JPH0257053B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a compound having a choleretic effect, and more particularly to a 2,4,6-3-substituted phenol derivative represented by the following general formula []. (In the formula, R ¹ is H, or CH ₃ , R ² is

[Formula] or

[Formula] R ³ is −CH=CH−R ⁵ or −CH ₂ −CH ₂ −R ⁵ or −CO ₂ H,
R ⁴ is H or

[Formula] R ⁵ is -CO ₂ H, -CO ₂ CH ₃ or -CH ₂ OH. However, R ¹ is H and R ² is

〔Example〕

Example 1 3-(4-Hydroxyphenyl)-2(E)-propenic acid (1, 140.0 g 0.84 mol) was dissolved in 6.2% sodium hydroxide solution (1084 ml, 1.68 mol) and heated with stirring to r. , r-dimethylallyl bromide (2, 128.0 g, 0.84 mol) was added dropwise, and stirring was continued for 3 hours at room temperature. Add this reaction solution to 2N
- Acidify with HCI solution and extract three times with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dissolved in ether, a diazomethane-ether solution is added and after 5 minutes the excess diazomethane is decomposed by dropwise addition of acetic acid. The crude product (225.4 g) obtained by distilling off the solvent under reduced pressure was treated with silica gel column chromatography [n-hexane-ethyl acetate (=10.1), acetone],
From the n-hexane-ethyl acetate eluate, 3-{3-
Methyl-2-butenyl)-4-hydroxyphenyl}-2(E)-propenic acid methyl ester [3, 33.2 g, yield (considering raw material recovery, the same applies hereinafter); 75.5%] was obtained in colorless prism crystals. , methyl ester compound 3-(4-
Hydroxyphenyl)-2(E)-propenic acid methyl ester (108.4 g) was recovered as a white powder. 3-{3-(3-methyl-2-butenyl)-4-
Physical properties of hydroxyphenyl}-2(E)-propenic acid methyl ester (3) mp. 84-85°C. It has a molecular composition of 2 C ₁₅ H ₁₈ O ₃ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has a characteristic absorption of 3400 (broad), 1968, 1630, and 1601. 4 Ultraviolet absorption spectrum (methanol, nm)
are 215 (ε, 15100), 232 (ε, 14400), 315 (ε,
22000) has an absorption maximum. 5 It has no odor and is colorless prismatic crystals (crystallized from methanol). 6 methanol, ethanol, n-butanol,
Soluble in ethyl acetate, acetone, chloroform dimethyl sulfoxide, pyridine, and ether; insoluble in benzene, n-hexane, and petroleum ether. 7 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: n-hexane-ethyl acetate (=
2:1)] shows an Rf value of 0.45. TLC 1
When sprayed with a 10% cerium sulfate-10% sulfuric acid solution and heated, it turns brown. Example 2 Lithium aluminum hydride (1.0 g, 0.026 mol) was added to 200 ml of tetrahydrofuran, and 3-
{3,5-bis-(3-methyl-2-butenyl)-
4-Hydroxyphenyl}-2(E)-Brobenik solution <<3-(4-hydroxyphenyl)-2
(E)-Propenicic acid (1, 100.0g, 0.60mol)
was dissolved in 6.2% sodium hydroxide solution (1160 ml, 1.80 mol), and r,r-dimethylallyl bromide (2, 177.6 g, 1.20 mol) was added dropwise with stirring, and the mixture was continued to be stirred at room temperature for 3 hours. . The reaction solution was made acidic with 2N-HCl solution and diluted with ethyl acetate for 3 hours.
Extract times. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Excess diazomethane is decomposed by dissolving the residue in ether, adding a diazomethane-ether solution and, after 5 minutes, adding acetic acid dropwise.
