JPH0160474B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel furo[2,3-b]indolizine derivative and a method for producing the same. The present inventors have long conducted various studies on a series of indolizine derivatives obtained using a specific pyridinium compound as a starting material, and in the process, as shown in the reaction scheme below, It has been discovered that a furo[2,3-b]indolizine derivative, which has not been described in any literature, can be easily obtained. The present invention was completed based on this new knowledge. The furo[2,3-b]indolizine derivative of the present invention is represented by the following general formula (1). (In the formula, R means a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl group having a halogen atom as a substituent, and Y means a hydrogen atom, a halogen atom, a lower alkyl group, or a phenyl group.) The above general formula In (), the lower alkyl group defined by R and Y is an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl,
Examples include hexyl group. Examples of the halogen atom which is a substituent of the phenyl group defined by R and the halogen atom defined by Y include chlorine, bromine, fluorine, and iodine atoms. The compound of the present invention represented by the above general formula () has antiallergic action, platelet aggregation inhibiting action, antiinflammatory action, etc., and is useful as a medicine. The method for producing the compound of the present invention will be explained below.
The compound of the present invention can be produced, for example, according to the method shown in the following reaction scheme. (In the formula, R and Y are the same as above, R ₁ is a lower alkyl group, and X is a halogen atom.) That is, the production of the compound of the present invention involves converting the starting material pyridinium compound ( ) to the intermediate. The process consists of a first step for obtaining a vinyl indolizine derivative () and a second step for obtaining a furo[2,3-b]indolizine derivative () from the vinyl indolizine derivative (). First step: After a basic compound is reacted with the pyridinium compound (), ethoxymethylenemalondinitrile and a halogen compound () are reacted to obtain a vinyl handridine derivative (). Examples of the basic compound include metal alkoxides such as sodium methoxide, sodium ethoxide, and sodium propoxide, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The amount of the basic compound to be used can be selected as appropriate, but generally 1
It is advantageous to use about -2 equivalents. The reaction between the pyridinium compound () and the basic compound is usually carried out in a solvent. The solvent is not particularly limited as long as it is an inert solvent, but examples include lower alcohols such as methanol, ethanol, and propanol, ethers such as dioxane and tetrahydrofuran, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. They are appropriately selected and used depending on the type of pyridinium compound () and basic compound used.
Although the reaction temperature is not particularly limited, the reaction usually proceeds advantageously at around 50-70°C. After allowing the basic compound to react for several minutes, ethoxymethylenemalondinitrile and the halogen compound () are sequentially added. The amounts of ethoxymethylenemalondinitrile and the halogen compound () to be used can be selected as appropriate, but it is generally advantageous to use about 1 to 2 equivalents of each of the pyridinium compound (). When reacted at 50-70℃ for 0.5-5 hours, vinylindolizine derivative ()
is produced, which can be easily isolated by conventional separation means. 2nd step The vinylindolizine derivative () is reacted with a basic compound to produce the compound of the present invention [2,3-
b] Obtain an indolizine derivative (). As the basic compound, alkali hydroxides such as sodium hydroxide and potassium hydroxide dissolved in water are generally preferably used. The amount of the basic compound used can be selected as appropriate, but generally vinyl indolizine derivatives ()
It is advantageous to use about 5 to 50 times the equivalent amount. The reaction between the vinyl indolizine derivative () and the basic compound is usually carried out in a solvent. The solvent is not particularly limited as long as it is an inert solvent, and for example, the solvents shown in the first step can be used. The reaction temperature is not particularly limited, but is usually 50-70℃.
It is advantageous to carry out the process at temperatures around 0.degree. The above reaction produces compound (), which can be easily isolated by conventional separation means. Furthermore, the compound of the present invention () can be produced in exactly the same manner by carrying out the first step and the second step continuously without isolating the intermediate vinyl indolizine derivative () from the reaction system. is possible. The physicochemical constants of typical compounds of the furo[2,3-b]indolizine derivatives represented by the general formula () of the present invention are shown in Tables 1 and 2, followed by Examples. Note that the numbers in parentheses in the yield section in Table 1 indicate the yield according to the production method in which the intermediate () is not isolated.

