JPH0217549B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 3,3-disubstituted indolizine-
Relating to 2-one compounds. The present inventors have long conducted various studies on a series of indolizin-2-one derivatives obtained using a specific pyridinium compound as a starting material. The fact that 2,3-dihydroindolizin-2-ones, which are obtained by reacting a basic compound with a pyridinium compound, easily reacts with a specific olefin compound, and the above-mentioned reaction results in the discovery of an unpublished literature. It has been discovered that 3,3-disubstituted indolizin-2-one compounds can be obtained. The present invention was completed based on this new knowledge. The 3,3-disubstituted indolizin-2-one compound of the present invention is represented by the following general formula (). (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl group, or a halogen-substituted phenyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, and R ⁴ is a cyano group or a carbamoyl group. As represented by the above general formula (), the compounds of the present invention include stereoisomers based on asymmetric carbon atoms when R ³ is other than a hydrogen atom. Examples of the lower alkyl group defined by R, R ¹ and R ³ in the above general formula () include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, and hexyl groups. Examples of the halogen atom include chlorine, bromine, and iodine atoms. The compound of the present invention represented by the above general formula () is:
It has antiallergic effects, platelet aggregation inhibitory effects, antibacterial effects, etc., and is useful as an antiallergic agent, antithrombotic agent, antibacterial agent, etc. in the pharmaceutical field. 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 equation> (In each formula, R, R ¹ , R ³ and R ⁴ are the same as above. ^{R 2}
represents a lower alkyl group, and X represents a halogen atom) In other words, the compound of the present invention can be obtained by reacting a pyridinium compound represented by the above general formula () with a basic compound and an olefin compound represented by the general formula (). Manufactured by. The pyridinium compound () used as a raw material in the above is a known compound, for example, by the method described in Journal of Organic Chemistry (J.Org.Chem.) 36, 2451 (1971) or a method analogous thereto. Can be easily synthesized. Examples of basic compounds include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Metals, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxy In addition to inorganic basic compounds such as metal alkoxides such as carbon dioxide, potassium butoxide, etc., organic basic compounds such as pyridine, picoline, triethylamine, and N-methylpiperidine can be mentioned. The amount of the basic compound to be used can be selected as appropriate, but it is generally advantageous to use about 1 to 2 equivalents relative to the pyridinium compound (). 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 ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, and chloroform. , methylene chloride, halogenated hydrocarbons such as carbon tetrachloride, dimethyl sulfoxide, dimethyl formamide, etc., 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 room temperature to around 50°C. The above reaction produces a dihydroindolizin-2-one compound () represented by the general formula (). This can be isolated from the reaction system by a conventional method, but in the present invention, the dihydroindolizin-2-one compound () is not isolated, but the dihydroindolizin-2-one compound () is subsequently added to the reaction system as shown by the general formula (). An olefin compound () can be introduced and reacted. Of course, it is also possible to isolate the above compound () and react it with the olefin compound () separately, or it is also possible to simultaneously charge the pyridinium compound (), the basic compound, and the olefin compound () in a suitable container to achieve almost the same result. The desired reaction can proceed. In either case, it is advantageous that the amount of the olefin compound () to be used is usually about 2 to 5 moles relative to the pyridinium compound (). The reaction temperature between the above compound () and compound () is not particularly limited, but is generally room temperature to 100°C.
It is advantageous to do this in moderation. The 3,3-disubstituted indolizin-2-one compound () produced in this reaction can be easily isolated by conventional separation methods such as recrystallization, column chromatography, etc. 3,3 represented by the general formula () of the present invention below:
Representative examples of -disubstituted indolizin-2-one compounds will be given, and then examples of the production of these compounds will be given as examples.