The solvent was distilled off under reduced pressure to obtain a crude product (182.4
g) by silica gel column chromatography [n
-hexane-ethyl acetate (=20:1), acetone]
3-{3,5-bis-(3-methyl-2-butenyl)-4-hydroxyphenyl}-2(E)-propenic acid methyl ester (4 , 14.4g yield;
23.2%) obtained as a colorless oil≫100 ml was added dropwise, and the mixture was then stirred for 1 hour. Water-saturated ether is added to the reaction solution to decompose unreacted lithium aluminum hydride. Further water is added, followed by an aqueous sodium hydroxide solution and the precipitate is filtered off. After drying the liquid over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product (5.22 g).
was treated with silica gel column chromatography [n-hexane-ethyl acetate (=5:1)] to obtain 3-
{3,5-bis-(3-methyl-2-butenyl)-
4-Hydroxyphenyl}-2(E)-propenyl alcohol (6, 4.51 g, yield: 97.8%) is obtained as a colorless oil. Physical properties of 3-{3,5-bis-(3-methyl-2-butenyl)-4-hydroxyphenyl}-2(E)-propenyl alcohol (6) 1 It is a colorless oily substance with no odor. It has a molecular composition of 2 C ₁₉ H ₂₆ O ₂ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has absorption specific to 3460 (broad) 1596. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 206 (ε, 31400) 266 (ε, 13900). 5 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, chloroform, pyridine, dimethyl sulfoxide,
Insoluble in benzene, n-hexane and petroleum ether. 6 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: n-hexane-ethyl acetate (=
2:1)] shows an Rf value of 0.55. TLC 1
% Cerium Sulfate - When sprayed with a 10% sulfuric acid solution and heated, it develops a brown color. Example 3 3-{3-(3-methyl-2 obtained in Example 1)
-butenyl)-4-hydroxyphenyl}-2
(E)-Propenic acid methyl ester (3, 14.0
g, 0.056 mol) in 100 ml of ether and add diazomethane-ether solution. The reaction solution is allowed to stand for 12 hours while being cooled with ice water, and excess diazomethane is decomposed by dropping acetic acid into the reaction solution. The crude product (17.1 g) obtained by distilling off the solvent under reduced pressure was treated with silica gel column chromatography [n-hexane-ethyl acetate (=25:1)] to give 3-{3-(3-methyl- 2-butenyl)
-4-methoxyphenyl}-2(E)-propenic acid methyl ester (7, 5.54 g, yield: 37.4
%) as a colorless oil. 3-{3-(3-methyl-2-butenyl)-4-
Physical properties of methoxyphenyl}-2(E) propenic acid methyl ester (7) 1 It is a colorless oily substance with no odor. It has a molecular composition of 2 C ₁₆ H ₂₀ O ₃ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has a characteristic absorption of 1698, 1632, and 1601. 4 Ultraviolet absorption spectrum (methanol, nm)
are 214 (ε, 12900), 222 (ε, 13000), 312 (ε,
20000) has an absorption maximum. 5 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, chloroform, benzene, pyridine, dimethyl sulfoxide,
Insoluble in n-hexane, petroleum ether. 6 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: n-hexane-ethyl acetate (=
5:1)] shows an Rf value of 0.40. TLC 1
% cerium sulfate-10% sulfuric acid solution is sprayed and heats to produce a brown color. Example 4 3-{3-(3-
Methyl-2-butenyl)-4-methoxyphenyl}
-2(E)-propenic acid methyl ester (7,
1.12 g, 0.0043 mol) was added with 10% sodium hydroxide solution (50 ml) and heated under reflux at 100°C for 1 hour.
After cooling, acidify with 2N-HCl solution and dilute with ethyl acetate.
