypertensive effects.

As a result of further research, it has been found that 5-(halobutyl)picolinic acid amides have the above-mentioned effects, have extremely low side effects such as gastric and intestinal disorders, and exhibit particularly useful medical effects.

The present inventor used the previously invented ester of 5-(halobutyl)picolinic acid as a starting material to produce 5-(halobutyl)
As a result of research into a method for producing picolinic acid amide, the present invention was completed.

The purpose of the present invention is to develop a novel 5-molecule that has few side effects and is medically useful.
- To provide a method for producing (halobutyl)picolinic acid amide.

The object of the present invention can be achieved by reacting 5-(butyl)picolinate with a nitrogen compound having active hydrogen.

The reaction of the present invention preferably involves reacting a nitrogen compound having active hydrogen in an alcoholic solution of 5-(halobutyl)picolinic acid ester.

The 5-(halobutyl)picolinic acid ester used in the reaction of the present invention can be obtained by reacting 5-(halobutyl)picolinic acid, a salt thereof, or an acid chloride thereof with an alcohol or an alkyl halide.

In particular, an alcoholic solution of the ester can be easily obtained by dissolving 5-(halobutyl)picolinic acid in alcohol in the presence of a dehydrating agent such as hydrogen chloride, sulfuric acid, or p-)luenesulfonic acid. .

The alcohol used in this reaction is preferably methanol,
It is preferable to use a solution such as ethanol, propatool, butanol, cyclohexanol, phenol, substituted phenol, etc., and it is particularly preferable to use methanol or ethanol.

The ratio of alcohol to 5-(halobutyl)picolinic acid or its acid halide is 1 to 500 i, and alcohol can be used as a solvent.

Note that a suitable inert solvent other than alcohol can be used.

The reaction temperature is -30 to 150°C, and when esterifying with an alcohol and a dehydrating agent, heating is preferably carried out under reflux.

The reaction product can be used in the next reaction as it is in its solvent solution, or with the addition of a suitable solvent.

Note that the acidic substance used as a dehydrating agent may be removed by evaporation or neutralized in advance, but it can be used in the next reaction as it is neutralized by a nitrogen compound containing active hydrogen, which is also used in the next reaction. There are features that can be used.

By dissolving the salt of 5-(-butyl)picolinic acid in a suitable solvent, such as alcohol, acetone, tetrahydrofuran, benzene, chloroform, dichloromethane, dimethylformamide, ethyl acetate, etc., and treating it with an alkyl halide. , the ester can be obtained.

Preferred alkyl halides used in this case include methyl iodide, ethyl iodide, p-bromophenacetyl furomite, and the like.

Note that other alkyl halides can be used, but since alkyl halides are expensive, they are economically disadvantageous compared to the esterification method described above.

This reaction is completed in a short time at low temperature.

It is economically preferable to use an equivalent amount or a slight excess of the alkyl halide.

This reaction product solution can also be used as it is in the next reaction.

In addition, the acid chloride can be obtained by reacting 5-(halobutyl)picolinic acid or a salt thereof with a halide such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfuryl, or chloride. can be reacted with an alcohol to produce its ester.

When using thionyl chloride or phosphorus oxychloride, without solvent,
Although the acid chloride can be removed, this reaction is usually carried out in an inert solvent, i.e. chloroform, dichloromethane,
This is carried out by dissolving K5-(halobutyl)picolinic acid such as benzene, toluene, cyclohexane, acetone, methyl ethyl ketone, ether, dioxane, tetrahydrofuran, pyridine, n-hexane, etc.

After this reaction, the alcohol is added to form its ester.

5-(Halobutyl)picolinate is the above-mentioned 5-(
It can be produced by introducing a nitrogen compound having active hydrogen into a solvent solution of halobutyl picolinate in a gaseous state, adding it as a liquid, or adding it in a solution state.

Examples of nitrogen compounds having active hydrogen include ammonia, methylamine, ethylamine, dimethylamine, diethylamine, n-propylamine, isopropylamine, n-propylamine, and n-propylamine.
Typical examples include lower amines such as -butylamine, 5ec-butylamine, and t-butylamine.

However, cyclohexylamines such as cyclopropylamine, cyclopentylamine, and cyclohexylamine can be used in place of these lower amines.

Furthermore, ethanolane, propatoolamine, butanolamine, benzylamine, phenylethylamine, aniline, toluidine, hydrazine, methylhydrazine, phenylhydrazine, halogenated phenylhydrazine, piperidine, pyrrolidine, morpholine, piperazine, etc. can be used. can.

However, when ammonia or a lower alkylamine is used, 5-(halobutyl)picolinic acid lower amide is obtained, which is particularly favorable.

When using these nitrogen compounds having active hydrogen as a solvent solution, alcohols, acetone, methyl ethyl ketone, chloroform, dichloromethane, benzene, toluene, ethyl acetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane, etc. are used.

Moreover, water can be used depending on the case.

The amount of the nitrogen compound having active hydrogen is usually a large excess equivalent to sufficiently convert the 5-(halobutyl)picolinic acid ester into its amide.

Usually 1 to 10 equivalents are used. 5-(Halobutyl)picolinic acid amide produced by the method of the present invention can be obtained as a pure product by a separation method such as an extraction method, a partition method, a recrystallization method, or a separation method such as chromatography.