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[Table] Example 1 After dissolving 0.822 g (3 mmol) of 1-ethoxycarbonyl-2-ethylpyridinium bromide in 50 ml of ethanol, 6 ml of sodium ethoxide-ethanol solution (6 mmol of sodium ethoxide) was dissolved at 50-70°C. ). After 2-3 minutes, 0.366g of ethoxymethylenemalondinitrile
(3 mmol) and stir. After 3 minutes, add 0.700 g (3.5 mmol) of phenacyl bromide and add 50-
Stir at 70°C for 3 hours. The reaction mixture was poured into water, the precipitated crystals were collected by filtration, dried, and recrystallized from chloroform to obtain 0.624 g of 3-(2,2-dicyanovinyl)-1-methyl-2-(phenaciloxy)indolizine. . (Yield 61%) mp225-227℃ Elemental analysis (as C ₂₁ H ₁₅ N ₃ O ₂ ) C H N Calculated value (%) 73.89 4.43 12.31 Actual value (%) 73.81 4.37 12.44 Example 2-4 Example 1 The following vinylindolizine derivatives were obtained in the same manner as above. 3-(2,2-dicyanovinyl)-2-(phenaciloxy)indolizine mp211-213℃ Elemental analysis (as C ₂₀ H ₁₃ N ₃ O ₂ ) C H N Calculated value (%) 73.38 4.00 12.84 Actual value (%) ) 73.53 4.10 12.60 3-(2,2-dicyanovinyl)-1-ethyl-2-(phenaciloxy)indolizine mp203-207℃ Elemental analysis (as C ₂₂ H ₁₇ N ₃ O ₂ ) C H N Calculated value (%) ) 74.35 4.82 11.82 Actual value (%) 74.28 4.93 11.78 3-(2,2-dicyanovinyl)-2-(phenacyloxy)-1-phenylindolizine mp198-201℃ Elemental analysis (C ₂₆ H ₁₇ N ₃ O ₂ ) C H N Calculated value (%) 77.41 4.25 10.42 Actual value (%) 77.37 4.19 10.51 Example 5 3-(2,2-dicyanovinyl)-1-methyl-2-(phenacyloxy)indolizine 0.341
g (1 mmol) was added to 50 ml of ethanol, stirred for 5 minutes, and poured into water. Neutralized with concentrated hydrochloric acid, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was separated using an alumina column, and then recrystallized from ethanol to obtain 2-
0.261 g of benzoyl-9-methylfuro[2,3-b]indolizine (compound 2) was obtained. (yield 95
%) Example 6 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide 1.008 g (3 mmol)
After heating and dissolving in 50 ml of ethanol, 6 ml of sodium ethoxide-ethanol solution (containing 6 mmol of sodium ethoxide) was added and stirred.
After 3 minutes, ethoxymethylenemalondinitrile
Add 0.366 g (3 mmol) and stir. 3 minutes later,
Furthermore, p-chlorphenacyl bromide 0.82g (3.5
mmol) and stirred at 50-70°C for 3 hours.
Next, 5 ml of potassium hydroxide solution (potassium hydroxide 2
g) and stir. After 5 minutes, the reaction mixture is poured into water and neutralized with concentrated hydrochloric acid. After extraction with chloroform and drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was separated using an alumina column, and then recrystallized from chloroform-ethanol to obtain 2-
(p-chlorobenzoyl)-9-phenylfuro[2,3-b]indolizine (compound 9) 0.346g
I got it. (yield 31%).

Claims (1)

[Claims] 1. General formula (In the formula, R means a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl group having a halogen atom as a substituent, and Y means a hydrogen atom, a halogen atom, a lower alkyl group, or a phenyl group.) Furo[2,3-b]indolizine derivative.