Extract times. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3-{3-(3-methyl-2-butenyl)-4-methoxyphenyl}-2( E)-Propenic acid (8, 1.02 g, yield: 96.2%) was obtained as colorless needles. 3-{3-(3-methyl-2-butenyl)-4-
Physical properties of methoxyphenyl}-2(E)-propenic acid (8). 1 mp.150-152°C. It has a molecular composition of 2 C ₁₅ H ₁₈ O ₃ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) is 3000-2500 (broad), 1686, 1617,
It has an absorption characteristic of 1597. 4 Ultraviolet absorption spectrum (methanol, nm)
are 213 (ε, 17900), 227 (ε, 17000), 304 (ε,
19900). 5 It has no odor and is colorless needle crystals. 6 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, chloroform, pyridine, dimethyl sulfoxide,
Insoluble in benzene, n-hexane and petroleum ether. 7 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: chloroform-methanol (=
10:1)] shows an Rf value of 0.50. TLC 1
% cerium sulfate - 10% sulfuric acid solution is sprayed and heated to produce a brown color. Example 5 Tetrahydrofuran (80 ml) was added to lithium aluminum hydride (400 mg, 0.011 mol) and, with stirring, the 3-
A tetrahydrofuran solution (60 ml) of {3-(3-methyl-2-butenyl)-4-methoxyphenyl}-2(E)-propenic acid methyl ester (7, 2.8 g 0.011 mol) was added dropwise, Stir the mixture for 1 hour. Water-saturated ether is added to the reaction solution to decompose unreacted lithium aluminum hydride. Water is added to this solution followed by sodium hydroxide solution to filter the precipitate. After drying the liquid over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product (3.21 g) was subjected to silica gel column chromatography [n-hexane-ethyl acetate (=5:
1)] to give 3-{3-(3-methyl-2-butenyl)-4-methoxyphenyl}-2(E)-propenyl alcohol (9, 1.32 g, yield: 52.8%)
is obtained as a colorless oil. 3-{3-(3-methyl-2-butenyl)-4-
Physical properties of methoxyphenyl}-2(E)-propenyl alcohol (9) 1 It is a colorless oily substance with no odor. It has a molecular composition of 2 C ₁₅ H ₂₀ O ₂ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has a unique absorption of 3400 (broad) and 1603. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 261 (ε, 16600). 5 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, chloroform, pyridine, dimethyl sulfoxide,
Insoluble in benzene, n-hexane and petroleum ether. 6 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: n-hexane-ethyl acetate (=
2:1)] shows an Rf value of 0.35. TLC 1
% cerium sulfate - 10% sulfuric acid solution is sprayed and heated to produce a brown color. Example 6 Ether (200 ml) was added to lithium aluminum hydroxide (608 mg, 0.016 mol) and, with stirring, the 3-{3-(3-methyl-2-butenyl)-4-hydroxy obtained in Example 1 was added. Phenyl}-2(E)-propenic acid methyl ester (3, 3.96 g, 0.016 mol) in ether solution (50
ml) dropwise and the mixture is stirred for 1 hour. Water-saturated ether is added to the reaction solution to decompose unreacted lithium aluminum hydride. Water is added to this solution followed by sodium hydroxide solution to filter out the precipitate. The solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product (3.46 g) was treated with silica gel column chromatography [n-hexane-ethyl acetate (=5:1)] to give 3- {3
-(3-Methyl-2-butenyl)-4-hydroxyphenyl}-2(E)-propenyl alcohol (10, 1.44 g, yield: 41.3%) was obtained as colorless prism crystals. 3-{3-(3-methyl-2-butenyl)-4-
Physical properties of hydroxyphenyl}-2(E)-propenyl alcohol (10) mp.95-97°C. It has a molecular composition of 2 C ₁₄ H ₁₈ O ₂ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has a unique absorption of 3440 (broad) and 1605. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 211 (ε, 27300) and 265 (ε, 18700). 5 It has no odor and is colorless prismatic crystals (crystallized from acetone). 6 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, chloroform, pyridine, dimethyl sulfoxide,
Insoluble in benzene, n-hexane and petroleum ether. 7 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: chloroform-methanol (=
20:1)] shows an Rf value of 0.50. TLC 1
% cerium sulfate - 10% sulfuric acid solution is sprayed and heated to produce a brown color. Example 7 3-{3-(3-
Methyl-2-butenyl)-4-hydroxyphenyl}-2(E)-propenic acid methyl ester (3, 3.00 g, 0.012 mol) was dissolved in 50 ml of methanol, and to this solution was added 5% palladium on activated carbon (1.50 g, 0.012 mol).
