JPH0228177A - Novel production of imidazopyridine derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound having inhibitory action on secretion of acid in the stomach and antitumor activity readily and in high yield by reacting an aminopyridine ether with an acrylic acid derivative as raw materials and reacting the reaction product with ammonia and then with a dehydrating agent. CONSTITUTION:An aminopyrdine ether shown by formula I (R<1> is alkyl which may be replaced with cycloalkyl group or 4-6C alkenyl) is reacted with an acrylic acid derivative shown by formula II (R<2> and R<3> are lower alkyl) in equimolar amounts or somewhat an excess amount of one compound at room temperature-under heating in a solvent such as ethanol to give a 3-lower alkoxycarbonylmethylimidazopyridine derivative shown by formula III. Then this compound is reacted with ammonia to give a 3- carbamoylmethylimidazopyridine derivative shown by formula IV, which is successively reacted with somewhat an excess amount of a dehydrating agent such as phosphorus pentachloride under cooling-room temperature to give a compound shown by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention has H+,K''-adenosine triphosphatase inhibitory activity and is useful as a preventive and therapeutic agent for gastric diseases.
This invention relates to a novel method for producing imidazopyridi/derivatives represented by formula (I).

Method l.

(In the formula, R1 is an alkyl group which may be substituted with a cycloalkyl group or an alkenyl group having 4 to 6 carbon atoms, and R2 is a lower alkyl group. The same applies hereinafter) (Prior art) The imidazopyridine derivative represented by the general formula CI
As described in No. 25382, it is a new compound that has excellent gastric acid secretion suppressing action and anti-ulcer action. In the application.

For example, the following methods are described as methods for producing these compounds.

Method 2゜In the formula, Rla is an alkyl group optionally substituted with a cycloalkyl group, arb is an alkenyl group having 4 to 6 carbon atoms, R2a and Rla are lower alkyl groups, and X is a means a rogen atom. The same applies hereinafter) (Means for Solving the Problems) The present inventors completed the present invention as a result of intensive research on a method for industrially obtaining the compound represented by the general formula (I) in high yield.

The present invention is based on -Math. general formula and aminopyridine ethers represented by

-Mathematical formula %formula%() React with the acrylic acid derivative shown in

-Mathematical formula (In the formula, R3 means a lower alkyl group.

A 3-lower alkoxylponylmethylimitazoviridine derivative represented by the formula (the same applies hereinafter) is obtained, and then reacted with ammonia.

This is a new method for producing an imidazopyridine derivative represented by the general formula, which is characterized in that after obtaining a 3-carbamoylmethylimidazopyridine derivative represented by the formula, the 3-carbamoylmethylimidazopyridine derivative is reacted with a dehydrating agent.

As defined herein, 2-lower R- means a carbon chain having 1 to 5 carbon atoms unless otherwise specified. Therefore, “
Examples of the "lower alkyl group" include methyl group, ethyl group, propyl group, 1so-propyl group, butyl group,
1so-butyl group.

Straight or branched carbon chains such as lert-phtyl group, pentyl group, 1) 430-pentyl group, tert-pentyl group, etc. are further defined as ``alkyl group J.''

Straight or branched alkyl groups having 1 to 10 carbon atoms are preferred, and specifically, in addition to the above-mentioned examples of lower alkyl groups, heptyl groups are also preferred.

5-methylhexyl group, 1-methylhexyl group.

3-ethylpentyl group, 2-furobylbutyl group.

Octyl group, 6-methylhegutyl group, nonyl group.

Examples include 7-methyloctyl group, decyl group, and 8-methylnonyl group.

[Alkenyl group J having 4 to 6 carbon atoms includes 1-butenyl group and 2-butenyl group.

3-7'thenyl group, 2-methyl-1-propenyl group, 2
-Methyl-2-propenyl group, 1-pentenyl group, 2-
pentenyl group, 3-pentenyl group, 4-pentenyl group,
3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2,2-dimethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group.

5-hexenyl group, 4-, If-1-pentenyl group,
Preferred examples include 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 4-methyl-4-pentenyl group, and 3-methyl-2-pentenyl group.

Moreover, as the "cycloalkyl group", those having preferably 3 to 6 carbon atoms are mentioned.

Specifically, cyclopropyl group and cyclobutyl group.

These include cyclopentyl group, cyclohexyl group, etc.

(Manufacturing method) Next, the manufacturing method of the second invention is carried out by the steps shown below.

