JPS6348270B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 2(5H)-furanone derivatives. The 2(5H)-furanone derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R ¹ is a lower alkyl group, a naphthyl group,
A mono- or diphenyl lower alkyl group (the phenyl ring may be substituted with a lower alkyl group), a phenyl group (a halogen atom on the ring, a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group) may have one or two substituents), or the formula

In the group represented by the formula (m=an integer of 1 to 3), R ² represents a hydrogen atom or a lower alkoxycarbonyl group. However, this excludes the case where R ² is a hydrogen atom and R ¹ is a benzyl group.] In the above general formula (1), the groups represented by R ¹ and R ² include the following. That is, lower alkyl groups include methyl,
Examples of naphthyl groups such as ethyl, propyl, butyl, and tert-butyl groups include mono- or di-phenyl lower alkyl groups in which the phenyl ring may be substituted with a lower alkyl group such as α-naphthyl and β-naphthyl groups. is 2-methylbenzyl, 4
-Methylbenzyl, α-phenethyl, β-phenethyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl,
2,2-diphenylethyl, 1-(2-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 1-(4-methylphenyl)-2-phenylethyl, 2-(2-methylphenyl)-2-phenylethyl, 1- (4-methylphenyl)-2
- phenylpropyl group, etc. Examples of the phenyl group which may have one or two substituents selected from a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkoxy group include phenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chlorphenyl,
4-fluorophenyl, 2-fluorophenyl,
2-bromphenyl, 3-fluorophenyl, 4
-methoxyphenyl, 2-methoxyphenyl, 3
-methoxyphenyl, 3-ethoxyphenyl, 4
-butoxyphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2-ethylphenyl, 4-butylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dimethoxyphenyl,
2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,
3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5
-dimethylphenyl, 4-chloro-5-methylphenyl, 2-bromo-4-methylphenyl, 2-
Chlor-5-methylphenyl, 4-chloro-2-
Examples include methylphenyl, -4-chloro-3-methylphenyl, and 3-methoxy-2-methylphenyl groups. formula

