JPH0443069B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl group, or an unsubstituted, lower alkyl-substituted, lower alkyloxy-substituted phenyloxy group-substituted, or coumarin-7-yloxy group-substituted alkenyl group, and R ¹ and R ² is a lower alkyl group, and R ¹
and R ² can be combined to form an alkylene group. )
The present invention relates to a dihydrofuran derivative represented by and a method for producing the same. Among the dihydrofuran derivatives of the present invention represented by the general formula (), for example, R ¹ and R ² are methyl groups, and R is (E)-3-(coumarin-7-yloxy)-1-methylpropenyl group. Geiparvarin, (Acta Pharm.19734), which has an anticancer effect when oxidized,
(1)1-9)] (see reference example below). Furthermore, the dihydrofuran derivative of the present invention can be used as a general precursor for producing not only gay parvalin but also compounds having a 3(2H)-furanone structure. Many of these compounds having a 3(2H)-furanone structure are known to exhibit anticancer effects, such as diatrophone and elemantride.
[J.Am.Chem.Soc., 103 , 1501 (1981)]. Furthermore, the dihydrofuran derivative represented by the general formula () can also be used as a synthetic precursor for anticancer substances and antibiotics having a tetrahydrofuran structure such as ascofuranone. Conventionally, the method for producing gay parvarin is 5-ethyl-2,2-dimethyl-3(2H)-
It was obtained by aldol condensation of dihydrofuranone and the corresponding aldehyde [J.Org.Chem.,
46, 577 (1981)]. However, this method has a low yield and 50% of the olefin isomer is produced as a by-product, so it cannot be said to be an effective method for synthesizing gay parvarin. As a result of studies to overcome the drawbacks of conventional methods, the present inventors have discovered a compound and method for producing gay parvarin in a short process, in high yield, and with high selectivity from readily available raw materials, and have completed the present invention. . The manufacturing method of the present invention can be expressed by the following formula. (In the formula, R is a hydrogen atom, a lower alkyl group, a phenyl group, or an unsubstituted, lower alkyl-substituted, lower alkyloxy-substituted phenyloxy group-substituted, or coumarin-7-yloxy group-substituted alkenyl group, and R ¹ and R ² is a lower alkyl group, and R ¹
and R ² can be combined to form an alkylene group. [First step] In this step, a 2-butyne-1,4-diol derivative represented by the above general formula () is reacted with acetic anhydride in the presence of a base to form a 2-butyne-1,4-diol derivative represented by the above general formula (). -1,4-diol monoacetate derivatives are produced. The 2-butyne-1,4-diol derivative represented by the above general formula () in this step is a compound that can be easily obtained by adding acetylene at both ends to an aldehyde (RCHO) and a ketone (R ¹ COR ² ), respectively. be. This step needs to be carried out in the presence of a base. Examples of the base include carbonates such as potassium carbonate, aromatic amines such as pyridine and quinoline, and tertiary amines such as triethylamine, ethyldiisopropylamine and diethylaniline. Although the reaction does not necessarily require a solvent, solvents that are not directly involved in the reaction, such as dichloromethane, hexane, benzene, diethyl ether, etc., can be used as a solvent. Although the reaction temperature can be selected from the range of -10°C to 100°C, the reaction at room temperature is preferred because it is easy to operate and the reaction proceeds efficiently. [Second step] In this step, the 2-butyne-1,4-diol monoacetate derivative represented by the general formula () obtained in the first step is cyclized in the presence of a silver () catalyst, A dihydrofuran derivative represented by the above general formula () is produced. This step must be carried out in the presence of a silver () catalyst. Silver () catalysts include silver perchlorate, silver borofluoride, silver nitrate, silver acetate,
