JPH08176134A - New synthetic method of phthalide derivative - Google Patents

Abstract

PURPOSE: To provide a new synthetic method of phthalide derivatives in a high selectivity and a high yield by reacting an acetylene carboxylic acids mixed with a silver salt and/or silver. CONSTITUTION: This new synthetic method of phthalide derivatives comprises reacting by mixing a compound of formula I (R1 is an alkyl; R2 , R3 are each H, an alkyl or R2 and R3 linked to form a ring) with one or more silver salt (e.g. silver iodide, silver chloride, silver carbonate and silver sulfate) and/or silver in an anhydrous aprotic polar solvent (e.g. anhydrous dimethylformamide) with adding amines if necessary at -40 to 100 deg.C to obtain the compounds of formula II. The phthalide derivatives are useful as medicines having the inhibitory effect of prostaglandin F2α, the reducing effect of blood viscosity, the suppressing effect of cell proliferation, etc.

Description

Detailed Description of the Invention

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TECHNICAL FIELD The present invention relates to a novel synthetic method capable of synthesizing a phthalide derivative with high selectivity and high yield.

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2. Description of the Related Art The following general formula (3) [In the formula, R ₂ and R ₃ are each independently a hydrogen atom or a substituted or unsubstituted alkyl group, or a substituted or unsubstituted ring represented by the following formula (2) (In the formula, the broken line is a bond forming a ring, and each represents a saturated or unsaturated bond), and R ₁ represents a substituted or unsubstituted alkyl group. ] It is reported that the phthalide derivative represented by the following (hereinafter simply referred to as phthalide derivative) has a prostaglandin F2α inhibitory action, a blood viscosity lowering action, a cell growth inhibitory action, etc. and is a useful drug for pharmaceuticals. ing. (Patent publication 1988 No. 83081, Patent publication 1992 No. 77480 publication, Patent publication 1992 No. 208278 publication, Patent publication 1993 33106)
No. 0 bulletin etc.)

On the other hand, the phthalide derivative can be synthesized by the following general formula (1) [Wherein R ₁ , R ₂ and R ₃ are the same as defined above] are known to be obtained by a cyclization reaction of an acetylenecarboxylic acid (hereinafter, simply abbreviated as acetylenecarboxylic acid). As a by-product thereof, the following general formula (4) A compound represented by the formula: wherein R ₁ , R ₂ and R ₃ are the same as defined above is produced.

The degree of formation of by-products varies depending on the reaction reagent and reaction conditions. For example, acetylene carboxylic acid condensed with a benzene ring is used as a starting material for copper iodide (Cu).
When I), mercury sulfate (HgSO ₄ ) or sulfuric acid is used as a reaction reagent, an isocoumarin derivative is obtained as a main product. Further, when acetylenecarboxylic acid in which the benzene ring is not condensed is used as a starting material and silver nitrate (AgNO ₃ ) or mercury oxide (HgO) is used as a reaction reagent, pentenolide is obtained as a main product, or butenolide and a phthalide derivative. Is obtained in a mixture close to 1: 1. Therefore, when the phthalide derivative was synthesized according to the conventional synthesis method, the yield was very low.

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SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel synthetic method capable of synthesizing a phthalide derivative with high selectivity and high yield.

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DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies in view of the above-mentioned drawbacks of the conventional method, and as a result, as a result, a phthalide derivative is obtained by reacting acetylenecarboxylic acid with a silver salt or silver. It was found that it can be synthesized with high selectivity and high yield, and completed the present invention.

That is, the present invention is a method for synthesizing a phthalide derivative by mixing acetylenecarboxylic acid with one or more silver salts and / or silver and reacting them.

The method of the present invention is nothing but a method of synthesizing a phthalide derivative by mixing one or more kinds of silver salts and / or silver with acetylenecarboxylic acid and reacting them as described above. The details of this will be described below.

The method of the present invention uses one or more silver salts and / or silver. Especially for silver salts, silver iodide (AgI) and silver bromide (AgB) can be
r), silver chloride (AgCl), silver carbonate (Ag ₂ CO ₃ ), silver periodate (AgIO ₃ ), silver sulfate (Ag ₂ SO ₄ ), silver chromate (Ag ₂ CrO ₄ ), silver sulfide (Ag) It is preferable to use one or more silver salts and / or silver selected from ₂ S).

As the conditions of the method of the present invention, any conditions can be used as long as they can cause a cyclization reaction of acetylenecarboxylic acid, and the conditions will be described below.

The solvent used in the reaction is acetone, acetonitrile, ethyl acetate, tetrahydrofuran, benzene,
A solvent such as dioxane, methylene chloride or methanol can be used, but it is preferable to use an anhydrous aprotic polar solvent (such as dimethylformamide or dimethylsulfoxide).

The reaction temperature can be appropriately selected from the range of -40 ° C to 100 ° C, but it is 0 ° C to 30 ° C.
The temperature is preferably ° C.

If necessary, lower alkylamines such as triethylamine and diisopropylethylamine and suitable amines such as pyridine can be added for the purpose of promoting the reaction.

After completion of the reaction, the phthalide derivative is obtained by purifying the reaction solution by a usual purification step. For example, the reaction solution is filtered through Celite, a paper filter, a glass filter, etc., and water is added to the filtrate. Extraction with an organic solvent (ethyl acetate, chloroform, ether), washing of the organic layer with saturated brine, drying (MgSO ₄ ) and evaporation of the solvent under reduced pressure, and further recrystallization or distillation under reduced pressure. It can be purified or, if necessary, purified by flash column chromatography (silica gel, alumina, Sephadex, etc.).

Next, more detailed description will be given by showing examples of the present invention, but the present invention is not limited thereto.

Example 1 Preparation of (Z) -3-butylidenephthalide 100 mg of 2- (1-pentynyl) benzoic acid, silver iodide (AgI), silver (Ag), silver chloride (AgCl) were placed in a 25 ml round-bottomed flask. , Silver bromide (AgBr), silver carbonate (Ag
₂ CO ₃ ) or 10% molar amount of silver sulfate (Ag ₂ SO ₄ ) was added and the atmosphere was replaced with argon, and then 1 ml of anhydrous dimethylformamide was used.
Was added, and the mixture was vigorously stirred at room temperature for 18 hours. Next, the reaction solution was filtered through Celite, water was added to the filtrate, extracted with ethyl acetate,
The ethyl acetate layer was washed with saturated saline and dried (MgS
O ₄ ) and the solvent were distilled off under reduced pressure to obtain a reaction residue. By separating and purifying this by flash column chromatography (silica gel; eluent, chloroform-benzene = 1: 4), it has the following physicochemical properties (Z) -3-
Obtained butylidene phthalide. The results of the yield of (Z) -3-butylidenephthalide with respect to each reaction reagent and the production ratio with its by-product, 3-propylisocoumarin (analysis of integrated value of NMR of reaction residue) are shown below. .

Name: (Z) -3-butylidenephthalide Molecular formula: C ₁₂ H ₁₂ O ₂ Molecular weight: 188.22 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1777, 1686. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.99 (3H,} t, J = 7.3Hz),
1.56 (2H, tq, J = 7.3, 7.3Hz),
2.46 (2H, dt, J = 7.8, 7.3Hz),
5.65 (1H, t, J = 7.8Hz), 7.51 (1
H, ddd, J = 7.8, 6.0, 2.4 Hz), 7.
60-7.78 (2H, m), 7.89 (1H, dd
d, J = 7.8, 1.0, 1.0 Hz). Mass spectrum (EI-MS) m / z: 188 (M
+, 22), 159 (100).

Name: 3-propylisocoumarin Molecular formula: C ₁₂ H ₁₂ O ₂ Molecular weight: 188.22 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1730, 1656. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.00 (3H,} t, J = 7.3Hz),
1.74 (2H, tq, J = 7.5, 7.3Hz),
2.51 (2H, t, J = 7.5Hz), 6.26 (1
H, s), 7.36 (1H, ddd, J = 7.6, 1.
5,1.0 Hz), 7.44 (1H, ddd, J = 7.
6,7.6,1.5Hz), 7.67 (1H, ddd,
J = 7.6, 7.6, 1.5 Hz), 8.25 (1H,
ddd, J = 7.6, 1.5, 1.0 Hz). Mass spectrum (EI-MS) m / z: 188 (M
+, 74), 83 (100).

Example 2 Preparation of (Z) -3-cyclohexylmethylidenephthalide In a 25 ml round-bottomed flask, 100 mg of 2- (cyclohexylethynyl) benzoic acid, 10% molar amount of silver iodide (AgI) or silver (Ag) was added. After charging and substituting with argon, 1 ml of anhydrous dimethylformamide was added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure to obtain a reaction residue.
Next, the reaction residue was subjected to flash column chromatography (silica gel; eluent, benzene-n-hexane = 1: 1).
By separating and purifying in 2), (Z) -3-cyclohexylmethylidenephthalide having the following physicochemical properties was obtained. The following are the results of the yield of (Z) -3-cyclohexylmethylidenephthalide with respect to each reaction reagent and the production ratio with 3-cyclohexylisocoumarin which is a by-product thereof (the integrated value of NMR of the reaction residue is analyzed). Indicates.

[00] Name: (Z)-3-cyclohexyl methylidene phthalide molecular formula: C ₁₅ H ₁₆ O ₂ molecular weight: 228.29 Properties: colorless needles, mp: 85-87 ° C IR absorption spectrum ν KBr max cm ^{- 1} :
1770, 1719, 1680. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.05-1.85 (10H,} m), 2.
80 (1H, m), 5.50 (1H, d, J = 9.5H
z), 7.50 (1H, ddd, J = 7.6, 6.1,
2.0 Hz), 7.55-7.75 (2H, m), 7.
89 (1H, ddd, J = 7.6, 1.0, 1.0H
z). Mass spectrum (EI-MS) m / z: 228 (M
+, 16), 147 (100).

Name: 3-cyclohexylisocoumarin Molecular formula: C ₁₅ H ₁₆ O ₂ Molecular weight: 230.30 Property: colorless needles Melting point: 91-93 ° C Infrared absorption spectrum ν KBr max cm ⁻¹ :
1722, 1647. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.10-2.10 (10H,} m), 2.
45 (1H, m), 6.23 (1H, s), 7.37
(1H, d, J = 7.8Hz), 7.44 (1H, dd
d, J = 7.8, 7.8, 1.2 Hz), 7.67 (1
H, ddd, J = 7.8, 7.8, 1.5 Hz), 8.
25 (1H, d, J = 7.8Hz). Mass spectrum (EI-MS) m / z: 228 (M
+, 100), 172 (23).

Example 3 Preparation of (Z) -3- (2,2-dimethylpropylidene) phthalide 2- (3,3-dimethyl-1) in a 25 ml eggplant type flask.
-Butynyl) benzoic acid 100 mg, silver iodide (AgI)
Alternatively, 50% molar amount of silver (Ag) was added and the atmosphere was replaced with argon, 1 ml of anhydrous dimethylformamide was added, and the mixture was vigorously stirred at room temperature for 18 hours. Next, the reaction solution was filtered through Celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure to obtain a reaction residue. By recrystallizing this from n-hexane, (Z) -3- having the following physicochemical properties is obtained.
(2,2-Dimethylpropylidene) phthalide was obtained. The yield of (Z) -3- (2,2-dimethylpropylidene) phthalide with respect to each reaction reagent and the production ratio with its by-product, 3- (t-butyl) isocoumarin (reaction residue NMR The result of analysis of the integrated value of is shown.

Name: (Z) -3- (2,2-dimethylpropylidene) phthalide Molecular formula: C ₁₃ H ₁₄ O ₂ Molecular weight: 202.25 Property: colorless prism crystal Melting point: 88-90 ° C Infrared absorption spectrum ν KBr max cm ^-1 :
1782, 1674. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.32 (9H,} s), 5.60 (1H,
s), 7.49 (1H, ddd, J = 7.6, 6.3,
1.7 Hz), 7.61 (1H, ddd, J = 7.6,
1.7, 1.0 Hz), 7.67 (1H, ddd, J =
7.6, 6.3, 1.0 Hz, 7.88 (1H, dd
d, J = 7.6, 1.0, 1.0 Hz). Mass spectrum (EI-MS) m / z: 202 (M
+, 15), 187 (100).

Name: 3- (t-butyl) isocoumarin Molecular formula: C ₁₃ H ₁₄ O ₂ Molecular weight: 202.25 Property: colorless prism Melting point: 59-60 ° C Infrared absorption spectrum ν KBr max cm ^-1 :
1734, 1646. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.33 (9H,} s), 6.31 (1H,
s), 7.39 (1H, d, J = 7.3 Hz), 7.4
9 (1H, ddd, J = 7.3, 7.3, 1.2H
z), 7.67 (1H, ddd, J = 7.3, 7.3,
1.2 Hz), 8.26 (1H, ddd, J = 7.3,
1.2, 0.7 Hz). Mass spectrum (EI-MS) m / z: 202 (M
+, 1), 149 (100).

Example 4 Preparation of (Z) -3-heptylidenephthalide 100 mg of 2- (1-octynyl) benzoic acid, silver iodide (AgI) or silver (Ag) 1 in a 25 ml round-bottomed flask.
After adding 0% molar amount and substituting with argon, 1 ml of anhydrous dimethylformamide was added, and the mixture was vigorously stirred at room temperature for 18 hours. Next, the reaction solution was filtered through Celite, and water was added to the filtrate,
Extracted with ethyl acetate, washed the ethyl acetate layer with saturated saline,
It was dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure to obtain a reaction residue. This was separated and purified by flash column chromatography (silica gel; eluent, chloroform-benzene = 1: 1) to obtain (Z) -3-heptylidenephthalide having the following physicochemical properties. The results of the yield of (Z) -3-heptylidenephthalide for each reaction reagent and the production ratio with its by-product, 3-hexylisocoumarin (analysis of the integrated value of NMR of the reaction residue) are shown below. Show.

Name: (Z) -3-heptylidenephthalide Molecular formula: C ₁₅ H ₁₈ O ₂ Molecular weight: 230.30 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1780, 1686. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.89 (3H,} t, J = 6.4Hz),
1.20-1.60 (8H, m), 2.48 (2H, d
t, J = 7.8, 7.3 Hz), 5.64 (1H, t,
J = 7.8 Hz), 7.50 (1H, ddd, J = 8.
3, 6.1, 2.0 Hz), 7.60-7.70 (2
H, m), 7.90 (1H, ddd, J = 7.6, 1.
0, 1.0 Hz). Mass spectrum (EI-MS) m / z: 230 (M
+, 20), 159 (100).

Name: 3-hexylisocoumarin Molecular formula: C ₁₅ H ₁₈ O ₂ Molecular weight: 230.30 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1728, 1656. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.89 (3H,} t, J = 6.6Hz),
1.15 to 1.45 (6H, m), 1.60 to 1.80
(2H, m), 2.53 (2H, t, J = 7.3H
z), 6.25 (1H, s), 7.35 (1H, d, J
= 8.1 Hz), 7.44 (1H, ddd, J = 8.
1, 7.8, 1.5 Hz), 7.67 (1H, ddd,
J = 7.8, 7.3, 1.5 Hz), 8.25 (1H,
ddd, J = 7.3, 1.5, 0.7 Hz). Mass spectrum (EI-MS) m / z: 230 (M
+, 38), 118 (100).

Example 5 Preparation of (Z) -3-benzylidenephthalide 100 mg of 2- (phenylethynyl) benzoic acid, silver iodide (AgI) or silver (Ag) was placed in a 25 ml round-bottomed flask.
A 50% molar amount was added, the atmosphere was replaced with argon, 1 ml of anhydrous dimethylformamide was added, and the mixture was stirred at room temperature overnight. Next, the reaction solution was filtered through Celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, and dried (MgS
O ₄ ) and the solvent were distilled off under reduced pressure to obtain a reaction residue. This is n
Recrystallization from -hexane gave (Z) -3-benzylidenephthalide having the following physicochemical properties. The results of the yield of (Z) -3-benzylidenephthalide with respect to each reaction reagent and the production ratio with the by-product, 3-phenylisocoumarin (analysis of the integrated value of NMR of the reaction residue) are shown below. .

Name: (Z) -3-benzylidenephthalide Molecular formula: C ₁₅ H ₁₀ O ₂ Molecular weight: 222.24 Property: colorless needle crystal Melting point: 92-94 ° C Infrared absorption spectrum ν KBr max cm ⁻¹ :
1774, 1656. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 6.43 (1H,} s), 7.32 (1H,
dddd, J = 7.4, 7.4, 1.0, 1.0H
z), 7.41 (2H, ddd, J = 7.4, 1.0,
1.0 Hz), 7.55 (1H, ddd, J = 7.7,
7.2, 1.0 Hz), 7.73 (1H, ddd, J =
7.9, 7.2, 1.0 Hz), 7.78 (1H, dd
d, J = 7.9, 1.0, 1.0 Hz), 7.85 (2
H, ddd, 7.4, 1.0, 1.0 Hz), 7.95
(1H, ddd, J = 7.7, 1.0, 1.0 Hz). Mass spectrum (EI-MS) m / z: 222 (M
+, 100), 165 (59).

Example 6 (Z) -3-Benzylidene-4,5
-Preparation of methylenedioxyphthalide 50 ml 3,4-methylenedioxy-2- (phenylethynyl) benzoic acid 1.0 g, silver iodide 50% molar amount, anhydrous dimethylformamide 10 ml in a 3-necked eggplant type flask.
Was added and the mixture was vigorously stirred overnight under a nitrogen atmosphere. Next, the reaction solution was filtered through Celite, the filtrate was washed once with saturated aqueous sodium hydrogen carbonate and twice with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure to give a white solid. By recrystallizing this from ethyl acetate-n-hexane, (Z) -3-benzylidene-4,5-methylenedioxyphthalide (yield 92%) having the following physicochemical properties was obtained. The production ratio of (Z) -3-benzylidene-4,5-methylenedioxyphthalide and its by-product, 3-phenyl-5,6-methylenedioxyisocoumarin, is the integration of NMR of the reaction residue. The value was 100: 0.

Name: (Z) -3-benzylidene-4,5-methylenedioxyphthalide Molecular formula: C ₁₆ H ₁₀ O ₄ Molecular weight: 266.25 Melting point: 169-171 ° C. Property: colorless rimpene crystals Infrared absorption Spectrum ν KBr max cm ⁻¹ :
1770, 1646. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 6.27 (2H,} s), 6.37 (1H,
s), 6.99 (1H, d, J = 8.1Hz), 7.3
0 (3H, m), 7.54 (1H, d, J = 8.1H
z), 7.80 (2H, m). Mass spectrum (EI-MS) m / z: 266 (M
+, 100), 152 (27).

Example 7 (Z) -3-Butylidene-5,6-
Manufacture of dimethoxyphthalide 4,5-dimethoxy-2-
80 g of (1-pentynyl) benzoic acid, silver iodide (Ag
I) or 10% molar amount of silver carbonate (Ag ₂ CO ₃ ) and 800 ml of anhydrous dimethylformamide were added and stirred overnight in a nitrogen stream (using a mechanical stirrer rotating at high speed). Next, the reaction solution was filtered through Celite (washed well with ethyl acetate),
The filtrate was washed once with saturated aqueous sodium hydrogen carbonate and twice with saturated brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure to give a white solid. This was recrystallized from ethyl acetate. Further, the mother liquor was separated and purified by flash column chromatography (silica gel, eluent; methylene chloride) to obtain (Z) -3-butylidene-5,6 having the following physicochemical properties.
-Dimethoxyphthalide was obtained. Below, the yield of (Z) -3-butylidene-5,6-dimethoxyphthalide with respect to each reaction reagent and the production ratio with its by-product 6,7-dimethoxy-3-propylisocoumarin (reaction residue N
The result of analysis of the integrated value of MR) is shown.

Name: (Z) -3-butylidene-5,6-dimethoxyphthalide Molecular formula: C ₁₄ H ₁₆ O ₄ Molecular weight: 248.28 Properties: colorless prism crystals Melting point: 129-130 ° C Infrared absorption spectrum ν KBr max cm ^-1 :
1752, 1688. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.99 (3H,} t, J = 7.3Hz),
1.55 (2H, tq, J = 7.6, 7.3Hz),
2.44 (2H, dt, J = 7.8, 7.6Hz),
3.95 (3H, s), 4.00 (3H, s), 5.4
9 (1H, t, J = 7.8Hz), 7.00 (1H,
s), 7.25 (1H, s). Mass spectrum (EI-MS) m / z: 248 (M
+, 32), 219 (100).

[00] Name: 6,7-dimethoxy-3-propyl-isocoumarin Molecular formula: C ₁₄ H ₁₆ O ₄ Molecular weight: 248.28 Properties: colorless needles, mp: 139-140 ° C IR absorption spectrum ν KBr max cm ^{- 1} :
1702, 1650. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.99 (3H,} t, J = 7.3Hz),
1.74 (2H, tq, J = 7.3, 7.3Hz),
2.50 (2H, t, J = 7.3Hz), 3.97 (3
H, s), 3.99 (3H, s), 6.19 (1H,
s), 6.74 (1H, s), 7.63 (1H, s). Mass spectrum (EI-MS) m / z: 248 (M
+, 100), 233 (16), 219 (46).

Example 8 (Z) -3-Butylidene-4,5,
Preparation of 6,7-tetrahydrophthalide 2- (1-pentynyl) -1 in a 25 ml eggplant-shaped flask.
-Cyclohexenecarboxylic acid 100 mg, silver iodide (A
gI) or 10% molar amount of silver (Ag) was added and the atmosphere was replaced with argon. Then, 1 ml of anhydrous dimethylformamide was added, and the mixture was stirred at room temperature overnight. Next, the reaction solution was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure to obtain a reaction residue. . This was separated and purified by flash column chromatography (silica gel; eluent, ethyl acetate-hexane = 1: 4) to give (Z) -3-butylidene-4,5,6,7 having the following physicochemical properties.
-Tetrahydrophthalide was obtained. Below, the yield of (Z) -3-butylidene-4,5,6,7-tetrahydrophthalide for each reaction reagent and its by-product 5,
The result of the production ratio with 6,7,8-tetrahydro-3-propylisocoumarin (the integrated value of NMR of the reaction residue is analyzed) is shown.

Name: (Z) -3-butylidene-4,5,6,6
7-Tetrahydrophthalide Molecular formula: C ₁₂ H ₁₆ O ₂ Molecular weight: 192.26 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1770, 1678, 1640. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.95 (3H,} t, J = 7.3Hz),
1.48 (2H, tq, J = 7.3, 7.3Hz),
1.60-1.85 (4H, m), 2.20-2.45
(6H, m), 5.11 (1H, t, J = 7.9H
z). Mass spectrum (EI-MS) m / z: 192 (M
+, 36), 163 (100).

Example 9 (Z) -3-Butylidene-4,5-
Preparation of dihydrophthalide 2- (1-pentynyl) -in a 25 ml eggplant-shaped flask.
50 mg of 1,5-cyclohexadienoic acid, silver iodide (A
gI) or silver (Ag) 10% molar amount was added and the atmosphere was replaced with argon, and then 0.5 ml of anhydrous dimethylformamide was added,
Stir at room temperature for 18 hours. Next, the reaction solution was filtered through Celite, water was added to the filtrate, and then extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure to obtain a reaction residue. It was This was separated and purified by flash column chromatography (silica gel; eluent, ethyl acetate-hexane = 1: 10) to obtain (Z) -3-butylidene-having the following physicochemical properties.
4,5-Dihydrophthalide was obtained. Below, the yield of (Z) -3-butylidene-4,5-dihydrophthalide with respect to each reaction reagent and the production ratio with its by-product 5,6-dihydro-3-propylisocoumarin (reaction residue N
The result of analysis of the integrated value of MR) is shown.

Name: (Z) -3-butylidene-4,5-dihydrophthalide Molecular formula: C ₁₂ H ₁₄ O ₂ Molecular weight: 190.24 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1766, 1670, 1634. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.96 (3H,} t, J = 7.3Hz),
1.51 (2H, tq, J = 7.3, 7.3Hz),
2.38 (2H, dt, J = 7.9, 7.3Hz),
2.40-2.70 (4H, m), 5.23 (1H,
t, J = 7.9 Hz), 6.00 (1H, dt, J =
9.8, 4.0 Hz), 6.29 (1H, dt, J =
9.8, 2.0 Hz). Mass spectrum (EI-MS) m / z: 190 (M
+, 12), 159 (25), 105 (30), 43
(100).

Example 10 Preparation of (Z) -3-butylidene-5-hydroxy-4,5,6,7-tetrahydrophthalide 5-hydroxy-2- (1-
After 800 mg of pentynyl) -1-cyclohexenoic acid and 10% molar amount of silver iodide (AgI) or silver (Ag) were added and the atmosphere was replaced with argon, 8 ml of anhydrous dimethylformamide was added, and the mixture was stirred at room temperature overnight. Next, the reaction solution was filtered through Celite, water was added to the filtrate, and then extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure to obtain a reaction residue. It was This was separated and purified by flash column chromatography (silica gel; eluent, ethyl acetate-hexane = 1: 1) to give (Z) -3-butylidene-5-having the following physicochemical properties.
Hydroxy-4,5,6,7-tetrahydrophthalide was obtained. Below, the yield of (Z) -3-butylidene-5-hydroxy-4,5,6,7-tetrahydrophthalide to each reaction reagent and its by-product, 7-hydroxy-3-propyl-5, were obtained. Production ratio with 6,7,8-tetrahydroisocoumarin (Analysis of integrated value of NMR of reaction residue)
The result is shown.

Name: (Z) -3-Butylidene-5-hydroxy-4,5,6,7-tetrahydrophthalide production Molecular formula: C ₁₂ H ₁₆ O ₃ Molecular weight: 208.25 Properties: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
3452, 1752, 1676, 1640 (C = C). Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.95 (3H,} t, J = 7.3Hz),
1.49 (2H, tq, J = 7.3, 7.3Hz),
1.62 (1H, br), 1.91 (2H, td, J =
6.4, 5.0 Hz), 2.25-2.75 (4H,
m), 2.34 (2H, dt, J = 7.8, 7.3H)
z), 4.23 (1H, tt, J = 5.0, 5.0H
z), 5.16 (1H, t, J = 7.8Hz). Mass spectrum (EI-MS) m / z: 208 (M
+, 60), 179 (76), 135 (100).

Example 11 (Z) -2,4-octadiene-
Preparation of 4-Olid In a 25 ml eggplant-shaped flask, (Z) -2-octene-4-
Inmic acid 100 mg, silver iodide (AgI) or silver (Ag)
After adding a 10% molar amount and replacing with argon, 1 ml of anhydrous dimethylformamide was added, and the mixture was heated with stirring at an external temperature (100 ° C.) for 5 hours. Next, the reaction solution was filtered through Celite, water was added to the filtrate, the mixture was extracted twice with ethyl acetate, the ethyl acetate layer was washed once with saturated brine, dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the reaction residue was removed. Got This was separated and purified by flash column chromatography (silica gel; eluent, ethyl acetate-hexane = 1: 6), and 4-butylidene butenolide having the following physicochemical properties was obtained from the first eluted fraction. Below, the yield of (Z) -2,4-octadiene-4-olide with respect to each reaction reagent and the production ratio with its by-product 2,4-octadiene-5-olide (integration of NMR of reaction residue The results of (analyzing the values) are shown.

Name: (Z) -2,4-octadiene-4-olide Molecular formula: C ₈ H ₁₀ O ₂ Molecular weight: 138.16 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1776. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.96 (3H,} t, J = 7.3Hz),
1.52 (2H, tq, J = 7.3, 7.3Hz),
2.39 (2H, dt, J = 8.1, 7.3Hz),
5.31 (1H, t, J = 8.1Hz), 6.15 (1
H, d, J = 5.4 Hz), 7.34 (1H, d, J =
5.4). Mass spectrum (EI-MS) m / z: 138 (M
+, 4), 99 (18), 71 (86), 43 (10
0).

Name: 2,4-octadiene-5-olide Molecular formula: C ₈ H ₁₀ O ₂ Molecular weight: 138.16 Property: colorless oil Infrared absorption spectrum ν KBr max cm ⁻¹ :
1734, 1634. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 0.97 (3H,} t, J = 7.3Hz),
1.70 (2H, tq, J = 7.6, 7.3Hz),
2.47 (2H, t, J = 7.6Hz), 5.97 (1
H, dd, J = 7.3, 1.0 Hz), 6.15 (1
H, dd, J = 9.3, 1.0 Hz), 7.26 (1
H, dd, J = 9.3, 7.3 Hz). Mass spectrum (EI-MS) m / z: 138 (M
+, 24), 95 (100).

Example 12 (Z) -5-phenyl-2,4-
Preparation of pentadiene-4-olide (Z) -5-phenyl-2-in a 25 ml eggplant-shaped flask.
Penten-4-ynoic acid 100 mg, silver iodide (AgI)
Alternatively, after adding 10% molar amount of silver (Ag) and substituting with argon, 1 ml of anhydrous dimethylformamide was added and the external temperature (
The mixture was heated and stirred at 00 ° C) for 5 hours. Next, the reaction solution was filtered through Celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure to obtain a reaction residue. By separating and purifying this by flash column chromatography (silica gel; eluent, ethyl acetate-hexane = 1: 2),
(Z) -4-benzylidene butenolide having the following physicochemical properties was obtained. Below, (Z) for each reaction reagent
Yield of -5-phenyl-2,4-pentadiene-4-olide and production ratio of its by-product, 5-phenyl-2,4-pentadiene-5-olide (integrated value of NMR of reaction residue was analyzed. ) Shows the result.

Name: (Z) -5-phenyl-2,4-pentadiene-4-olide Molecular formula: C ₁₁ H ₈ O ₂ Molecular weight: 172.18 Property: colorless needle crystal Infrared absorption spectrum ν KBr max cm ^-1 :
1746. Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 6.04 (1H,} s), 6.22 (1H,
dd, J = 5.4 Hz), 7.25-7.45 (3H,
m), 7.50 (1H, d, J = 5.4 Hz), 7.7
0-7.85 (2H, m). Mass spectrum (EI-MS) m / z: 172 (M
+, 89), 115 (51), 43 (100).

The acetylenecarboxylic acid as a starting material was synthesized with reference to the following documents. References Heterocycles,
29 , 1255 (1989) Tetrahedron Letters, 446.
7 (1975). Journal of Organic Chemistry [Journal of Organic Chemi
story], 31 , 4071 (1966). Chemical and Farm Social Bulletin [Chemical and Pharmaceuti
calBulletin] 34 , 2754 (198)
6). Organic Synthesis [Organic Sy
nthesis], 52 , 128 (1972). that's all

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Claims (3)

[Claims] 1. The following general formula (1) [In the formula, R ₂ and R ₃ are each independently a hydrogen atom or a substituted or unsubstituted alkyl group, or a substituted or unsubstituted ring represented by the following formula (2) (In the formula, the broken line is a bond forming a ring, and each represents a saturated or unsaturated bond), and R ₁ represents a substituted or unsubstituted alkyl group. ] The following general formula (3) is characterized in that the acetylene carboxylic acid represented by the formula (1) is mixed with one or more kinds of silver salts and / or silver and reacted. [Wherein R ₁ , R ₂ and R ₃ are the same as defined above]. 2. One or more silver salts and / or silver selected from silver iodide, silver bromide, silver chloride, silver carbonate, silver periodate, silver sulfate, silver chromate, and silver sulfide. The synthetic method according to claim 1, which is used. 3. The synthetic method according to claim 1, wherein the reaction is carried out in an anhydrous aprotic polar solvent.