(First Step) The first step of the production method of the present invention is carried out by reacting the aminopyridine ether represented by the general formula (n) with the acrylic acid derivative represented by the general formula (2).

The reaction involves methanol and ethanol.

In alcohols such as panol, organic solvents that are inert to reactions such as benzene, toluene, xylene, etc.

Compounds (U) and (m) are used in approximately equal moles to a slightly excess amount of one of them, and optionally in the presence of a base.

It is carried out at room temperature or under heating.

Examples of the base added during the reaction include trimethylamine, triethylamine, pyridine, picoline, lutidine, and dimethylaniline.

Potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.

The reaction time is appropriately adjusted depending on the type of compound (II), reaction temperature, etc., and is usually several hours to several days.

The compound (TV) obtained in one step can be isolated and purified after the completion of one reaction, or can be directly subjected to the next second step.

(Second Step) The second step of the production method of the present invention is a step of reacting the compound (TV) obtained in the first step with ammonia (NH3) to amidate the lower alkyl ester at the 3-position of the imidazopyridine ring. .

Amidation is usually carried out in methanol under water cooling or room temperature.

Ammonia gas is applied in an alcohol solvent such as ethanol. Alternatively, concentrated ammonia water may be used.

Note that this ammonolysis by ammonia is promoted by the presence of ammonium chloride.

(Third Step) Next, the 3-carbamoylmethylimidazopyridine derivative (v) obtained here is treated with a dehydrating agent to be led to an imidazopyridine derivative represented by the general formula (T).

The dehydrating agent in this reaction is phosphorus pentoxide.

Phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, trifluoroacetic acid m hydrate, triphenylphosphine 7+)
I) Su() IJ phenylphosphine) chlororhodium, phosphonitrile chloride, thionyl chloride, phosgene, aluminum chloride, dicyclohexyl carna° diimide, trialkylsilyl chloride, acetyl chloride, benzoyl chloride.

Sulfonium chloride, polyphosphoric acid, tin oxide.

Titanium tetrachloride, trichlorotriazine, etc. are used.

Among these, phosphorus pentachloride is particularly preferred.

Further, the reaction solvent is not particularly limited as long as it is inert to the reaction.For example, dichloromethane can be used.

Chloroform, dichloroethane, benzene, toluene,
The dehydrating agent is used in these organic solvents in a slightly excess amount than the theoretical amount. The reaction temperature is usually set between cooling and room temperature.

The compound represented by the general formula (1>) can also be isolated as its salt. For the salt-forming reaction, reactions commonly performed in the field can be applied. General formula (I)
Examples of salts of compounds represented by 1 include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, citric acid, succinic acid, fumaric acid, and maleic acid. and salt.

Isolation and purification of the compound (I) or a salt thereof thus obtained is carried out by conventional methods, such as crystallization, column chromatography, etc., as appropriate.

(Effects of the Invention) The present invention provides a novel method for producing an imidazopyridine derivative represented by general formula (I). Furthermore, according to the production method of the present invention, the compound represented by the general formula (I) can be obtained in high yield, so it is considered to be an extremely advantageous production method as an industrial production method for compound (I). For example, [3-
(cyanmethyl)-2-methyl-8-(3-methyl-2
-butenyloxy)coimidazo[1,2-a]copyridineAccording to the applicant's earlier application, the yield was about 32%, but the production method of the present invention had a yield of about 75%. The yield is improved by more than double.

(Example) Examples are listed below to further explain the present invention in detail.Example 1
゜3-(3-Methyl-2-butenyloxy)-2-aminopyridine Log,, Methyl 3-acetylacrylate 1
Add 20 rol of toluene to 0.8 g, dissolve by heating, and stir at 25° C. for 7 days. Add 100 ml of toluene and 50 ml of water, and wash the toluene layer with 50 ml of water.

When toluene was distilled off under reduced pressure, [3-(methoxycarbonylmethyl)-2-methyl-8-(3-methyl-2-
butenyloxy)coimidazo[1,2-a copyridine is obtained. This product can be subjected to the next reaction without purification.

The total amount of the crude [3-(methoxycarbonylmethyl)-2-methyl-8-(3-methyl-2-phthynyloxy)coimidazo[1,2-a]pyridine obtained in (1) was dissolved in 50 ml/kg of methanol, and the mixture was dissolved in an ice water bath. While cooling with water, pass ammonia gas until saturation.

