JPS5959689A - Furo(2,3-b)indolizine derivative and its preparation - Google Patents

Abstract

NEW MATERIALA compound shown by the formul I [R is H, lower alkyl, or (halogen-substituted) phenyl; Y is H, halogen, lower alkyl, or phenyl). EXAMPLE:3-(2,2-Dicyanovinyl)-1-methyl-2-(phenacyloxy)indolizine. USE:An antiallergic, inhibitor of blood platelet aggregation, and anti-inflammatory agent. PROCESS:A pyridinium compound shown by the formula II(R1 is lower alkyl; X is halogen) is reacted with preferably 1-twice equivalent amount of a basic compound (e.g., sodium methoxide, etc.), and reacted with ethoxymethlene malodinitrile and a halogen compound shown by the formula III (preferably 1- twice equivalent amount, respectively), to give a vinylindolizine derivative shown by the formula IV. This compound is treated with a basic compound (preferably NaOH, etc.), to give a compound shown by the formula I .

Description

[Detailed description of the invention]

The present invention relates to a novel furo[2,3-b]intolidine derivative and a method for producing the same. The Ministry of the Invention and others 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 from a pyridinium compound. The present invention was completed based on this new knowledge. The furo[2,3-bl indolizine derivative of the present invention is represented by the following general formula (1). (In the formula, R is 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. ) In the above general formula (1), the lower alkyl group defined by R and Y includes an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl,
Examples include hexyl group. Examples of the halogen atom that is a substituent of the phenyl group defined by R and the halogen atom defined by Y include chlorine, bromine, and fluorine iodine atoms. The compound of the present invention represented by the above general formula (1) 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.

[Reaction T equation]

