JPS5826339B2 - 5-(Halobutyl) Picolin Sanamide Noseiho - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 5-(halobutyl)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 5-(...butyl)picolinic acid halide 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 new novel drug 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-(halobutyl) birophosphate...ride with a nitrogen compound having active hydrogen.

The reaction of the present invention involves the reaction of 5-(-butyl)picolinic acid...
This method involves reacting a nitrogen compound containing active hydrogen in a solvent solution of a compound.

5-(Halobutyl)picolinic acid halide used in the present invention is produced by reacting 5-(halobutyl)picolinic acid or a salt thereof with a halogenating agent.

Examples of the halogenating agent include thionyl chloride, phosphorus pentachloride,
Preferred are phosphorus chloride, phosphorus oxychloride, sulfuryl, chloride, and the like.

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,
5-(Halobutyl)picolinic acid is dissolved in benzene, toluene, cyclohexane, acetone, methyl ethyl ketone, ether, dioxane, tetrahydrofuran, pyridine, n-hexane, etc.

The inert solvent is mixed with 5-(halobutyl)picolinic acid or its salt at a ratio of 0.5 to 500 times the volume.

The halogenating agent is 1 to 500 equivalents, preferably 1 to 10i
5-(Halobutyl)picolinic acid or its salt in the proportion of the amount.

The reaction temperature is -30 to 200°C, preferably -10 to 200°C.
The temperature is 100°C.

The reaction product contains 5-(halobutyl)picolinate halide, which can be separated and used in the next reaction, either as a solvent solution or with the addition of an appropriate solvent. It can be used in the next reaction.

Note that the unreacted halogenating agent may be removed in advance or inactivated by neutralization, decomposition, etc., but since it is inactivated by reacting with the nitrogen compound having active hydrogen used in the next reaction, It has the characteristic that unreacted halogenating agent can be used in the next reaction without being separated.

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

Nitrogen compounds having active hydrogen include ammonia, methylamine, ethylamine, dimethylamine, diethylamine, n-globilamine, inglobilamine, n
Typical examples include lower amines such as -butylamine, 5ee-7thylamine, and t-butylamine.

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

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

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, acetone, methyl ethyl ketone, chloroform, dichloromethane, benzene, toluene, ethylacetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane water, etc. are used.

If acid is produced in this reaction, sodium hydroxide,
Although a neutralizing agent such as calcium hydroxide, sodium bicarbonate, or sodium carbonate may be used, the nitrogen compound itself having active hydrogen serves as a neutralizing agent.

The reaction between 5-(halobutyl)picolinic acid halide and a nitrogen compound having active hydrogen is carried out in an amount of 1 to 10 equivalents in anhydrous conditions, but in aqueous conditions, a large excess of the latter is used to fully react the former with 5-( It is desirable to convert the latter to halobutinolipicolinic acid amide, and usually the latter is converted to 10 to 500
Use equivalent amount.

The reaction temperature is -30 to 200°C, preferably 0 to 100°C.
It is ℃.

5-(Halobutyl)picolinic acid amide produced by the method of the present invention can be obtained in a pure form by separation and purification methods such as extraction, distribution, recrystallization, and 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-(halobutyl)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, 20f?
was added to thionyl chloride 157d, and the reaction was carried out at 50°C for 30 minutes.

The reaction mixture was evaporated under reduced pressure, and the oily residue was dissolved in chloroform.
It was dissolved in 00ml.

Dry ammonia gas was passed through this chloroform solution for about 5 minutes under cooling, and the resulting white precipitate was separated from P and washed with chloroform.

After combining the p solution and washing solution and evaporating under reduced pressure, the solid residual aroma was recrystallized from benzene, resulting in plate-like crystals of 5-(3.
4-dibromobutyl)picolinic acid amide lO,2P was obtained.

m, p, 138.5-140.5°C Elemental analysis value (%): CIOH12OH2Br 2 actual value: C35,98, H: 3.88, H8,51, Br
47.15 Theoretical value: C35.74, H3.60, H8.34, B
r47.56 Infrared absorption spectrum (potassium bromide): 1680.1
660CrrL-1 Ultraviolet absorption spectrum (methanol): λmaX269
mμ (e 5400) Thin layer chromatography (silica gel, chloroform)
Methanol-acetic acid = 45:4:1): Rf value 0.72 Solubility: Easily soluble in alcohol, acetone, benzene, chloroform, water, insoluble in ether Example 2 5-(3,4-dichlorobutyl)picolinic acid salt Do5-(3,4-dichlorobutyl)picolinic acid 101 in chloroform solution (130 ml) of thionyl chloride 30 ml
The mixture was dissolved in water and refluxed for 15 minutes on a hot water bath.