After stirring at room temperature overnight, ammonia gas was introduced again until saturation, and the mixture was stirred at room temperature overnight. After removing most of the ammonia under reduced pressure, 75 ml of inglovir ether was added, and the mixture was stirred while cooling with water. The precipitated crystals were collected by P and [3
-(carbamoylmethyl)-2-methyl-8-(3-methyl-2-butenyloxy)]imidazo[1,2-a]
12 g (yield 78.2%) of pyridine are obtained.

xy)]imidazo[1,2-a]pyridine 24.7 g,
Add 19.7 g of phosphorus pentachloride to a suspension of 15 g of pyridine and 370 ml of methylene chloride while stirring and keeping the temperature below 5°C. After stirring for 30 minutes at the same temperature, 180 ml of cold water
Add. Furthermore, add 352 g of sodium carbonate to 530 g of water.
Wash twice with water. After distilling off the solvent under reduced pressure.

Add ethanol 12'3+nZ to the residue and heat to dissolve. After cooling this solution to 30°C, 370 ml of water was added.

After stirring overnight under water cooling, the precipitated crystals were separated by P [3-(
cyanmethyl)-2-methyl-8-(3-methyl-2-
butenyloxy)coimidazo[1゜2-a]pyridine 2
Obtain 2.1 g.

Yield 958% mp, 1) 8-121°C Example
[3-(carbamoylmethyl)-2- obtained in 2゜(2)
Methyl-8-(3-methyl-2-butenyl 3-amyloxy-2-aminopyridine Log.

8.52 g of methyl 3-acetylacrylate are refluxed for 8 hours with 50 mt of isopropanol. When isopropanol is washed and distilled off under reduced pressure, crude [3-(meth(·quincarbonylmethyl)-2-methyl-8-amyloxy]
Imidazo[1,2-a]pyridine is obtained. This product does not need to be purified (it can be subjected to the next reaction).

The crude [3-(methoxycarbonylmethyl)-2-methyl-8-myloxy]imidazo[1,2-
a] Dissolve the entire amount of pyridine in 80 ml of methanol, and while cooling in an ice-water bath, ammonia gas is passed until saturation is achieved, and the mixture is stirred at room temperature for 3 days. After removing most of the ammonia under reduced pressure.

Stir while cooling with water, and remove the precipitated crystals.

1). 85 g (yield 77.6%) is obtained.

[3-(Carbamoylmethyl)-2-methyl-8-amyloxycoimidazo[1,2-a]pidgin 9.26 g
, 6.03 g of pyridine, 90 m of methylene chloride
94 g of lymph pentachloride are added to the suspension of 1 ml while stirring and maintaining the temperature at 5°C. After stirring at the same temperature for 40 minutes, cool water
Add ml. Furthermore, a solution of 17.4 g of potassium carbonate dissolved in 50 ml of water was added at a temperature below 15°C, and 1
Stir for 2 hours at 0-20°C. The aqueous layer is diluted with methylene chloride 5
After extraction with 0ml, the methylene chloride layers are combined and washed twice with water. After distilling off the solvent under reduced pressure, the residue was dissolved in 40 ml of ethanol with heating. After cooling this solution to 30°C, 120 m7 of water was added, and after stirring overnight under water cooling, the precipitated crystals were collected by P [3-(cyanmethyl)-2-methyl-8-amyloxy]imidazo[1,2-a ] 771 g of pyridine are obtained.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^1 is an alkyl group that may be substituted with a cycloalkyl group or an alkenyl group having 4 to 6 carbon atoms. aminopyridine ethers represented by the general formula R^2COCH=CHCOOR^3 (III) (wherein R^2 and R^3 are the same or different and mean a lower alkyl group). The same applies hereafter) to obtain a 3-lower alkoxycarbonylmethylimidazopyridine derivative represented by the general formula ▲Mathematical formula, chemical formula, table, etc.▼(IV), and then react with ammonia. , General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼General formula characterized by obtaining the 3-carbamoylmethylimidazopyridine derivative represented by (V) and then reacting it with a dehydrating agent▲Mathematical formulas, chemical formulas, tables, etc. There is a method for producing imidazopyridine derivatives shown in ▼(I). (2) Claim No. 1 in which the dehydrating agent is phosphorus pentachloride
) The manufacturing method described in section 2. (3) R^1 is a 3-methyl-2-butenyl group, and R
The manufacturing method according to claim (1), wherein ^2 is a methyl group.