JPH07108906B2 - Phthalide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel phthalide derivative having a prostaglandin F2α inhibitory action and useful as a medicine.

A river of crude drugs, which is a plant in the Aeriaceae family (Cnidii Rhizoma) is known to have central depressant action, muscle relaxant action, antithrombotic action, etc., and it is a Chinese medicine, Unkeito, Unseiin, Kakkonto Kagawa. It is a crude drug that is distributed in Chinese cabbage.

The present inventors As a result of intensive studies, focusing on phthalide, which is one of the components contained in the above, the inventors have succeeded in synthesizing a phthalide derivative having a prostaglandin F2α inhibitory action and completed the present invention.

That is, the present invention relates to the general formula I (In the formula, R ₁ represents a hydrogen atom, a hydroxyl group, a methoxy group or a nitro group, R ₂ represents a hydrogen atom, a hydroxyl group, a methoxy group or a methoxymethoxy group, R ₃ represents a hydrogen atom or a methoxy group, and R ₄ Represents a hydrogen atom or a nitro group, R ₅ represents hydrogen, an alkyl group, —C ₃ H ₆ COOH, —C ₃ H ₆ COOC ₂ H ₅ or —C ₄ H ₈ OH.

However, when R ₁ , R ₂ , R ₃ and R ₄ are hydrogen atoms in common, R ₁ is a hydrogen atom, R ₂ is a hydroxyl group, R ₃ and R ₄ are both hydrogen atoms, R ₅ is an n-propyl group, and R ₁ and R ₂ are both hydrogen atoms, and R ₃
Is a methoxy group, R ₄ is a hydrogen atom, R ₅ is a methyl group, and R ₁ and R ₂ are methoxy groups,
When R ₃ and R ₄ are hydrogen atoms, R ₅ is a methyl group, and R ₁ is a hydroxyl group, R ₂ , R ₃ and R ₄ are both hydrogen atoms, and R ₅ is a propyl group. Excluding cases. ) Is a novel phthalide derivative.

The phthalide derivative of the present invention represented by the general formula I (hereinafter referred to as the compound of the formula I) has the formula II (In the formula, R _{1 to} R ₄ have the same meanings as described above) A compound represented by formula (3) R ₅ —CHO III (R ₅ is the same as above) Of the formula IV) (hereinafter referred to as the compound of formula III) (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above) (hereinafter referred to as the compound of formula IV), and mesylate this in an organic solvent. Formula V (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as described above and Ms represents a mesyl group) (hereinafter referred to as a compound of formula V) After that, it can be obtained by reacting a base such as amines.

The compound of formula II, which is a starting material, is prepared by converting commercially available m-anisic acid, 3,4-dimethoxybenzoic acid, 3,4,5-trimethoxybenzoic acid or the like into acyl chloride and then using 2-amino By reacting with 2-methyl-1-propanol for further cyclization (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above) (hereinafter referred to as the compound of formula A), formaldehyde is then allowed to act, and then an acid is allowed to act. Can be obtained.

Acyl chloride can be obtained by adding thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, etc. to m-anisic acid, 3,4-dimethoxybenzoic acid, 3,4,5-trimethoxybenzoic acid, etc. with ice-cooling. Add below to react. The reaction temperature is from room temperature
About 60 ℃ is suitable. After the reaction, the acyl chloride can be obtained by a commonly used general purification method such as distillation of the solvent at atmospheric pressure or reduced pressure, distillation.

Then, this acyl chloride is treated with 2-amino-2 in an organic solvent.
-Methyl-1-propanol is added and reacted to form an amide form. Specific examples of the organic solvent include methylene chloride,
Examples of the reaction temperature include benzene and chloroform, and a suitable reaction temperature is 0 to 30 ° C. Although the reaction can be sufficiently carried out by a conventional method, it is preferable to carry out the reaction under anhydrous conditions, such as by performing argon substitution. After the reaction, the amide compound is obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

Further, this amide compound is cyclized by reacting with thionyl chloride to obtain a compound of the formula A. A suitable reaction temperature is about room temperature. After the reaction, the compound of the formula A can be obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

Next, the compound of formula A obtained as described above is reacted with formaldehyde in the presence of a base in an organic solvent, and then an acid is added to hydrolyze the compound to give a compound of formula II. Examples of the organic solvent used include ethers such as anhydrous tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether.
Specific examples of the base include n-butyllithium, sec-butyllithium, tert-butyllithium and the like.
As the reaction temperature, about −45 ° C. to room temperature is suitable,
Particularly at low temperatures, it is preferable to add tetramethylethylenediamine as a chelating agent. Subsequently, an acid is added to carry out the hydrolysis, but it is preferable to remove the formaldehyde and the like used in the previous reaction and then carry out the hydrolysis. Specific examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and the solvent to be used is preferably water, alcohols or a mixed solvent thereof. The reaction temperature is preferably room temperature to the boiling point of the solvent used for the reaction. After the reaction, the compound of the formula II can be obtained by combining commonly used general purification techniques such as extraction, drying, evaporation of the solvent and recrystallization.

Another method for obtaining the compound of formula II is 3,4,5-
Trimethoxybenzoic acid, benzoic acid such as 3,5-dimethoxy-4-hydroxybenzoic acid in the presence of an acid, in the presence of an acid, a method of reacting dimethoxymethane or paraformaldehyde, and also a method of methoxymethylating a hydroxyl group, if necessary. be able to. The acid used here is
Mineral acids such as hydrochloric acid and sulfuric acid may be mentioned, and the reaction temperature is preferably from room temperature to about 70 ° C. Since the reaction here is a substitution reaction at the ortho position of the carboxyl group of benzoic acids, the reaction proceeds similarly regardless of the presence of any substituents at other positions. Further, in order to prevent the formation of by-products, it is preferable to use one in which one ortho position of the carboxyl group is substituted, or one in which the same substituent is present in two meta positions of the carboxyl group.

Further, if necessary, in an organic solvent such as anhydrous tetrahydrofuran, acetone, dimethylformamide, a base such as N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine is added, and chloromethylmethyl is added. The hydroxyl group can be methoxymethylated by reacting with ether or the like.

In the above reaction, dimethylformamide used as a solvent is hydrolyzed in the presence of a strong base, and therefore, when dimethylformamide is used, N, N-
It is preferable to use amines such as diisopropylethylamine or triethylamine.

The following are specific examples of the production of the compound of formula II.

Example 1 Thionyl chloride was added to 30.0 g of 3,4-dimethoxybenzoic acid under ice cooling.
58.8 g was added, and the mixture was stirred at room temperature overnight. After distilling off excess thionyl chloride from this reaction mixture at atmospheric pressure, it was distilled under reduced pressure to obtain 3,4-dimethoxybenzoic acid chloride 3 as a green-white powdery crystal.
0.2 g was obtained (yield 91%).

After replacing 22.3 g of 2-amino-2-methyl-1-propanol with argon, 50 ml of anhydrous methylene chloride was added and dissolved, and this solution was stirred under ice-cooling with stirring and stirring for cooling with 25.1 g of 3,4-dimethoxybenzoic acid chloride (25.1 g). 150 ml of methylene solution was added dropwise, and the mixture was further stirred at room temperature for 2 hours. Water is added to this reaction mixture.
After adding 50 ml, extract with chloroform (350 ml x 2),
Chloroform layer is 5% sodium hydroxide aqueous solution 50 ml, 5
The extract was washed with 50% hydrochloric acid (50 ml) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a colorless foam substance. This N- (1,1-dimethyl-2-hydroxyethyl) -3,4-
Thionyl chloride was added to dimethoxybenzamide, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 200 ml of ether and crystallized to give 2- (3,4-dimethoxyphenyl) -4,4
-The hydrochloride of dimethyloxazoline was filtered off as white crystals. The white crystals were dissolved in 100 ml of water, made alkaline with 20% aqueous sodium hydroxide solution, extracted with ether (250 ml × 2), dried over potassium carbonate and magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily substance. It was This was distilled to obtain 24.4 g of colorless viscous substance 2- (3,4-dimethoxyphenyl) -4,4-dimethyl-2-oxazoline (yield 83%).

2960,2925,2895,2836, 1646,1604,1586,1514, 1464,1422,1358,1310, 1272,1260,1232,1172, 1140,1078,1026,974, 764,714 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.38 (6H, s), 3.91 (3H, s), 3.93 (3H, s), 4.08 (2H, s), 6.86 (1H, d, J = 8.3Hz), 7.46 (1H, d, J) = 2.0Hz), 7.53 (1H, dd, J = 8.3,2.0Hz) Mass spectrum: M / Z (%) 235 (M ⁺ , 35), 220 (100), 205 (7), 192 (25), 164 (24), 148 (5) This 2- (3,4-dimethoxyphenyl) -4,4-dimethyl-
After replacing 29.98 g of 2-oxazoline with argon and adding 270 ml of anhydrous tetrahydrofuran to dissolve it, the mixture was cooled to −45 ° C. and 95.6 ml of 1.6 Mn-butyllithium was added with stirring to give −45
The mixture was stirred at 0 ° C for 2 hours. 11.48 g of paraformaldehyde was added to this reaction solution at -45 ° C, and the mixture was stirred at -45 ° C for 1 hour.
Stir overnight at room temperature. Water was added to this reaction mixture, which was extracted with ether (300 ml × 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a yellow oily substance. To this was added 1.2 L of 3N hydrochloric acid aqueous solution, and the mixture was heated under reflux for 3 hours. The reaction mixture was left at room temperature overnight, and the precipitated needle crystals were collected by filtration to obtain 19.14 g of 4,5-dimethoxyphthalide (yield 77%).

2992,2964,2944,2836, 1752,1616,1498,1462, 1432,1368,1322,1276, 1226,1086,1024,996, 944,894,832,774,742, 656,562 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 3.95 (3H , s), 3.96 (3H, s), 5.32 (2H, s), 7.08 (1H, d, J = 8.3Hz), 7.62 (1H, d, J = 8.3Hz) Mass spectrum: M / Z (%) 194 (M ⁺ , 94), 179 (5), 165 (100), 151 (18), 137 (11), 123 (11), 108 (5), 92 (5), 77 (13), 63 ( 7) Concrete Example 2 28.88 g of silicic acid (3,5-dimethoxy-4-hydroxy-benzoic acid) was added to 570 ml of 35% hydrochloric acid and 1 part of dimethoxymethane.
4.2 ml was added, and the mixture was heated and stirred for 1.5 hours. The reaction solution was returned to room temperature, extracted with chloroform (500 ml × 2), washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 4,6-dimethoxy-5-. 16.97 g of hydroxyphthalide was obtained.

Furthermore, after dissolving this in 290 ml of anhydrous acetone, 80.56 g of potassium carbonate and 22.1 of methyl chloromethyl ether were added.
ml was added, and the mixture was stirred at room temperature overnight. The reaction mixture was removed under reduced pressure to remove acetone, water was added to dissolve excess potassium carbonate, and the insoluble material was collected by filtration. This was recrystallized from benzene to give 4,6-dimethoxy-5-white fine needle crystals.
12.10 g of methoxymethoxy-phthalide was obtained (yield 33
%).

2952,2840,1758,1616, 1482,1446,1432,1408, 1374,1344,1254,1210, 1138,1120,1100,1042, 1012,928,856,760 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 3.61 (3H , s), 9.62 (3H, s), 3.98 (3H, s), 5.20 (2H, s), 5.32 (2H, s), 7.16 (1H, s) Mass spectrum: M / Z (%) 254 (3 , M ⁺ ), 224 (2), 209 (1), 195 (1), 181 (2), 178 (1), 147 (1), 93 (1), 45 (100) Then, as described above The compound of formula II thus obtained is treated with a lithiating agent in an organic solvent and then with an acid to give a compound of formula II
React with I aldehyde. As a lithiating agent,
Lithium diisopropylamide and the like, and Lewis acid is preferably zinc halide, magnesium halide and the like, and specifically, zinc chloride, zinc bromide, zinc iodide, magnesium chloride, magnesium bromide, magnesium iodide and the like. Can be mentioned. The organic solvent used is preferably anhydrous tetrahydrofuran, ethers such as diethyl ether, and specific examples of the alkyl group of R ₅ in the aldehyde of formula III include a lower or middle alkyl group, preferably an alkyl group having about 1 to 10 carbon atoms. Groups, specifically, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, se
c-butyl group, n-pentyl group, isopentyl group, n-
Examples thereof include a hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group and an n-decyl group, and it is suitable to react at -70 ° C to room temperature.

After completion of the reaction, the compound of the formula IV can be obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

The secondary hydroxyl group of the compound of formula IV is then mesylated in an organic solvent to give the compound of formula V. Examples of the mesylation reagent include methanesulfonyl chloride-pyridine and the like, and specific examples of the organic solvent include anhydrous tetrahydrofuran, chloroform, methylene chloride and the like. The reaction is preferably carried out by heating from room temperature to about the boiling point of the solvent used.

Further, the mesyl group is eliminated by reacting the compound of formula V with an amine to give a compound of formula I. Specific examples of amines include 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) and 1,5-diazabicyclo [4,3,
[0] Nona-5-ene (DBN) and the like can be mentioned. As the solvent to be used, an organic solvent such as benzene can be mentioned, which is preferably carried out by heating from room temperature to about the boiling point of the solvent to be used.
After completion of the reaction, the compound of the formula I can be obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

The compound of formula I obtained as described above may be optionally subjected to operations such as demethylation, demethoxymethylation and reduction, if necessary.

Demethylation can be achieved by reacting an acid in water or an organic solvent. Specific examples of the acid include:
Examples include Lewis acids such as boron tribromide, boron trichloride, boron trifluoride, aluminum tribromide, aluminum trichloride, aluminum trifluoride, hydroiodic acid, hydrobromic acid or hydrochloric acid and trifluoroacetic acid. To be Specific examples of the organic solvent used include anhydrous methylene chloride, chloroform, ethanol and the like. 0 as reaction temperature
A temperature of about ℃ to room temperature is suitable.

Demethoxymethylation can be achieved by adding an acid and heating. Specific examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and Lewis acids such as zinc bromide and titanium chloride, and the solvent is preferably alcohols such as methanol and ethanol or ethers such as dioxane. Is.

The reduction is performed by reacting diborane in an organic solvent. Specific examples of the organic solvent include ethers such as anhydrous tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether.
Examples of the reducing agent include diborane, and the like.
Any reagent may be used as long as it can reduce only the carboxyl group of the compound of formula I.

Another method for obtaining the compound of formula I is the following formula VI (Wherein R _{1 to} R ₄ have the same meanings as described above) (hereinafter referred to as a compound of formula VI) in the presence of a base, by reacting an aldehyde of formula III (Wherein R _{1 to} R ₅ have the same meanings as described above) (hereinafter referred to as a compound of formula VII), and then oxidized to form a compound of formula VIII (In the formula, R _{1 to} R ₅ have the same meanings as described above.) A compound (hereinafter, referred to as a compound of formula VIII) is obtained, and a method of cyclizing and dehydrating the compound can also be mentioned.

Examples of the compound of formula VI as a raw material include commercially available 3-methoxybenzyl alcohol, 3,4-dimethoxybenzyl alcohol, 3,5-dimethoxybenzyl alcohol, and 3,4,5-trimethoxybenzyl alcohol. Examples of the organic solvent used include ethers such as anhydrous tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether. Specific examples of the base include n-butyllithium, sec-butyllithium, and tert-butyl. Lithium and the like, formula II
Examples of the aldehyde of I include the same aldehydes as described above. A suitable reaction temperature is from -80 ° C to a reflux temperature, but it is preferable to add tetramethylethylenediamine as a chelating agent especially at low temperatures. After the reaction, the compound of formula VII can be obtained by a commonly used general purification technique.

Since the above reaction is a substitution reaction at the 2-position of benzyl alcohols, the reaction proceeds similarly even if any substituent is present at other positions.

The compound of formula VII is then oxidized in an organic solvent. Examples of the oxidizing agent used include tetrabutylammonium permanganate and the like, and specific examples of the organic solvent include pyridine, benzene and the like, and the reaction is preferably carried out at about room temperature. After completion of the reaction, the compound of the formula VIII can be obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

Further, this is subjected to cyclization dehydration in an organic solvent to obtain a compound of formula I. Examples of the dehydrating agent used include thionyl chloride and sulfuric acid, and specific examples of the organic solvent include benzene, chloroform, methylene chloride and the like. The reaction temperature is preferably heated from room temperature to around 80 ° C., and after completion of the reaction, the compound of the formula I can be obtained by a commonly used general purification technique such as extraction, drying and solvent removal.

The compound of formula I obtained as described above may be optionally subjected to operations such as demethylation, demethoxymethylation and reduction, if necessary. Demethylation, demethoxymethylation, reduction and the like are achieved under the same conditions as described above.

Furthermore, as another method for obtaining the compound of the formula I, phthalic anhydrides previously substituted with a hydroxyl group, a methoxy group, a nitro group or the like and a compound of the formula B (R ₅ CO) ₂ O B (R ₅ are the same as those described above. The compound represented by the formula (hereinafter referred to as the compound of formula B) (hereinafter referred to as the compound of the formula B) can be reacted in the presence of sodium acetate.

Specific examples of the phthalic anhydrides include 3-nitrophthalic anhydride, 4-nitrophthalic anhydride and the like, and specific examples of the compound of the formula B include acetic anhydride, propionic anhydride,
Butyric anhydride, valeric anhydride, caproic anhydride, etc. are mentioned. As the reaction temperature, it is preferable to heat from room temperature to the temperature of the boiling point of the solvent used. Further, since the reaction is carried out in an anhydrous system, it is preferable to use anhydrous sodium acetate.

After the reaction, flash column chromatography,
The compound of formula I can be obtained by a general purification technique such as recrystallization. Examples of carriers for column chromatography include silica gel and the like, and as elution solvents, organic solvents such as ethyl acetate, n-hexane, chloroform, and benzene may be used alone, or a mixed solvent of two or more thereof may be used. it can. Further, as the solvent for recrystallization, the same solvent as described above can be used.

In addition, the compound of formula I obtained as described above may be further optionally demethylated, demethoxymethylated,
Operations such as reduction may be performed. Demethylation, demethoxymethylation, reduction and the like are achieved under the same conditions as described above.

Next, the present invention will be described more specifically with reference to examples.

Example 1 7.2 ml of diisopropylamine was added to 90 ml of anhydrous tetrahydrolane.
After dissolving in 1 l, the mixture was cooled to -10 ° C, 1.6M n-butyllithium (35.4 ml) was added with stirring, and the mixture was stirred for 30 minutes. Further, this solution was cooled to -70 ° C. and stirred under stirring to obtain 4,5-
A solution of 10.0 g of dimethoxyphthalide in anhydrous tetrahydrolane (200 ml) was added and stirred for 30 minutes, then the temperature was raised to -40 ° C and a solution of 8.42 g of anhydrous tetrahydrolane in zinc chloride (100
ml) was added and stirred for 1 hour. Then, at -40 ° C, a solution of 6.8 ml of n-butyraldehyde in anhydrous tetrahydrolane (30 m
l) was added and the mixture was stirred for 30 minutes and then at room temperature overnight.
The reaction mixture was poured into iced 5% aqueous hydrochloric acid solution, extracted with diethyl ether (300 ml × 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a brown oil. Flash column chromatography (silica gel 230-400 mesh, 150 g; diameter 6.5 cm, length 10 cm;
The eluate, ethyl acetate: n-hexane = 1: 1,0.2 kg / cm ² ) was collected in 150 ml aliquots and the 8th to 14th fractions were combined to give a yellow solid 4,5-dimethoxy-3. 13.24 g of-(1-hydroxybutyl) -phthalide was obtained (yield 97%).

3488,3004,2952,2932, 2860,2844,1746,1614, 1502,1456,1444,1402, 1358,1284,1226,1108, 1078,1022,974,958,878, 838,744,644 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ). : 0.88,0.96 (3H, t, J = 6.8Hz), 1.20-1.70 (4H, m), 1.92,2.79 (1H, d, J = 6.8,10.0Hz, disappears with addition of D ₂ O), 3.95,3.96 , 3.98,3.98 (6H, s), 5.50,5.53 (1H, d, J = 2.2,4.9Hz), 7.09,7.10 (1H, d, J = 8.3Hz), 7.64,7.65 (1H, d, J = 8.3Hz) Mass spectrum: M / Z (%) 266 (9, M ⁺ ), 248 (3), 219 (4), 194 (100), 179 (37), 166 (24), 151 (20), 136 (12), 122 (14), 107 (16), 77 (26) Next, 12.42 g of this 4,5-dimethoxy-3- (1-hydroxybutyl) -phthalide was replaced with argon, and then 30 ml of anhydrous benzene was added. Was added and dissolved, and 7.6 ml of anhydrous pyridine and 7.2 ml of methanesulfonyl chloride were added at room temperature, the mixture was stirred for 10 minutes, and further heated under reflux for 1 hour. The reaction mixture was returned to room temperature, poured into ice water and extracted with diethyl ether (300 ml × 2), washed with water and saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a brown oil. Apply this to flash column chromatography (silica gel, 230-400 mesh, 80 g, diameter 4.5 cm, length 10 cm; eluent, chloroform: methylene chloride = 1: 1,0.2 kg / cm ² ) in 100 ml increments. Fractionation was performed and the 3rd to 10th fractions were combined to obtain 16.03 g of 4,5-dimethoxy-3- (1-methanesulfonyloxybutyl) -phthalide as a colorless oily substance (yield 99%).

2960,2876,2840,1770, 1726,1614,1500,1462, 1352,1282,1226,1176, 1088,1076,1010,938,922, 898,800,738,526 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.84,1.03 (3H , t, J = 7.3Hz), 1.20-2.10 (4H, m), 2.55,3.13 (3H, s), 3.97,3.98,3.99,4.05 (6H, s), 5.26,5.41 [1H, ddd, (J = 1.0,1.5,8.0Hz), (J = 2.0,3.0,10.0Hz)], 5.55,5.92 (1H, d, J = 1.5Hz, J = 2.0Hz), 7.11,7.12 (1H, d, J = 8.3Hz), 7.60,7.64 (1H, d, J = 8.3Hz) Mass spectrum: M / Z (%) 344 (4, M ⁺ ), 248 (7), 219 (10), 206 (4), 193 (100), 179 (3), 163 (5), 150 (6), 135 (4), 122 (9), 79 (14), 55 (16) Furthermore, this 4,5-dimethoxy-3- ( After replacing 16.03 g of 1-methanesulfonyloxybutyl) -phthalide with argon, 150 ml of anhydrous benzene was added and dissolved, and then 1,8-
Diazabicyclo [5,4,0] undec-7-ene (9.75 ml) was added and the mixture was stirred at room temperature for 10 minutes and heated under reflux for 1 hour. The reaction mixture was returned to room temperature, poured into 100 ml of a 2% aqueous solution of hydrochloric acid in ice, extracted with ether (300 ml × 2), washed with water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid. . This was recrystallized from n-hexane to obtain 8.4 g of white needle crystals of (Z) -4,5-dimethoxy-3-butylidene-phthalide. Then, the mother liquor was distilled off under reduced pressure and then recrystallized from n-hexane to give (E) -4,5-dimethoxy-3-butylidene-phthalide 1 as white feathery crystals.
Obtained 65 mg. In addition, the mother liquor was further subjected to flash column chromatography (silica gel, 230-400 mesh, 200 g;
4.5 cm, length 25 cm; eluate, methylene chloride; 0.2 kg / cm ² ) to finally obtain (Z) -4,5-dimethoxy-
3-Butylidene-phthalide 8.58 g (74% yield), (E)
-4,5-dimethoxy-3-butylidene-phthalide 461mg
(Yield 4.0%) was obtained.

(Z) -4,5-dimethoxy-3-butylidene-phthalide 2948,2912,2872,2832, 1774,1680,1614,1498, 1458,1428,1342,1278, 1258,1194,1074,1054, 1020,992,934,888,816, 786,732,654,608 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.00 (3H, t, J = 7.3Hz), 1.56 (2H, tq, J = 7.3,7.3Hz), 2.45 (2H, dt, J = 7.9,7.3Hz), 3.95 (3H, s), 3.97 (3H, s), 5.98 (1H, t, J = 7.9Hz), 7.04 (1H, d, J = 8.3Hz), 7.62 (1H, d, J = 8.3Hz) Mass spectrum: M / Z (%) 248 (24 , M ⁺ ), 219 (100), 206 (18) 191 (19), 176 (8), 163 (8), 148 (6), 135 (11), 133 (6), 118 (6), 105 (9), 91 (6), 77 (11) (E) -4,5-dimethoxy-3-butylidene-phthalide 3096,2976,2948,2868, 2840,1784,1766,1668, 1612,1588,1496,1466, 1434,1374,1332,1280, 1266,1220,1192,1102, 1074,1018,926,888,872,828,792,732,652,580 Proton Nuclear Magnetic Resonance spectrum (δppm in CDCl ₃ ): 1.00 (3H, t, J = 7.3Hz), 1.56 (2H, tq, J = 7.3,7.3Hz), 2.73 (2H, dt, J = 8.4,7.3Hz), 5.91 (1H, t, J = 8.4Hz), 7.12 (1H, d, J = 8.3Hz), 7.67 (1H, d, J = 8.3Hz) Mass spectrum: M / Z (%) 248 (29, M ⁺ ) , 219 (100), 206 (18) 191 (12), 176 (4), 163 (4), 148 (3), 135 (4), 133 (2), 131 (2), 105 (3), 77 (3) Example 2 7.5 g of (Z) -4,5-dimethoxy-3-butylidene-phthalide obtained in Example 1 was replaced with argon, and 75 ml of anhydrous methylene chloride was added and dissolved, followed by cooling with ice. 151 ml of a 0.8 M solution of boron tribromide in methylene chloride was added, and the mixture was stirred for 30 minutes and further stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, extracted with methylene chloride, and then extracted with ethyl acetate (300 ml × 2). The extracts were combined and washed with saturated saline,
After drying over magnesium sulfate, the solvent was removed under reduced pressure to obtain a yellow solid. Flash column chromatography (silica gel, 230-400 mesh, 35 g; diameter 4.5 cm, length 5 cm;
Eluate, acetone: ethyl acetate = 1: 10,0.2 kg / cm ² ) and collect 50 ml each, and combine the 12th to 23rd fractions to obtain 4,5-dihydroxy-3-butylidenephthalide 5.38. g
Was obtained (yield 81%).

3388,3170,2960,2932, 2872,1724,1678,1626, 1614,1530,1512,1456, 1394,1332,1302,1256, 1192,1156,1098,1040, 926,780,726 Proton nuclear magnetic resonance spectrum (δppm in CD ₃ OD): 1.00 (3H, t, J = 7.3Hz), 1.56 (2H, tq, J = 7.3,7.3Hz), 2.41 (2H, dt, J = 7.8,7.3Hz), 5.95 (IH, t, J = 7.8Hz), 6.95 (1H, d, J = 8.1Hz), 7.23 (1H, d, J = 8.1Hz) Mass spectrum: M / Z (%) 220 (34, M ⁺ ), 191 (100) , 178 (60) 163 (27), 150 (5), 145 (6), 135 (8), 117 (4), 108 (6), 89 (5), 77 (4), 55 (9) Example 3 5.5 ml of diisopropylamine was added to 70 m of anhydrous tetrahydrolane.
After dissolving in 1 l, the mixture was cooled to -10 ° C, 27.0 ml of 1.6Mn-butyllithium was added with stirring, and the mixture was stirred for 30 minutes. Further, while stirring this solution at -10 ° C, an anhydrous tetrahydrolane solution (120 ml) of 10.0 g of 4,6-dimethoxy-5-methoxymethoxyphthalide obtained in Example 2 was added and stirred for 10 minutes,
The temperature was raised to 0 ° C. and the mixture was stirred for 1 hour, an anhydrous tetrahydrolane solution (100 ml) of 6.7 g of zinc chloride was added, and the mixture was stirred for 30 minutes. Then cooled to -40 ℃, n- butyraldehyde 5.2m
l anhydrous tetrahydrolane solution (20 ml) was added, and the mixture was stirred for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice 2% aqueous hydrochloric acid and extracted with diethyl ether (400 m
1 × 2), washed with water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a brown oily substance. Flash column chromatography (silica gel)
230-400 mesh, 300 g: 6.5 cm in diameter, 20 cm in length; eluate, ethyl acetate: n-hexane = 2: 3, 0.2 kg / cm ² ) A colorless oily substance, 4,6-dimethoxy-5-methoxymethoxy-3-, was combined with Fraction.
4.98 g of (1-hydroxybutyl) -phthalide was obtained (yield 39%).

3476,1956,1764,1616, 1480,1426,1344,1160, 1112,1086,1020,942, 854,766 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.88,0.97 (3H, t, J = 6.8Hz) , 1.20-1.65 (4H, m), 1.84,2.77 (1H, d, J = 9.3Hz, J = 7.0Hz, disappeared by adding D ₂ O), 3.60 (3H, s), 3.91,3.92,3.98,3.99 (6H, s), 3.80-4.05 (1H, m), 5.20,5.23,5.29,5.32 (2H, d, J = 6.0Hz), 5.46,5.49 (1H, d, J = 1.7Hz, J = 4.9Hz ), 7.17,7.18 (1H, s) Mass spectrum: M / Z (%) 326 (1, M ⁺ ), 308 (1), 279 (4), 264 (9), 254 (25), 235 (2) ), 224 (4), 222 (4), 209 (30), 192 (4), 167 (9), 149 (18), 113 (3), 45 (100) Next, this 4,6-dimethoxy -5-methoxymethoxy-3
After 2.33 g of-(1-hydroxybutyl) -phthalide was replaced with argon, 5 ml of anhydrous benzene was added and dissolved, and 1.1 ml of anhydrous pyridine and 1.1 ml of methanesulfonyl chloride were added at room temperature and stirred for 10 minutes, and further heated for 15 minutes. Refluxed.
The reaction mixture was returned to room temperature, poured into ice water and extracted with diethyl ether (100 ml × 2), washed with water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. Flash column chromatography (silica gel, 230-400 mesh, 80 g, diameter 4.5 c
m, length 10 cm; eluate, ethyl acetate: n-hexane = 2: 3, 0.2
kg / cm ² ), 50 ml aliquots were collected and the 8th to 11th fractions were combined, and white amorphous 4,6-dimethoxy-5-methoxymethoxy-3- (1-methanesulfonyloxybutyl)- 1.91 g of phthalide was obtained (yield 66%).

3024,2952,2870,2840, 1770,1620,1480,1430, 1354,1250,1176,1162, 1116,1106,1080,1028, 966,942,918,896,852, 804,764,558,526 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.85,1.03 (3H, t, J = 7.3Hz), 0.95-1.80,1.90-2.10 (4H, m) 2.54,3.14 (3H, s), 3.59,3.60 (3H, s), 3.92,3.93,4.01,4.07 (6H , s), 5.17,5.20,5.21,5.24 (2H, s), 5.25,5.35 (1H, ddd, J = 1.5,3.0,10.0Hz, J = 2.2,3.0,10.
0Hz), 5.53,5.89 (1H, d, J = 1.5Hz, J = 2.2Hz), 7.16,7.17 (1H, s) Mass spectrum: M / Z (%) 404 (5, M ⁺ ), 372 (2 ), 309 (2), 308 (2), 279 (2), 264 (33), 253 (4), 235 (10), 223 (4), 209 (6), 45 (100) , 6-Dimethoxy-5-methoxymethoxy-3- (1-methanesulfonyloxybutyl) -phthalide
After replacing 1.66 g with argon, 13 ml of anhydrous benzene was added to dissolve it, then 0.92 ml of 1,8-diazabicyclo [5,4,0] undec-7-ene was added, and the mixture was stirred at room temperature for 10 minutes and heated under reflux for 1 hour. did. The reaction mixture is allowed to come to room temperature and ice 2%
Pour into 50 ml of aqueous hydrochloric acid and extract with diethyl ether (100 m
lx2), washed with water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. Flash column chromatography (silica gel, 2
30-400 mesh, 200 g; diameter 4.5 cm, length 25 cm; eluent, methylene chloride: chloroform = 1: 1; 0.2 kg / cm ² ), 30 m
Fractions 8 to 29 were combined by fractionation to give 802 mg of colorless oily substance (Z) -4,6-dimethoxy-5-methoxymethoxy-3-butylidenephthalide (yield 63
%). Further, the 31st to 42nd fractions were combined to obtain 182 mg of colorless oily substance (E) -4,6-dimethoxy-5-methoxymethoxy-3-butylidenephthalide (yield 14
%).

(Z) -4,6-dimethoxy-5-methoxymethoxy-3
-Butylidene-phthalide 2956,1870,2840,1776, 1681,1609,1481,1429, 1398,1337,1267,1207, 1161,1130,1100,1044, 1022,991,960,936,766 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.99 (3H , t, J = 7.3Hz), 1.55 (2H, tq, J = 7.3,7.3Hz), 2.44 (2H, dt, J = 7.9,7.3Hz), 3.62 (3H, s), 3.92 (3H, s) , 3.98 (3H, s), 5.22 (2H, s), 5.84 (1H, t, J = 7.9Hz), 7.15 (1H, s) Mass spectrum: M / Z (%) 308 (7, M ⁺ ), 279 (5), 265 (3), 263 (4), 249 (3), 246 (2), 235 (2), 233 (3), 221 (1), 217 (1), 207 (1), 205 (1), 93 (1), 45 (100) (E) -4,6-dimethoxy-5-methoxymethoxy-3
-Butylidenephthalide 2956,1770,1664,1610, 1480,1430,1370,1336, 1238,1204,1160,1112, 1072,1040,968,936, 848,766 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.00 (3H, t, J = 7.3Hz), 1.56 (2H, tq, J = 7.3,7.3Hz), 2.70 (2H, dt, J = 8.4,7.3Hz), 3.63 (3H, s), 3.93 (3H, s), 3.94 (3H , s), 5.22 (2H, s), 5.83 (1H, t, J = 8.4Hz), 7.20 (1H, s) Mass spectrum: M / Z (%) 308 (7, M ⁺ ), 279 (5) , 265 (3), 263 (4), 249 (3), 246 (2), 235 (2), 233 (3), 221 (1), 217 (1), 207 (1), 93 (1) , 45 (100) Example 4 To 1.23 g of (Z) -4,6-dimethoxy-5-methoxymethoxy-3-butylidenephthalide obtained in Example 3 was dissolved 10 ml of dioxane, and then 2 ml of phosphoric acid. Add at room temperature 1
The mixture was stirred for 0 minutes and heated under reflux for 10 minutes. The reaction solution was returned to room temperature, water 1 was added to precipitate crystals, and the crystals were collected by filtration to obtain 873 mg of (Z) -4,6-dimethoxy-5-hydroxy-3-butylidenephthalide as white fine needle crystals. (Yield 8
3%) 3384,2988,2948,2864, 2832,1744,1680,1614, 1596,1502,1480,1458, 1428,1372,1336,1280, 1228,1204,1180,1152, 1098,1052,1018,960, 924,868,780,754,706, 528 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.98 (3H, t, J = 7.3Hz), 1.55 (2H, tq, J = 7.3,7.3Hz), 2.44 (2H, dt, J = 7.9,7.3) Hz), 3.98 (3H, s), 4.03 (3H, s), 5.85 (1H, t, J = 7.9Hz), 6.12 (1H, s, disappears by adding D ₂ O), 7.26 (1H, s) mass Spectrum: M / Z (%) 264 (30, M ⁺ ), 235 (100), 222 (9), 207 (14), 192 (2), 179 (3), 164 (2), 149 (2) , 137 (3), 55 (4) Example 5 1 ml of dioxane was added to 145 mg of (E) -4,6-dimethoxy-5-methoxymethoxy-3-butylidenephthalide obtained in Example 3 and dissolved Phosphoric acid (0.25 ml) was added, the mixture was stirred at room temperature for 10 minutes, and heated under reflux for 10 minutes. The reaction solution is returned to room temperature and 100 ml of water is added to precipitate crystals,
(E) -4,6-dimethoxy-5 in the form of fine white needle crystals was obtained by filtration.
91 mg of -hydroxy-3-butylidenephthalide was obtained (yield 73%).

3448,2952,2868,2844, 1782,1666,1620,1502, 1478,1436,1376,1332, 1266,1190,1154,1108, 1044,1026,928,866, 848,782,750,556 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ). : 1.00 (3H, t, J = 7.3Hz), 1.55 (2H, tq, J = 7.3,7.3Hz), 2.71 (2H, dt, J = 8.4,7.3Hz), 4.00 (3H, s), 4.02 ( 3H, s), 5.83 (IH, t, J = 8.4Hz), 6.14 (1H, s, disappears by adding D ₂ O), 7.17 (1H, s) Mass spectrum: M / Z (%) 264 (29, M ⁺ ), 235 (100), 222 (9), 207 (14), 192 (2), 179 (4), 164 (2), 149 (3), 137 (3), 55 (4) Example 6 After replacing 3.0 g of 3-methoxybenzyl alcohol with nitrogen,
75 ml of anhydrous n-hexane and 6.9 ml of tetramethylethylenediamine were added and dissolved. To this solution was added 1.6M n-butyllithium (28.5 ml), the mixture was stirred at room temperature for 10 minutes, and then heated under reflux on an oil bath for 5 hours. The obtained reddish brown suspension was-
After cooling to 78 ° C, propionaldehyde 2.52g anhydrous n
-Hexane solution (15 ml) was added, and the mixture was stirred at -78 ° C for 1 hr and then at room temperature overnight. After adding 50 ml of water-containing diethyl ether to the reaction mixture to terminate the reaction, under cooling, dilute hydrochloric acid was added to acidify, extraction with diethyl ether (150 ml x 2), washing with water and saturated saline, and drying with magnesium sulfate. The solvent was removed under reduced pressure to give a yellow oil. This oily matter was subjected to flash column chromatography (silica gel, 230-400 mesh, 300 g, diameter 6.5 cm, length 20 c).
m; eluate, ethyl acetate: chloroform = 1: 1), 5
Fractions from the 12th to 14th fractions were combined to obtain 1.93 g of 3-methoxy-2- (1-hydroxypropyl) -benzyl alcohol (yield 45%).

3384,2964,2932,2872, 2836,1584,1464,1254, 1076,1040,1012,964,744 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.93 (3H, t, J = 7.5Hz), 2.62-3.02 (2H, m), 3.50 (disappeared by adding 1H, bs, D ₂ O), 3.85 (disappear by adding 1H, bs, D ₂ O), 3.82 (3H, s), 4.53 (1H, d, J = 12.0 Hz), 4.69 (1H, d, J = 12.0Hz), 4.94 (1H, bs), 6.84 (1H, d, J = 8.0Hz), 6.94 (1H, d, J = 8.0Hz), 7.19 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 196 (1, M ⁺ ), 167 (28), 149 (100) 91 (33) Next, 3-methoxy-2- (1 -Hydroxypropyl) -benzyl alcohol (100 mg) was dissolved in anhydrous pyridine (1 ml), and a solution of tetrabutylammonium permanganate (515 mg) in anhydrous pyridine (4 ml) was added dropwise with stirring at room temperature, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid under ice cooling, acidified, and extracted with diethyl ether (50
ml × 2), the ether layer was extracted with 5% sodium hydroxide solution, gradually acidified with dilute hydrochloric acid under ice cooling, extracted with benzene (50 ml × 3), washed with saturated saline solution, dried with magnesium sulfate, and used as a solvent. Was removed under reduced pressure to obtain 75 mg of 3-methoxy-2-propionyl-benzoic acid as white needles (yield 70%).

3348,2976,2940,2844, 1738,1614,1494,1304, 1282,1136,1056,928, 868,754 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.86 (3H, t, J = 7.0Hz), 1.70 -2.60 (Disappeared by adding 1H, br, D ₂ O) 2.36 (2H, q, J = 7.0Hz), 3.94 (3H, s), 7.15 (1H, d, J = 8.0Hz), 7.44 (1H, d , J = 8.0Hz), 7.52 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 208 (2, M ⁺ ), 179 (100) 3-methoxy-2-propionyl-benzoic acid Dissolve 54 mg of acid in 0.3 ml of anhydrous benzene, then add 0.06 ml of thionyl chloride at room temperature.
Was added, stirred for 30 minutes, and heated on an oil bath for 30 minutes. The reaction mixture was removed under reduced pressure to remove excess thionyl chloride to obtain a crystalline solid. Flash column chromatography (silica gel, 230-400 mesh, 50
g; diameter 3.5 cm, length 10 cm; eluate, chloroform)
37 mg of (Z) -4-methoxy-3-ethylidenephthalide was obtained (yield 75%).

3012,2980,2944,2840, 1764,1684,1600,1494, 1434,1304,1274,1042, 996,756 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 2.01 (3H, d, J = 7.3Hz), 3.98 (3H, s), 5.99 (1H, q, J = 7.3Hz), 7.12 (1H, dd, J = 1.5,7.5Hz), 7.41 (1H, dd, J = 7.5,7.5Hz), 7.47 (1H, dd, J = 1.5,7.5Hz) Mass spectrum: M / Z (%) 190 (100, M ⁺ ), 175 (9), 171 (10), 161 (22), 147 (13), 144 (14) , 134 (25), 133 (25), 131 (13), 105 (19), 104 (21), 76 (25) Example 7 After substituting 3.0 g of 3-methoxybenzyl alcohol with nitrogen,
75 ml of anhydrous n-hexane and 6.9 ml of tetramethylethylenediamine were added and dissolved. To this solution was added 1.6M n-butyllithium (28.5 ml), the mixture was stirred at room temperature for 10 minutes, and then heated under reflux on an oil bath for 5 hours. The obtained reddish brown suspension was-
After cooling to 78 ° C., a solution of 3.1 g of n-butyraldehyde in anhydrous n-hexane (15 ml) was added, and the mixture was stirred at −78 ° C. for 1 hour and then at room temperature overnight. After 50 ml of water-containing diethyl ether was added to the reaction mixture to terminate the reaction, under cooling,
Add dilute hydrochloric acid to acidify and extract with diethyl ether (15
It was washed with 0 ml × 2), water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oil. This oily substance was subjected to flash column chromatography (silica gel, 230-400 mesh, 300 g, diameter 6.5 cm, length 20 cm; eluent, ethyl acetate: chloroform = 1: 2), collecting 50 ml each. , And the 13th to 18th fractions were combined to obtain 2.13 g of 3-methoxy-2- (1-hydroxybutyl) -benzyl alcohol (yield 47%).

3384,2956,2868,1584, 1468,1256,1078,1060, 1026,786,744 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.91 (3H, t, J = 3.0Hz), 1.04-2.04 (4H, m ), 3.50 (disappeared by adding 1H, bs, D ₂ O), 3.83 (3H, s), 3.84 (disappear by adding 1H, bs, D ₂ O), 4.53 (1H, d, J = 12.0Hz), 4.70 (1H, d, J = 12.0Hz), 5.04 (1H, bs), 6.85 (1H, d, J = 8.0Hz), 6.95 (1H, d, J = 8.0Hz), 7.19 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 210 (1, M ⁺ ), 167 (29), 149 (100) 91 (26) Next, 3-methoxy-2- (1-hydroxybutyl) -After dissolving 150 mg of benzyl alcohol in 1 ml of anhydrous pyridine,
An anhydrous pyridine solution (4 ml) of tetrabutylammonium permanganate (695 mg) was added dropwise with stirring at room temperature, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid under ice cooling, acidified, and extracted with diethyl ether (50 ml x
2) The ether layer was extracted with 30 ml of 5% sodium hydroxide solution, gradually acidified with dilute hydrochloric acid under ice cooling, extracted with benzene (50 ml x 3), washed with saturated saline solution, dried with magnesium sulfate, and the solvent was added. Removal under reduced pressure gave 115 mg of 3-methoxy-2-butyryl-benzoic acid as a colorless oil (yield 73%).

3348,2952,2872,2844, 1744,1616,1492,1276, 1138,1056,932,858,756 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.91 (3H, t, J = 7.0Hz), 1.15-1.45 (2H , m), 2.31 (2H, t, J = 7.0Hz), 1.95-2.80 (1H, br, D ₂ O disappears when added), 3.94 (3H, s), 7.14 (1H, d, J = 8.0Hz) , 7.44 (1H, d, J = 8.0Hz), 7.52 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 222 (2, M ⁺ ), 179 (100) 3-methoxy After 1.21 g of 2-butyryl-benzoic acid was dissolved in 5 ml of anhydrous benzene, 1.2 ml of thionyl chloride was added at room temperature, stirred for 30 minutes, and further heated on an oil bath for 30 minutes. The reaction mixture was removed under reduced pressure to remove excess thionyl chloride to obtain a crystalline solid. Flash column chromatography (silica gel, 230-400 mesh, 80 g; diameter
4.5cm, length 10cm; eluate, chloroform)
792 mg of (Z) -4-methoxy-3-propylidenephthalide was obtained (71% yield).

2956,2872,2840,1768, 1682,1604,1494,1432, 1294,1270,1042,986, 746 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 1.14 (3H, t, J = 7.5Hz), 2.49 (2H, dq, J = 8.0,7.5Hz), 3.99 (3H, s), 5.96 (1H, t, J = 8.0Hz), 7.12 (1H, dd, J = 1.5,7.5Hz), 7.42 (1H, dd, J = 7.5,7.5Hz), 7.48 (1H, dd, J = 1.5,7.5Hz) Mass spectrum: M / Z (%) 204 (50, M ⁺ ), 189 (100), 176 (11), 161 (14), 134 (13), 105 (8), 76 (11) Example 8 After substituting 5.0 g of 3-methoxybenzyl alcohol with nitrogen,
130 ml of anhydrous n-hexane and 11.4 ml of tetramethylethylenediamine were added and dissolved. To this solution, 47.3 ml of 1.6 M n-butyllithium was added, and the mixture was stirred at room temperature for 10 minutes and then heated under reflux on an oil bath for 5 hours. The obtained reddish brown suspension was cooled to -78 ° C, and then n-valeraldehyde 6.2 g of anhydrous n-
A hexane solution (20 ml) was added, and the mixture was stirred at -78 ° C for 1 hr and then at room temperature overnight. After 50 ml of water-containing diethyl ether was added to the reaction mixture to terminate the reaction, under cooling,
Add dilute hydrochloric acid to acidify and extract with diethyl ether (20
It was washed with 0 ml × 2), water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oil. This oily substance was subjected to flash column chromatography (silica gel, 230-400 mesh, 380 g, diameter 6.5 cm, length 25 cm; eluent, ethyl acetate: chloroform = 1: 2), collecting 50 ml each. , 15th to 24th fractions were combined to give 4.72 g of 3-methoxy-2- (1-hydroxypentyl) -benzyl alcohol (yield 58%).

3410,2952,2928,2860, 1584,1465,1254,1038, 1014,754 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.89 (3H, t, J = 3.0Hz), 096-2.04 (6H, m ), 2.96 (disappeared by adding 1H, bs, D ₂ O), 3.64 (disappear by adding 1H, bs, D ₂ O), 3.85 (3H, s), 4.58 (1H, d, J = 12.0Hz), 4.75 (1H, d, J = 12.0Hz), 5.05 (1H, bs), 6.87 (1H, d, J = 8.0Hz), 6.96 (1H, d, J = 8.0Hz), 7.21 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 224 (1, M ⁺ ), 167 (27), 149 (100), 91 (19) Next, 3-methoxy-2- (1-hydroxypentyl) ) -Benzyl alcohol (3.01 g) was dissolved in anhydrous pyridine (20 ml), and a solution of tetrabutylammonium permanganate (12.09 g) in anhydrous pyridine (40 ml) was added dropwise with stirring at room temperature, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid containing a small amount of sodium sulfite under ice cooling, acidified and extracted with diethyl ether (300 ml × 2), the ether layer was extracted with 5% sodium hydroxide solution 100 ml, and cooled under ice cooling. Gradually acidify with dilute hydrochloric acid and extract with benzene (300 ml
X2), washed with saturated saline solution, dried with magnesium sulfate,
The solvent was removed under reduced pressure to obtain 2.35 g of 3-methoxy-2-valeryl-benzoic acid as a colorless oily substance (yield 74%).

3288,2952,2928,2868, 1726,1614,1492,1278, 1158,1056,852,756 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.85 (3H, t, J = 7.0Hz), 1.05-1.40 (4H , m), 2.32 (2H, t, J = 7.0Hz), 3.93 (3H, s), 3.50-3.98 (disappeared by addition of 1H, br, D ₂ O), 7.14 (1H, dd, J = 1.0,8.0) Hz), 7.42 (1H, dd, J = 1.0,8.0Hz), 7.50 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 236 (1, M ⁺ ), 179 (100 ) 2.08 g of 3-methoxy-2-valeryl-benzoic acid was dissolved in 10 ml of anhydrous benzene, 2.0 ml of thionyl chloride was added at room temperature, the mixture was stirred for 30 minutes, and further heated on an oil bath for 30 minutes. The reaction mixture was removed under reduced pressure to remove excess thionyl chloride to obtain a crystalline solid. Flash column chromatography (silica gel, 230-400 mesh, 80 g; diameter
4.5 cm, length 10 cm; eluent, chloroform),
1.52 g of (Z) -4-methoxy-3-butylidenephthalide was obtained (yield 78%).

2952,2864,1768,1682, 1604,1494,1434,1282, 1042,746 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.99 (3H, t, J = 7.3Hz), 1.55 (2H, tq, J = 7.3,7.3Hz), 2.45 (2H, dt, J = 8.0,7.3Hz), 3.99 (3H, s), 5.97 (1H, t, J = 8.0Hz), 7.13 (1H, dd, J = 1.5, 7.5Hz), 7.42 (1H, dd, J = 7.5,7.5Hz), 7.48 (1H, dd, J = 1.5,7.5Hz), mass spectrum: M / Z (%) 218 (23, M ⁺ ), 189 (100), 176 (6), 161 (12), 131 (10), 105 (10), 76 (15) Example 9 After replacing 3.0 g of 3-methoxybenzyl alcohol with nitrogen,
75 ml of anhydrous n-hexane and 6.9 ml of tetramethylethylenediamine were added and dissolved. To this solution was added 1.6M n-butyllithium (28.5 ml), the mixture was stirred at room temperature for 10 minutes, and then heated under reflux on an oil bath for 5 hours. The obtained reddish brown suspension was-
After cooling to 78 ° C, a solution of 4.6 g of n-caproaldehyde in anhydrous n-hexane (15 ml) was added, and the mixture was stirred at -78 ° C for 1 hr and then at room temperature overnight. After 50 ml of water-containing diethyl ether was added to the reaction mixture to terminate the reaction, under cooling,
Add dilute hydrochloric acid to acidify and extract with diethyl ether (15
It was washed with 0 ml × 2), water and saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oil. This oily substance was subjected to flash column chromatography (silica gel, 230-400 mesh, 300 g, diameter 6.5 cm, length 20 cm; eluent, ethyl acetate: chloroform = 1: 2), collecting 50 ml each. , 12th-18th fraction were combined to obtain 2.26 g of 3-methoxy-2- (1-hydroxyhexyl) -benzyl alcohol (yield 44%).

3292,2956,2928,2852, 1582,1468,1262,1054, 1004,798,748 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 0.86 (3H, t, J = 7.0Hz), 0.96-2.00 (8H, m ), 3.60 (disappeared by adding 1H, bs, D ₂ O), 3.81 (3H, s), 4.04 (disappear by adding 1H, bs, D ₂ O), 4.51 (1H, d, J = 12.0Hz), 4.68 (1H, d, J = 12.0Hz), 5.02 (1H, bs), 6.83 (1H, d, J = 8.0Hz), 6.93 (1H, d, J = 8.0Hz), 7.18 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 238 (1, M ⁺ ), 167 (21), 149 (100) 91 (25) Next, 3-methoxy-2- (1-hydroxyhexyl) After dissolving 329 mg of -benzyl alcohol in 2 ml of anhydrous pyridine, a solution of 1.35 g of tetrabutylammonium permanganate in anhydrous pyridine (6 ml) was added dropwise with stirring at room temperature and further stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid containing a small amount of sodium sulfite under ice cooling, acidified and extracted with diethyl ether (50 ml × 2), and the ether layer was extracted with 5 ml of 5% sodium hydroxide solution under ice cooling. Gradually acidify with dilute hydrochloric acid and extract with benzene (100 ml x
2), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 275 mg of 3-methoxy-2-hexanoyl-benzoic acid as a colorless oil (yield 80%).

3328,2952,2928,2864, 1772,1614,1492,1276, 1140,1050,926,866,764 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.83 (3H, t, J = 7.0Hz), 1.03-1.47 (6H , m), 2.10-2.50 (2H, m), 3.90 (3H, s), 5.05-6.20 (disappeared by adding 1H, br, D ₂ O), 7.12 (1H, d, J = 8.0Hz), 7.35- 7.55 (2H, m) Mass spectrum: M / Z (%) 250 (1, M ⁺ ), 179 (100) 3-methoxy-2-hexanoyl-benzoic acid 1.04 g was dissolved in anhydrous benzene 4 ml, then at room temperature. 0.9 ml of thionyl chloride was added thereto, and the mixture was stirred for 30 minutes and further heated on an oil bath for 30 minutes.
The reaction mixture was removed under reduced pressure to remove excess thionyl chloride to obtain a crystalline solid. Flash column chromatography (silica gel, 230-400 mesh, 80 g; diameter
4.5cm, length 10cm; eluate, chloroform), 50ml
Each of the 5th and 8th fractions will be merged,
719 mg of (Z) -4-methoxy-3-pentylidenephthalide was obtained (yield 74%).

2948,2920,2848,1764, 1682,1604,1496,1434, 1294,1274,1042,988,746 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.94 (3H, d, J = 7.3Hz), 1.30-1.60 (4H, m), 2.48 (2H, dt, J = 8.0,7.3Hz), 3.99 (3H, s), 5.96 (1H, t, J = 8.0Hz), 7.12 (1H, dd, J = 1.5,7.5) Hz), 7.42 (1H, dd, J = 7.5,7.5Hz), 7.48 (1H, dd, J = 1.5,7.5Hz), mass spectrum: M / Z (%) 232 (21, M ⁺ ), 189 ( 100), 176 (26), 161 (10), 131 (7), 105 (14), 76 (5) Example 10 After replacing 1.38 g of 3-methoxybenzyl alcohol with nitrogen, 20 ml of anhydrous n-hexane and tetra 3.2 ml of methylethylenediamine was added and dissolved. To this solution was added 1.6M n-butyllithium 13.2 ml, and after stirring at room temperature for 10 minutes,
The mixture was heated under reflux on an oil bath for 5 hours. The obtained reddish brown suspension was cooled to -78 ° C, and then an anhydrous n-hexane solution (5 ml) of 1.74 g of 5-formyl-valeric acid ethyl ester was added, and the mixture was -78 ° C.
After stirring for 30 minutes at room temperature, the mixture was stirred at room temperature for 1 hour. After adding 20 ml of water-containing diethyl ether to the reaction mixture to terminate the reaction, add 2% hydrochloric acid to make it weakly acidic under cooling, extract with diethyl ether (100 ml × 2), wash with water and saturated saline, and add sulfuric acid. The extract was dried over magnesium and the solvent was removed under reduced pressure to give a yellow oily substance. This oily matter was subjected to flash column chromatography (silica gel, 230-400 mesh, 300
g, diameter 4.5 cm, length 25 cm; eluate, ethyl acetate: chloroform = 1: 2), 50 ml aliquots were added, and the 15th-18th fractions were combined to form 6- (2-hydroxymethyl). Ethyl-6-methoxyphenyl) -6-hydroxyhexanoate 645mg
Was obtained (yield 22%).

3432,2940,2864,1730, 1584,1466,1374,1256, 1182,1074,1028,782,746 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 1.23 (3H, t, J = 7.0Hz), 1.30-2.05 (6H, m), 2.27 (2H, t, J = 7.0Hz), 3.50 (disappeared by adding 1H, bs, D ₂ O), 3.83 (3H, s), 3.93 (by adding 1H, bs, D ₂ O) Loss), 4.09 (2H, q, J = 7.0Hz), 4.53 (1H, d, J = 12.0Hz), 4.72 (1H, d, J = 12.0Hz), 5.03 (1H, bs), 6.85 (1H, d, J = 8.0Hz), 6.94 (1H, d, J = 8.0Hz), 7.19 (1H, dd, J = 8.0,8.0Hz) Mass spectrum: M / Z (%) 278 (12, M ⁺ ), 233 (8), 167 (34), 149 (100), 91 (16) Next, 6- (2-hydroxymethyl-6-methoxyphenyl)
600 mg of ethyl 6-hydroxyhexanoate was added to anhydrous pyridine 6
After being dissolved in ml, a solution of 1.82 g of tetrabutylammonium permanganate in anhydrous pyridine (6 ml) was added dropwise with stirring at room temperature and further stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid containing a small amount of sodium sulfite under ice cooling, acidified, extracted with benzene (100 ml × 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a yellow color. 508 mg of 3-methoxy-2- (5-ethoxycarbonylvaleryl) -benzoic acid was obtained as an oil (yield 81
%).

3416,2936,1730,1658, 1596,1468,1276,1180, 1060,762,728 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): (1.00-1.80 (disappeared by addition of 1H, br, D ₂ O), 1.20 ( 3H, t, J = 7.0Hz), 1.30-1.80 (4H, m), 2.10-2.48 (4H, m), 3.92 (3H, s), 4.06 (2H, q, J = 7.0Hz), 7.14 (1H , d, J = 8.0Hz), 7.24-7.68 (2H, m) Mass spectrum: M / Z (%) 308 (1, M ⁺ ), 256 (38), 179 (100), 149 (27), 135 (78), 101 (27) 3-methoxy-2- (5-ethoxycarbonylvaleryl) -benzoic acid (500 mg) was dissolved in anhydrous benzene (3 ml), thionyl chloride (0.35 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The mixture was further heated on an oil bath for 30 minutes, and the reaction mixture was removed under reduced pressure to remove excess thionyl chloride to obtain a brown oily substance, which was then subjected to flash column chromatography (silica gel, 230-4).
00 mesh, 160 g; diameter 4.5 cm, length 20 cm; eluate, ethyl acetate: n-hexane = 1: 2.5)
Merged the 13th fraction, (Z) -4-methoxy-
3- (4-ethoxycarbonylbutylidene) phthalide 273mg
Was obtained (yield 58%).

2980,2944,1764,1730, 1684,1604,1496,1434, 1272,1160,1040,988,746 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.25 (3H, t, J = 7.3Hz), 1.88 (2H , tt, J = 7.3,7.3Hz), 2.39 (2H, t, J = 7.3Hz), 2.51 (2H, dt, J = 8.0,7.3Hz), 3.99 (3H, s), 4.13 (2H, q, J = 7.3Hz), 5.93 (1H, t, J = 8.0Hz), 7.06-7.10 (1H, m), 7.40-7.48 (2H, m) Mass spectrum: M / Z (%) 290 (23, M ⁺ ), 245 (12), 216 (8), 202 (100), 189 (19), 174 (6), 161 (3), 131 (3), 83 (14) Example 11 Obtained in Example 6. After replacing 200 mg of (Z) -4-methoxy-3-ethylidenephthalide with argon, anhydrous methylene chloride 2.5
ml was added to dissolve it, and a 0.8 M solution of boron tribromide in methylene chloride (2.8 ml) was added thereto under ice-cooling stirring, and the mixture was stirred at room temperature for 4 minutes.
Stir for hours. The reaction mixture was poured into 50 ml of ice water, extracted with diethyl ether (100 ml × 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a white solid. This was recrystallized from benzene to give (Z) -4-hydroxy-3-ethylidenephthalide (153m) as white powder.
g was obtained (83% yield).

3252,2940,1744,1690, 1690,1610,1502,1468, 1312,1276,1088,1002, 976,958,748 Proton Nuclear Magnetic Resonance Spectrum (δppm in CD ₃ OD): 1.98 (3H, d, J = 7.3Hz), 6.00 (1H, q, J = 7.3Hz), 7.11 (1H, dd, J = 1.5,7.5Hz), 7.31 (1H, dd, J = 7.5Hz), 7.36 (1H, dd, J = 7.5,7.5Hz) ) Mass spectrum: M / Z (%) 176 (100, M ⁺ ), 148 (20), 147 (19), 120 (63), 92 (24), 74 (11) Example 12 Obtained in Example 7 (Z) -4-Methoxy-3-propylidenephthalide (200 mg) was replaced with argon, and then anhydrous methylene chloride was added.
2.5 ml was added and dissolved, 0.8M methylene chloride solution of boron tribromide (2.6 ml) was added thereto with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hours. Pour the reaction mixture into 50 ml of ice water,
Extraction with diethyl ether (100 ml × 2), washing with saturated brine, drying over magnesium sulfate, and removal of the solvent under reduced pressure gave a white solid. This was recrystallized from benzene to give (Z) -4-hydroxy-3-propylidenephthalide as white powder.
185 mg was obtained (99% yield).

3224,2964,2932,2872, 1740,1682,1610,1496, 1468,1300,1162,1102, 994,970,752 Proton nuclear magnetic resonance spectrum (δppm in CD ₃ OD): 1.14 (3H, t, J = 7.5Hz), 2.46 (2H, dq, J = 8.0,7.5Hz), 5.98 (1H, t, J = 8.0Hz), 7.11 (1H, dd, J = 1.5,7.5Hz), 7.31 (1H, d, J = 7.5Hz) ), 7.36 (1H, dd, J = 7.5,7.5Hz) Mass spectrum: M / Z (%) 190 (43, M ⁺ ), 175 (100), 162 (26), 147 (35), 120 (61) ), 92 (26) Example 13 After 200 mg of (Z) -4-methoxy-3-pentylidenephthalide obtained in Example 9 was replaced with argon, anhydrous methylene chloride was used.
2.5 ml was added and dissolved, 0.8M methylene chloride solution of boron tribromide (2.3 ml) was added thereto with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hours. Pour the reaction mixture into 50 ml of ice water,
Extraction with diethyl ether (100 ml × 2), the ether layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a white solid. This was recrystallized from a mixed solvent of benzene and n-hexane to give a white powder (Z) -4-
180 mg of hydroxy-3-pentylidenephthalide was obtained (96% yield).

3252,2952,2924,2856, 1740,1682,1610,1496, 1468,1298,1162,1098, 994,748 Proton Nuclear Magnetic Resonance Spectrum (δppm in CD ₃ OD): 0.96 (3H, t, J = 7.3Hz), 1.30-1.62 (4H, m), 2.45 (2H, dt, J = 8.0,7.3Hz), 5.98 (1H, t, J = 8.0Hz), 7.11 (1H, dd, J = 1.5,7.5Hz), 7.32 (1H, d, J = 7.5Hz), 7.36 (1H, dd, J = 7.5,7.5Hz) Mass spectrum: M / Z (%) 218 (24, M ⁺ ), 175 (100), 162 (55) 147 (34), 134 (18), 120 (19), 91 (17), Example 14 60 mg of (Z) -4-methoxy-3- (4-ethoxycarbonylbutylidene) phthalide obtained in Example 10 After purging with argon, 0.9 ml of anhydrous methylene chloride was added and dissolved, and 0.8 M boron tribromide solution in methylene chloride (0.
8 ml) was added and the mixture was stirred at room temperature for 4 hours. Ice water was added to this reaction solution, extraction with diethyl ether (50 ml × 2), washing with saturated saline, drying with magnesium sulfate, and removal of the solvent under reduced pressure gave a brown solid. This was subjected to thin layer chromatography (developing solvent, ethyl acetate: n-hexane = 1: 2),
32 mg of (Z) -4-hydroxy-3- (4-ethoxycarbonylbutylidene) phthalide was obtained as a white solid (yield 55%).

3224,2976,2932,1744, 1729,1680,1608,1498, 1460,1304,1288,1160, 1080,970,756 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.28 (3H, t, J = 7.0Hz) , 1.50-2.00 (Disappeared by adding 1H, br, D ₂ O), 1.89 (2H, tt, J = 7.3,7.3Hz), 2.44 (2H, t, J = 7.3Hz), 2.52 (2H, dt, J) = 8.0,7.3Hz), 4.18 (2H, q, J = 7.0Hz), 5.94 (1H, t, J = 8.0Hz), 7.11 (1H, dd, J = 1.0,7.5Hz), 7.32 (1H, t) , J = 7.5Hz), 7.44 (1H, dd, J = 7.5Hz) Mass spectrum: M / Z (%) 276 (14, M ⁺ ), 231 (10), 202 (7), 188 (100), 175 (22) 166 (12), 147 (9), 91 (9) Example 15 200 mg of 3-methoxy-2- (5-ethoxycarbonylvaleryl) -benzoic acid obtained as an intermediate in Example 10 was added to methanol. 1
After dissolving in 1 ml, add 1 ml of 5% sodium hydroxide,
Stir for 30 minutes at room temperature. After removing the reaction solution under reduced pressure,
The mixture was acidified with diluted hydrochloric acid under ice cooling, extracted with diethyl ether (100 ml × 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. This was recrystallized from a mixed solvent of chloroform and n-hexane to obtain 163 g of white needle crystals of 6- (2-carboxy-6-methoxy-phenyl) -6-oxohexanoic acid (yield 89%). .

3300-2500,2936,1692, 1582,1464,1300,1260, 1204,1060,762 Proton Nuclear Magnetic Resonance Spectrum (δppm in ozone-
d ₆ ): 1.20-1.70 (4H, m), 2.27 (2H, t, J = 7.0Hz), 2.37 (2H, t, J = 7.0Hz), 3.95 (3H, s), 7.36 (2H, d, J = 8.0Hz), 7.56 (1H, t, J = 8.0Hz) Mass spectrum: M / Z (%) 280 (10, M +), 262 (17), 202 (72), 180 (100), 151 ( 15) 135 (17) Next, this 6- (2-carboxy-6-methoxy-phenyl)
After dissolving 40 mg of -6-oxohexanoic acid in 0.2 ml of anhydrous benzene, 0.03 ml of thionyl chloride was added at room temperature and the mixture was stirred for 30 minutes, and further heated on an oil bath for 30 minutes. After the reaction,
The reaction solution was removed under reduced pressure to remove excess thionyl chloride to obtain a crystalline solid. This was subjected to thin layer chromatography (developing solvent; 5% methanol / methylene chloride) to obtain 27 mg of (Z) -4-methoxy-3- (4-carboxybutylidene) phthalide as white powdery crystals ( Yield 73%).

3300-2500,2948,2918, 1766,1718,1694,1604, 1496,1434,1272,1042, 988,746 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ -CD ₃ O
D): 1.88 (2H, tt, J = 7.5Hz), 2.40 (2H, t, J = 7.5Hz), 2.54 (2H, dt, J = 8.0,7.5Hz), 4.02 (3H, s), 6.00 ( 1H, t, J = 8.0Hz), 7.23 (1H, dd, J = 1.5,7.0Hz), 7.40-7.56 (2H, m) Mass spectrum: M / Z (%) 262 (12, M ⁺ ), 244 (3), 216 (6), 202 (100), 189 (34) 174 (8), 161 (9), 131 (8), 105 (6), 103 (7), 76 (7) Example 16 34 mg of (Z) -4-methoxy-3- (4-carboxybutylidene) phthalide obtained in Example 15 was dissolved in 0.5 ml of anhydrous methylene chloride, and 0.8 M boron tribromide solution in methylene chloride was cooled with ice.
0.5 ml was added, and the mixture was stirred at room temperature for 2 hours. Ice water was added to this reaction solution, extraction with diethyl ether (50 ml × 2), washing with saturated saline, drying with magnesium sulfate, and removal of the solvent under reduced pressure gave a brown solid. This was subjected to open column chromatography (silica gel: 80-230 mesh, about 5 g, eluent: 10% methanol / methylene chloride) to give a white solid (Z) -4-hydroxy-3- (4-carboxybutyrate). 16 mg of (ridene) phthalide was obtained (yield 51%).

2340,2928,1746,1690, 1608,1498,1462,1296, 1166,1130,1078,970,754 Proton nuclear magnetic resonance spectrum (δppm in ozone-
d ₆ ): 1.85 (2H, tt, J = 7.3,7.3Hz), 2.41 (2H, t, J = 7.3Hz), 2.52 (2H, dt, J = 8.0,7.3Hz), 5.99 (1H, t, J = 8.0Hz), 7.26 (1H, dd, J = 7.5Hz), 7.36-7.48 (2H, m) Mass spectrum: M / Z (%) 248 (11, M ⁺ ), 230 (7), 202 ( 10), 188 (100), 175, 160 (11), 149 (20), 147 (17), 120 (9), 91 (13) Example 17 (Z) -4-methoxy obtained in Example 15 20 mg of 3- (4-carboxybutylidene) phthalide was added to anhydrous tetrahydrofuran.
After dissolving in 5 ml, 0.16 ml of a 1 M tetrahydrofuran solution of diborane was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 30 minutes, and further stirred at room temperature for 3 hours. Ice water (5 ml) was added to the reaction solution, which was extracted with diethyl ether, washed with saturated brine and dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a white solid. Apply this to thin layer chromatography (developing solvent; ethyl acetate: chloroform),
(Z) -4-Methoxy-3- (5-hydroxypentylidene)
10 mg of phthalide was obtained (yield 53%).

3360,2940,2586,1768, 1682,1604,1494,1434, 1274,1042,986,746 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.40-1.80 (5H, m), 2.51 (2H, dt, J = 8.0,7.0Hz), 3.69 (2H, t, J = 6.0Hz), 3.99 (3H, s), 5.96 (1H, t, J = 8.0Hz), 7.13 (1H, dd, J = 7.5,1.5Hz) , 7.43 (1H, t, J = 7.5Hz), 7.49 (1H, dd, J = 7.5,1.5Hz) Mass spectrum: M / Z (%) 248 (41, M ⁺ ), 220 (45), 202 ( 36), 189 (100), 177 (91) 163 (26), 161 (24), 149 (73), 129 (36), 73 (75) Example 18 25 g of 3-nitrophthalic anhydride, anhydrous sodium acetate 10.6 g and 50.7 ml of valeric anhydride at room temperature, add 140-160 on an oil bath.
Heated at 0 ° C. with stirring for 3 hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, water and 50 ml of aqueous ammonia were added to the residue, extracted with diethyl ether (500 ml x 2), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a brown oily substance. Obtained. Flash oil column chromatography (silica gel, 230-400 mesh; diameter 6.5 cm, length 30 cm; about 4
50 g; eluate, ethyl acetate: n-hexane = 1: 2.5),
Fractions of 50 ml each are collected, and the 13th to 16th fractions are combined, and the column is again subjected to flash column chromatography (silica gel, 230-400 mesh; diameter 6.5 cm, length 30 cm; about 450 g; eluent, chloroform: benzene = 1: 2), collect 50 ml each, combine the 12th to 15th fractions, (Z)
0.90 g of 4-nitro-3-butylidenephthalide was obtained (yield 3%). Also, by merging the 29th to 44th fractions,
1.55 g of (Z) -7-nitro-3-butylidenephthalide was obtained (yield 5%).

(Z) -4-Nitro-3-butylidenephthalide 3092,2964,2936,2860, 1786,1662,1616,1530, 1468,1340,1268,1150, 1094,1028,990,832,784, 766,742,690,602 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 1.01 (3H, t, J = 7.3Hz), 1.60 (2H, tq, J = 7.3,7.3Hz), 2.54 (2H, dt, J = 7.8,7.3Hz), 6.60 (1H, t, J = 7.8Hz), 7.51 (1H, t , J = 7.5Hz), 8.24 (1H, dd, J = 7.5,1.0Hz), 8.39 (1H, dd, J = 7.5,1.0Hz) Mass spectrum: M / Z (%) 233 (M ⁺ , 25) , 204 (35), 188 (64), 175 (34), 161 (25), 147 (15), 146 (15), 130 (32), 104 (60), 102 (64), 89 (45) , 75 (100) (Z) -7-nitro-3-butylidenephthalide 3084,2956,2932,2860, 1776,1686,1620,1536, 1472,1354,1238,1156, 1096,1000,826,776,732, 682 Proton Nuclear Magnetic Resonance Spectrum (δppm in CDCl ₃ ): 1.00 (3H, t, J = 7.3Hz), 1.58 (2H, tq, J = 7.3,7.3Hz), 2.49 (2H, dt, J = 7.9,7.3Hz), 5.82 (1H, t, J = 7.9Hz), 7.78-7.96 (3H) , m) Mass spectrum: M / Z (%) 233 (M ⁺ , 57), 204 (100), 191 (52), 177 (55), 161 (54), 148 (23), 130 (30), 104 (53), 103 (53), 75 (94) The compound of the present invention has a prostaglandin F2α inhibitory action and is useful as a pharmaceutical. This will be described with reference to experimental examples.

Experimental Example The ovaries of the Wistar female rat were removed, and about 3 weeks after that, the uterine horns were removed. Each uterine horn was suspended in a Magnus tube, immersed in Rock-Ringer's solution kept at 25 ° C. through air bubbles, and contraction due to addition of prostaglandin F2α was recorded with a pen recorder. The compounds obtained in Examples 8, 10, 13 and 15 were dissolved in ethanol so that the final concentration was 5 × 10 ⁻⁶ g / ml, and prostaglandin F2α was added 3-5.
Added minutes before. From the result of the contraction, the prostaglandin F2α inhibition rate of the compound obtained in Example was calculated by the following formula.

A: Shrinkage when the compound obtained in the example is not included B: Shrinkage when the compound obtained in the example is added The results are shown in Table 1.

Further, it was confirmed that the compounds obtained in the examples have blood viscosity lowering action, anti-hyaluronidase action, anti-platelet aggregation action, anti-histamine action and anti-fungal action.

The compound of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as necessary. Oral agents such as tablets, capsules and granules, injections,
Parenteral agents such as suppositories may be mentioned. Oral preparations such as tablets, capsules and granules are manufactured according to a conventional method. Tablets are produced by mixing and shaping the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. It is produced by mixing with an active pharmaceutical filler or diluent and filling it into a hard gelatin capsule, a soft gelatin capsule or the like. Syrups and elixirs are produced by mixing the compound of the present invention with sweeteners such as sucrose, preservatives such as methyl and propylparabens, colorants, seasonings, fragrances, and auxiliary agents.

The parenteral preparation is produced according to a conventional method, and distilled water for injection, physiological saline, dextrose aqueous solution, propylene glycol or the like can be generally used as a diluent. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added.
In addition, from the viewpoint of stability, this parenteral preparation is frozen after filling into ampoules and the like, and water is removed by a normal freeze-drying technique.
It is also possible to reconstitute a solution from a lyophilized product just before use.

Other parenteral agents include liquid preparations for external use, coating agents such as ointments, suppositories for rectal administration, and the like, and they are manufactured by a conventional method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References J. Nat. Prod. , 49 (1), 184-5 (1986) Plaut. Med. Phytothe v. , 17 (3), 147-56 (1983) Planta Medica, 50 (1), 105-6 (1984)

Claims (1)

[Claims] 1. A general formula I (In the formula, R ₁ represents a hydrogen atom, a hydroxyl group, a methoxy group or a nitro group, R ₂ represents a hydrogen atom, a hydroxyl group, a methoxy group or a methoxymethoxy group, R ₃ represents a hydrogen atom or a methoxy group, and R ₄ Represents a hydrogen atom or a nitro group, R ₅ represents hydrogen, an alkyl group, —C ₃ H ₆ COOH, —C ₃ H ₆ COOC ₂ H ₅ or —C ₄ H ₈ OH, provided that R ₁ , R ₂ , R ₃ and R ₄ are a hydrogen atom in common, R ₁ is a hydrogen atom, R ₂ is a hydroxyl group, R ₃ and R ₄ are both hydrogen atoms, and R ₅ is an n-propyl group. And R ₁ and R ₂ are both hydrogen atoms, and R ₃
Is a methoxy group, R ₄ is a hydrogen atom, R ₅ is a methyl group, and R ₁ and R ₂ are methoxy groups,
When R ₃ and R ₄ are hydrogen atoms, R ₅ is a methyl group, and R ₁ is a hydroxyl group, R ₂ , R ₃ and R ₄ are both hydrogen atoms, and R ₅ is a propyl group. Excluding cases. ) A novel phthalide derivative represented by: