JPH10287661A - Production of furanone ether derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a furanone ether derivative expectable of more effective preventing.curing effect to senile cataract at a high yield by reacting furanone with an alkene in the presence of an acid catalyst. SOLUTION: This furanone ether derivative, concretely 2,5-dimethyl-4- isopropyloxy-3(2H)-furaraone, etc., is obtained by reacting a furanone e.g. 4-hydroxy-2,5-dimethyl-3(2H)-furanone} expressed by the formula (R1 to R3 are each H, hydroxyl, amino, a halogen, mercapto, etc.) or its salt with an alkene (e.g. propylene) in the presence of an acid catalyst (e.g. boron trifluoride- phosphoric acid). Preferably, e.g. the former portion of the reaction is performed in a cooling bath and the latter portion of the reaction is performed at a temp. of >=0 deg.C in the reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a furanone ether derivative.

[0002]

2. Description of the Related Art The present inventors previously filed a patent application for a furanone ether derivative (4-alkoxyfuranone derivative) (Japanese Patent Application No. Hei 7-264527). According to the present invention, a furanone ether derivative can be obtained, but it has been found that there is room for improvement in the yield per raw material.

[0003]

Accordingly, an object of the present invention is to obtain a furanone ether derivative in high yield.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and finally completed the present invention. That is, the present invention provides the following formula:

Embedded image (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, and represent a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group,
Alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, alkoxyl group, acyloxy group,
A furanone represented by an alkenyloxy group, an alkynyloxy group, an aryloxy group or an alkoxycarbonyl group) or a salt thereof is reacted with an alkene in the presence of an acid catalyst. It is.

Hereinafter, the present invention will be described in detail. As the furanone or a salt thereof used in the present invention, the following formula

Embedded image (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, and represent a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group,
Alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, alkoxyl group, acyloxy group,
Furanone represented by an alkenyloxy group, an alkynyloxy group, an aryloxy group or an alkoxycarbonyl group) or a salt thereof such as sodium and potassium.

Specific examples of the above compounds include, for example, 4-hydroxy-2,5-dimethyl-3 (2H) -furanone, 4-hydroxy-5-methyl-3 (2H) -furanone, 2 (or 5 ) -Ethyl-4-hydroxy-5 (or 2) -methyl-3 (2H) -furanone, 2,5-diethyl-4-hydroxy-3 (2H) -furanone and their alkali metal salts such as sodium and potassium And other alkaline earth metal salts, ammonium salts, amine salts and the like.

The alkenes used in the present invention include propylene, isobutylene, 2-methyl-1-butene,
-Ethyl-1-butene, 1-methyl-1-cyclopentene, 1-methyl-1-cyclohexene and the like.

[0008] Examples of the acid catalyst include inorganic acids such as hydrochloric acid and sulfuric acid, trifluoromethanesulfonic acid, hydrogen fluoride, tetrafluoroboron-phosphoric acid, boron trifluoride-phosphoric acid and the like.

In order to carry out the present invention, the above-mentioned furanone or a salt thereof is reacted with the above-mentioned alkene in the presence of the above-mentioned acid catalyst.

[0010] Furanone or a salt thereof is dichloromethane,
It is preferable to use it after dissolving it in a halogen-based solvent such as chloroform or carbon tetrachloride so as to have a final concentration of 0.1 to 10 g / 100 ml.

The acid catalyst is preferably used in an amount of 0.1 to 1.0 equivalent to the concentration of furanone.

The alkene is preferably used in an amount of 2.0 to 10.0 equivalents to the concentration of the furanone.

In order to carry out the present invention, they are placed in a reaction vessel, sealed, and then stirred under anhydrous conditions under an inert gas atmosphere. Examples of the inert gas include argon, nitrogen, and the like.

The first-stage reaction is carried out in a cooling bath (at a temperature of -78 ° C to -40 ° C), and the second-stage reaction is carried out at a temperature of 0 ° C or higher.

In the reaction of the first step, the reaction solution is collected over time and analyzed by thin-layer chromatography. The spots derived from the raw material furanone gradually decrease and, for example, 1 point until the spot of the product is observed. Performing the reaction for 10 to 10 hours is preferable because the furanone ether derivative can be reliably obtained at a high yield.

