JPH0637471B2 - New method for producing 4-pyridylpimelic acid compound - Google Patents

Description

TECHNICAL FIELD The present invention is an invention of a novel method for producing 4-pyridylpimelic acid and its ester or its hydrochloride, which is an important intermediate for the production of isoquinolinone compounds useful as pharmaceuticals, especially as cardiotonic agents. .

[Background technology]

As isoquinolinone compounds useful as cardiotonic agents, Japanese Patent Application No. 60-071182 (see Japanese Patent Application Laid-Open No. 61-229865) and Japanese Patent Application No. 60
-144008 (see JP-A-62-5963) and the like, 4-cyano-1-methyl-7- (4-pyridyl) -5,6,7,8-tetrahydro-3 ( 2H) -isoquinolinone.

Conventionally, when producing these isoquinolinone compounds, 4-pyridylpimelic acid and its ester as an intermediate thereof,
A method via a hydrochloride is known. For example, as a method for producing a 4-pyridylpimelic acid compound, Japanese Patent Application No. 60-1
42573 (see JP-A-62-4266), -142574 (see JP-A-62-4265), and -149165 (see JP-A-62-10063).

However, the methods described in these have problems in terms of economics such as expensive raw materials. Therefore, a more economical method for producing 4-pyridylpimelic acid and its ester or its hydrochloride is desired.

[Object of the Invention] An object of the present invention is to provide a new method for economically producing 4-pyridylpimelic acid and its ester or its hydrochloride, which is an important intermediate in the production of isoquinolinone compounds useful as cardiotonic agents. And

[Disclosure of Invention]

The object of the present invention is to condense α- (4-pyridyl) -β-dimethylaminoacrolein and malonic acid diester, then carry out hydrogenation reaction, and further heat in an acidic aqueous solution to give 4-pyridylpimelic acid. It is achieved by manufacturing.

Further, in some cases, hydrochloric acid can be converted to the hydrochloride, or a suitable alcohol can be converted to the ester.

The reaction routes are shown below to further explain the present invention in detail.

Reaction pathway to 4-pyridylpimelic acid That is, Z. Arnold (Collect.Czechoslov.Chem.Commun.
28 864 1963 ) using the method of synthesizing α- (4-pyridyl) -β-dimethylaminoacrolein (I) reported in the present invention, inexpensive γ-picoline containing phosphorus oxychloride and dimethylformamide or phosgene and dimethylformamide To produce (I).

The (I) thus obtained was dehydrated and condensed with malonic acid diethyl or dimethyl ester in the presence of a base to give 2-carboxy.
-4-Pyridyl-hepta-2,5-dienedicarboxylic acid diethyl or dimethyl ester (III) and 2,6-dicarboxy-
It is diethyl or dimethyl ester (II) of 4-pyridyl-hepta-2,5-dienedicarboxylic acid.

Although various solvents can be used as the solvent, alcohol solvents such as ethanol and methanol are preferable.

Suitable bases are metal alcoholates such as sodium ethoxide, sodium methoxide and potassium t-butoxide.

The reaction temperature is applicable from room temperature to the boiling point of the solvent used.

Although water is produced in this reaction, the presence of this water may produce (III) and, as a by-product, 2,6-dicarboxy-4-pyridylphenol. It is preferable to react in the presence of a water removing agent such as magnesium.

Subsequently, these mixtures are directly subjected to a hydrogenation reaction.
A metal catalyst such as palladium, nickel or platinum is used as the catalyst, and water, methanol, ethanol, ethyl acetate or the like is used as the solvent. Depending on the case, an acidic solvent such as hydrochloric acid or acetic acid may be used.

Although room temperature is sufficient as the temperature, the reaction may be carried out under heating in some cases.