Examples include silver cyanide, silver hexafluorophosphate, silver hexafluoroantimonate, silver oxide, silver acetylacetonate, silver phosphate, silver sulfate, silver trifluoromethanesulfonate, and silver tungstate. It is sufficient that the amount of silver () catalyst used is 15 mol % or less based on the substrate, and the reaction proceeds quickly. In carrying out this step, it is preferable to use a solvent, and for example, hydrocarbon solvents such as benzene and hexane, ether solvents such as diethyl ether and tetrahydrofuran, and dichloromethane can be used. The reaction proceeds at room temperature to 120°C, but 60 to 100°C is preferred for efficient reaction. Further, this step is desirably carried out while blocking visible light and ultraviolet rays in order to prevent decomposition of the catalyst. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 4-methyl-1-phenyl-2-pentyne-
1,4-Diol (0.21 g, 1.09 mmol) was dissolved in dichloromethane (0.25 ml) and stirred with acetic anhydride (0.5 ml) and pyridine (0.05 ml) at room temperature for 2 hours. Concentrate under reduced pressure and purify by column chromatography (using silica gel, eluting with a mixed solvent of hexane-ethyl acetate 10:1 to 2:1) to obtain 0.25 g of the starting material in which only the 1-position hydroxyl group was acetylated ( (99% yield) was obtained as a viscous colorless oil. IR (neat): 3400, 1740cm ^-1 . NMR (CCl) ₄ : δ1.51 (s, 6H), 2.03 (s, 3H),
2.96 (br s, 1H), 6.41 (s, 1H), 7.2−7.6
(m, 5H). This monoacetate (77 mg, 0.33 mmol) was dissolved in benzene (1 ml) and silver perchlorate (4 mg)
At the same time, silver paper blocks visible light and ultraviolet rays,
The mixture was stirred at 80°C for 10 hours. Dichloromethane (10
ml), washed with 10% aqueous ammonia (3 ml), and then washed with saturated saline. After drying and concentration, column chromatography (silica gel,
3-acetoxy-2,2-dimethyl-5-phenyl-1 was purified with hexane-ethyl acetate 10:1).
-oxa-3-cyclopentene (65 mg, yield 84
%) was obtained. bp: 122-124℃ (bath temperature) / 0.04 Torr. IR (neat): 1781, 1698, 1658 cm ^-1 . NMR (CCl) ₄ : δ1.36 (s, 3H), 1.38 (s, 3H),
2.17 (s, 3H), 5.70 (d, J=1.5Hz, 1H),
5.81 (d, J=1.5Hz, 1H), 7.26 (br s,
5H). Elemental analysis value Calculated value C, 72.39; H, 6.94%. Measured C, 72.48; H, 6.84%. Examples 2 to 7 Reactions were carried out under the same conditions as in Example 1 using various 2-butyne-1,4-diol derivatives and various silver catalysts. The results are shown in Table 1. The physical properties of the obtained dihydrofuran derivative are shown in Table 2. [Table] [Table] [Table] [Table] Reference example 3-acetoxy-5-[(E)-3-(coumarin-7
-yloxy)-1-methylpropenyl]-2,2
-Dimethyl-1-oxa-3-cyclopentene (compound obtained in Example 7) (50 mg, 0.14 mmol) was dissolved in benzene (1 ml) with dicyanodichloroparabenzoquinone (DDQ) (60 mg, 0.26 mmol) and at room temperature ( The mixture was stirred at 20°C for 2.5 hours. The organic layer was washed with an aqueous sodium sulfite solution, and the aqueous layer was extracted with dichloromethane (3 ml x 5 times).
did. The organic layers were combined and dried, concentrated, and then subjected to column chromatography (Wakogel C-100,
4 g, eluted with hexane-ethyl acetate 1:1) to give gayparvarin (44 mg, yield 100%). mp(MeOH): 159.5-160.5°C agreed with the literature value. The IR and NMR spectra also matched the literature values, and no mixture of the (Z) isomer was observed.

Claims (1)

[Claims] 1. General formula A dihydrofuran derivative represented by (wherein R is a hydrogen atom, a lower alkyl group, a phenyl group, or unsubstituted, substituted with a lower alkyl group, substituted with a lower alkyloxy group, substituted with a phenyloxy group, or coumarin-7-
It is an alkenyl group substituted with an yloxy group, and R ¹ and
R ² is a lower alkyl group, and R ¹ and R ² can be combined to form an alkylene group. ). 2 In the presence of a silver () catalyst, the general formula The general formula consists of cyclizing a 2-butyne-1,4-diol monoacetate derivative represented by A method for producing a dihydrofuran derivative represented by group, R ¹ and R ² are lower alkyl groups, and R ¹ and
R ² can be taken together to form an alkylene group. ). 3 In the presence of a base, the general formula The 2-butyne-1,4-diol derivative represented by the formula is reacted with acetic anhydride, and the general formula The general formula consists of obtaining a 2-butyne-1,4-diol monoacetate derivative represented by and then cyclizing in the presence of a silver() catalyst. A method for producing a dihydrofuran derivative represented by group, R ¹ and R ² are lower alkyl groups, and R ¹ and
R ² can be taken together to form an alkylene group. ).