The reaction mixture was evaporated under reduced pressure and the oily residue was removed with benzene (100m/
? ), 50 m of 28% ammonia water was added while stirring vigorously under cooling, and the mixture was stirred for 1 hour.

When the benzene extract was evaporated under reduced pressure, crude crystals were obtained.

When this crude crystal was recrystallized from benzene-n-hexane, 6.52 acicular crystals were obtained.

m, p, 115-117°C Elemental analysis value: C1oH1□0N2C12 Actual value: C48.82, H4.83, N11.54, C
l28.25 Calculated value: C48.60, H4.89, N11.34, C
l28.69 Infrared absorption spectrum (potassium bromide): 1680.
1650cm' Ultraviolet absorption spectrum (methanol): λmax268
77Zμ (ε5370) Thin layer chromatography (silica gel benzene-pyridine-acetic acid-30:5:1): Rf value 0.78 Solubility: Easily soluble in methanol, acetone, benzene, chloroform, water, insoluble in ether Example 3 5- (3-bromobutyl)picolinic acid amide 5-(3-
When reaction and purification were carried out in the same manner as in Example 1 using bromobutyl)picolinic acid 2i, needle-like crystals of 5-(3
1.12 -bromobutyl)picolinic acid amide was obtained.

m, p, 130-131°C Elemental analysis value: C1oH13ON2Br Actual value: C46.34, N5.32, N10.97, B
r30.63 Calculated value: C46.71, N5.10. ,NlO,89
, Br31.08 Infrared absorption spectrum (potassium bromide): 1680α-
1 Ultraviolet absorption spectrum (methanol): λmax268
mμ (e 5450) Thin layer chromatography (silica gel, chloroform)
Methanol-acetic acid = 45:421) Rf value 0.69 Example 4 5-(3,4-siph'romobutyl)picolinate monomethylamide 5-(3,4-dibromobutyl)picolinate 10F and thionyl chloride A chloroform solution of acid chloride obtained from 10 mA' and 1001 rL of 30% methylamine water
When these were reacted and treated in the same manner as in Example 3, 8.71 g of crude oil was obtained.

This was separated and purified by column chromatography using silica gel and ethyl acetate as a developing solvent.
5-(3,4-dibromoptyl)picolinic acid monomethylamide was obtained as a viscous colorless oil.

Infrared absorption spectrum (1quid film):
1670a "UV absorption spectrum (methanol) λmax 2687
7Zμ thin layer chromatography (silica gel, ethyl acetate):
Rf value 0.60 Example 5 5-(3,4-dichlorobutyl)picolinic acid monomethylamide Reacted in exactly the same manner as in Example 4 using 10 g of 5-(3,4-dichlorobutyl)picolinic acid. After purification, 5-(3,4-dichlorobutyl)picolinic acid monomethylamide was obtained as a viscous colorless oil.

Infrared absorption spectrum (1quid film):
1670m -■ Ultraviolet absorption spectrum (methanol): λmax268
772μ thin layer chromatography (silica gel, ethyl acetate):
Rf value 0.58 Example 6 5-(3,4-dibromobutyl)picolinic acid dimethylamide A chloroform solution of acid chloride obtained from 5-(3,4-dibromobutyl)picolinic acid 10P and thionyl chloride 10ml and 40% When 100 ml of % dimethylamine water was reacted, treated, and purified in the same manner as in Example 4, a viscous substance that gave a single spot (Rf value 0.33) was obtained by thin layer chromatography (silica gel, ethyl acetate). 5-(3,4-dibromobutyl)picolinic acid dimethylamide was obtained as a viscous colorless oil.

Infrared absorption spectrum (1quid film):
1630α-1 Ultraviolet absorption spectrum (methanol): λmax268
mμ Example 7 5-(3,4-dichlorobutyl)picolinic acid dimethylamide 5-(3,4-dichlorobutyl)picolinic acid 102 was reacted and purified in the same manner as in Example 6. 5-(3,4-dichlorobutyl)picolinic acid dimethylamide was obtained as a viscous colorless oil which gave a single spot (Rf value 0.30) on layer chromatography (silica gel, ethyl acetate).

Infrared absorption spectrum (1quid film)
: 1630-1 Ultraviolet absorption spectrum (methanol): λmax 26
8mμ

Claims (1)

[Claims] 15-(3,4-dibrombutyl)picolinate chloride or 5-(3,4-dichlorobutyl)picolinate chloride with ammonia, an alkylamine containing 1 to 4 carbon atoms, or an alkylamine containing 1 to 4 carbon atoms. 5- characterized by reacting with a dialkylamine containing
Process for producing (butyl) picolinate.