A mixture of the ethyl or methyl ester of 2,6-dicarboxy-4-pyridyl-pimelic acid (IV) and the ethyl or methyl ester of 2-carboxy-4-pyridyl-pimelic acid (V) obtained by the above method was used. 4-pyridylpimelic acid (VI) by heating in aqueous hydrochloric acid or sulfuric acid
Can be obtained.

The reaction temperature is from room temperature to the boiling point of the solvent,
Desirably, the temperature is about 100 to 110 ° C.

4-Pyridylpimelic acid (VI) obtained by the above method
Can be converted to the hydrochloride with hydrochloric acid and its ester with a suitable alcohol. That is, if (VI) and hydrochloric acid are mixed and then dried, the hydrochloric acid salt dissolves (VI) in methanol, ethanol, etc., and sulfuric acid or hydrogen chloride is added as a catalyst and allowed to react at room temperature or under heating. Thus, the corresponding ester form can be produced.

The isoquinoline compound useful as a cardiotonic agent is produced from the 4-pyridylpimelic acid ester produced in this manner, for example, by the method shown in the following reaction route.

That is, as shown in Japanese Patent Application No. 60-149165, 4-pyridylpimelic acid dimethyl ester is dissolved in a solvent such as tetrahydrofuran and toluene, and potassium t-butoxide, a base such as sodium methoxide are added, and the so-called
Dieckmann reaction is carried out, followed by heating with hydrochloric acid or sulfuric acid aqueous solution to obtain 4-pyridylcyclohexanone. Further, it is acetylated by the method described in Japanese Patent Application No. 60-131940 (see Japanese Patent Application Laid-Open No. 61-291570) to give 2-acetyl-4-pyridylcyclohexanone. Furthermore, for example, 4-cyano-1-methyl-7- (4-pyridyl) -5,6,7,8- having strong cardiotonic activity
When tetrahydro-3- (2H) -isoquinolinone (VII) is produced, cyanoacetamide may be reacted in the presence of a base such as piperidine or sodium methoxide.

The isoquinoline compound produced in this manner has a very strong cardiotonic effect and is therefore useful as an anti-heart failure therapeutic agent.

〔Example〕

 Next, the present invention will be described more specifically with reference to Examples.

Example 1 a) α- (4-pyridyl) -β-dimethylaminoacrolein Dimethylformamide 700 ml was ice-cooled and phosphorus oxychloride 3
85 ml was gradually added dropwise over 3.5 hours. Γ with stirring
135.5 ml of picoline was added dropwise below 20 ° C.

After stirring for 20 minutes, it was heated at 70 ° C. for 6 hours.

After cooling, 3.5 kg of potassium carbonate was dissolved in 3.5 of water, and the above reaction solution was gradually added thereto while cooling with ice.

After 1 hour, the precipitate was filtered off, and the filtrate was extracted with benzene: ethanol = 1: 1 mixed solution 3.

The extract was washed with 500 ml of a saturated aqueous solution of potassium carbonate and further dried over anhydrous sodium sulfate.

When the solvent was distilled off, 273.3 g of α- (4-pyridyl) -β-dimethylaminoacrolein was obtained.

Recrystallization of part of it from methyl ethyl ketone gives a melting point of 90.
It showed ~ 91 ° C.

b) 2-Ethoxycarbonyl-4- (4-pyridyl) -pimelic acid diethyl ester 15 g of sodium metal pieces were added to ethanol 1 and completely dissolved, and then 105.6 g of malonic acid diethyl ester was added dropwise.

After further adding 100 g of anhydrous magnesium sulfate, 52.8 g of α- (4-pyridyl) -β-dimethylaminoacrolein obtained in Example 1a) was added, and the mixture was heated with stirring under reflux for 1 hour.

After cooling to room temperature, the mixture was filtered to remove insoluble matter, and the filtrate was evaporated under reduced pressure.

Neutralize the base in the residue with hydrochloric acid, then 400 ml of ethyl acetate
It was extracted twice with. The ethyl acetate extracts were combined, 50 g of activated carbon was added thereto, and the mixture was stirred well and then silica gel 2
Silica gel column chromatography was performed using 00 g. As the effluent, a mixed solvent 1 having a ratio of ethyl acetate: hexane = 3: 1 was used.