(In the formula, R and Y are the same as above, 1-1 means lower alkyl, and X means a halogen atom.) That is, the production of the compound of the present invention is carried out using the pyridinium compound (I
I) to intermediate vinyl indolizine derivative (rV)
The first step is to obtain a 1′ vinylintolidine derivative (■
) to obtain the furo[2,3-b) indolizine derivative (1). First step: After treating the pyridinium compound (n) with a salt-41 compound, the engineered tokydinothylene malondinitrile and the halogen compound (Tll) are reacted with anti-LE to form the vinyl intridine derivative (rV). Examples of basic compounds include metal alkoxides such as sodium methoxide, sodium oxide, sodium proboxoxide, alkali hydroxides such as sodium hydroxide and potassium hydroxide,
Examples include alkali carbonates such as thorium carbonate and potassium carbonate. The basic compound used m can be selected as appropriate, but
- Generally, it is advantageous to use about 1-2 m per can of pyridinium compound (11). The above Viriginilla J,
The reaction between compound (II) and a 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 propatool; The pyridinium compound (II) and the basic compound are appropriately selected from polar polar media and the like.
The reaction 2M4 degree is not limited to '15, but is usually 50-7
When the temperature approaches 0°0\1, the reaction proceeds favorably. After reacting the salt-occupying compound for several minutes, the mixture of l-ximethylene, dinitrile and halogen compound (III) is formed.
Add sequentially. The amounts of ethoxymethylene, cinnitrile, and halogen compound (III) to be used can be selected as appropriate, but it is generally advantageous to use about 1 to 2 cans of each relative to pyridinium compound (II). After reacting for 0.5-5 hours at 50-70°C, a vinyl intolidine derivative (1) is formed, which can be easily separated by conventional separation means. Second Step A basic compound is allowed to act on the vinyl indolizine derivative (TV) to obtain the furo[2,3-b]indolizine derivative (+) of the compound of the present invention. -jlT as a basic compound
78f on ice at h! Alkali hydroxides such as thorium hydroxide and potassium hydroxide are suitably used. The amount of the basic compound used can be selected as appropriate, but
In general, vinyl intridine derivatives (IV) are combined with 5
- It is advantageous to use about 50 times the amount in the can. The reaction between the hinyl indolizine derivative (N) and the basic compound is carried out under lightning 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 culm can be used. The degree of reaction 'IXA is not particularly limited, but it is advantageous to carry out the reaction at a temperature of 50-7 (1°C) near MaJ.' The second reaction produces a compound (+), which can be used as a suitable separation means. The compound (1) of the present invention can be easily isolated by directly carrying out the first culm and the second step without removing the intermediate vinylyne-1-lysine derivative (1v) from the reaction system. It is also possible to produce the product in exactly the same manner by
The physicochemical constants of representative compounds of b'l intolidine derivatives are shown in Tables 1 and 2, and then in Examples, the number stripes in parentheses in the yield section in Table 1 indicate the intermediate (IV
) is shown in Table 1. Example 1 in the blank space below ■-Ethoxyluponyl-2-ethylpyridinium bromide 0.822g (3 mmol) was added to 50ml of ethanol.
1/8, then at 50-70°C] - Add Riuno, ethoxide-ethanol/8 solution 5 rn 1 (containing 6 mmol of sodium ethoxide). After 2-3 minutes, 0.366 g of ethoxymethylenemalondinitrile (
3 mmol) and stir. After 3 minutes, add 0.100 g (3.5 mmol) of phenacylbromide to 50-70
Stir at ℃ for 3 hours. The reaction mixture was poured into water, the precipitated crystals were collected by filtration, dried, and recrystallized from chloroform.
3-(2,2-dicyanovinyl)-1-methyl-2
-(Phenacyloxy)indolizine 0.624 g was obtained. (Yield 61%) m, p 225 227°C Elemental analysis (as C2+H15N302) CHN Calculated value (%”) 73.89 4.43 12.3] Actual value (%) 73.8] 4.37 12.44 Example
2-4 The following vinyl indolizine derivatives were obtained in the same manner as in Example 1. 3- (2',2-dicyanovinyl)-2-(phenacyloxy)indolizine m, p 211-213°C Elemental analysis (as C2oH+3N302) CHN Calculated value (%) 73.38 4.00 12.84 Actual value (%) 73.53 4.10 12.603-(2,2
-dicyanovinyl)-1-ethyl-2-(phenacyloxy)indolizine m, p 203-207°C Elemental analysis (as C22HI yN302) CHN Calculated value (%) 74.35 4.82 '11.82 Actual value (%) 74.28 4.93 11.78:3-
(2,2-dicyanovinyl)-2-(phenacyloxy)-1-phenylindolizine m, p 198 20
1°C Elemental analysis (as C26H17N302) CHN B1 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 0.341g (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 give 2-benzoyl-9-methylfuro[2,3
-b] 0.261 g of indolizine (compound 2) was obtained. (Yield 95%) Example 6 1.008 g (3 mmol) of 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide was heated and dissolved in ethanol 5'Om+, and then 6 ml (6 ml) of sodium ethoxide-ethanol solution was added. (containing mmol of sodium ethoxide) and stir. After 3 minutes, 0.366 g (3 mmol) of ethoxymethylenemalondinitrile is added and stirred. After 3 minutes, add 0.0% p-chlorphenacyl bromide. Add 112 g (3.5 mmol) of potassium hydroxide and stir for 3 hours at 50-70"C. Then add 5 ml of potassium hydroxide solution (containing 2 g of potassium hydroxide) and stir. After 5 minutes, pour the reaction mixture into water. The mixture was poured into water and neutralized with concentrated hydrochloric acid. Extracted with chloroform, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was separated using an alumina column, and then recrystallized from chloroporum-ethanol to obtain 2- 0.346 g of (p-chlorohendiyl)-9-phenylfuro[23-b]intolidine (compound 9) was obtained. (Yield 3+910
)

Claims (1)

[Claims] (1) General formula (wherein R is a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl group having a halogen atom as a substituent, Y
means a hydrogen atom, a halogen atom, a lower fulkyl group, or a phenyl group. ) Furo[2,1-b]intolidine derivative (2) general formula (wherein, R is a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl group having a halogen atom as a substituent group, Y
is a hydrogen atom, a halogen atom, a lower alkyl group, or)1
．． means nyl group. ) is characterized by causing a basic compound to act on the vinyl indolizine derivative represented by
Furo[2] represented by the general formula (wherein R and Y are the same as above)
, 3-b] Method for producing indolizine derivative (3) -f
l> Formula (wherein R represents a hydrogen atom, a lower alkyl group, a phenyl group, or a substituent having a halogen atom) -Znyl group,
R represents a lower alkyl group, and X represents a halogen atom. ), a basic compound is applied to the pyridinium compound represented by ) is reacted to form a vinylindolizine derivative represented by the general formula (wherein R and Y are the same as above), and then treated with a basic compound. In the general formula, which is characterized by,! '2 and Y are between the above. ) A method for producing a furo[2,3-11]indolizine derivative represented by