When we investigated the antihypertensive effect and toxicity of 5-(halobutyl)picolinic acid amide obtained by the method of the present invention, we found that
It was as shown in the table.

From the above test results, it was found that 5-(...butyl)picolinic acid amide maintains a strong antihypertensive effect on hypertensive rats, and has extremely reduced toxic effects on mice compared to the free acid. .

This makes it possible to administer it continuously for a long period of time or in large doses for therapeutic purposes, making it extremely useful as a medicine.

Next, the method of the present invention will be explained in detail with reference to Examples, but the method is not limited thereto.

Example 1 5-(3,4-dibromobutyl)picolinic acid amide 5-(3,4-dibromobutyl)picolinic acid 10S' was dissolved in 200 ml of dry hydrogen chloride gas-saturated ethanol,
Reflux was performed for 6 hours.

The reaction mixture was evaporated under reduced pressure, and the pale yellow oily residue was dissolved in 30011 L of dry ammonia gas-saturated ethanol, and the solution was left to stand at room temperature for 3 days under a tightly stopper.

The reaction mixture was evaporated under reduced pressure, and the solid residue was recrystallized from benzene to give platelet crystals, 6.52.

m, p, 138-140°C Infrared absorption spectrum (potassium bromide): 1680.1
660Cr/L-1 Ultraviolet absorption spectrum (methanol): λmax269
mμ (ε5350) Thin layer chromatography (silica gel, chloroform)
Methanol-acetic acid-45:4:1) Rf value 0.72 Example 2 5-(3,4-dibromobutyl)picolinic acid dimethylamide 5-(3,4-siph'romobutyl)picolinic acid 10P was dried with hydrogen chloride Dissolved in gas-saturated methanol 200M, 5
Reflux was performed for an hour.

The reaction mixture was evaporated under reduced pressure, and pale yellow oily 5-(3,4-dibromobutyl)picolinate methyl ester was dissolved in 250 ml of methanol. To this was added 5011 liters of a 40% dimethylamine aqueous solution, and the mixture was poured over a tightly stopper at room temperature for 2 hours. It was left to react for several days.

The reaction solution was evaporated under reduced pressure, and the residual oil was separated and purified by silica gel column chromatography using ethyl acetate as a developing solvent.
8 grams of 4-dibromobutyl)picolinic acid dimethylamide were obtained.

Infrared absorption spectrum (liquid film): 1630rr
L1 Ultraviolet absorption spectrum (methanol): λmaX268
mμ Thin layer chromatography (silica gel, ethyl acetate):
Rf value 0.33 Example 3 5-(3-bromobutyl)picolinic acid amide 5-(3-
Using bromobutyl) picolinic acid 22, reaction and purification were carried out in the same manner as in Example 1, resulting in needle-like crystals of 5-(3-bromobutyl) picolinic acid □1.05f.
? It was returned.

m, p, 130-131℃ Infrared absorption spectrum (potassium bromide): 1680α
1 Ultraviolet absorption spectrum (methanol): λmax268
77Zμ (ε5400) Thin layer chromatography (silica gel, chloroformmethanol-acetic acid = 45:4:1): Rf value 0.69 Example 4 5-(3,4-digron convex)゛thyl)picolinic acid amide 5-( When reaction and purification were carried out in the same manner as in Example 1 using 10 3,4-dichlorobutyl)picolinic acid, needle-like crystals of 5-(3,4-dichlorobutyl)picolinic acid amide, 7 ? It was returned.

m, p, 115-116°C Infrared absorption spectrum (potassium bromide): 1680.1
650CrIl-1 Ultraviolet absorption spectrum (methanol): λmax268
mμ (ε5350) Thin layer chromatography (silica gel benzene-pyridine-acetic acid = 30:5:1): Rf value 0.78 Example 5 5-(3.4-dichlorobutyl)picolinic acid dimethylamide 5-(3. An acid chloride obtained from 10 f of 4-dichlorobutyl)picolinic acid and 10 M of thionyl chloride was dissolved in 250 ml of methanol, and an esterification reaction was carried out at room temperature for 30 minutes.

A methanol solution of 5-(3,4-dichlorobutyl)picolinate methyl ester thus obtained was added to
10,011 liters of dimethylamine aqueous solution was added, and ammonolysis was carried out at room temperature for 2 days with a tightly stoppered lid.

The reaction solution was evaporated under reduced pressure, and the oily substance with residual odor was separated and purified in the same manner as in the lower part of Example 2 to obtain 5-(3,4-dichlorobutyl)picolinic acid dimethylamide as a viscous colorless oil. I got 11.

Infrared absorption spectrum (liquid film): 1630TL
1 Ultraviolet absorption spectrum (methanol); λmaX268
mμ Thin layer chromatography (silica gel, ethyl acetate: R
f value 0.30

Claims (1)

[Claims] An ester of 15-(3,4-dibrombutyl)picolinic acid or 5-(3,4-dichlorobutyl)picolinic acid and an alcohol containing 1 to 4 carbon atoms, ammonia, and an alcohol containing 1 to 4 carbon atoms. or dialkylamine containing 1 to 4 carbon atoms (5-()-butyl)
Method for producing pico-177 acid amide.