The reaction in the latter stage is carried out by leaving the reaction-terminated liquid in the former stage at 0 ° C. or higher (for example, at room temperature of 15 to 25 ° C.) with stirring (or setting the temperature of the reaction vessel to 0 ° C.). Set and let the temperature rise naturally). After that, if necessary, a reflux condenser is attached, and heating is performed to gradually raise the temperature over a slow time (at least 2 hours, preferably 5 to 10 hours).

In the latter reaction, a part of the reaction solution is collected and analyzed by thin-layer chromatography to confirm the intended furanone ether derivative of the present invention. The reaction is stopped by adding an aqueous alkaline solution, such as aqueous ammonia or aqueous sodium hydrogen carbonate.

In order to isolate the desired furanone ether derivative from the reaction solution, first neutralize with an alkali (aqueous ammonia or an aqueous solution of sodium hydrogen carbonate), and then add a halogen-based solvent such as dichloromethane or chloroform. The desired ether derivative of furanone is extracted into the solvent.

Next, the organic solvent layer is washed with water and saturated saline in this order, and the obtained washed organic solvent layer is dried by adding a dehydrating agent such as magnesium sulfate or sodium sulfate.
Then, the organic solvent layer is heated and concentrated under reduced pressure, and the solvent is distilled off. The residue is further purified by distillation under reduced pressure or purified by silica gel column chromatography, liquid chromatography or the like, and isolated.

The thus purified ether derivative of furanone can be confirmed by MS spectrum, IR spectrum, NMR spectrum, elemental analysis and the like. The purity can be confirmed by UV spectrum, liquid chromatography,
It can be performed by gas chromatography or the like.

Examples of the ether derivatives of furanone thus obtained include, for example, 4-tert-butoxy-2,5
-Dimethyl-3 (2H) -furanone, 2,5-dimethyl-4- (2-methyl-2-butoxy) -3 (2H) -furanone, 2,5-dimethyl-4- (3-methyl-3- (Pentyloxy) -3 (2H) -furanone, 2,5-dimethyl-4- (1-methyl-1-cyclopentyloxy)
-3 (2H) -furanone, 2,5-dimethyl-4- (1
-Methyl-1-cyclohexyloxy) -3 (2H)-
Furanone or a salt thereof.

The furanone ether derivative obtained according to the present invention can be expected to have a more effective preventive or therapeutic effect on senile cataract caused by oxidative damage and the like than conventionally known furanone derivatives. And according to the present invention, a furanone ether derivative can be obtained in a high yield.

[0023]

The present invention will be described more specifically with reference to the following examples.

Example 1 (4-tert-butoxy-2,
Production example of 5-dimethyl-3 (2H) -furanone)

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -furanone (6.1 g, 48 mol) was dissolved in dichloromethane (80 ml) and stirred at -75 ° C., to which was added phosphoric acid (0.40 g of P ₂ O ₅ and 1.1 m of 85% H ₃ PO _4).
1) and boron trifluoride etherate complex (47% B
F ₃ .Et ₂ O 2.0 ml) and liquid isobutylene (40
ml) was added thereto, and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After adding a 2N aqueous ammonia solution (80 ml), the mixture was extracted with dichloromethane, and purified by a conventional method. That is, after drying with sodium sulfate, the solvent is distilled off under reduced pressure. Further, this was purified by silica gel column chromatography and then purified by distillation under reduced pressure to give the following physicochemical properties, 4-tert-butoxy-
5.3 g of 2,5-dimethyl-3 (2H) -furanone
(60% yield). Note that P ₂ O ₅ is H ₃ P
Used for dehydration of O ₄ .

(Physicochemical properties) b. p. 73-74 ° C / 2 mmHg; IRν _max c
m ^{- 1} : 1705, 1620, 1370, 1310, 12
05, 1170, 1005; NMR δ (200 MHz,
CDCl ₃ ) 1.31 (s, 9H), 1.44 (d, J
= 7.3 Hz, 3H), 2.19 (d, J = 1.0H)
z, 3H), 4.40 (dq, J ₁ = 7.3 Hz, J ₂ =
1.0Hz, 1H)

[0026]

Embedded image

Comparative Example 1 For comparison, the compound represented by Chemical Formula 5 obtained in Example 1 was used.
-Tert-butoxy-2,5-dimethyl-3 (2H)
-When synthesizing furanone, following the conventional method,

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -Furanone (6.1 g, 48 mmol) was dissolved in tetrahydrofuran (100 ml) (solvent), stirred under ice-cooling, and added with sodium hydride (1.1 g, 48 mm).
ol) and reacted for 1 hour. Te
rt-butoxy iodide (9.7 g, 53 mmo
l) was added thereto, and the temperature was gradually returned to room temperature, followed by heating under reflux overnight. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid and extracted with ether. The extracted organic solvent layer was purified after the usual treatment. As a result, the desired product, 4-tert-butoxy-2,5-dimethyl-3 represented by Chemical Formula 5, was contained in the reaction purified product.
(2H) -furanone could not be confirmed.

Comparative Example 2 For comparison, the compound represented by Chemical Formula 5 obtained in Example 1 was used.
-Tert-butoxy-2,5-dimethyl-3 (2H)
-When synthesizing furanone, following the conventional method,

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -Furanone (6.1 g, 48 mmol) was dissolved in trimethylamine (100 ml), and the mixture was stirred under ice-cooling, and added with 4-dimethylaminopyridine (trace amount 0.05 g) and tert-butoxyiodide (9.7 g). , 53m
mol), the temperature is gradually returned to room temperature, and the mixture is stirred overnight. After completion of the reaction, the mixture is neutralized with 1N hydrochloric acid and extracted with ether. The extracted organic solvent layer was purified after a conventional treatment. 4-te represented by chemical formula 5 from the reaction solution
26 mg (0.3% yield) of rt-butoxy-2,5-dimethyl-3 (2H) -furanone was collected.

The above Example 1, Comparative Example 1 and Comparative Example 2 are summarized in Table 1.

[0030]

Table 1 4-tert-butoxy-2,5-dimethyl-
Yield of 3 (2H) -furanone Category Yield (%) Comparative Example 1-Comparative Example 2 0.3% The present invention (Example 1) 60.0%

From the results shown in Table 1, in Comparative Example 1 using tert-butoxyiodide and sodium hydride as reagents, the target compound 4-tert-butoxy-2,5-dimethyl-3 (2H) -furanone Can not get at all. Similarly, in Comparative Example 2 in which tert-butoxyiodide, triethylamine, and dimethylaminopyridine are used as reagents, only a very small amount of 0.3% of the compound can be obtained. In contrast, according to the present invention, it can be seen that the compound can be obtained in a high yield of 60%.

Example 2 (2,5-dimethyl-4- (2-
Production example of methyl-2-butoxy) -3 (2H) -furanone

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -furanone (5.0 g, 39 mmol) was dissolved in dichloromethane (80 ml) and stirred at -75 ° C., to which 0.35 g of phosphoric acid (P ₂ O ₅ and 85% H ₃ PO ₄ 0.
90 ml) and 47% BF ₃ .Et ₂ O (2.0
ml) and 2-methyl-1-butene (5.5 g, 78 mm)
ol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After addition of 2N aqueous ammonia (66 ml), the mixture was extracted with dichloromethane and purified by a conventional method to give the following physicochemical properties.
4.3 g (56%) of (2-methyl-2-butoxy) -3 (2H) -furanone were isolated.

(Physicochemical properties) b. p. 80-81 ° C / 1mmHg; IRν _max c
m ^{- 1} : 1700, 1620, 1370, 1310, 12
00, 1165, 1005; NMR δ (200 MHz,
CDCl ₃ ) 0.97 (s, J = 7.4 Hz, 3H),
1.22 (s, 3H), 1.23 (s, 3H), 1.4
3 (d, J = 7.0 Hz, 3H), 1.66 (q, J =
7.4 Hz, 2H) 2.18 (d, J = 0.8 Hz, 3
H), 4.41 (dq, J ₁ = 7.4 Hz, J ₂ = 0.8
Hz, 1H)

[0034]

Embedded image

Example 3 (2,5-dimethyl-4- (3-
Production Example of Methyl-3-pentyloxy) -3 (2H) -furanone

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -furanone (5.0 g, 40 mmol) was dissolved in dichloromethane (80 ml) and stirred at -75 ° C., to which was added phosphoric acid (0.35 g of P ₂ O ₅ and 85% H ₃ PO ₄ .0).
90 ml) and 47% BF ₃ .Et ₂ O (1.9)
8 ml) and 2-ethyl-1-butene (6.7 g, 80 m
mol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After addition of 2N aqueous ammonia (66 ml), the mixture was extracted with dichloromethane and purified by a conventional method to give 2,5-dimethyl-4 having the following physicochemical properties.
-(3-Methyl-3-pentyloxy-3 (2H) -furanone (4.2 g, 51%) was isolated.

(Physicochemical properties) IRν _max cm ^{- 1} : 1702, 1619, 1459, ¹
310, 1198, 1135, 1004; NMR δ (2
00 MHz, CDCl ₃ ) 0.93 (dt, J ₁ = 7.6
Hz, J ₂ = 0.4 Hz, 3H), 1.14 (d, J =
4.4 Hz, 3H), 1.42 (d, J = 7.0 Hz,
3H), 1.46-1.76 (m, 4H), 4.41.
(Dq, J ₁ = 7.0 Hz, J ₂ = 1.0 Hz, 1H)

[0037]

Embedded image

Example 4 (2,5-dimethyl-4- (1-
Production example of methyl-1-cyclopentyloxy) -3 (2H) -furanone

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) - furanone (3.0 g, was stirred at dissolving 24 mmol) in dichloromethane (50ml) -75 ℃, this phosphoric acid (P ₂ O ₅ 0.20g and 85% H ₃ PO ₄ 0.
93% BF ₃ .Et ₂ O (0.9%)
6 ml) and 1-methyl-1-cyclopentene (3.9)
g, 48 mmol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight.
After adding 2N aqueous ammonia (40 ml), the mixture was extracted with dichloromethane and purified by a conventional method to give 2,5-dimethyl-4- (1-methyl) having the following physicochemical properties and represented by Chemical formula 13: -1-cyclopentyloxy)
-3 (2H) -furanone (1.6 g, 32%) was isolated.

(Physicochemical properties) IRν _max cm ^{- 1} : 1705, 1619, 1450, ¹
370, 1310, 1195, 1115, 1055, 1
000,930; NMR δ (200 Mz, CDCl ₃ )
1.36 (s, 3H), 1.43 (d, J = 7.2H
z, 3H), 1.48-2.08 (m, 8H), 2.1
8 (d, J = 0.8 Hz, 3H) 4.42 (dq, J ₁
= 7.2 Hz, J ₂ = 0.8 Hz, 1H)

[0040]

Embedded image

Example 5 (2,5-dimethyl-4- (1-
Production Example of Methyl-1-cyclohexyloxy) -3 (2H) -furanone

Embedded image 4-hydroxy-2,5-dimethyl-3 (2
H) -furanone (13.4 g, 105 mmol) was dissolved in dichloromethane (150 ml) and stirred at -75 ° C.
To this, 0.89 g of phosphoric acid (P ₂ O ₅ and 85% H ₃ PO ₄
Mixture with 2.4 ml) and 47% BF ₃ .Et ₂ O
(4.2 ml) and 1-methyl-1-cyclohexene (2
0 g, 210 mmol), and the reaction was carried out with stirring at -75 ° C for 1.5 hours, then left at room temperature and stirred overnight. After adding 2N aqueous ammonia (87 ml), the mixture was extracted with dichloromethane to give 2,5-dimethyl-4- (1-
Methyl-1-cyclohexyloxy) -3 (2H) -furanone (6.6 g, 28%) was isolated.

(Physicochemical properties) IRν _max cm ^{- 1} : 1705, 1615, 1445, ¹
415, 1370, 1310, 1200, 1155, 1
105, 1075, 1005; NMR δ (200 MH
z, CDCl ₃ ) 1.22 (d, J = 5.6 Hz, 3
H), 1.3-2.0 (m, 10H), 1.43 (d,
J = 7.2 Hz, 3H), 2.19 (d, J = 0.8H)
z, 3H), 4.42 (dd, J ₁ = 7.2 Hz, J ₂ =
0.8Hz, 1H)

[0043]

Embedded image

Application Example 1 Anti-cataract effect on galactose cataract (in vivo)
(Tro test) (Test method) A lens extracted from a 7-week-old, male, Crj: Wistar rat was treated with 30 mM galactose-added T
The cells were immersed in 10 ml of C199 bicarbonate buffer medium (manufactured by Nissui Pharmaceutical) and cultured at 37 ° C. for 7 days in the presence of 5% CO ₂ . In a galactose-supplemented medium soaked with the lens (5 / group),
Was added (0.1% of the furanone ether derivative of the present invention obtained in Examples 1 to 5). For comparison, the lenses were cultured in a medium with or without galactose in the same manner as described above. The medium to which these samples were added or not was changed every day. After culturing each lens for 7 days, the degree of cloudiness of the lens was determined by the method of Hattori et al. (Journal of the Japanese Society of Ophthalmology, Vol. 95, No. 3, pp. 228-234, 199).
1 year), the score is evaluated according to the following criteria.
The average value was shown. Criteria for white opacity 0: No opacity was observed, 1: Mild opacity was observed in the cortex, 3: Turbidity was observed throughout the cortex and higher opacity, 2: Score between 1 and 3. The results are shown in Table 2.

[0045]

[Table 2]

From the results shown in Table 2, the lenses of the first and second sections without galactose showed slight opacity in the cortex (scores 0.2 and 0.4), but almost no transparency. Indicated. In contrast, it can be seen that the lenses of the third and fourth sections to which galactose was added show remarkable cloudiness (scores of 2.8 and 2.6), respectively. That is,
It can be seen that the lens to which galactose was added at a high concentration became cloudy. On the other hand, the lenses of the fifth to ninth categories to which the furanone ether derivative of the present invention was added, despite the addition of galactose at a high concentration, showed only slight turbidity in the cortex and were almost transparent ( Score 0.6-1.
From 2), it can be seen that the furanone ether derivative of the present invention has a cataract treatment effect. And it turns out that the furanone ether derivative of the present invention can be expected to more effectively prevent or treat senile cataract caused by oxidative damage and the like.

Application Example 2 (Toxicity test) Ether derivative of furanone (4-tert)
-Butoxy-2,5-dimethyl-3 (2H) -furanone) (sample) was examined for toxicity tests. Animals are ICR / o
rj male mice (Charles River Japan) were purchased at 6 weeks of age and used at 7 weeks of age for experiments. Sample is 1% CMC
-Na solution to give a stock solution. The sample was intraperitoneally administered to the mouse at 500 mg / kg. Immediately after the administration, the condition was observed, the body weight was measured for 2 weeks, and the condition was observed. Two weeks later, the mice were sacrificed by the cervical dislocation method, and appearance and internal organs and brain abnormalities were observed. Dead animals were dissected at any time and observed. The results showed that none of the derivatives died at an intraperitoneal dose of 500 mg / kg, no abnormalities were observed even after 2 weeks of observation, and the toxicity was low.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Koichi Kasai 339 Noda, Noda-shi, Chiba Kikkoman Co., Ltd. (72) Inventor Takanao Matsudo 339 Noda, Noda-shi, Chiba Kikkoman Co., Ltd. (72) Inventor Kenji Mori 1-20-6-1309 Mukooka, Bunkyo-ku, Tokyo

Claims (2)

[Claims] (1) The following formula: (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, and include a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a carboxyl group, a carbamoyl group,
Alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, alkoxyl group, acyloxy group,
A furanone represented by an alkenyloxy group, an alkynyloxy group, an aryloxy group or an alkoxycarbonyl group) or a salt thereof is reacted with an alkene in the presence of an acid catalyst to produce an ether derivative of furanone. Law. 2. The furanone ether derivative is 2,5-dimethyl-4-isopropyloxy-3 (2H) -furanone, 4-tert-butoxy-2,5-dimethyl-3.
(2H) -furanone, 2,5-dimethyl-4- (2-methyl-2-butoxy) -3 (2H) -furanone, 2,5
-Dimethyl-4- (3-methyl-3-pentyloxy)
-3 (2H) -furanone, 2,5-dimethyl-4- (1
-Methyl-1-cyclopentyloxy) -3 (2H)-
Furanone, 2,5-dimethyl-4- (1-methyl-1-
The method for producing a furanone ether derivative according to claim 1, which is cyclohexyloxy) -3 (2H) -furanone or a salt thereof.