JPS5826340B2 - 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-(halobutyl)picolinic acid and its derivatives significantly inhibit dopamine-β hydroxylase and have good antihypertensive effects.

As a result of further research, it was found that 5-(...butyl)picolinic acid amides not only have the above-mentioned effects, but also have extremely low side effects such as gastric and intestinal disorders, and exhibit particularly useful medicinal effects.

As a result of research on a method for producing 5-(halobutyl)picolinic acid amide using the previously invented 5-(halobutyl)picolinic acid anhydride as a starting material, the present inventor found that
The present invention has now been 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 invention can be achieved by reacting 5-()-butyl)picolinic anhydride with a nitrogen compound having active hydrogen.

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

5-(...butyl)picolinic anhydride used in the present invention is 5-(halobutyl)picolinic acid or a salt thereof.
It is prepared by reacting acid halides or alkyl chloroformates, preferably in solvent solution.

Suitable acid halides include aliphatic acid halides such as acetyl chloride, pentyl chloride, and isovaleryl chloride; aromatic acids such as benzyl chloride.

Preferred alkyl chloroformates include isobutyl chloroformate and benzyl chloroformate.

This reaction is preferably carried out in an inert solvent.

Inert solvents include chloroform and dichloromethane.
Preferred are benzene, toluene, cyclohexane, acetone, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, and the like.

The reaction temperature of this reaction is -30 to 100°C, preferably -11°C.
The temperature is 0 to 30°C.

The amount of acid halide or alkyl chloroformate used is 1 to 500% relative to 5-(halobutyl)picolinic acid.
It is equivalent.

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.
If unreacted acid halide or alkyl chloroformate remains, it can be used in the next reaction after being reacted with a lower fatty acid such as acetic acid to form an inert compound.

By-products such as acids generated by the reaction may be neutralized in advance, but they are neutralized by the nitrogen compound containing active hydrogen used in the next reaction, so they can be used as is for the next reaction. .

Usually, if 5-(halobutyl)picolinic acid is required, it is dissolved in an inert solvent such as chloroform together with a neutralizing agent such as triethylamine, and an alkyl chloroformate is added dropwise to carry out the reaction. 5-(Halobutyl)picolinic acid amide can be obtained in high yield by forming an anhydride and reacting the anhydride with a nitrogen compound having active hydrogen under cooling.

Thus, a production process without anhydride separation has significant advantages.

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 anhydride 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,
Lower amines such as n-butylamine, 5ee-butylamine, and t-butylamine are typical.

However, cyclohexylamines such as cyclopropylamine, 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, ethyl acetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane, etc. are used.

The amount of the nitrogen compound having active hydrogen is usually such that 5-(halobutyl)picolinic anhydride is sufficient as an excess equivalent.
It is desirable to convert it to its amide.

Usually 1 to 10 equivalents are used. This reaction temperature is -30 to 20
The temperature is 0°C, preferably 20 to 50°C.

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, or chromatography.

When the antihypertensive effect and toxicity of 5-(halobutyl)picolinic acid amide obtained by the method of the present invention were investigated, it was 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. Served.

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-dichlorobutyl)picolinic acid morpholinoamide 5-(3,4-dichlorobutyl)picolinic acid, 248 g and triethylamine, 14TrLl, chloroform 40
13.2 ml of inbutyl chloroformate was added dropwise thereto under cooling, and the reaction was carried out at 5° C. for 30 minutes.

12 ml of morpholine was added dropwise to the reaction solution under cooling, and the reaction was further stirred for 1 hour.

After washing the reaction mixture with water, it was evaporated under reduced pressure, yielding 31.5f of an oily crude product.

This material was coated on silica gel with chloroform-ethanol (
Purification was carried out by developing with 20:1) to yield 5-(3,4-dichlorobutyl)picolinic acid morpholinoamide as a viscous colorless oil.

Infrared absorption spectrum (liquid film): 1630 crn Ultraviolet absorption spectrum (methanol): λmax 268 mμ (
ε5110) Thin layer chromatography (silica gel, chloroform:
Ethanol-20: 1): Rf value 0.5 Example 2 5-(3,4-dichlorobutyl)picolinic acid piperidinamide 5-(3,4-dichlorobutyl)picolinic acid 4. The mixed acid anhydride prepared from 96f was reacted with 2.47 mg of piperidine to yield 2.81 g of 5-(3,4-dichlorobutyl)picolinic acid piperidinamide as a viscous colorless oil.

Infrared absorption spectrum (liquid film): 1630c7n' Ultraviolet absorption spectrum (methanol): λmax 268m
μ (ε5410) Thin layer chromatography (silica gel, chloroform:
Ethanol-20:1): R4 value 0.55 Example 3 ■・4-bis(5-(3,4-dichlorobutyl)picolinylcopiperazine) 5-(3・4- The mixed acid anhydride prepared from dichlorobutyl)picolinic acid 4.91' (20 mmol) was reacted with piperazine 0.85S' (10 mmol) to give product 42 as a solid.

By recrystallizing this from chloroform-n-hexane, 2.81 crystals of 1,4-bis(5-(3,4 dichlorobutyl)picolinylcopiperazine) were obtained.

m, p, 180-182℃ Infrared absorption spectrum (potassium bromide): 1630Cm
1 Ultraviolet absorption spectrum (methanol): λmax269
mμ (ε10820) Example 4 ■・4-bis(5-(3,4-dibromobutylpicolinylcopiperazine) 5-(3,4-dibromobutyl)picolinic acid, 6.74f by the same method as in Example 3 (20 mmol), the reaction product 5.11 was obtained as a solid, which was recrystallized from chloroform to give 1,4-bis[5
-(3,4-dibromobutyl)picolinylcopiperazine crystal, 3.75? I was returned.

m, p, 159-160℃ Infrared absorption spectrum (potassium bromide): 1630cm
1 Ultraviolet absorption spectrum (methanol): λmax269
mμ (ε9970) Example 5 1,2-bis(5-(3,4-dichlorobutyl:picolinyl)hydrazine 4.96 fl of 5-(3,4-dichlorobutyl)picolinic acid ( 05T
Reaction with Ll (1029 mol) gave 4.92 of the product as a solid.

By recrystallizing this from benzene-n-hexane, 1,2-bis(5-(3,4-dichlorobutyl)
34 grams of picolinyl hydrazine crystals were obtained.

m, p, 107~1O9℃ Infrared absorption spectrum (potassium bromide): 1710.1
67Qcnl Ultraviolet absorption spectrum (methanol): λmax269
mttCe 13700) Example 6 5-(3,4-dibromobutyl)picolinic acid amide 5-(3,4-dibromobutyl)picolinic acid, 10? Ammonolysis was carried out by blowing dry ammonia gas into a chloroform solution of mixed acid anhydride prepared from.

When the residual aroma of the reaction solution was crystallized from benzene,
5g of 5-(3,4-dibromobutyl)picolinic acid amide in the form of platelets was obtained.

m, p, 138-140°C Infrared absorption spectrum (potassium bromide): 1680.1
660C1rL' Ultraviolet absorption spectrum (methanol): λmax269
mμ (ε5300) Thin layer chromatography (silica gel, chloroform)
Methanol-acetic acid-45:4:1): Rf value 0.72 Example 7 5-(3,4-dichlorobutyl)picolinic acid amide 5-(3,4-dichlorobutyl) was prepared in the same manner as in Example 6. Needle-shaped 5(3,4-dichlorobutyl)picolinic acid amide, 6.11, was obtained from picolinic acid 10f.

m, p, 115-116°C Infrared absorption spectrum (potassium bromide): 1680.1
65QCm 1 Ultraviolet absorption spectrum (methanol): λmax268
rrLμ (ε5350) Thin layer chromatography (silica gel benzenepyridine-acetic acid-30:5:1): Rf value 0.78 Example 8 5-(3-bromobutyl)picolinic acid amide 5- (3-bromobutyl)picolinic acid 21 to needle-shaped 5-(3fromobutyl)picolinic acid amide, 0.8? I was returned.

m, p, 129-131'C Infrared absorption spectrum (potassium bromide): 1680Cr
rL-1 Ultraviolet absorption spectrum (methanol): λmax268
mμ (a: 5400) Thin layer chromatography (silica gel, chloroform)
Methanol-acetic acid-45:4:1) Rf value 0.69 Example 9 5-(3,4-dibromobutyl)picolinic acid dimethylamide 5-(3,4-dibromobutyl) was prepared in the same manner as in Example 1. Amitrilysis was carried out by blowing dry dimethylamine gas into a chloroform solution of a mixed acid anhydride prepared from 1 oz of picolinic acid.

The oil obtained by evaporating the reaction solution under reduced pressure was separated and purified by silica gel column chromatography using ethyl acetate as a developing solvent.
6 grams of -(3,4-dibromobutyl)picolinic acid dimethylamide were obtained.

Infrared absorption spectrum (liquid film): 1630CT
L-1 Ultraviolet absorption spectrum (methanol): λmax268
mμ thin layer chromatography (silica gel, ethyl acetate)
: Rf value 0.33 Example 10 5-(3,4-dichlorobutyl)picolinic acid dimethylamide 5-(3,4-dichlorobutyl)picolinic acid 10? 5-(3) as a viscous colorless oil
・4-dichlorobutyl) picolinate dimethylamide, 5
72 was obtained.

Infrared absorption spectrum (liquid film): 1630Cr
rL-1 Ultraviolet absorption spectrum (methanol): λmax268
mμ thin layer chromatography (silica gel, ethyl acetate)
m Rf value 0.30

Claims (1)

[Claims] 15-(3,4-dibrombutyl)picolinic anhydride or 5-(3,4-dichlorobutyl)picolinic anhydride with ammonia, an alkylamine containing 1 to 4 carbon atoms, or 1 to 4 carbon atoms A method for producing 5-(halobutyl)picolinic acid amide, which comprises reacting with a dialkylamine containing a carbon number.