The effluent was distilled off under reduced pressure to obtain 66 g of an oily substance containing the main product 2-ethoxycarbonyl-4- (4-pyridyl) -hepta-2,5-dienedicarboxylic acid diethyl ester as a residue.

This oily substance was dissolved in 400 ml of ethanol as it was, and 5 g of 10% palladium-carbon was added thereto, and then hydrogen gas was added to about 8 at room temperature and normal pressure.
Absorbed.

After completion of the reaction, the reaction mixture was filtered, the catalyst was removed, and the solvent was distilled off under reduced pressure to obtain 60 g of an oily substance containing 2-ethoxycarbonyl-4- (4-pyridyl) -pimelic acid diethyl ester as a main product.

The physical properties of 2-ethoxycarbonyl-4- (4-pyridyl) -pimelic acid diethyl ester purified by silica gel column are as follows.

c) 4- (4-pyridyl) -pimelinic acid hydrochloride 60 g of the oil obtained by the method of Example 1b) was added to 360 ml of 6N-hydrochloric acid.
It was dissolved in and was heated and stirred under reflux for 3 hours.

The hydrochloric acid aqueous solution was evaporated under reduced pressure, the residue was crystallized with ether, and filtered to obtain 57 g of 4- (4-pyridyl) -pimelinic acid hydrochloride.

Example 2 4- (4-pyridyl) -pimelic acid diethyl ester 2-ethoxycarbonyl-4-obtained by the method of Example 1b)
(4-pyridyl) -pimelic acid diethyl ester 10.0 g 6N-
It was dissolved in 60 ml of hydrochloric acid water and heated under stirring for 3 hours under reflux.

The hydrochloric acid aqueous solution was distilled off under reduced pressure, and the residue was once mixed with 20 ml of ethanol.
After being dissolved in ethanol, ethanol was distilled off. This operation was repeated twice.

50 ml of ethanol was added to the residue after this, and hydrochloric acid gas 2 was added.
I understand about it.

After leaving it at room temperature for 12 hours, ethanol was distilled off, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate under ice cooling.

Further, after extracting twice with 100 ml of ethyl acetate, the ethyl acetate solutions were combined and dried over anhydrous sodium sulfate.

After filtering out the sodium sulfate, the filtrate was concentrated to give 4- (4-pyridyl) -pimelic acid diethyl ester as an oily substance in an amount of 7.8 g.
Was obtained.

The physical properties of the product purified with a silica gel column were as follows.

Example 3 4- (4-pyridyl) -pimelic acid dimethyl ester 100 g of 4- (4-pyridyl) -pimelinic acid hydrochloride obtained by the method of Example 1c) was dissolved in 700 ml of methanol, and 12.4 g of concentrated sulfuric acid was dissolved.
After the addition, the mixture was heated and stirred under reflux for 2 hours.

This was cooled to 20 ° C. or lower, 24 g of sodium bicarbonate was added thereafter, and methanol was distilled off.

To the obtained residue, 500 ml of toluene was added, 130 ml of ice water was added, and then an aqueous caustic soda solution was added dropwise under cooling to neutralize.

The layers were separated and the toluene layer was collected and dried over anhydrous Glauber's salt.

The toluene layer was once filtered and the filtrate was concentrated to give 89 g of 4- (4-pyridyl) -pimelic acid dimethyl ester as an oil.
Was obtained.

The physical properties of the product purified by a silica gel column are as follows.

Claims (1)

[Claims] 1. A 4-pyridylpimelin characterized by condensing α- (4-pyridyl) -β-dimethylaminoacrolein and malonic acid diester, followed by hydrogenation reaction, and further heating in an acidic aqueous solution. A novel method for producing an acid and its ester or its hydrochloride.