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[Table] Example 1 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide 1.01g (3 mmol)
Add a potassium hydroxide aqueous solution (0.3 g of 85% potassium hydroxide and 0.5 ml of water) to an ethanol solution (40 ml), stir at room temperature for 10 minutes, and add ethyl methacrylate.
Add 1.03g (9 mmol). After stirring for 1 hour, the reaction solution was filtered to remove insoluble matter.
Concentrate the liquid. The residue was separated using an alumina column using ether and then chloroform as a solvent, and then recrystallized from chloroform-hexane to give 3,3-bis(2-ethoxycarbonylpropyl)-1-phenyl- with a melting point of 101-102°C. 2.3-dihydroindolizin-2-one (compound No. 19)
1.05g was obtained (yield 80%). Compounds No. 9 and 10 were prepared in the same manner as in Example 1.
and 15 were synthesized. Example 2 10 g of potassium carbonate was added to an ethanol solution of 0.86 g (3 mmol) of 1-(ethoxycarbonylmethyl)-2-propylpyridinium bromide, and after stirring at room temperature for 2 hours, 0.48 g of acrylonitrile was added.
(9 mmol) and stirred for an additional 3 hours.
The reaction solution is filtered to remove insoluble matter, and the liquid is concentrated. The residue was separated on an alumina column using chloroform as a solvent, and then recrystallized from chloroform-hexane to give 3,3-bis(2-
0.43 g of (cyanoethyl)1-ethyl-2,3-dihydroindolizin-2-one (compound No. 2) was obtained (yield 54%). Compound No. 6,
7, 8, 13, 16 (16a and 16b), 17 and 20 were synthesized. The synthesis of compound No. 16 will be described in further detail. 1-(ethoxycarbonylmethyl)-2-(p-
Chlorbenzyl) pyridinium bromide 1.11g
Potassium carbonate (3 mmol) in ethanol solution
After adding 10 g of the mixture and stirring at room temperature for 2 hours, 0.60 g (9 mmol) of methacrylonitrile was added and stirring was further continued for 3 hours. The reaction solution was filtered to remove insoluble matter, and the solution was concentrated. When the residue was separated on an alumina column using chloroform as a solvent, a fraction of compound 16a was eluted first, and then a fraction of compound 16b was eluted. These were recrystallized from chloroform-hexane to give 3,3-bis(2-cyanopropyl)-1
Compound 16a, a diastereomer of -(p-chlorophenyl)-2,3-dihydroindolizin-2-one, with a melting point of 226-227°C (yield 22%), and compound 16b0 with a melting point of 203-204°C. 48g (yield 42%)
I got it. NMR (CDCl ₃ ), δ (ppm): 16a1.33 (6H, d, J = 7.0Hz, CH ₃ × 2) 2.0−2.6 (6H, m, 1′, 1″, 2′, 2″−H ) 6.78 (1H, m, 6-H) 7.4-7.9 (7H, m, -H on phenyl ring, 5,
7,8-H) 16b1.28 (3H, d, J=7.0Hz, CH ₃ ) 1.33 (3H, d, J=7.0Hz, CH ₃ ) 1.9-3.3 (6H, m, 1′, 1″, 2′, 2″-H) 6.75 (1H, m, 6-H) 7.4-7.9 (7H, m, phenyl ring-H, 5,
7,8-H) IR (KBr.cm ^-1 : 16a2241(CN), 1605(C=O), 1510, 1482, 1291, 1143, 830, 759 16b2235(CN), 1603(C=O), 1508 , 1480, 1285, 1139, 828, 754 Comparing Compounds No. 16a and 16b, it can be seen that they have structural differences in steric configuration. In other words, their IRs are very similar, but
Regarding NMR, the underlined methyl group is 1 in 16a.
Two species appear in 16b; 16a is an optically inactive diastereomer with a symmetry element, and 16b is considered to be a mixture of optically active diastereomers. Example 3 Sodium ethoxide was added to an ethanol solution (70 ml) of 1.37 g (5 mmol) of 1-(ethoxycarbonylmethyl)-2-ethylpyridinium bromide.
Add ethanol solution (5 ml of ethanol solution containing 5 mmol of sodium ethoxide) and incubate for 10 minutes at room temperature.
After stirring, add 0.80 (15 mmol) of acrylonitrile and stir for an additional hour. After neutralizing this reaction solution using diluted hydrochloric acid, insoluble matter was removed by filtration, the liquid was concentrated, the residue was separated using an alumina column using chloroform as a solvent, and then recrystallized from chloroform-ether to obtain the melting point. 74-75
0.85 g of 3,3-bis(2-cyanoethyl)-1-methyl-2,3-dihydroindolizin-2-one (compound No. 1) was obtained (yield: 63%). By the same method as in Example 3, compound No. 3,
4, 5, 11, 12, 14 and 18 were synthesized.

Claims (1)

[Claims] 1. General formula (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl group, or a halogen-substituted phenyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, and R ⁴ is a cyano group or a carbamoyl group. A 3,3-disubstituted indolizin-2-one compound represented by: