JPH0477480A - Phthalide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I(R1 to R3 are methoxyl, OH or H). EXAMPLE:(Z)-3-Butylidene-6,7-dimethoxyphthalide. USE:A prostaglandin F2alpha inhibitor. PREPARATION:Commercially available 2,3-dimethoxybenzoic acid, etc., are chloromethylated, etc., to provide a compound expressed by formula II (R8 is methoxymethoxyl, methoxyl or H), which is then converted into the objective compound expressed by formula I. Compounds expressed by formula III (R4 and R5 are methoxyl or OH) and formula IV (R5 and R6 are methoxyl or OH) are cited as the phthalide derivative obtained by the aforementioned method.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel phthalide derivatives useful as pharmaceuticals.

[Conventional technology and problem 1 Cnidium officinalis, a plant of the Umbelliferae family
Kawa'4 (Cni
Rhizoma) is known to have central depressant effects, muscle relaxant effects, antithrombotic effects, etc., and is used in Chinese herbal medicines such as Tokishon Yakusan, Onkeito, Onseinn, and Kakkonto Kayo Kaishini. It is a concentrated medicine.

Also, this calyx contains various phthalides,
Since many of the phthalides used for these purposes are unstable, it has been desired to synthesize phthalides that are more stable and useful as pharmaceuticals.

[Means for Solving the Problems] The present inventors focused on phthalide, which is one of the components contained in the calyx, and as a result of extensive research, they synthesized a phthalide derivative that has a prostaglandin F2a inhibitory effect. This led to the completion of the present invention.

That is, the present invention provides phthalide derivatives represented by the following formula Ni-Pr (wherein R1, R2, and R3 represent a methoxyl group, a hydroxyl group, or a hydrogen atom), a compound of the following formula II and the above formulas 1, II, and (2). A phthalide derivative represented by the following formula ■ Brown (in the formula, and - represents a methoxyl group or a hydroxyl group) and a phthalide derivative represented by the following formula ■ (Daito R6 and R7 represent a methoxyl group or a hydroxyl group) as raw materials for This is a phthalide derivative represented by:

(In the formula, R8 represents a methoxymethoxyl group, a methoxyl group, or a hydrogen atom.) Chloromethylation of benzoic acids such as acids, conversion of commercially available benzoic acids such as 3,5-dimethoxybenzoic acid into oxazolines, and then ordo-rethietion;
After reacting with formaldehyde, each phthalide obtained by hydrolyzing oxazoline, rectifying benzyl alcohol such as commercially available 3,5-dimethoxybenzyl alcohol, and reacting with carbon dioxide, It can be obtained by coupling with n-butyraldehyde in the presence of a Lewis acid.

For chloromethylation, a mineral acid such as hydrochloric acid or sulfuric acid is used in the presence of formaldehyde, and the reaction temperature is preferably heated from room temperature to about 70°C.

Specific examples of bases used for the rectation of oxazolines and alcohols include n-butyllithium, 5e
Examples include e-butyllithium and tert-butyllithium. Examples of the solvent include ethers such as anhydrous tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether, and hydrocarbons such as n-hexane.The reaction temperature is as follows:
A temperature of 45° C. to about the boiling point of the solvent is suitable, but it is preferable to add tetramethylethylenediamine as a chelating agent if necessary.

Formaldehydes include paraformaldehyde,
Examples include dimethoxymethane.

Hydrolysis of oxazoline is preferably carried out by removing formaldehyde and the like used in the previous reaction, and then adding an acid for hydrolysis. Specific examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, and suitable solvents include water, alcohols, or mixed solvents thereof. The reaction temperature is preferably from room temperature to the boiling point of the solvent used.

Examples of bases used for coupling include lithium-forming agents such as lithium diisopropylamide and lithium diethylamide, and sodium-forming agents such as sodium hydride and sodium amide. Examples of Lewis acids include zinc chloride,
Examples include aluminum chloride and tin chloride. As a solvent, anhydrous tetrahydrofuran, diethyl ether, 1
, 2-dimethoxyethane and the like, and the reaction temperature is suitably from 45°C to room temperature.

Specifically, the compound of formula (1) can be obtained as follows.

Specific example 1-■ 2.3 in a 300 mJ eggplant-shaped flask equipped with a reflux condenser
-dimethoxybenzoic acid 10. Og, 35% hydrochloric acid 100
ryz? Then, 5.4 ml of dimethoxymethane were added thereto, and the mixture was heated at an external temperature (70 to 80° C.) for 3 hours while stirring. This reaction solution was returned to room temperature and extracted with chloroform twice (200 mJ
X 2), the chloroform layer was washed once each with 5% aqueous sodium hydroxide solution 1002FLJ and saturated brine, dried (magnesium sulfate), filtered through Celite, and evaporated under reduced pressure to obtain a white solid. This was recrystallized from ethyl acetate-n-hexane, and 6,7-simethoxyphthalide 3.
46 g was obtained as white granular crystals.

6.7-Dimethoxyphthalide Melting point = 103-104°C Infrared absorption spectrum νKBj ern-1: 3012
, 2948.2840.1752.1596.1498
．． 1458°1372, 1312.1268.1224
．． 1164.1108.1054゜1034, 1008
．． 960.880.814.788.7081H-Nuclear magnetic resonance spectrum (200MHz) (δppm in
CDC13): 3.92 (3H, s), 4.11 (3H, s), 5
．． 20 (2H, s).

7.08 (IH, d, J=8.3Hz).

7.24 (IH, d, J = 8.3 Hz) Mass spectrum EI-MS m/z (%): 194 (M”, 95)
, 176(65), 165(100,M-CHO)
.

147 (72), 135 (15), 122 (32)
, 107(16), 90(17).

Specific Example 1-■ 7.2 mJ of diisopropylamine was placed in a 500 m1 two-necked flask equipped with a septum rubber, and the atmosphere was replaced with argon.
After adding and dissolving 90ml of anhydrous tetrahydrofuran,
36 mj of 1.6 M n-butyllithium was added at -10°C, and the mixture was stirred at -10°C for 30 minutes. Further, a suspension of 10.0 g of 6,7-cymethoxyphthalide obtained in Example 1-■ in 150 ml of tetrahydrofuran was added to this reaction solution at 40°C over about 5 minutes, and after stirring at 40°C for 1 hour, A solution of 8.42 g of zinc chloride (finely crushed, stirred, and dried by heating under reduced pressure) in 80 mx of tetrahydrofuran was added at 40° C., and the mixture was stirred at 40° C. for 30 minutes. Further, a solution of 6.8 ml of butyraldehyde in 20 ml of tetrahydrofuran was added to this reaction solution at 40°C, and the mixture was stirred at 40°C for 1 hour and then at room temperature for 2 hours. This reaction solution was ice-cooled.
Pour into 200ml of % hydrochloric acid and extract with ether twice (300r
rtJ X2), wash the ether layer once with saturated saline,
After drying (magnesium sulfate) and removing the solvent under reduced pressure, a yellow oil was obtained. This was subjected to flash column chromatography (silica gel, 230-400 mesh, 9!6.5
X20, approximately 300 g; eluate, ethyl acetate: n-hexane = 1:1, pressure 0.2 kg/cm'', 1 fraction = 80 ml).
0 to 1600 m1), 3-(1
-hydroxybutyl)-6,7-cymethoxyphthalide 1
0.67 g (yield 77.8%) was obtained as a colorless oil.

3-(1-Hydroxybutyl)-6,7-simethoxyphthalide infrared absorption spectrum-'cm': 3464
(OH), 2956.2872.1758 (C=0
), 1598°1502, 1462.1424.12
72.1120.1036IH-nuclear magnetic resonance spectrum (200MHz) (δppm in CDC13): 0.94 and 0.97 (3H, t, J=6.8
Hz andt, J=6.8Hz).

1.30-1.80 (4H, m).

1.30-1.80 (IH, br, D20 exch
ang,).

3.80-4.00 (IH, m), 3.91 (3H,
s).

4.10 and 4.11 (3H, s and s)
.

5.20 and 5.26 (IH, d, J = 0.
9Hz and dd, J = 4.9Hz).

7.10-7.30 (2H, m) Mass spectrum EI-MS m/z (%): 266 (M
”, 6), 194 (100, M-CH3CH2CH
2CHO).

179 (62,194-CH3), 166 (6,19
4-Co), 150(5).

122(6), 107(4), 77(7) Specific example 2
-■ 500rrL with calcium chloride pipe! 3,5-dimethoxybenzoic acid in an eggplant-shaped flask. Add Og and 30ml of anhydrous benzene, and add 39.0ml of thionyl chloride under water cooling.
After adding 5 mJ and stirring at room temperature for 30 minutes, the mixture was heated under reflux for 1 hour. After removing excess thionyl chloride and benzene from this reaction mixture at normal pressure, the residue was distilled off under reduced pressure (157
~b was obtained as a colorless oil (317 g, yield 87.3%). Next, 28.1 g of 2-amino-2-methyl-1-propanol was added to a 500 ml eggplant flask equipped with a dropping funnel.
After dissolving in 12 OFFLJ anhydrous methylene chloride, a solution of 31.7 g of the above benzoyl chloride in 50 ml of anhydrous methylene chloride was added dropwise over 30 minutes under water cooling, and the mixture was further stirred at room temperature for 2 hours. Add 100 nzl of water to this reaction solution.
was added, followed by chloroform extraction twice (250mj x 2
), the chloroform layer was washed once with 1N hydrochloric acid, dried (magnesium sulfate), and evaporated under reduced pressure to obtain the amide compound as a colorless oil. Add 34m of thionyl chloride to this amide compound under ice-cooling.
1 was added thereto, and the mixture was stirred at room temperature for 2 hours. 500 ml of anhydrous ether was added to this reaction solution to crystallize it, and after removing only the supernatant liquid, it was made basic with 20% sodium hydroxide.
Extract with chloroform twice (200rnlX 2), wash the chloroform layer once with water, dry (magnesium sulfate),
Distillation under reduced pressure yielded a white solid. This is ethyl acetate-n-
Recrystallized from hexane to give 2-(3,5-dimethoxyphenyl)4,4-dimethyloxazoline as colorless needle-shaped crystals.
．． 9 g (yield 70.3%).

2-(3,5-dimethoxyphenyl)-4,4-dimethyloxazoline melting point = 63-65°C Infrared absorption spectrum, ll-5・em-1:2964
, 2936.2896.1646, 1600.1476
, 1460°1422, 1358.1314.1264
．． 1204.1154.1066°1038,978.
922.860.826.786.724.668.6
22゜544.444 1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min CDC13): 1.38 (3H, s), 3.82 (6H, s), 4
．． 11 (2H, s).

6.56 (IH, dd, J = 2.4.2.4Hz
).

7.09 (2H, d, J = 2.4Hz) Mass spectrum EI-MS m/z (%): 235 (M +,
41), 220 (100, M-CH3), 205 (
22).

192(45), 164(49) Specific Example 2-■ 2-(3,5-dimethoxyphenyl)- obtained in Specific Example 2-■ in a 300 ml two-necked flask with septum rubber
4,4-dimethyloxazoline 11. After adding 90 ml of anhydrous tetrahydrofuran and dissolving it, 1.6 M n-butyllithium 3 was added at -50°C.
5ml was added over about 5 minutes and stirred at -50°C for 2 hours.

Further, 4.2 g of paraformaldehyde was added to this reaction solution at -50°C, followed by stirring at -50°C for 1 hour and at room temperature overnight. The reaction solution was poured into ice water, extracted with ether twice (200 mj x 2), the ether layer was washed once with water, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. Next, add 360 r of 2N hydrochloric acid to this oil.
yz7 was added, and the mixture was heated and stirred at an external temperature (100° C.) for 30 minutes. After cooling, this reaction solution was extracted with ether twice (300 m
j X2), the ether layer was washed once each with 5% sodium hydroxide and water, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow solid. Add this to ethyl acetate
Recrystallization from n-hexane gave 1.9 g of 4,6-simethoxyphthalide as colorless needles.

4.6-Simethoxyphthalide Melting point: 174-175°C Infrared absorption spectrum, IJr cm・l: 3088,
3004, 2948.2840, 1754.1616.
1504°1454, 1338, 1244.1160.
1110.1038.996.944°846,772
．． 506 IH-Nuclear Magnetic Resonance Spectrum (200MHz) (δpp
min CDC13): 3.86 (3H, s), 3.87 (3H, s), 5.2
1 (2H, s).

6.68 (IH, d, J = 2.0Hz), 6.
93 (IH, d, J = 2.0Hz) Mass spectrum EI-MS m/z (%): 194 (M+, 56)
, 165 (100, M-CHO).

137 (28,165-CH20), 122 (17)
, 107(12).

92(5), 77(19) Specific Example 2-■ 0.65 ml of diisopropylamine was placed in a 100 mj two-necked flask equipped with a septum rubber, the atmosphere was replaced with argon, and 8 ml of anhydrous tetrahydrofuran was added and dissolved.
3.2 ml of 1.6M n-butyllithium was added at -10°C, and the mixture was stirred at -10°C for 30 minutes. Further, a suspension of 900 mg of 4,6-cymethoxyphthalide obtained in Example 2-2 in 14 ml of tetrahydrofuran was added to this reaction solution at 40°C over about 5 minutes, and after stirring at 40°C for 1 hour, the mixture was stirred at -40°C.
Zinc chloride (finely crushed, stirred, heated under reduced pressure and dried) 760rrLg of tetrahydrofuran 7rn
1 solution and stirred at 40°C for 30 minutes. Further, a 1 rnl solution of 0.6 ml of n-butyraldehyde in tetrahydrofuran was added to this reaction solution at 40°C, and the mixture was stirred at 40°C for 1 hour and then at room temperature for 2 hours. This reaction solution was poured into 100 m7 of ice-cooled 5% hydrochloric acid, and extracted with ether twice (1
The ether layer was washed once with saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ4.5
X20, about 160 g; eluate, ethyl acetate: n-hexane = 1:1, pressure 0.2 kg / cm2.1 fraction = 100 mj), and the eluate fraction (400 ~
500 mj), 720 mg of 3-(1-hydroxybutyl)4,6-simethoxyphthalide represented by the above formula (■)
was obtained as a colorless oil.

3-(1-Hydroxybutyl)-4,6-simethoxyphthalide infrared absorption spectrum ν:””-1: 3464(OH), 2960.2872.1758(
C=O), 1628°1504.1458.143
4.1332.1228.1204.1156°112
2, 1040.976, 936.846.7741H-
Nuclear magnetic resonance spectrum (200MHz) (δppm i
n CDC13): 0.87 and 0.97 (3H, t, J = 7.
OHz and t.

J=7.0Hz), 1.10-1.70 (4H, m)
.

2.47 (IH, br, D20 exchange,)
.

3.80-420 (IH, m).

3.86 and 3.87 (3H, s and s)
, 3.89 (3H, s).

5.43 and 5.50 (IH, d, J = 1
．． 7Hz and d.

J=4.6Hz).

6.70 and 6.94 (IH, d, J = 2
．． OHz and d, 2.0Hz) Mass spectrum EI-MS ml (%): 266 (M”, 2), 1
94 (100, M-CH3CH2CH2CHO).

179(5,194-CH3), 165(13),
149(19), 135(4).

121(5), 77(5) Specific example 3-■ 3.
Add 20.0 g of 5-dimethoxybenzyl alcohol (in powder form), replace the atmosphere with argon, add 250 mj of anhydrous n-hexane, suspend, and then cool with water to 1.6 M
156 mJ of n-butyllithium was added over about 5 minutes, and the mixture was vigorously stirred for 2.5 hours under water cooling. This reaction solution was poured into a large excess of dry ice whose surface was covered with n-hexane, and left until it reached room temperature. Add 250 ml of water to this reaction solution, wash with ether 3 times (100 ri x 3, remove raw materials), add 200 mJ of 5% hydrochloric acid to the aqueous layer while cooling with water to make it acidic, stir for 10 minutes, and then extract with chloroform twice (300 ml).
m2 X2), the chloroform layer was washed once with 100 mj of 5% sodium hydroxide and water, dried (magnesium sulfate), and evaporated under reduced pressure to obtain a white solid. This was recrystallized from ethyl acetate, and 7.2 g of 5,7-dimethoxyphthalide was obtained.
(yield 31.1%) was obtained as a colorless scale-like product.

5.7-Dimethoxyphthalide Melting point = 153-156°C Infrared absorption spectrum-I c, n-1: 3108, 3
012.2976, 2944.2840.1748.1
606°1498, 1470.1454, 1426.1
344.1224.1198°1160, 1092.1
050.1030.1006,838.778,686
゜556, 450 IH-nuclear magnetic resonance spectrum (2ooMH2) (δpp
min CD013): 3.89 (3H, s), 3.96 (3H, s), 5
．． 17 (2H, s).

6.43 (IH, d, J = 1.7Hz), 6.4
8 (IH, d, J = 1.7 Hz) Mass spectrum EI-MS m/z (%): 194 (M”, 63), 1
76(54), 165(40, M-CHO).

148 (100), 135 (29), 120 (14),
107(12).

92(8), 77(16) Specific Example 3-■ Put 4.7 ml of diisopropylamine into a 500 mJ two-necked flask with a septum rubber, and replace with argon.
After adding and dissolving 50ml of anhydrous tetrahydrofuran,
23 ml of 1.6M n-butyllithium was added at -10°C, and the mixture was stirred at -10°C for 30 minutes. Furthermore, the 5, 7. A suspension of 6.5 g of dimethoxyphthalide in 130 ml of tetrahydrofuran was added over about 5 minutes, stirred at 40°C for 1 hour, and then zinc chloride (finely crushed, stirred and dried by heating under reduced pressure) at -40°C. ) A solution of 5.5 g of tetrahydrofuran in 50 ml was added, and the mixture was stirred at 40° C. for 30 minutes. Further, a solution of 4.4 ml of n-butyraldehyde in 10 ml of tetrahydrofuran was added to this reaction solution at 40°C, and the mixture was stirred at 40°C for 10 minutes and then at room temperature for 2 hours. This reaction solution was poured into 150ml of ice-cooled 5% hydrochloric acid, and extracted with ether twice (300ml).
M? X2), the ether layer was washed once with saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ6.5X2
0, about aoog; eluate, ethyl acetate: n-hexane =
1 = 1, pressure 0.2 kg/cm', 1 fraction = 100 m? ) to separate and purify the eluted fraction (2400 ~
500 (W ), 3-(1-hydroxybutyl)-5,7-dimethoxyphthalide represented by the above formula (■) 7.3
9 g (82.9% yield) was obtained as a colorless oil.

3-(1-hydroxybutyl)-5,7-dimethoxyphthalide infrared absorption spectrum-j cm-1:3464
(OH), 1758 (C=0) IH-nuclear magnetic resonance spectrum (200 MHz) (δppm in CDC1
3): 0.93 and 0.97 (3H, t, J = 6
．． 8Hz and t.

J = 6.8Hz).

1.20-1.75 (4H, m).

1.90~2.00 (IH, br, D20 excha
ng,).

3, 0-4.00 (IH, m), 3.90 (3H, s
), 3.95 (3H, s).

5.17 and 5.24 (IH, d, J = 0
．． 7Hz and d.

J=5. IHz), 6.45 (IH, d, J=1.7H
z).

6.52 and 6.58 (IH, d, J= 1.
7Hz and d.

J = 1.7Hz) Mass spectrum EI-MS m/z (%): 266 (M
", 3), 194 (100, M-CH3CH2CH
2CHO).

179 (7,194-CH3), 166 (11,19
4-Co), 148(14).

120(5), 107(4), 77(7) Specific example 4
-■ 1000m with reflux condenser? 2. Into an eggplant-shaped flask.
5-Dimethoxybenzoic acid 40. Og, 35% hydrochloric acid 400
rnl and 29 ml of dimethoxymethane were added, and the mixture was heated at an external temperature (70 to 80° C.) for 3 hours while stirring. This reaction solution was returned to room temperature and extracted with chloroform twice (200mj
2) Wash the chloroform layer once each with 300 mJ of 5% aqueous sodium hydroxide solution and saturated saline,
Drying (magnesium sulfate), filtration through Celite, and distillation under reduced pressure gave a white solid. This was recrystallized from ethyl acetate-n-hexane, and 4,7. Dimethoxyphthalide 9.07g (
Yield: 21.3%) was obtained as colorless needles.

4.7-Dimethoxyphthalide Melting point = 174-175°C Infrared absorption spectrum ν: “” ' 3088, 3012.2964.2936.2840.
1758.1608°1504, 1456.1440.
1366.1316.1270.1232°1194,
1068.1030.1014.824.782.73
8.716°694, 580.470 1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min CDC13): 3.86 (3H, s), 3.94 (3H, s), 5.1
8 (2H, s).

6.86 (IH, d, J = 8.8Hz), 7.05 (I
H, d, J = 8.8Hz) Mass spectrum EI-MS
m/z (%): 194 (M+, 100), 176 (
27), 165 (68, M-CHO).

148 (91), 135 (17), 120 (19)
, 107(23), 93(14).

Specific side number ■ Put 6.5 ml of diisopropylamine into a 500 m1 two-necked flask with a septum rubber, and replace with argon.
After adding and dissolving 80ml of anhydrous tetrahydrofuran,
32rnl of 1.6M n-butyllithium was added at -10°C, and the mixture was stirred at -10°C for 30 minutes. Furthermore, 4,7-cymethoxyphthalide 9. obtained in Example 4-■ was added to this reaction solution at 40°C. A suspension of Og in 150 m7 of tetrahydrofuran was added over about 5 minutes, and after stirring at 40°C for 1 hour, -40
7.6 g of zinc chloride (finely crushed, stirred, heated and dried under reduced pressure) at 70 mJ of tetrahydrofuran
The solution was added and stirred at 40°C for 30 minutes. Further, a solution of 6.2 ml of n-butyraldehyde in 15 ml of tetrahydrofuran was added to this reaction solution at 40°C, and the mixture was stirred at 40°C for 1 hour and then at room temperature for 2 hours. This reaction solution was poured into 200 mj of ice-cooled 5% hydrochloric acid, and extracted with ether twice (30 mj).
0mj x 2), wash the ether layer once with saturated saline,
After drying (magnesium sulfate) and removing the solvent under reduced pressure, a yellow oil was obtained. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ6.5X
20. Approximately 300 g; Eluate, ethyl acetate: n-hexane = 1 = 1, pressure 0.2 kg / cm2.1 fraction = 100 m? ), and the eluted fraction (190
0-3500m? ), 3-( expressed by the above formula ■
1-Hydroxybutyl) 4,7-cymethoxyphthalide 8
．． 98 g (yield 72.8%) was obtained as a colorless oil.

3-(1-Hydroxybutyl 4,7-cymethoxyphthalide infrared absorption spectrum T cm-1:3504,
3 H (OR), 2956.2868.28.

1754 (C=O), 1608.1504.1444
．． 1272.1234°1082.1046.994.
824.730.712.490IH-Nuclear magnetic resonance spectrum (200MHz) (δppm in CDC13
): 0.86 and 0.96 (3H, t, J = 7.
OHz and t.

J=7.0Hz).

1.10-1.60 (4H, m).

2.50-2.60 (IH, br, D20 excha
ng,).

3.80-4.20 (IH, m), 3.88 (3H,
s).

3.94 and 3.95 (3H, s and s)
.

5.41 and 5.49 (IH, d, J = 1.
5 and d.

J=4.6Hz).

6.88 and 6.90 (IH, d, J = 8
．． 8Hz and d.

8.8Hz), 7.08 and 7.10(IH,
d, J=8.8Hz and d.

J = 8.8Hz) Mass spectrum EI-MS m/z (%): 266 (M
”, 5), 194 (100, M-CH3CH2C
H2CHO).

179(39,194-CH3), 165(8),
163(8), 149(7).

135(3), 120(4), 77(5) Specific example 5
−■ In a 20OFFLJ eggplant-shaped flask equipped with a reflux condenser,
．． 4-dimethoxybenzoic acid 5.0g, 35% hydrochloric acid 50m
1. 0.5ml of concentrated sulfuric acid and 2-9ml of dimethoxymethane
1 and heated at an external temperature (90-100°C) for 7 hours while stirring. This reaction solution was returned to room temperature, and chloroform extraction 2
The chloroform layer was washed once with 100 mJ of a 5% aqueous sodium hydroxide solution and once with saturated brine, dried (magnesium sulfate), filtered through Celite, and evaporated under reduced pressure to obtain a white solid. This was recrystallized from ethyl acetate-n-hexane to obtain 1.36 g (yield 25.4%) of 5,6-simethoxyphthalide as colorless scaly crystals.

5.6-Dimethoxyphthalide Melting point = 163-164°C Infrared absorption spectrum ν: “” ' 3088, 3012.2980.2936.2836.
1754.1604゜1504, 1454.1348.
1296.1226.1124.1044.996°8
62, 832.764.674.596.548.45
61H-nuclear magnetic resonance spectrum (200MHz) (δp
pm in CD013): 3.95 (3H, s) t 3.98 (3H, s),
5.23 (2H, s included 6.91 (IH, s ), 7
．． 31 (IH, s) Mass spectrum EI-MS m/
z (%): 194 (M+, 61), 165 (100
, M-CHO), 137(11).

122(7), 107(5), 95(9), 77
(12) Specific example 5-■ 4.4 ml of diisopropylamine was placed in a 500 ml two-necked flask equipped with a septum rubber, and the atmosphere was replaced with argon.
After adding and dissolving 50ml of anhydrous tetrahydrofuran,
22 ml of 1.6M n-butyllithium was added at -10°C, and the mixture was stirred at -10°C for 30 minutes. Further, a suspension of 6.0 g of 5,6-dimethoxyphthalide obtained in Example 5-2 in 130 ml of tetrahydrofuran was added to this reaction solution at 40°C over about 5 minutes, and after stirring at 40°C for 1 hour, A solution of 5.1 g of zinc chloride (finely crushed, stirred, and dried by heating under reduced pressure) in 50 ml of tetrahydrofuran was added at 40° C., and the mixture was stirred at 40° C. for 30 minutes. Furthermore, a solution of 4.1 ml of n-butyraldehyde in 10 ml of tetrahydrofuran was added to this reaction solution at 40°C, and the mixture was stirred at 40°C for 1 hour and then at room temperature for 2 hours. This reaction solution was cooled with 5%
Pour into 150ml of hydrochloric acid and extract with ether twice (300mj
X2), the ether layer was washed once with saturated saline and dried (
(magnesium sulfate) and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ6.5×20,
Approximately 300g; Eluate, ethyl acetate: n-hexane = 1
:1, pressure 0.2kg1cm2.1 fraction = 1
00mj), and the elution fraction (1900-60mj) was separated and purified.
00 mJ), 3-(1-hydroxybutyl)-5,6-cymethoxyphthalide represented by the above formula (■) 5.74
g (yield 69.7%) was obtained as a colorless oil.

3-(1-hydroxybutyl)-5,6-dimethoxyphthalide infrared absorption spectrum νn-ern-1=346
4(OH), 2956, 2932, 2872, 2840
゜1724 (C=O), 1600.1502.147
6, 1330.1286°1226, 1140.104
8.1000.864.854.774.638.53
8IH-Nuclear magnetic resonance spectrum (200MHz) (δp
pm in CDC13): 0.95 and 0.97 (3H,t, J = 6
．． 8Hz and t.

J = 6.8Hz).

1.20-1.70 (4H, m).

1.90~2.10 (IH, br, D20exchan
g, 3.80-4.00 (IH, m), 3.96 (
3H,s), 4.02(3H,s).

4.48 and 4.54 (IH, d, J = 5
．． 6Hz and d.

J=3-7Hz).

6.97 and 7.04 (IH, s and s)
, 7.30 (IH, s) mass spectrum El-MS
m/z (%): 266 (M'', 4), 194 (1
00, M-CH3CH2CH2CHO).

179 (8,194-CH3), 166 (18,19
4-Co), 151(7).

135(2), 120(2), 77(6) Specific example 6
-■ Syringic acid (3,5-dimethoxy4-hydroxybenzoic acid) 28.88. 570m of 35% hydrochloric acid? and 14-2 mJ of dimethoxymethane were added, and the mixture was heated and stirred for 1.5 hours. This reaction solution was returned to room temperature, extracted with chloroform (500 mJ
The solvent was removed under reduced pressure to obtain 16.97 g of 4,6-simethoxy-5-hydroxyphthalide.

Furthermore, after dissolving this in 290 mJ of anhydrous acetone,
80.56 g of potassium carbonate and 22.1 mJ of methyl chloromethyl ether were added, and the mixture was stirred at room temperature overnight.

After removing acetone from the reaction mixture under reduced pressure,
Water was added to dissolve excess potassium carbonate, and insoluble matter was filtered off. This was recrystallized from benzene to give white fine needle-like crystals of 4,6-simethoxy-5-methoxymethoxyphthalide 1.
2.10 g (yield 33%) was obtained.

4.6-Simethoxy5-methoxymethoxyphthalide Infrared absorption spectrum 1111 cm-1:2952,2
840.1758.1616.1482.1446.1
432°1408.1374.1344,1254.1
210.1138.1120゜1100, 1042.1
012.928.856.760IH-Nuclear magnetic resonance spectrum (200MHz) (δppm in CDC13
): 3.61 (3H, s), 9.62 (3H, s), 3.
98 (3H, s).

5.20 (2H, s), 5.32 (2H, s), 7
．． 16 (IH, s).

Mass spectrum EI-M8 m/z (%): 254 (3
, M”), 224(2), 209(1), 195(1
).

181(2), 178(1), 147(1), 9
3(1), 45(100) Specific Example 6-0 5.5 mj of diisopropylamine was placed in a 500 m1 three-necked flask equipped with a septum rubber, and the atmosphere was replaced with argon.
After adding and dissolving 70ml of anhydrous tetrahydrofuran,
While stirring at -10°C, 27 ml of 1.6M n-butyllithium was added over 2 to 3 minutes, and the mixture was stirred at -10°C for 30 minutes. Further, this reaction solution was heated to -10°C and 4,6-cymethoxy-5-methoxymethoxyphthalide 1 obtained in Example 6-■ was added.
Approximately 120 ml of 0.0 g of tetrahydrofuran suspension
After stirring for 10 minutes at -10°C, stirring for 1 hour at 0°C, a solution of 6.7 g of zinc chloride (finely crushed, stirred, and dried by heating under reduced pressure) in 100 mJ of anhydrous tetrahydrofuran. was added and stirred for 30 minutes. The mixture was then cooled to 40° C., and a solution of 5.2 ml of n-butyraldehyde in 20 ml of anhydrous tetrahydrofuran was added, stirred for 30 minutes, and then stirred overnight at room temperature. The reaction mixture was poured into 200ml of ice-cooled 2% hydrochloric acid, extracted with diethyl ether twice (400ml x 2), and the diethyl ether layer was extracted with water,
Wash once with saturated saline and dry (magnesium sulfate)
The solvent was distilled off under reduced pressure to obtain a brown oil. This was subjected to flash column chromatography (silica gel, 230~
400 mesh, φ6.5 x 20, approximately 300g;
Eluent, ethyl acetate: n-hexane = 223, pressure 0.
2kg1cm", 1 fraction = 80raJ), and from the elution fraction (1360-2720rrz?), 4,6-simethoxy5.methoxymethoxy-3-(1-hydroxybutyl)phthalide represented by the above formula (■) was obtained. 4
．． 98 g (yield 39%) was obtained as a colorless oil.

4.6-Simethoxy5-methoxymethoxy-3-(1
-Hydroxybutyl)phthalide infrared absorption spectrum ν:! cm-1=3476(OH
Enter 2956, 1764 (C=0), 1616, 1480
゜1426, 1344, 1160, 1112, 1086
．． 1020.942.854゜IH-Nuclear Magnetic Resonance Spectrum (200MZ) (δppm in CDC13)
: 0.88 and 0-97 (3H, t, J = 6.
8Hz).

1.25-1.65 (4H, m).

1.84 and 2.77 (LH, d, D20 e
xchang,).

3.60 (3H,s, 0-C-0-CH3), 3.
91.3.92゜3.98 and 3-99 (6H,
s, -0CH3X 2).

3.80-4.05 (IH, m), 5.20.5.2
3゜5-29 and 5.32 (2H, d, J =
6.0Hz, -0-CH2-0-).

5.46 and 5.49 (IH, d, J= 1.7
and 4.9Hz) 7, 17 and 7.18(
IH, s) Mass spectrum EI-MS m/z (%):
326(1,M”), 308(1,M-H2O).

279 (4,308-02H5), 264 (9,27
9-CH3).

254 (25, M, -CH5CH2CH2CHO),
235(2).

224(4), 222(4), 209(30,25
4-CH30CH2) 192(4), 167(9),
149(18), 113(3).

45 (100, CH30CH2) Specific Example 7-■ 58.8 g of thionyl chloride was added to 30.0 g of 3.4-dimethoxybenzoic acid under water cooling, and the mixture was stirred at room temperature overnight. Excess thionyl chloride was distilled off from the reaction mixture at normal pressure, and then distilled under reduced pressure to obtain 30.2 g of 3,4-dimethoxybenzoic acid chloride in the form of green-white powder (yield: 91%).

2-Amino-2,methyl-1-propatol 22.3g
After replacing with argon, 50 ml of anhydrous methylene chloride was added and dissolved, and to this solution was added dropwise a solution of 25.1 g of 3,4-dimethoxybenzoic acid chloride in 150 ml of anhydrous methylene chloride while stirring and cooling with ice, followed by further stirring at room temperature for 2 hours. Stirred.

After adding 50 ml of water to this reaction mixture, extraction with chloroform (350 mJ x 2) was carried out, and the chloroform layer was reduced to 5%
The mixture was washed with 50 ml of aqueous sodium hydroxide solution, 50 ml of 1.5% hydrochloric acid, and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless foamy substance. This N-(1,
Thionyl chloride was added to 1-dimethyl-2-hydroxyethyl)-3,4-dimethoxybenzamide, and the mixture was stirred at room temperature for 2 hours. Add 200ml of ether to this reaction mixture to crystallize 2-(3,4-dimethoxyphenyl).
-4,4-dimethyloxazoline hydrochloride was collected by filtration as white crystals. The white crystals were dissolved in 100 mJ of water, made alkaline with 20% aqueous sodium hydroxide solution, extracted with ether (250 ml x 2), dried over potassium carbonate and magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily substance. This was distilled to give 2-(3,4-dimethoxyphenyl)4,4-dimethyl-2-oxazoline 2
4.4 g (83% yield) was obtained as a colorless viscous substance.

2-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline infrared absorption spectrum νnv cm-1: 2960, 2
925.2895.2836.1646.1604.1
586°1514, 1464.1422.1358.1
310.1272.1260°1232, 1172.1
140.1078.1026.974.764.714
1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min CD013): 1.38 (6H, s), 3.91 (3H, s), 3
．． 93 (3H, s).

4.08 (2H, s), 6.86 (IH, d, J
= 8.3Hz).

7.46 (IH, d, J = 2.0Hz).

7.53 (IH, dd, J = 8.3, 2.0 Hz) Mass spectrum EI-MS m/z (%): 235 (M",
35), 220 (100), 205 (7), 192 (2
5).

164(24), 148(5) This 2-(3,4-dimethoxyphenyl)4,4dimethyl-2-oxazoline 29.98. was replaced with argon,
After adding and dissolving 270 ml of anhydrous tetrahydrofuran, the mixture was cooled to 45°C, and while stirring, 95.6 ml of 1.6M n-butyllithium was added, and the mixture was stirred at 45°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 and then at room temperature overnight. Water was added to this reaction mixture and extracted with ether (300
mJ To this was added 1.21 mJ of a 3N aqueous hydrochloric acid solution, and the mixture was heated under reflux for 3 hours. This reaction mixture was allowed to stand overnight at room temperature, and the precipitated needle crystals were collected by filtration and 4,5-dimethoxyphthalide 19.
A yield of 77%) was obtained.

4.5-dimethoxyphthalide infrared absorption spectrum νn-cm-1=2992, 29
64.29 shrine, 2836.1752.1616.14
98°1462, 1432.1368.1322,12
76, 1226.1086°1024, 996.944
．． 894.832.774.742.656.562 Proton nuclear magnetic resonance spectrum (Jppm in CDC13): 3.95 (3H, s), 3.96 (3H, s), 5
．． 32 (2H, s).

7.08 (LH, d, J = 8.3Hz), 7.
62 (IH, d, J = 8.3 Hz) Mass spectrum EI-MS m/z (%): 194 (M”, 94),
179(5), 165(100), 151(18
).

137(11), 123(11), 108(5), 92
(5), 77(13).

Specific Example 7-■ After dissolving 7.2 mj of diisopropylamine in 90 ml of anhydrous tetrahydrofuran, it was cooled to -10°C, and 35.4 ml of 1.6 M n-butyllithium was added with stirring.
Stir for 30 minutes. Further, this solution was cooled to -70°C, and while stirring, 200ml of anhydrous tetrahydrofuran solution containing 10.0g of 4,5-dimethoxyphthalide obtained in Specific Example 7-■
After adding J and stirring for 30 minutes, the temperature was raised to 40°C and a solution of 8.42 g of zinc chloride in anhydrous tetrahydrofuran was added.
0ml was added and stirred for 1 hour. Next, 30 ml of a solution of 6.8 ml of n-butyraldehyde in anhydrous tetrahydrofuran was added at 40°C, stirred for 30 minutes, and then stirred overnight at room temperature. The reaction mixture was poured into an iced 5% aqueous hydrochloric acid solution, extracted with diethyl ether (300 mJ x 2), washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a brown oil. This was subjected to flash column chromatography (silica gel 230 to 400 mesh!, 1
50g; diameter 6.5cm, length 10cm; eluent, ethyl acetate: n-hexane = 1:1.0.2kg/am
2), fractionated in 150 mJ portions and combined the 8th to 14th fractions to obtain 4,5-dimethoxy-3°(l-hydroxybutyl)phthalide 13.
Obtained 24 g (97% yield) as a yellow solid.

4.5-dimethoxy-3-(1-hydroxybutyl)phthalide infrared absorption spectrum νKlr crn-1:3
488, 3004.2952.2932.2860.2
844,1746°1614,1502.1456.1
444.1402,1358,1284°1226,1
108.1078.1022.974.958.878
．． 838°744.644 IH-nuclear magnetic resonance spectrum (200MHz) (δpp
min CDC13): 0.88, 0.96 (3H, t, J=6.8Hz).

1.20~1.70 (4H, m), 1.92°2.7
9 (IH, d, J = 6.8, 10.0Hz, D2
disappears when 0 is added).

3.95.3.96.3.98.3.98 (6H, s)
, 5.50°5.53 (IH, d, J=2.2.4.
9Hz), 7.09°7.10 (IH, d, J=8.
3Hz), 7.64°7.65 (IH, d, J = 8
．． 3Hz) Mass spectrum EI-MS mHz (%):
266 (9, M+), 248 (3), 219 (4), 1
94 (100).

179 (37), 166 (24), 151 (20), 1
36(12).

122 (14), 107 (16), 77 (26) Next, using the compound represented by the above formula (■) as a raw material, the above formula 1, I
A method for obtaining compounds represented by I and ■ is shown.

After mesylating the compound represented by the above formula (■), the mesyl group is removed by the action of an amine, and if necessary, the mesyl group is removed as is or after catalytic reduction, and then the mesylated compound is treated with an acid in water or an organic solvent. It can be obtained by reacting and demethylating.

As a mesylation reagent, methanesulfonyl chloride
Examples include pyridine, methanesulfonyl chloride, triethylamine, etc., and specific examples of organic solvents include anhydrous tetrahydrofuran, chloroform, methylene chloride, etc. The reaction is preferably carried out by heating from room temperature to about the boiling point of the solvent used.

Specific examples of organic solvents used for demethylation include anhydrous methylene chloride, chloroform, ethanol, etc. Specific examples of acids include boron tribromide, boron trichloride,
Examples include Lewis acids such as boron trifluoride, aluminum tribromide, aluminum trichloride, and aluminum trifluoride, hydroiodic acid, hydrobromic acid, or hydrochloric acid, and trifluoroacetic acid. The reaction temperature is suitably between 0°C and the boiling point of the solvent used.

Examples of the catalyst used in the catalytic reduction include 5 to 10% palladium on carbon, platinum oxide, Raney nickel, etc., and examples of the solvent used include alcohols such as methanol and ethanol, and organic solvents such as ethyl acetate. The reaction pressure is suitably about 1 to 10 atm, and the reaction temperature is suitably room temperature.

Specific examples of amines include 1,8-diazabicyclo[
5,4,Ol undec-7-ene (DBU), 1,5-
Diazabicyclo[4,3,01non-5-ene (DBN
), and examples of the solvent used include organic solvents such as benzene, and the reaction is preferably carried out by heating from room temperature to about the boiling point of the solvent used.

Next, examples of the present invention will be shown.

Example 1 3-(1-hydroxybutyl)-6,7- obtained in Example 1-■ was placed in a 500 ml eggplant flask equipped with a reflux condenser.
Add 10.0 g of cymethoxyphthalide and replace with argon.
After adding and dissolving 80 ml of anhydrous benzene and 7.6 ml of anhydrous pyridine, 5.8 ml of methanesulfonyl chloride was added.
1 was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water, extracted with ether twice (200 mJ x 2), and the ether layer was washed once each with 5% hydrochloric acid and saturated saline.
Dry (magnesium sulfate), remove the solvent under reduced pressure, and give 3-(
1-methanesulfonyloxybutyl)-6,7-dimethoxyphthalide was obtained as a yellow oil. Next, this oil was dissolved in 100 ml of anhydrous benzene, and DBU8.4 m
1 was added thereto, and the mixture was heated under reflux for 1 hour. This reaction solution was poured into 200 mJ of ice-cooled 2% hydrochloric acid, and extracted with ether twice (200 mJ).
nzlX 2), the ether layer was washed once each with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ7.5X20. Approximately 450 g; eluent, chloroform, pressure 0.2 kg/cm2.1 fraction =
100 mJ), and the first elution fraction (1100
~2400mJ) to 3.75g of colorless amorphous (
yield 40%), and the second elution fraction (2500-3900
m? ) 2.1 g (yield 22%) of a colorless oil was obtained. Since these have the physical and chemical properties shown below,
(Z)-3-butylidene- each represented by the above formula 1
They were determined to be 6,7-dimethoxyphthalide and (E)-3-butylidene-6,7-dimethoxyphthalide.

(Z)-3-butylidene-6,7,dimethoxyphthalide infrared absorption spectrum-'cm·l: 2956, 2872.2840.1778 (C: o)
, 1688.1594°1502, 1464.143
8.1346.1274.1078.1030°101
6, 932.878.818.796.766, 730
．． 672IH-Nuclear magnetic resonance spectrum (200MHz)
(δppm in CDC13) 0.98 (3H,t,J = 7.3Hz).

1.53 (2H, t-q, J = 7.6, 7.3Hz)
.

2.41 (2H, dt, J=7.8.7.6Hz).

3.92 (3H, s), 4.13 (3H, s).

5.46 (IH, t, J = 7.8Hz).

7.22 (IH, d, J=8.5Hz).

7.28 (IH, d, J = 8.5 Hz) Mass spectrum EI-MS m/z (%): 248 (M”, 28)
, 219 (100, M-CH3CH2).

206 (12, M-CH3CH=CH2).

191(25,219-Co), 177(9), 1
63(10), 148(7).

135(12), 105(11), 91(7),
77(11)(E)-3-Butylidene-6,7-dimethoxyphthalide infrared absorption spectrum ν:! c, n-1:
2960, 2872.1778 (C=O), 168
6,1594,1504゜1462.1440.134
6.1274.1078,1058,1030°936
, 886.820.740.672IH-nuclear magnetic resonance spectrum (200MHz) (δppm in CDC1
3) 1.02 (3H, t, J=7.3Hz).

1.60 (2H, t-q, J=7.6.7.3H7).

2.46 (2H, d-t, J = 8.2.7.6H
z).

3.94 (3H, s), 4.12 (3H, s).

5.70 (IH, t, J=8.2Hz).

7.25 (IH, d, J = 8.3Hz).

7.46 (IH, d, J = 8.3Hz) Mass spectrum EI-MSm/z (%): 248 (M'',
28), 219 (100, M-CH3CH2).

206 (13, M-CH3CH=CH2).

191(25,219-Co), 177(8), 1
63(11), 148(7).

135(12), 105(11), 91(6),
77(10) Example 2 3-(1-hydroxybutyl)-4,6- obtained in Example 2-■ was placed in a 200 mJ eggplant-shaped flask equipped with a reflux condenser.
Add 720rrLg of dimethoxyphthalide, replace with argon, and add 2ml of anhydrous benzene and 0.55ml of anhydrous pyridine.
After adding and dissolving 0.1 of methanesulfonyl chloride.
42m7 of the mixture was added, and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water, extracted with ether twice (100 mj x 2), the ether layer was washed once each with 5% hydrochloric acid and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure.
(1-Methanesulfonyloxybutyl)4,6-simethoxyphthalide was obtained as a yellow oil. Next, dissolve each of the oily substances in 9 ml of anhydrous benzene, and add 6 ml of DBUO.
The mixture was heated under reflux for 1 hour. This reaction solution was poured into 200 m2 of ice-cooled 2% hydrochloric acid, and extracted with ether twice (100 m2).
mj×2), the ether layer was washed once each with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was separated and purified using Fura Nosch column chromatography (silica gel, 230-400 mesh, φ6.5 x 30, about 450 g; eluent, chloroform, pressure 0.2 kg/cm2.1 fraction = 200 rnJ). One elution fraction (
1,000 to 1,800 ml) was obtained as a white solid (460 mg, yield 68%), which was further recrystallized from ethyl acetate-n-hexane to obtain colorless needle crystals. In addition, white solid 13 was obtained from the second elution fraction (2000 to 30000 mj).
0 rng (yield 19%) was obtained, which was further recrystallized from ethyl acetate and n-hexane to obtain colorless flaky crystals. These colorless needle-like crystals and colorless scale-like crystals have the physical and chemical properties shown below. It was determined to be -3-butylidene-4,6-cymethoxyphthalide.

(Z)-3-Butylidene-4,6-simethoxyphthalide Melting point: 129-131°C Infrared absorption spectrum ν: xcrn-1: 2948, 2
868.1772 (C=O), 1686.1604.
1504°1464, 1434.1324.1240.
1152.1052.1032゜1018, 982.9
22.846.778.738.636IH-Nuclear magnetic resonance spectrum (200MHz) (δppm in CD
013) 0.98 (3H,t,J =7.3Hz).

1.54 (2H, t-q, J=7.6, 7.3Hz).

2.42 (2H, d-t, J = 7.9.7.6H
z), 3.87 (3H, s).

3.94 (3H, s), 5.79 (IH, t, J
= 7.9Hz).

6.69 (IH, d, J = 2.0Hz), 6.
91 (IH, d, J = 2.0Hz) Mass spectrum EI-MS m/z (%): 248 (M+, 26
), 219 (100, M-CH3CH2).

206(1,M-CH3CH=CH2).

191(30,219-Co), 177(1), 1
63(9), 148(7).

135(7), 106(7), 91(5), 77
(7) (E)-3-Butylidene-4,6-dimethoxyphthalide Melting point = 97-98°C Infrared absorption spectrum': ""' 2956, 2868.2840.1754 (C=O),
1622,1590°1502.1468,1456
,1342,1318,1230.1210°1158
．． 1040.996.936.842.780.734
．． 714°634,494 1H-a magnetic resonance spectrum (200MH7) (δpp
min CD013) 0.97 (3H,t, J = 7.3Hz).

1.52 (2H, t-q, J=7.6.7.3Hz).

2.67 (2H, d-t, J=8.5.7.6Hz)
.

3.89 (3H, s), 3.92 (3H, s).

5.79 (IH, t, J = 8.5Hz).

6.70 (IH, d, J = 2.0Hz).

6.94 (IH, d, J = 2.0Hz) Mass spectrum EI-MS m/z (%): 248 (M +, 29)
, 219 (100, M-CH3CH2).

206(1,M-CH3CH=CH2), 191(
31,219-Co).

176(4), 163(10), 148(7),
135(7).

106(8), 91(5), 77(7) Example 3 3-(1-hydroxybutyl)-5,7- obtained in Example 3-■ in a 300 mJ eggplant flask equipped with a reflux condenser.
Add 7.3 g of cimethoxyphthalide, replace the atmosphere with argon, add and dissolve 22 ml of anhydrous benzene and 5.5 ml of anhydrous pyridine, and then add 4.2 ml of methanesulfonyl chloride.
was added and heated under reflux for 1 hour. The reaction solution was poured into ice water, extracted with ether twice (200 mJ 1
-methanesulfonyloxybutyl)-5,7-simethoxyphthalide was obtained as a yellow oil. Next, this oil was dissolved in 90 ml of anhydrous benzene, 6.2 ml of DBU was added, and the mixture was heated under reflux for 1 hour. This reaction solution was ice-cooled with 2%
Pour into 200ml of hydrochloric acid and extract with ether twice (200mJ
×2), the ether layer was diluted with water and saturated saline for 1 hour each.
The mixture was washed twice, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. This was divided into halves by flash column chromatography (silica gel, 230-400 mesh, φ6.5 x 30, about 450 g; eluent, chloroform, pressure 0.2 kg, 1 cm 2.1 fraction =
200 mJ), and the first elution fraction (1600
~3200mj) to 3.70g white solid (yield 5
4%) was further recrystallized from ethyl acetate-n-hexane to obtain colorless prism crystals. In addition, 2.08 g of white solid was obtained from the second elution fraction (4000-4200 mJ).
(yield: 31%), which was further recrystallized from ethyl acetate-n-hexane to obtain colorless needles. These colorless prism crystals and colorless needle crystals each have the physical and chemical properties shown below, so they are represented by the above formula 1 (Z)
-3-butylidene-5,7-dimethoxyphthalide and (E)-3-butylidene-5,7,dimethoxyphthalide.

(Z)-3-Butylidene-5,7-simethoxyphthalide Melting point: 96-98°C Infrared absorption spectrum -1,.1: 2952, 2872.2840.1768 (C=Q)
, 1688.1598°1494.1466.143
2.1342.1208,1160.1046°102
2, 988.926.832.788.690.588
．． 5121H-Nuclear magnetic resonance spectrum (200MHz)
(δppm in CD013) 0.98 (3H,t,J =7.3Hz).

1.53 (2H, t-q, J = 7.6, 7.3Hz)
.

2.42 (2H, d-t, J = 7.9.7.6H
z).

3.91 (3H, s), 3.95 (3H, s).

5.56 (IH, t, J = 7.9Hz).

6.42 (IH, d, J = 1.7Hz), 6.
62 (IH, d, J = 1.7 Hz) Mass spectrum EI-MS m/z (%): 248 (M”, 16
), 219 (93, M-CH3CH2).

206 (100, M-CH3CH=CH2).

191(48,219-Co), 177(8), 163
(19).

161(25), 148(12), 133(15)
, 105(8), 91(10).

(E)-3-Butylidene-5,7-dimethoxyphthalide Melting point = 79-81°C Infrared absorption spectrum l/"cm-": 2960.
2932, 2872, 1762 (C=O), 167
0.1598°1494, 1476, 1455.143
4.1376.1352.1306°1224, 120
2,1164,1056,996,934,886,8
36°818, 696.550 1H-nuclear magnetic resonance spectrum (2ooMH2) (δpp
min CDC13) 1.03 (3H, t, J=7.3Hz).

1.62 (2H, t-q, J = 7.6.7.3Hz
).

2.48 (2H, d-t, J = 7.9.7.6Hz
).

3.93 (3H, s), 3.97 (3H, s).

5.79 (LH, t, J = 7.9Hz).

6.48 (IH, d, J=1.7Hz).

6.80 (IH, d, J = 1.7 Hz) Mass spectrum EI-MS m/z (%): 248 (M”, 14)
, 219 (96, M-CH3CH2).

206 (100, M-CH3CH=CH2).

191(50,219-Co), 176(5), 1
63(20).

161(24), 148(11), 135fl)
, 106(17), 91(10).

Example 4 3-(1-hydroxybutyl)-4,7 obtained in Specific Example 4-■ was placed in a 300 mJ eggplant-shaped flask equipped with a reflux condenser.
- Add 8.9 g of cymethoxyphthalide and replace with argon.
After adding and dissolving 27 ml of anhydrous benzene and 6.8 ml of anhydrous pyridine, 5.2 ml of methanesulfonyl chloride was added.
1 was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water, extracted with ether twice (200mj
-methanesulfonyloxybutyl)-4,7-dimethoxyphthalide was obtained as a yellow oil. Next, this oily substance was dissolved in 100rrLl of anhydrous benzene, and DBU7.5
rnJ was added and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice-cooled 2% hydrochloric acid (2θOml), extracted with chloroform twice (200ml x 2), the chloroform layer was washed once each with water and saturated saline, dried (magnesium sulfate),
The solvent was distilled off under reduced pressure to obtain a yellow oil. This was divided into halves by flash column chromatography (silica gel, 2
30-400 mesh, φ6.5 x 30, about 45Q
g; Eluate, chloroform, pressure 0-2 kg/cm
2.1 fraction = 100 mJ),
6.46 g (yield 78%) of a white solid was obtained from the first elution fraction (1100-2000 mJ), which was further recrystallized from ethyl acetate-n-hexane to obtain colorless scales.

Further, 0.45 g (yield 5.4%) of a white solid was obtained from the second elution fraction (2500 to 3600 ml), which was further diluted with ethyl acetate.

Recrystallization from n-hexane gave colorless prism crystals. These colorless scales and colorless prismatic crystals have the physical and chemical properties shown below, so they are (Z)-3-butylidene-4,7-dimethoxyphthalide and (E)- It was determined to be 3-butylidene-4,7-dimethoxyphthalide.

(Z)-3-Butylidene 4,7-simethoxyphthalide Melting point: 164-166°C Infrared absorption spectrum-j cm-1: 2956, 28
64.1768 (C=O), 1680, 1606.1
516°1452, 1360.1270,1208,1
070.1036.1016.996°942,812
．． 788.700 IH-Nuclear Magnetic Resonance Spectrum (200MHz) (δpp
min CD013) 0.98 (3H, t, J=7.3Hz).

1.54 (2H, t-q, J = 7.6.7.3H
z).

2.44 (2H, d-t, J = 8.1.7.6Hz
).

3.93 (3H, s), 3.95 (3H, s).

5.98 (IH, t, J=8.06Hz).

6.83 (IH, d, J = 8.8Hz), 7.
07 (IH, d, J = 8.8 Hz) Mass spectrum EI-MS m/z (%): 248 (M”, 29), 2
19 (100, M-CH3CH2).

206 (7, M-CH3CH=CH2), 191 (14
, 219-Co).

176(8), 163(9), 161(14), 148
(5), 133(10).

105(10), 91(6), 77(10)(E)
-3-Butylidene-4,7-simethoxyphthalide Melting point:
117-119°C Infrared absorption spectrum ν=, A-l: 2956, 2928.2872.2844.1758 (
C:0), 1658°1616.1506,1440
,1324.1276,1232.1196°1052
．． 1000.946.814.710IH ~ Nuclear magnetic resonance spectrum (200MHz) (δppm in CDC
l5) 0.97 (3H, t, J = 7.3Hz).

1.52 (2H, t-q, J=7.6, 7.3Hz).

2.71 (2H, d-t, J = 8.5.7.6Hz)
.

3.91 (3H, s), 3.95 (3H, s).

5.89 (IH, t, J=8.5Hz).

6-92 (IH, d, J=9.0Hz).

7.11 (IH, d, J = 9.0Hz) Mass spectrum EI-MS m/z (%): 248 (M”, 26)
, 219 (100, M-CH3CH2).

206 (8, M-CH3CH=CH2).

191(15,219-CO), 176(9), 1
63(10).

161 (14), 148 (5), 135 (10), 10
5(10), 91 (5 people Example 5 3-(1-hydroxybutyl)-5,6- obtained in Example 5-■ in a 300 ml eggplant-shaped flask equipped with a reflux condenser.
Add 5.7 g of cimethoxyphthalide and replace with argon, 20 ml of anhydrous benzene and 4.0 ml of anhydrous pyridine. 'aml was added and dissolved, then 3.3 m of methanesulfonyl chloride
1 was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water, extracted with ether twice (200?FIJX 2), the ether layer was washed once each with 5% hydrochloric acid and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure.
(1-Methanesulfonyloxybutyl)-5,6-dimethoxyphthalide was obtained as a yellow oil. Next, this oil was dissolved in 70 ml of anhydrous benzene, and DBU4.8 m
J was added, and the mixture was heated under reflux for 1 hour. This reaction solution was poured into 200 mJ of ice-cooled 2% hydrochloric acid, and extracted with ether twice (200 mJ).
mlX2), the ether layer was washed once each with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow oil. Half of this was subjected to flash column chromatography (silica gel, 230-400
Mesh, φ6.5×30, approximately 450 g; eluent, chloroform, pressure 0.2 kg/cm2.1 fraction = 200 mJ) was used to separate and purify the first eluate fraction (22
00-4000 mJ) to produce 1.2 g of white solid (yield: 2
3%) was further recrystallized from ethyl acetate-n-hexane to obtain colorless needles. In addition, the second elution fraction (
4200-6000m? ) to 0.8 g of white solid (
This was further recrystallized from ethyl acetate-n-hexane to obtain colorless fine needles. These colorless needle crystals and colorless microneedle crystals each have the physical and chemical properties shown below, and therefore are represented by the above formula 1 (2)-
3-Butylidene-5,6-simethoxyphthalide and (
E)-3-butylidene-5,6-cymethoxyphthalide.

(Z)-3-Butylidene-5,6-simethoxyphthalide Melting point: 129-130°C Infrared absorption spectrum ν1lJr CoI: 3092,
2956.2932, 2872.2836.1752 (
C=O).

1688, 1606.1504.1480.1458.
1318.1266°1222.1118.1074.
1008.948.878.824°772, 730.
670.528 1H-Nuclear Magnetic Resonance Spectrum (200MHz) (δpp
min CD013) 0.99 (3H, t, J=7.3Hz).

1.55 (2H, t-q, J = 7.6.7.3Hz
).

2.44 (2H, d-t, J = 7.8.7.6H
z), 3.95 (3H, s).

4.00 (3H, s), 5.49 (IH, t, J=
7.8Hz)y7.00(IH,s), 7.25(
IH, s) Mass spectrum EI-M 248 (M'', 32), 219 (100, M-C
H3CH2).

206 (58, M-CH3CH=CH2).

191(90,219-CO), 177(1), 1
63(32), 148(9).

136(9), 119(8), 105(5), 9
3(10), 77(12)(E)-3-butylidene-
5,6-Simethoxyphthalide Melting point: 2101-103°C Infrared absorption spectrum νU cm: 2956, 28
68.2832.1764 (C=O).

1668, 1592, 1498.1480, 1370.
1356.1294°1252, 1224.1112.
1076, 1014.944°862, 832.820
．． 778.678.5001H$ Magnetic Resonance Spectrum (
200MHz) (δppm in CDC13) 1.04 (3H,t,J==7.3Hz).

1.64 (2H, t-q, J=7.3, 7.3Hz).

2.50 (2H, d-t, J = EL1.7.3Hz
), 3.97 (3H, s).

4.01 (3H, s), 5.76 (IH, t, J=8.
1Hz).

7.18 (IH, s), 7.30 (IH, s) Mass spectrum EI-MSm/z (%): 248 (M”,
32), 219 (100, M-CH3CH2),.

206 (52, M-CH3CH=CH2).

191(88,219-Co), 175(5), 163
(34), 148(9).

136(10), 119(8), 93(10),
77(12) Example 6 (Z)-3 obtained in Example 3 was placed in a 100 ml eggplant flask.
-Add 2.0 g of butylidene-5,7 dimethoxyphthalide, replace the atmosphere with argon, add 40 ml of anhydrous methylene chloride, and dissolve. Under water cooling, add 40 ml of a 0.8 M boron tribromide methylene chloride solution, and at room temperature Stir for hours. This reaction solution was poured into ice water and extracted with ethyl acetate twice (200 ry
zJX2), the ethyl acetate layer was washed once with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow solid. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ4
, 5X15, about 120 g; Eluent, ethyl acetate: n-
(Z)-8-butylidene-7-hydroxy-5,methoxyphthalate was separated and purified using hexane = 1:3, pressure 0.2 kg/cm2.1 fraction = 50 ml), and from the first elution fraction (200 to 450 ml) white solid (
534WLg, yield 30%). This was further recrystallized from ethyl acetate-n-hexane to obtain white granular crystals. Furthermore, (Z)-3-butylidene-5,7-cyhydroxyphthalide was obtained as a white solid at 455 WLg (yield 26%) from the second elution fraction (500 to 1100 m?). This was further recrystallized from ethyl acetate-n-hexane to obtain white granular crystals. Also, the third elution fraction (1150-2
000mj ) to (Z)-3-butylidene-5-hydroxy-7-methoxyphthalide as a white solid 431WLg
(yield 24%). This was further mixed with ethyl acetate.
Recrystallization from n-hexane gave colorless prism crystals. These white granular crystals and colorless prism crystals are (Z)-3-butylidene-7-hydroxy-5,methoxyphthalide, (
It was determined to be Z)-S-butylidene-5,7-cyhydroxyphthalide, (Z)-3-butylidene-5-hydroxy-7-methoxyphthalide.

1.55 (2H, t-q, J = 7.6.7.3Hz
).

2.38 (2H, d-t, J=7.8, 7.6Hz),
3.84 (3H, s).

5.72 (IH, t, J = 7.8Hz), 6.36 (I
H, s), 6.73 (IH, s) mass spectrum EI-
MS m/z (%): 234 (M”, 30), 20
5 (100, M-CH3CH2).

192 (96, M-CH3CH=CH2).

177 (77, 205-CO), 149 (31),
122(16), 106(8).

91(11), 77(11) (Z)-3-butylidene-7-hydroxy-5,methoxyphthalide Melting point = 107-109°C Infrared absorption spectrum vnr Crn-”: 3444
(OH), 2960, 2932, 2868.1740 (
C=O).

1678, 1612.1468.1384.1300.
1202.1164゜1038, 830.790.69
6.640°582 (CC14): 1758 (C=0
) IH-a magnetic resonance spectrum (200MHz) (δp
pm in CD30D) 0.99 (3H, t, J=7.3Hz).

(Z)-3-Butylidene-5,7-cyhydroxyphthalide Melting point: 179-180°C Infrared absorption spectrum-'cm.1: 3124(OH), 2960.2932.2868.
1728 (C=O).

1686, 1616, 1482.1368.1338.
1218.1172°1036, 844.782.69
2.632.566 (CC14): 1758 (C=0
) IHH-nuclear magnetic resonance spectrum (200MHz) (δp
pm in CD30D) 0.99 (3H,t, J = 7.3Hz).

1.54 (2H, t-q, J = 7.6, 7.3Hz)
.

2.37 (2H, d-t, J = 7.8.7.6H
z).

5.61 (IH, t, J = 7.8Hz), 6.
31 (IH, s).

6.57 (IH, s) Mass spectrum EI-MS m/z (%): S m/
z (%) = 220 (M”, 29), 191 (100
, M-CH3CH2).

178 (77, M-CH3CH=CH2).

163 (77, 191-Co), 135 (32),
108(18), 77(11)(Z)-3-butylidene-5-hydroxy-7-methoxyphthalide Melting point: 160-162°C Infrared absorption spectrum-・C□・1°3280(OH), 2960.2872 .1742(
C: o), 1686°1608.1494.144
2.1348.1316,1196.1154゜105
8, 1020.970.846.786.696.54
8CC14:1788 (C:0) IH-nuclear magnetic resonance spectrum (200MHz) (δpp
min CD30D) 0.99 (3H, t, J = 7.3Hz).

1.55 (2H, t-q, J = 7.6.7.3Hz
).

2.37 (2H, d-t, J = 7.9.7.6H
z).

5.65 (IH, t, J = 7.9Hz), 3.
90 (3H, s).

6.46 (IH, s), 6.65 (IH, s) Mass spectrum EI-MS m/z (%): 234 (M”,
21), 205 (100, M-CH3CH2).

192 (89, M-CH3CH=CH2).

177(52,205-Co), 149(25), 1
34(11), 121(14).

92(20), 77(10) Example 7 (Z)- obtained in Example 4 was placed in a 300 mJ eggplant-shaped flask.
2.6 g of 3-butylidene 4,7-simethoxyphthalide was added, the atmosphere was replaced with argon, 52 ml of anhydrous methylene chloride was added, and after dissolving, 52 ml of a 0.8 M boron tribromide methylene chloride solution was added under water cooling. Stirred at room temperature for 2 hours.

This reaction solution was poured into ice water and extracted with ethyl acetate twice (200
mj x2), the ethyl acetate layer was washed once with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow solid. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ
4.5X15, about 120g; Eluate, ethyl acetate: n
-Hexane=l:2, pressure 0.2kg/em2.1
A white solid (965 mg,
A yield of 42%) was obtained. This was further recrystallized from ethyl acetate-n-hexane to obtain colorless needle crystals. In addition, a white solid (381 m
g, yield 17%). This was further ethyl acetate-n
- Recrystallization from hexane gave colorless needle crystals. These colorless needle crystals have the following physical and chemical properties:
(Z)-3-butylidene-4,7, represented by the above formula 1
Dihydroxyphthalide, (Z)-3-butylidene, was determined to be hydroxy-7-medoxyphthalide.

(Z)-3-Butylidene-4,7-cyhydroxyphthalide Melting point: 204-206°C Infrared absorption spectrum -'cm': 3292 (OH
), 2960.2932.2868.1730. (
C:O).

1680, 1630.1504, 1376.1306.
1286.1198°1026, 972.834.79
2.660.632.580.478 (CC14): 1
760 (C=0) IH-nuclear magnetic resonance spectrum (200MHz) (δpp
min CD30D) 1.00 (3H, t, J=7.3Hz).

1.55 (2H, Shiq, J=7.6, 7.3Hz).

2.40 (2H, d-t, J=7.9, 7.6Hz).

5.93 (IH, t, J=7.9Hz).

6.72 (IH, d, J = 8.6 Hz).

6.98 (IH, d, J = 8.6 Hz) Mass spectrum EI-MS m/z (%): 220 (M”, 33), 1
91 (100, M-CH3CH2).

178 (29, M-CH3CH=CH2).

163(45,191-Co), 135(15), 10
7(24), 91(7).

? 1(7), 77(11) (Z)-3-Butylidene-4,hydroxy-7-medoxyphthalide Melting point 2 150-152°C Infrared absorption spectrum vnr Hal: 3380 (OH
), 2964.2936.2872.2840°17
46(C-0), 1680.1618.1514.1
454.1436°1322,1302,1284,1
272.1238.1194,1064°1002,9
74.810.784.762.690.620.58
6° (CC14):1784 (C:0) IH-Nuclear Magnetic Resonance Spectrum (200MHz) (δpp
min CD30D) 1.00 (3H, t, J = 7.3Hz).

1.56 (2H, t-q, J = 7.6.7.8Hz)
.

2.41 (2H, d-t, J = 7.9.7.6H
z).

3.89 (3H, 8).

5-99 (IH, t, J = 7.9Hz).

6.91 (IH, d, J = 8.8Hz) 7.09 (IH
, d, J = 8.8Hz) Mass spectrum EI-MS
m/z (%): 234 (M+, 28), 205 (100
, M-CH3CH2).

192 (41, M-CH3CH=CH2).

177 (29,205-Co), 162 (16),
149(15), 134(10).

121 (20), 91 (12), 77 (9) Example 8 (Z)-3 obtained in Example 5 in a 100 mJ eggplant flask
-Butylidene-5,6-simethoxyphthalide 620mg
was replaced with argon, and 12.5 mJ of anhydrous methylene chloride was added.
After adding and dissolving, 12.5 m7 of a 0.8 M boron tribromide methylene chloride solution was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate twice (150 m2 x 2), the ethyl acetate layer was washed once with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow solid. Obtained. This was subjected to flash column chromatography (silica gel, 230-40
0) 7 bottles, φ3.5X10, about 50g; eluent, ethyl acetate:n-hexane=l:2, pressure 0.2kg1
cm2.1 fraction = 50rnl),
The first elution fraction (350-600 mJ) contained a white solid (
470rrLII, yield 86%) was obtained. This was further recrystallized from ethyl acetate-n and hexane to obtain a colorless prism product. This colorless prism crystal was determined to be (Z)-3-butylidene, 5,6-dihydroxyphthalide represented by the above formula I from the physical and chemical properties shown below.

(Z)-S-Butylidene-5,6-dihydroxyphthalide Melting point = 177-179°C Infrared absorption spectrum': ""' 3260 (OH), 2960.2932.2872.
1720 (C=O).

1682, 1598.1486.1326, 1182.
1156.1076°1016, 972.870.78
0.6581Hz magnetic resonance spectrum (200MHz)
(δppm in CD30D) 0.99 (3H,t, J = 7.3Hz).

1.54 (2H, t-q, J=7.6, 7.3Hz).

2.37 (2H, dt, J=7.9, 7.6Hz).

5.51 (IH, t, J = 7.9Hz), 7.0
6 (IH, s).

7.11 (IH, s) Mass spectrum EI-MS m/z (%): 220 (M
”, 30), 191 (100, M-CH3CH2)
.

178 (43, M-CH3CH=CH2), 163
(74,191-Co).

135 (30), 108 (19), 89 (15), 77
(10) Example 9 (Z)-3 obtained in Example 1 was placed in a 200 ml eggplant-shaped flask.
-butylidene-6,7-simethoxyphthalide 2.0 g,
After adding and dissolving 40 ml of anhydrous methylene chloride, 40 ml of a 0.8 M boron tribromide methylene chloride solution was added under water cooling, and the mixture was stirred at room temperature for 30 minutes.

The reaction solution was poured into ice water and stirred for 10 minutes, and the precipitated insoluble matter was collected by filtration and dried (between 50 and b) to obtain a white solid (1.20 g, yield 68%). This was recrystallized from ethyl acetate-n-hexane to obtain colorless fine needles. The colorless microacicular crystals were determined to be 6,7-hydroxy-3-valeryl benzoic acid represented by the above formula II from the physicochemical properties shown below.

6.7-hydroxy-3-valerylbenzoic acid melting point = 98-100°C Infrared absorption spectrum ν: xcrn4: 3364, 32
32(OH), 2956.2932.2872°17
26(C=O), 1618.1524.1460.1
404°1292.1204.1138.1086.9
36.870.846.782.728°662, 56
6,450 1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min CD30D) 0.88 (3H, t, J = 6.0Hz), 1.10
~1.40 (4H, m).

1.90-2.40 (2H, m), 6.87 (IH,
d, J = 7.6Hz).

7.06 (IH, d, J = 7.6 Hz) Mass spectrum EI-MS m/z (%): 238 (M”, 14),
220 (32, M-H2O).

191 (37,220-CH3CH2).

181 (71, M-CH3CH2CH2CH2), 1
7 fall 34).

163 (100, 191-Co), 150 (24),
136(19).

119 (13), 108 (17), 79 (36) Example 10 (E)-3 obtained in Example 5 in a 101O0 eggplant flask
-Butylidene-5,6-dimethoxyphthalide 350rn
After adding 7 ml of anhydrous methylene chloride and dissolving it, 7 mj (5.64 mmol) of a 0.8 M boron tribromide methylene chloride solution was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. . The reaction solution was poured into ice water, extracted with ethyl acetate twice (100nzj Obtained. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ3.5X10, approx.
0g; Eluent 1 ethyl acetate: n-hexane = 1:2, pressure 0.2kg/cm", 1 fraction = 50mJ)
Separate and purify the first elution fraction (100-500rn?
) 181rrLg of white solid (yield 58%) was obtained.

This was further recrystallized from ethyl acetate-n-hexane,
Colorless prismatic crystals were obtained. This colorless prism crystal is (E)-3 represented by the above formula 1 from the physical and chemical properties shown below.
-butylidene, 5,6-cyhydroxyphthalide.

(E)-3-Butylidene-5,6,dihydroxyphthalide Melting point = 182-184°C Infrared absorption spectrum ν■・ern-1 = 3260 (O
H), 2960.2932.2872.1720(C
: o).

1682, 1598.1486.1326.1182.
1156.1076°1016.972.870.78
0.6581H-a magnetic resonance spectrum (200MHz
) (δppm in CD30D) 1.04 (3H, t, J=7.3Hz).

1.61 (2H, t-q, J=7.6, 7.3Hz).

2.47 (2H, d-t, J=8.2.7.6Hz).

5.66 (LH, t, J = 8.2Hz), 7.
16 (IH, s).

7.26 (IH, s) Mass spectrum EI-MS m/z (%): 220 (M
+, 33), 191 (100, M-CH3CH2)
.

178 (31, M-CH3CH=CH2).

163(45,191-Co), 135(15),
108(14), 91(9).

Example 11-■ 4,6-Simethoxy-5-methoxymethoxy-3-(1-hydroxybutyl)phthalide obtained in Specific Example 6-■ 2.
After replacing 33g with argon, 5ml of anhydrous benzene was added and dissolved, and 1.1ml of anhydrous pyridine was dissolved. and 1 lrnl of methanesulfonyl chloride were added at room temperature, stirred for 10 minutes, and further heated under reflux for 15 minutes. After returning the reaction mixture to room temperature, it was poured into ice water, extracted with diethyl ether (100riJ X2), washed with water and saturated brine,
After drying over magnesium sulfate and removing the solvent under reduced pressure, a yellow oil was obtained. This was subjected to flash column chromatography (silica gel, 230-400 mesh, sog).

Diameter 4.5 cm, length 10 cm; eluent, ethyl acetate: n
-Hexane = 2: 3. Subjected to 0.2 kg/cm, 50
Fractions 8 to 11 were collected in 1 m increments and 1.91 g (yield 66%) of white amorphous 4,6-simethoxy-5-methoxymethoxy-3-(1-methanesulfonyloxybutyl) phthalide was obtained. Obtained.

4.6-Simethoxy5-methoxymethoxy-3-(1
-methanesulfonyloxybutyl) phthalide infrared absorption spectrum': ""' 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 1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min CDC13): 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), 3.92.3.93.4.0
1.4.07 (6H, s).

5.17, 5.20.5.21.5.24 (2H, s)
, 5.25.5.35 (IH, ddd, J = 1.
5.3.0.10.0Hz, J = 2.2.3.0
゜10.0Hz), 5.53.5.89 (IH, d,
J = 1.5Hz.

J = 2.2Hz), 7.16, 7.17 (IH, s) Mass spectrum EI-MS m/z (%): 404 (5,
M”), 372 (2), 309 (2), 308 (2 people 2
79(2), 264(33), 253(4), 235(
10), 223(4).

209(6), 45(100) Example 114 Next, 4, 6. obtained in Example 11-■. Dimethoxy-5-
After replacing 1.66 g of methoxymethoxy-3-(1-methanesulfonyloxybutyl) phthalide with argon, 13rrL1 of anhydrous benzene was added and dissolved, and then DBU
After adding O, 92 mJ, the mixture was stirred at room temperature for 10 minutes, and heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into 50ml of ice-cooled 2% aqueous hydrochloric acid solution, extracted with diethyl ether (100ryzJ I got it. This was subjected to flash column chromatography (silica gel, 230-400 mesh, 20
0g; diameter 4.5cm, length 25cm; eluent, methylene chloride:chloroform = 1:1; 0.2kg/cm2
), fractionated into 30 ml portions and combined the 8th to 29th fractions to obtain (Z) 4.6-Simethoxy 5.6-Simethoxy, a colorless oil. Methoxymethoxy-3-butylidenephthalide 8
02rrLg was obtained (yield 63%). Also, 31-42
By merging the 1st to 42nd sections, a colorless oil (E)-
182 mg (yield: 14%) of 4,6-simethoxy-5-methoxymethoxy-3-butylidenephthalide was obtained.

(Z)-4,6-simethoxy-5-methoxymethoxy-
3-butylidenephthalide infrared absorption spectrum, tmx'yo-1:2956, 1
870.2840, 1776, 1681.1609.1
481°1429, 1398.1337.1267, 1
207.1161.1130゜1100.1044,1
022.991.960.936.766IH-Nuclear magnetic resonance spectrum (200MHz) (δppm in C
DC13): 0.99 (3H, t, J = 7.3Hz).

1.55 (2H, t-q, J=7.3Hz).

2.44 (2H, d-t, J = 7.9.7.3H
z), 3.62 (3H, s).

3.92 (3H, s), 3.98 (3H, s), 5
．． 22 (2H, s).

5.84 (IH, t, J = 7.9Hz), 7.1
5 (IH, s) mass spectrum EI-MS m/z (%
):279(5), 265(3), 263(4),
249(3), 246(2).

235(2), 233(3), 221(1), 2
17(1), 207(1).

205(1), 93(1), 45(100) Example 11-■ Furthermore, (Z)-4,6-simethoxy-5-methoxymethoxy-3,butylidenephthalide obtained in Example 11-■ 1. After adding 10 ml of dioxane to 23 g and dissolving it, 2 ml of phosphoric acid was added and stirred at room temperature for 10 minutes.
The mixture was heated to reflux for 0 minutes. Return this reaction solution to room temperature, and add 1
1 was added to precipitate crystals, which were collected by filtration to produce white fine needle-like crystals (
873 rng (yield: 83%) of Z)-3-butylidene-5-hydroxy-4,6-dimethoxyphthalide was obtained.

(Z)-3-butylidene-5-hydroxy-4,6,dimethoxyphthalide infrared absorption spectrum': ""' 3384, 2988, 2948.2864.2B32.
1744.1680°1614, 1596.1502.
1480.1458.1428.1372°1336,
1280.1228.1204.1180.1152.
1098°1052, 1018.960.924.86
8.780.754.706.5281H-a magnetic resonance spectrum (200MH2) (δppm in CDC
13): 0.98 (3H, t, J = 7.3Hz).

1.55 (2H, tq, J = 7.3.7.3Hz).

2.44 (2H, dt, J=7.9, 7.3Hz).

3.98 (3H, s), 4.03 (3H, s).

5.85 (IH, t, J = 7.9Hz).

6.12 (LH,s, disappears with addition of D20), 7.2
6 (LH, s) mass spectrum EI-MS m/z (%
): 264 (30, M”), 235 (100), 2
22(9), 20? (14).

192(2), 179(3), 164(2), 1
49(2), 137(3).

Example 11-■ In a 200 mj eggplant flask, the mixture obtained in Example 11-■ (2
)-3-Butylidene-5-hydroxy-4,6-simethoxyphthalide (1.0 g) was added, the atmosphere was replaced with argon, 28 ml of anhydrous methylene chloride was added, and the mixture was dissolved.
8M boron tribromide in methylene chloride solution 28rnl (2
2,70rrLr+zol) was added thereto, and the mixture was stirred at room temperature for 2.5 hours. Pour this reaction solution into ice water and extract with ethyl acetate 2.
The ethyl acetate layer was washed once with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain a yellow solid. This was subjected to flash column chromatography (silica gel, 230-400 mesh, φ3.5X10, about 50 g; eluent, ethyl acetate: n-hexane = 1:1, pressure 0.2 kg/cm
2, 1 fraction = 50 ml), and 240 mg of white solid was obtained from the first elution fraction (350-600 ml).
(yield 27%). This was further mixed with ethyl acetate-n-
Recrystallization from hexane gave colorless needles. This colorless needle crystal is (Z)-3-butylidene represented by the above formula (2) from the physical and chemical properties shown below.

Determined to be 4.5.6-trihydroxyphthalide.

(Z)-3-Butylidene-4,5,6-dorihydroxyphthalide Melting point: 175-178°C Infrared absorption spectrum νnr crn-1: a little less than 35,
3412 (OH), 2956.2932.2868°1710 (C=0) 1678.1632.1530.1
498.1348°1220, 1188.1158.1
100.1024.7886.7741H-Nuclear magnetic resonance spectrum (200MHz) (δppm in CD3
0D) 0.99 (3H, t, J = 7-3Hz).

1.54 (2H, tq, J = 7.6.7.3Hz
) t2.38 (2H, d-t, J = 7.9.7.6
Hz).

5.78 (IH, t, J = 7.9Hz), 6.79 (I
H,s).

Mass spectrum EI-MS m/z (%): 250 (M
", 8), 236 (30), 221 (18, M
-CH3CH2)207(100,M-CH3CH2C
H2), 194(28).

179(74,207-Co), 166(12), 15
1(17), 133(24).

124(12), 105(12), 77(10) Example 12 Specific Example 7-■ After replacing 12.42 g of 4,5-dimethoxy 3-(1-hydroxybutyl) phthalide with argon, 30 ml of anhydrous benzene was added. 7.6 ml of anhydrous pyridine and 7.2 ml of methanesulfonyl chloride.
1 was added at room temperature, stirred for 10 minutes, and further heated under reflux for 1 hour. After returning the reaction mixture to room temperature, it was poured into ice water and extracted with diethyl ether (300nzJ x 2).
Washed with water and saturated saline, dried with magnesium sulfate,
The solvent was removed in vacuo to give a brown oil. This was subjected to flash column chromatography (silica gel, 230-4
00 mesh, 80g, diameter 4.5cm, length 10cm
; Eluent, chloroform:methylene chloride = 1:1.0.
2kg/cm2), aliquot each 100ml and collect 3~
Combine the 10th fractions and obtain 4,5% of the colorless oil.
16.03 g (yield: 99%) of -dimethoxy-3-(1-methanesulfonyloxybutyl)phthalide was obtained.

4.5-Dimethoxy-3-(1-methanesulfonyloxybutyl)phthalide infrared absorption spectrum-'cm.1: 2960, 2876, 2840.1770.1726.
1614.1500°1462, 1352.1282.
1226.1176, 1088.1076°1010,
938.922.898.800.738.5261H
-Nuclear magnetic resonance spectrum (200MHz) (δppm
in CD013): 0.84.1.03 (3H, t, J = 7.3Hz).

1.20-2.10 (4H, m), 2.55, 3.13
(3H,s), 3.97°3.98.3.99.4.0
5 (6H, s), 5.26° 5.41 [IH, ddd
, (J = 1.0.1.5.8.0Hz).

(J = 2.0.3.0.10.0Hz)], 5.55
゜5.92 (IH, d, J = 1.5Hz, J =
2.0Hz), 7.11゜7.12 (IH, d, J
= 8.3Hz), 7.60°7.64(IH, d
, J=8.3Hz) Mass spectrum EI-MS m/z
(%): 344 (4, M”), 248 (7), 219 (
10), 206 (4 people 193 (100), 179 (3)
, 163(5), 150(6), 135(4).

122(9), 79(14), 55(16) Furthermore, after replacing 16.03 g of this 4,5-dimethoxy-3-(1-methanesulfonyloxybutyl) phthalide with argon, 150 mJ of anhydrous benzene was added and dissolved. Then, 9.75 mJ of DBU was added and stirred at room temperature for 10 minutes.
The mixture was heated under reflux for 1 hour. The reaction mixture was brought to room temperature,
Pour into 100 ml of ice-cooled 2% aqueous hydrochloric acid solution, extract with ether (300 ml x 2), wash with water and saturated saline,
After drying over magnesium sulfate, the solvent was removed under reduced pressure to obtain a yellow solid. This was recrystallized from n-hexane to give white needle crystals (Z) 4,5-dimethoxy-3-butylidenephthalide 8
．． 4g was obtained.

(Z)J, 5-dimethoxy-3-butylidenephthalide infrared absorption spectrum ν:”'・1: 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 1H-nuclear magnetic resonance spectrum (200MHz) (δpp
min in CDC13): 1.00 (3H, t, J = 7.3Hz included 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 (IH, t, J = 7.9Hz), 7.04 (
IH, d, J = 8.3Hz).

7.62 (IH, d, J = = 8.3 Hz) Mass spectrum EI-MS m/z (%): 248 (24, M"),
219 (100), 206 (18), 191 (1
9).

176(8), 163(8), 148(6), 135(
11), 133(6).

118(6), 105(9), 91(6), 77(11
) 100rrLl wide Ronus type flask (Z)-4,5
-dimethoxy-3-butylidenephthalide 1.0 g (4,
03rnma? ) was dissolved in 10 ml of methanol, and 100 mz of 5% palladium on carbon was added thereto.The mixture was placed in an atmospheric pressure catalytic reduction apparatus and stirred at room temperature for 2 hours. This reaction solution was filtered through Celite (washed with methanol), and the filtrate was distilled off under reduced pressure to obtain 1.03 g of a white solid. This was recrystallized from n-hexane to obtain 0.95 g (yield 94%) of 3-butyl-4,5-dimethoxyphthalide as colorless needles.

3-Butyl-4,5-dimethoxyphthalide infrared absorption spectrum-'cm/l: 2952, 2868.1766 (C=O), 1614
．． 1498.1462°1440, 1344.1278
．． 1236.1222.1162.1092°1052
．． 970.820.736 tn-a magnetic resonance spectrum (200MH2) (δpp
min CDC13): 0.89 (3H, t, J=6-8Hz) + 1.15-
1.50 (4H, m).

1.65-1.85 (IH, m), 2.10-2.3
5 (IH, m).

3.92 (3H, s), 3.97 (3H, s).

5.51 (IH, dd, J=7.8.3.2Hz).

7.07 (IH, d, J = 8.3Hz), 7.
60 (LH, d, J = 8.3 Hz) Mass spectrum EI-MS m/z (%): 250 (M”, 17 people 1
93 (100, M-CH3CH2CH2CH2) Cal
cd;C:67.18. H Near, 25 Found; C
:67.24. H near, 43rd, 100m? 3-butyl-4,5-dimethoxyphthalide 1 in an eggplant-shaped flask
．． 2 g (4.79 mrnol) was added, the atmosphere was replaced with argon, 18 ml of anhydrous methylene chloride was added and dissolved, and then
Under water cooling, 0.8M boron tribromide methylene chloride solution 18
Add m1 (14,38mrrLoJ) and incubate at room temperature for 2
Stir for hours. The reaction solution was poured into ice water, stirred at room temperature for 30 minutes, and then distilled off under reduced pressure (to remove methylene chloride and methyl bromide), and the precipitated white insoluble matter was collected by filtration (washed thoroughly with water until pH 7). Drying (50 to 60°C under reduced pressure)
time) to obtain 865rrLg of a white solid. This was recrystallized from benzene to obtain colorless fine needle crystals (782 rrLg, yield 74%). These colorless microacicular crystals were determined to be 3°butyl 4,5-dihydroxyphthalide represented by the above formula III because they had the physical and chemical properties shown below.

3-Butyl-4,5-dihydroxyphthalide Melting point: 13
8-140℃ Infrared absorption spectrum, 0 cm-': 3484 (O
H), 3200(OH), 2952.2928.2
864°1716 (C=O), 1628.1532.
1472.1408.1300°1226, 1164.
1122.1096.1074.1052.948.9
36°892, 830.764.732.634.53
01H-Nuclear magnetic resonance spectrum (200MHz) (δp
pm in Acetone-d6): 0.90 (3H
, t, J=7.1Hz), 1.20-1.50 (4H,
m).

1.60-1.85 (IH, m), 2.10-2.4
0(IH, m).

5.51 (IH, dd, J = 7.3, 2.9Hz).

7.06 (IH, d, J = 8.3Hz), 7.21
(IH, d, J=8.3Hz).

8.25 (IH, s, D20 exchange,).

9.42 (IH, s, D20 exchange,) Mass spectrum EI-MS m/z (%): 222 (M
”, 18), 165 (100, M-CH3CH2C
H2CH2).

Ca1cd;C:64.85. H: 6.35 Foun
d;C:64.44. H: 6.29 Example 13 (2) obtained in Example 1 in a 100 ml wide Ronus flask
.

3-Butylidene-6,7-dimethoxyphthalide 1.52
g (6,12 mrrLDJ) and methanol 15
After adding 150 mg of 5% palladium on carbon, the mixture was placed in an atmospheric pressure catalytic reduction apparatus and stirred at room temperature for 2 hours. This reaction solution was filtered through Celite (washed with methanol),
The filtrate was distilled off under reduced pressure to obtain 1.53 g of a white solid. This was recrystallized from n-hexane and colorless needle crystals (1.43g,
A yield of 93% was obtained. From the physical and chemical properties shown below, this colorless needle crystal is 3-butyl-6,
It was determined to be 7-dimethoxyphthalide.

3-Butyl-6,7-dimethoxyphthalide melting point near 5~
76℃ Infrared absorption spectrum-'cm・1: 2952, 2928.2864.1746 (C: o)
, 1600.1502°1466, 1440.142
4.1352.1304.1274.1224゜112
4, 1050.1012.974.964.916.8
76, 826.796°760, 732.694.63
8.604IH-Nuclear Magnetic Resonance Spectrum (200MH2
) (δppm in CD013): (191 (3H, t, J=7.0Hz), 1.20-1
．． 50 (4H, m).

1.60-1.80 (IH, m), 1.80-2.1
0 (IH, m), 3.91 (3H, s).

4.11 (3H, s), 5.34 (IH, dd, J=7
．． 6,3.9Hz).

7.03 (IH, d, J = 8.3Hz), 7.22 (I
H, d, J = 8.3Hz) Mass spectrum EI-MS
m/z (%): 250 (M'', 26), 193 (
100, M-CH3CH2CH2CH2).

Calcd;C:67.18. H Near, 25. N:
Found; C: 67.24. H Near, 43. N:
Example 14 1.2 g of 3-butyl-6,7-cymethoxyphthalide (4,7
After adding 24 ml of anhydrous methylene chloride and dissolving it, add 24 ml of a 0.8 M boron tribromide methylene chloride solution (19,16
mmoJ) was added and stirred at room temperature for 2 hours. This reaction solution was poured into ice water, stirred at room temperature for 30 minutes, and then evaporated under reduced pressure (
(methylene chloride and methyl bromide were removed). Filter out the precipitated white insoluble matter (wash thoroughly with water until pH 7),
Drying (under reduced pressure, 50-60°C, 5-6 hours) yielded 914 mg of a white solid. The filtrate was extracted once with ethyl acetate (200 m7), and the ethyl acetate layer was washed once with water and saturated brine, dried (magnesium sulfate), and the solvent was distilled off under reduced pressure to obtain white solid 160F714F. The above white solids were combined and recrystallized from benzene to obtain colorless microneedle crystals (966 mg, yield 91%). This colorless microacicular crystal had the physical and chemical properties shown below, and was therefore determined to be 3-butyl-6,7-cyhydroxyphthalide represented by the above formula (■■).

3-Butyl-6,7-cyhydroxyphthalide Melting point: 13
1-133℃ Infrared absorption spectrum νKBv c,,・l: 3412
(OH), 3172(OH), 2952.2868
゜1728 (C=O), 1614.1522.14
68.1400.1326°1280, 1212.11
02.1006.968.938.894.832゜7
94, 774.728.610 1H, magnetic resonance spectrum (200MHz) (δpp
m in Acetone-d6): 0.90 (3H
, t, J = 7.1Hz), 1.20~1.50(
4H, m).

1.60-1.80 (IH, m), 190-2-10
(IH, m).

5.45 (LH, dd, J=7.3, 3.9Hz).

6.90 (IH, d, 7.8Hz), 7.20 (L
H, d, J=7.8Hz) Mass spectrum EI-MS
m/z (%): 222 (M'', 52), 20
4 (28).

165 (100, M-CH3CH2CH2CH2),
137(41)Calcd; C:64.85. H:
6.35 Found; C: 64.82. H:6.4
8 The compounds of the present invention represented by the above formulas 1 to m are prostaglandin F2. It has harmful effects and is useful as a medicine. This will be explained using an experimental example.

Experimental Example The ovaries of female Wistar rats were removed, and about 3 weeks later, the uterine horns were removed. Each uterine horn was suspended in a Magnus tube, immersed in Kug Ringer's solution maintained at 25° C. through an air bubble, and contractions caused by the addition of prostaglandin F2a were recorded using a pen recorder.

The compounds obtained in Example 6, Example 7, Example 8 and Example 10 were dissolved in ethanol to a final concentration of 5×10′g/mj and added 5 minutes before adding prostaglandin F2a. did. From the contraction results, the prostaglandin F2a inhibition rate of the compound obtained in the example was calculated using the following formula.

-B Inhibition rate -X100 (%) A: Shrinkage degree when the compound obtained in the example is not included B: Shrinkage degree when the compound obtained in the example is added The results are shown in Table 1.

From the above results, it was confirmed that the compound of the present invention has a prostaglandin F2a inhibitory effect.

The compounds of the present invention can be administered to animals and humans either neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as appropriate, and may include oral preparations such as tablets, capsules, and granules, and parenteral preparations such as injections and full-strength preparations. tablets, capsules,
Oral preparations such as granules are manufactured according to conventional methods. Tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc.; capsules are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc.; It is manufactured by mixing it with an inert pharmaceutical filler or diluent and filling it into hard gelatin capsules. Syrups and elixirs are prepared by mixing the compound of the present invention with sweetening agents such as sucrose, coloring agents, flavoring agents, flavoring agents, and adjuvants.

Parenteral preparations are manufactured according to conventional methods, and diluents generally include distilled water for injection, saline, dextrose aqueous solution,
Propylene glycol or the like can be used. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation can be filled into ampoules and the like, then frozen, water can be distilled off by ordinary freeze-drying techniques, and a liquid preparation can be re-prepared from the freeze-dried product immediately before use.

(Left below) Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and fully dilated preparations for intrarectal administration, and are manufactured according to conventional methods.

Claims (3)

[Claims] (1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (In the formula, R_1, R_2 and R_3 are methoxyl groups,
Indicates a hydroxyl group or a hydrogen atom. ) Phthalide derivatives. (2) A phthalide derivative represented by the following formula II ▲Mathematical formula, chemical formula, table, etc.▼II (In the formula, R_4 and R_5 represent a methoxyl group or a hydroxyl group.) (3) A phthalide derivative represented by the following formula III ▲Mathematical formula, chemical formula, table, etc.▼III (In the formula, R_6 and R_7 represent a methoxyl group or a hydroxyl group.)