Groups represented by [Formula] include prenyl, geranyl, neryl, and farnesyl groups; lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,
Examples include propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. Representative compounds of the present invention are listed below. 5-phenoxymethyl-2(5H)-furanone 5-(4-chlorophenoxy)methyl-2
(5H)-furanone 5-(4-methylphenoxy)methyl-2
(5H)-furanone 5-(4-methoxyphenoxy)methyl-2
(5H)-furanone 5-(3-trifluoromethylphenoxy)methyl-2(5H)-furanone 5-(2,6-dimethylphenoxy)methyl-
2(5H)-furanone 5-(3-chloro-4-methylphenoxy)methyl-2(5H)-furanone 5-(β-naphthoxy)methyl-2(5H)-furanone 5-(α-naphthoxy)methyl-2 (5H)-furanone 5-(3-methoxy-2-methylphenoxy)
Methyl-2(5H)-furanone 5-(2-bromophenoxy)methyl-2
(5H)-furanone 5-(3-fluorophenoxy)methyl-2
(5H)-furanone 5-(2,3-dimethylphenoxy)methyl-
2(5H)-furanone 5-(4-chloro-5-methylphenoxy)methyl-2(5H)-furanone 5-(α-phenethyloxy)methyl-2
(5H)-furanone 5-(β-phenethyloxy)methyl-2
(5H)-furanone 5-(4-phenylbutoxy)methyl-2
(5H)-furanone 5-diphenylmethoxymethyl-2(5H)-furanone 5-(2,2-diphenylethoxy)methyl-
2(5H)-furanone 5-prenyloxymethyl-2(5H)-furanone 5-geranyloxymethyl-2(5H)-furanone 5-phalnesyloxymethyl-2(5H)-furanone 5-methoxymethyl-2 (5H)-furanone 5-n-butoxymethyl-2(5H)-furanone 5-isopropoxymethyl-2(5H)-furanone 3-ethoxycarbonyl-5-phenoxymethyl-2(5H)-furanone 3-ethoxycarbonyl- 5-(4-chlorophenoxy)methyl-2(5H)-furanone 3-ethoxycarbonyl-5-(2,2-diphenylethoxy)methyl-2(5H)-furanone 3-ethoxycarbonyl-5-diphenylmethoxymethyl -2(5H)-furanone 3-ethoxycarbonyl-5-(β-naphthoxy)methyl-2(5H)-furanone 3-ethoxycarbonyl-5-(α-naphthoxy)methyl-2(5H)-furanone 3-ethoxy Carbonyl-5-geranyloxymethyl-2(5H)-furanone 3-methoxycarbonyl-5-n-butoxymethyl-2(5H)-furanone The compounds of the present invention include optical isomers, geometric isomers, etc. Although stereoisomers may also exist, the present invention encompasses these stereoisomers. The compound of the present invention can be produced by various methods, but a preferred example thereof is the following reaction formula-1.
There is a method shown in [In the formula, R ¹ and R ² are the same as above] The oxidation reaction from compound (2) to sulfinyl compound (3) in the above reaction formula-1 is carried out using commonly used organic solvents or water-containing organic solvents, such as methanol, ethanol, Using acetone, chloroform, dioxane, dichloromethane, etc., if desired, add pyridine,
This is carried out by using a suitable oxidizing agent in the presence of a dilute aqueous alkali solution. Examples of oxidizing agents used include periodate (NaIO ₄ ,
KIO ₄ , etc.), hydrogen peroxide, and organic peracids (peracetic acid, perbenzoic acid, perm-chlorobenzoic acid, etc.). This oxidation reaction is normally carried out at a temperature of -80 to 30°C. Next, the desulfenation reaction from compound (3) to target compound (1) is carried out using a solvent that does not adversely affect the reaction.
For example, in a solvent such as chloroform, dichloromethane, carbon tetrachloride, n-hexane, carbon disulfide, diethyl ether, benzene, toluene, xylene, pyridine, preferably benzene, toluene,
The reaction is carried out by heating the compound (3) in an aromatic hydrocarbon such as xylene or pyridine, and the reaction temperature is usually the reflux temperature of the above solvent.
The reaction is usually completed in 10 minutes to 10 hours, but it takes about 30 minutes to
6 hours is sufficient. In addition, in the above heating reaction, when compound (3) is an oily substance, it is heated at 100 to 130°C without solvent for 30 minutes.
The target compound (1) can be obtained by heating for minutes to 6 hours. In addition, in the heating reaction, if an inorganic basic substance such as sodium hydrogen carbonate, calcium carbonate, potassium carbonate, etc. is added to the above solvent in an equimolar to excess molar amount, preferably an equimolar to twice molar amount relative to compound (3). , side reactions of the desulfenic acid reaction can be suppressed, and the reaction can proceed advantageously. In Reaction Formula-1, when R ² is a lower alkoxycarbonyl group, the desired compound (1) can also be directly obtained by a reaction system in which compound (2) is oxidized. In order to lead to the target compound (1) from this compound (2), performic acid, peracetic acid, perbenzoic acid, perm-
An organic peracid such as chlorobenzoic acid, preferably perm
- Using chlorobenzoic acid as a solvent, e.g.
Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, benzene, toluene,
The reaction is carried out using aromatic hydrocarbons such as xylene. Preferred solvents are halogen hydrocarbons. The reaction temperature is generally -80° to 40°C, preferably -40°C to around room temperature. Reaction time is usually 1-20
time, preferably 2 to 10 hours. In addition, the amount of organic peracid used as an oxidizing agent is
It is 0.7 to 1.5 times the molar amount, preferably 0.9 to 1.1 times the molar amount. The compound of the present invention produced by the above method can be easily isolated and purified from the reaction solution by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. Of the starting material compound (2) in Reaction Formula-1 above, R ² is a hydrogen atom (2a) is produced by the method shown in Reaction Formula-2 below. [In the formula, R ¹ is the same as above] That is, the thioacetic acid derivative (4) and the compound (5) are reacted in the presence of a base at -78°C to room temperature, and the general formula (6) is obtained.
This compound is then subjected to dehydration and ring closure to obtain compound (2a). The reaction leading to the compound of general formula (6) above is usually carried out in a solvent such as tetrahydrofuran, ether, 1,2-dimethoxyethane, N,N-dimethylformamide, hexamethylphosphoric triamide, and the base used. Examples include n-butyllithium lithium diisopropylamine, lithium naphthalene, and the like. The base is compound (4)
It is preferable to use 2 to 2.5 equivalents based on the theoretical amount of compound (5). The reaction involves removing the carboxylic acid hydrogen and active methylene hydrogen of compound (4) at 0°C with a base, and alkylating the active methylene at -78°C to room temperature. Compound (6) obtained in this manner is generally led to compound (2a) by subjecting it to a dehydration ring-closing reaction in the presence of an acid catalyst, without purification. Further, among the compounds (2), the compound (2b) in which R ² is a lower alkoxycarbonyl group is produced by the method shown in Reaction Formula-3 below. [In the formula, R ¹ is the same as above. R ³ represents a lower alkyl group] That is, compound (5) and malonic acid di-lower alkyl ester (7) are heated and stirred in the presence of a base from room temperature to the boiling point of the solvent for 1 to several hours to form compound (8). ),
It is then easily produced by introducing a phenylthio group into this. The above reaction is usually carried out using a suitable solvent such as benzene, dioxane, tetrahydrofuran, methanol, ethanol, tert-butanol, 1,2-
This is carried out using dimethoxyethane, N,N-dimethylformamide, or the like. Bases include sodium hydride, sodium amide, potassium tert.
-butoxide, sodium ethoxide, sodium methoxide, etc. are preferably used. The amounts of the base and malonic acid di-lower alkyl ester used are 1 to 1 of the theoretical amount for compound (5).
1.3 equivalents is sufficient. The reaction of introducing a phenylthio group into compound (8) to lead to compound (2b) is carried out by reacting a phenylthio compound with compound (8) in the presence of an inorganic base in an anhydrous aprotic solvent. Examples of the aprotic solvent used in the above reaction include n-hexane, dioxane, ether, chloroform, carbon disulfide, benzene, toluene, xylene, tetrahydrofuran, N,N-
Examples include dimethylformamide. Examples of the inorganic base include sodium hydride, lithium hydride, sodium amide, lithium amide, etc., and the dosage thereof is usually per mol of compound (8).
The range is from equimolar to 2 times the molar amount, preferably from equimolar to 1.2 times the molar amount. Examples of phenylthio compounds include benzenesulfenyl chloride (C ₆ H ₅ SCl), S-phenylbenzenethiosulfonate (C ₆ H ₅ -S-SO ₂ -C ₆ H ₅ ), and S-phenyl-
p-Toluenethiosulfonate (C ₆ H ₅ -S-
SO ₂ --C ₆ H ₄ --p-CH ₃ ), etc., and the dosage is usually from equimole to 2 moles per mole of compound (8).
The amount is twice the molar amount, preferably equimolar to 1.2 times the molar amount. In general, the temperature range of the reaction may be appropriately selected from 0° C. to the boiling point of the solvent, and the reaction time is usually 0.5 hours to 20 hours, preferably 1 hour to 10 hours. The compound represented by the general formula (1) of the present invention has a platelet aggregation inhibiting effect and is useful as an antithrombotic agent. In addition, the compounds represented by general formulas (2a), (2b), (3) and (8) used as intermediates for the production of the compounds of the present invention are not only useful as intermediates, but also have anti-allergic properties. action, anti-ulcer action,
It has anti-inflammatory, platelet aggregation-inhibiting, and central nervous system depressing effects, and is useful as a pharmaceutical agent, such as an anti-allergic agent, an anti-ulcer agent, an anti-inflammatory agent, an anti-thrombotic agent, a therapeutic agent for schizophrenia, and a sedative. Next, reference examples and examples will be given to further specifically illustrate the compounds of the present invention, but the present invention is not limited thereto. Reference Example 1 Production of α-phenylthio-δ-(β-naphthyloxy)-γ-valerolactone 11.2 g of diisopropylamine was dissolved in 60 ml of tetrahydrofuran, the solution was cooled to -20°C, and n-butyllithium (15 % n-hexane solution) was slowly added dropwise while stirring. After stirring the mixture at -20°C for 20 minutes, 9.3 g of phenylthioacetic acid
A solution of -10 dissolved in 20 ml of tetrahydrofuran
Add at ˜0° C. and continue stirring at the same temperature for an additional hour. The reaction mixture was cooled again to -30°C and 1-
10 g of (β-naphthyloxy)-2,3-epoxypropane are added dropwise over 30 minutes. Thereafter, the reaction mixture is gradually warmed to room temperature and stirred for an additional 16 hours at room temperature. The reaction mixture was acidified with 10% hydrochloric acid, extracted with ether, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the ether was distilled off under reduced pressure to obtain 19 g of an oily substance. This stuff is benzene
Dissolve in 150 ml, add 2 drops of concentrated sulfuric acid, and reflux for 6 hours in a reflux vessel equipped with a dehydrator. The reaction mixture was diluted with ether, and the organic layer was washed with a 10% aqueous sodium bicarbonate solution, then washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 17.5 g of crystalline crude product. When this product is recrystallized from benzene-isopropyl ether, white crystals of α-phenylthio-δ-(β-naphthyloxy) are formed.
- Obtain 14.5 g of γ-valerolactone. Melting point 108~
109°C Compounds shown in the table below are obtained in the same manner as in Reference Example 1 above.

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[Table] Reference example 2 Production of α-phenylsulfinyl-δ-(diphenylmethoxy-γ-valerolactone α-phenylthio-δ-diphenylmethoxy-
Add m-chloroperbenzoic acid (70%) to a solution of 3.2 g of γ-valerolactone dissolved in 70 ml of methylene chloride.
Gradually add 2.2g under ice cooling. Then, cool on ice for 40 minutes.
After stirring for several minutes, the reaction mixture is transferred to about 150 ml of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure at below 40°C to obtain 3.3 g of a crude product. When this product is purified by silica gel chromatography, an oily substance α-phenylsulfinyl-δ-(diphenylmethoxy-γ
- Obtain 3.1 g of valerolactone. IR (cm ^-1 ); 1060 (SO) NMR (CDCl ₃ ,
TMS; ppm) 1.90-3.10 (2H), 3.80-3.88 (2H),
4.12-4.38 (m, 1H), 4.40-4.90 (m, 1H), 5.26
~5.43 (m, 1H), 7.00 ~ 7.60 (15H) Compounds shown in the table below are obtained in the same manner as in Reference Example 2 above.

【table】

[Table] Reference example 3 Production of α-ethoxycarbonyl-δ-(α-naphthoxy)-γ-valerolactone Sodium ethoxide solution (sodium 2.8
A solution of 17.6 g of diethyl malonate (prepared from 20 ml of absolute ethanol) and 50 ml of absolute ethanol
Add at °C. To this, 1-(α-naphthoxy)-
2,3-epoxypropane 20g absolute ethanol
Add 20 ml of the solution dropwise at 35°C with stirring. Then stir
Continue for 16 hours. The reaction mixture was cooled to 15°C, acidified with acetic acid, excess ethanol was distilled off under reduced pressure, water was added, extracted with chloroform, the organic layer was washed with an aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. Afterwards, the solvent is distilled off. The obtained crystals were collected and washed with isopropyl ether.
When the crude product is recrystallized from ethanol-n-hexane, white crystals of α-ethoxycarbonyl-δ
-(α-naphthoxy)-γ-valerolactone 21g
get. Melting point: 75-78°C Compounds shown in the table below are obtained in the same manner as in Reference Example 3 above.

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[Table] Reference example 4 α-ethoxycarbonyl-α-phenylthio-
Production of δ(4-chlorophenoxy)-γ-valerolactone 9 g of α-ethoxycarbonyl-δ-(4-chlorophenoxy)-γ-valerolactone in benzene
Add 20ml solution of sodium hydride to 60ml of benzene.
1.6 g was added dropwise to the stirred suspension over 30 minutes at room temperature. Then benzenesulfenyl chloride
A solution of 4.5 g of benzene in 5 ml was added dropwise to the reaction mixture;
Stir the reaction mixture at room temperature for 3 hours. The reaction mixture was extracted by a conventional method, dried, and the solvent was distilled off, followed by silica gel chromatography (ether-n-hexane).
After purification, 6.5 g of oily α-ethoxycarbonyl-α-phenylthio-δ-(4-chlorophenoxy)-γ-valerolactone was obtained. NMR (CHCl ₃ , TMS; ppm) 1.26 (t, 3H),
2.32-3.14 (m, 2H), 3.84-4.10 (m, 2H), 4.24
~4.24 (q, 2H), 4.60 (m, 1H) 6.63 ~ 7.69 (9H) Example 1 α-Phenylsulfinyl-δ-phenoxy-
Dissolve 6.4 g of γ-valerolactone in 100 ml of toluene and reflux for 1 hour. Thereafter, toluene was distilled off under reduced pressure, and silica gel chromatography (ether-
When the oily reaction mixture is purified with n-hexane), white crystals of 5-phenoxymethyl-2 (5H) are obtained.
- Obtain 3.3 g of furanone. Melting point 82-83℃ (n-hexane: recrystallized with benzene) Example 2 α-ethoxycarbonyl-α-phenylthio-
Dissolve 6.5 g of δ-(4-chlorophenoxy)-γ-valerolactone in 150 ml of methylene chloride, gradually add 3.9 g of m-chloroperbenzoic acid (70%) under ice-cooling, and further cool with ice for 2 hours. Continue stirring. Thereafter, the reaction mixture was transferred to a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, and the organic layer was washed with water.
After drying over anhydrous sodium sulfate at room temperature for 2 hours (during which time the desulfenic acid reaction is completed), the solvent is distilled off, and the resulting crude product is recrystallized from ether-chloroform. 3.2 g of white crystalline 3-ethoxycarbonyl-5-(4-chlorophenoxy)methyl-2(5H)-furanone is obtained. Melting point: 86-89°C Compounds shown in the table below are obtained in the same manner as in Examples 1 and 2 above. In the table, compounds 3 to 10 and 13 to 17 were obtained in the same manner as in Example 1, and compounds 11 and 12 were obtained in the same manner as in Example 2.

【table】

【table】

[Claims]

1 General formula: [wherein, R is a halogen-substituted phenyl group; R ¹ and R ² are each independently a C ₁ -C ₄ alkyl group or a 2-methoxyethyl group; Y is -(CH ₂ ) n --, --CH ₂ CH (CH ₃ ) -- or --CH ₂ C (CH ₃ ) ₂ --; X is unsubstituted or one or more C _1
-C4 alkyl group, phenyl group, benzyl group,
CN, -N( ^R3 ) ₂ , ( _CH2 ) _mCO2H , ( _CH2 )