g), and the reaction vessel was filled with hydrogen gas (pressure: 5Kg/
cm ² ) and shaken at room temperature for 3 hours. The solution was filtered and the solvent was distilled off under reduced pressure. The obtained residue (2.84 g) was subjected to silica gel column chromatography [n-hexane-ethyl acetate (=5:
1)] to give 3-{3-(3-methylbutyl)-
4-Hydroxyphenyl}-propenic acid methyl ester (11, 2.80 g, yield: 93.3%) was obtained as a colorless oil. Physical properties of 3-{3-(3-methylbutyl)-4-hydroxyphenyl}-propenic acid methyl ester (11) 1 It is a colorless oily substance with no odor. It has a molecular composition of 2 C ₁₅ H ₂₂ O ₃ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) has a unique absorption of 3350 (broad), 1728, and 1609. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 217 (ε, 5500) and 278 (ε, 2400). 5 methanol, ethanol, n-butanol,
Acetone, ethyl acetate, chloroform, ether, benzene, n-hexane, petroleum ether,
Soluble in pyridine and dimethyl sulfoxide. 6 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: n-hexane-ethyl acetate (=
3:1)] shows an Rf value of 0.50. TLC 1
% cerium sulfate - 10% sulfuric acid solution is sprayed and heated to produce a brown color. Example 8 A 10% potassium hydroxide solution (50 ml) was added to 3-{3-(3-methylbutyl)-4-hydroxyphenyl}-propenic acid methyl ester (11, 1.48 g, 0.006 mol) obtained in Example 7. ) and
Heat to reflux at 100 °C for 30 min. After cooling, the mixture is acidified with 2N HCl and extracted twice with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-{3-(3-methylbutyl)-4-hydroxyphenyl}-propenic acid (12 , 1.34g,
Yield: 95.9%) is obtained as a colorless oil. Physical properties of 3-{3-(3-methylbutyl)-4-hydroxyphenyl}-propenic acid (12) 1 It is a colorless oily substance with no odor. It has a molecular composition of 2 C ₁₄ H ₂₀ O ₃ . 3 Infrared absorption spectrum (chloroform, cm
^-1 ) is 3300 broad), 3000−2600 (broad),
It has a unique absorption at 1704 and 1606. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 218 (ε, 6100) and 278 (ε, 2100). 5 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, chloroform, pyridine, dimethyl sulfoxide,
Insoluble in benzene, n-hexane and petroleum ether. 6 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: chloroform-methanol (=
20:1)] shows an Rf value of 0.45. TLC 1
When sprayed with a 10% cerium sulfate-10% sulfuric acid solution and heated, it turns brown. Example 9 4-hydroxybenzoic acid (13, 15.0
g, 0.11 mol) in 6.7% sodium hydroxide solution (130 ml, 0.22 mol) and, with stirring, r,
r-dimethylallyl bromide (2, 14.0g,
0.095 mol) was added dropwise, and stirring was continued for an additional 4 hours at room temperature. The reaction solution was made acidic with 2N HCl solution and extracted three times with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dissolved in methanol, a diazomethane-ether solution is added, and after 5 minutes, acetic acid is added dropwise to decompose the excess diazomethane. The solvent was distilled off under reduced pressure, and the resulting crude product (19.34 g) was subjected to silica gel column chromatography [n-hexane-ethyl acetate (=
15:1), acetone], and 3-(3-methyl-2-butenyl)-4-hydroxybenzoic acid methyl ester (14, 2.98 g) was collected from the n-hexane-ethyl acetate eluate using colorless prism crystals. Gain,
Methyl ester of raw material 13 from the acetone elution part,
4-Hydroxybenzoic acid methyl ester (10.48 g) is recovered as a white powder. To the compound thus obtained (14, 2.98 g, 0.013 mol) was added 10% sodium hydroxide solution (100 ml) and
Heat to reflux at °C. After cooling, acidify with 2N HCl solution and extract twice with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to give 3-(3-methyl-2-butenyl)-4-hydroxybenzoic acid (15,
2.75 g, yield: 33.7%) were obtained as colorless needles. Physical properties of 3-(3-methyl-2-butenyl)-4-hydroxybenzoic acid (15) 1 mp. 100-101°C. It has a molecular composition of 2 C ₁₂ H ₁₄ O ₃ . 3 Infrared absorption spectrum (KBr, cm ^-1 ) is 3400
(Broad), 3000-2500 (Broad), 1684,
It has a unique absorption of 1600. 4 Ultraviolet absorption spectrum (methanol, nm)
has an absorption maximum at 259 (ε, 13200). 5 It has no odor and is colorless needle crystals. 6 methanol, ethanol, n-butanol,
Soluble in acetone, ethyl acetate, ether, dimethyl sulfoxide, pyridine, chloroform,
Insoluble in benzene, n-hexane and petroleum ether. 7 Thin layer chromatography [TLC, carrier: precoated silica gel 60F ₂₅₄ , 0.25 mm, manufactured by Merck; developing solvent: chloroform-methanol (=
5:1)] shows an Rf value of 0.50. TLC 1
When sprayed with a 10% cerium sulfate-10% sulfuric acid solution and heated, it turns brown. Biliary effect test <Experimental method> A group of 8 male Wistar rats weighing approximately 250 g were fasted for 6 to 8 hours, the abdomen was incised, a polyethylene cannula was inserted into the bile duct, and bile was injected for 1 hour. After a period of stable outflow,
The amount of bile flowing out for 30 minutes was used as the control amount. After administration of the test drug, the amount of bile flowing out was determined every 30 minutes until the second hour, and then every hour thereafter for a total of 6 hours. The dose of the test drug obtained in the above example and sodium dehydrocholate (Hani Chemicals) used as a control drug was 100 mg/Kg. Each drug was suspended in 4% gum arabic powder and administered into the duodenum at the time of use. <Experimental Results> The above test results are shown in Figures 1 to 3 as bile secretion rates. In addition, the mark * in the figure indicates the danger rate P<0.05, and the mark **
The mark means P<0.01. Also, each point in the figure (〓
〓〓〓, etc.) indicates the average value (± standard error) of the amount of bile discharged from 8 rats as described in the experimental method, and the error is shown above and below each point as originally written as 〓〓〓. should be shown, but in that case the lower part overlaps with the error of other points and becomes difficult to see, so the lower part is omitted. From the above results, it is considered that the compound of the present invention exerts a choleretic effect upon oral administration. When used for adult treatment, each dose is 50mg at a time.
It is estimated that the drug should be taken three times a day.

[Brief explanation of drawings]

FIGS. 1, 2, and 3 are graphs showing the results of the bile secretion rate of the 2,4,6-3-substituted phenol derivative having bile-loving activity according to the present invention. In the figure, C is the control, D is sodium dehydrocholate, 1 is the compound (3) of Example 1, 2 is the compound (6) of Example 2, 3 is the compound (7) of Example 3,
4 is the compound (8) of Example 4, 5 is the compound of Example 5
(9), 6 is the compound (10) of Example 6, 7 is the compound (11) of Example 7, 8 is the compound (12) of Example 8, and 9 is the bile compound of Example 9 (15). Each means a secretion rate curve.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is H or CH ₃ , R ² is [Formula] or [Formula] R ³ is −CH=CH− R ⁵ , or −CH ₂ −CH ₂ −R ⁵ or −
CO ₂ H, R ⁴ is H, or R ⁵ is -CO ₂ H, - CO ₂ CH ₃ or -CH ₂ OH. However, R ¹
is H, R ² is [Formula] R ³ is -CH = CH-R ⁵ , R ⁵ is -CO ₂ H)
A 2,4,6-3-substituted phenol derivative represented by: