JP2621194B2 - New phthalide derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel phthalide derivative having a blood viscosity lowering effect and useful as a pharmaceutical.

Plant of the Apiaceae family (Cnidium officinale MAKIN)
O) is the rhizome (Cnidii Phizoma) is known for its central depressant action, muscle relaxant action, antithrombotic action, etc. It is a Chinese medicine distributed to China.

The present inventors have As a result of focusing on phthalide, which is one of the components contained in the present invention, the present inventors have succeeded in synthesizing a phthalide derivative having a blood viscosity lowering effect, and have completed the present invention.

That is, the present invention relates to a compound of the general formula I [Wherein, R ₁ and R _{2 each} represent a hydrogen atom, a hydroxyl group or a methoxy group, R ₃ and R _{4 each} represent a hydrogen atom or a methoxy group, and R ₅ represents a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. , N-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group or n-decyl group, R ₆ is hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group,
Isopentyl group, n-hexyl group, n-heptyl group, n
Octyl, n-nonyl, n-decyl or formula II (In the formula, R ₇ represents a methyl group or a phenyl group.)

However, R ₁ , R ₂ , R ₃ and R ₄ are commonly a hydrogen atom, R ₅ is a methyl group, R ₆ is a hydrogen atom, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group or n R ₁ , R ₂ , R ₃ and R ₄ are a hydrogen atom in common, R ₅ is an ethyl group or an n-propyl group, and R ₆ is a methyl group, ₁ , R ₂ , R ₃ , R ₄ and R ₆ are commonly a hydrogen atom,
Except when R ₅ is an n-butyl group. ] It is a novel phthalide derivative represented by these.

The alkyl group represented by R ₅ and R ₆ is a lower or intermediate alkyl group, preferably an alkyl group having about 1 to 10 carbon atoms, specifically, a methyl group, an ethyl group,
-Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n- Decyl group and the like.

The phthalide derivative of the present invention represented by the formula (I)
A compound of formula I) has the formula III (Wherein, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above) (hereinafter referred to as a compound of formula III), which is reacted with an alkyl halide in the presence of a base. Let Formula IV (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meaning as described above) (hereinafter referred to as a compound of the formula IV), and then hydrolyzed Equation V (Wherein, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meaning as described above) (hereinafter, referred to as a compound of formula V), which was defined as methyl ester Then, the formula VI obtained by brominating the benzyl position (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meaning as described above) (hereinafter referred to as a compound of the formula VI) and a compound represented by the formula AX-NH ₂ A (Wherein, X represents a hydrogen atom or an alkyl group) (hereinafter, referred to as a compound of the formula A).

Also, if necessary, demethylation and / or formula B (Wherein, R ₇ has the same meaning as described above) (hereinafter, referred to as a compound of formula B).

Depending on the target substance, the compound of formula III as a raw material is obtained by salifying the carboxyl group of benzoic acids such as commercially available benzoic acid, m-anisic acid, 3,4-dimethoxybenzoic acid, and 3,4,5-trimethoxybenzoic acid. After converting to an acyl group, 2-amino-2
It can be obtained by reacting with -methyl-1-propanol and further cyclizing.

To convert a carboxyl group into an acyl chloride group, benzoic acid, m-anisic acid, 3,4-dimethoxybenzoic acid, 3,4,5-
Thionyl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride and the like are added to trimethoxybenzoic acid and the like under ice-cooling to react. The reaction temperature is suitably from room temperature to about 60 ° C. After the reaction, the solution can be purified by a commonly used general purification technique such as distillation under reduced pressure or distillation under normal pressure.

Then, the compound was dissolved in an organic solvent in 2-amino-2-
Methyl-1-propanol is added and reacted to form an amide. Specific examples of the organic solvent include methylene chloride, benzene, chloroform and the like, and a suitable reaction temperature is about 0 to 30 ° C. Although the reaction can be sufficiently performed by an ordinary method, the reaction is preferably performed under an anhydrous condition, for example, by replacing with argon. After the reaction, an amide is obtained by a commonly used general purification technique such as extraction, drying, or solvent evaporation.

Further, the amide is cyclized by reacting with thionyl chloride. The reaction temperature is suitably about room temperature. After the reaction, the compound of the formula III can be obtained by a commonly used general purification technique such as extraction, drying and solvent evaporation.

 Hereinafter, specific examples of the production of the compound of the formula III will be described.

Specific Example 1 Thionyl chloride (153 ml) was added to and dissolved in 85.5 g of benzoic acid under ice-cooling, followed by stirring at room temperature for 16 hours. After excess thionyl chloride was removed from the reaction solution by atmospheric distillation, the residue was distilled under reduced pressure to obtain 92.1 g of benzoyl chloride (yield 93.6%).

Then, 90.0 g of benzoyl chloride was replaced with argon, 250 ml of anhydrous methylene chloride was added, and a solution of 114.1 g of 2-amino-2-methyl-1-propanol in 200 ml of anhydrous methylene chloride was added dropwise under ice cooling. For 2 hours. 300 ml of water was added to the reaction solution, extracted with chloroform (300 ml × 2), washed with 1N hydrochloric acid (300 ml), dried over magnesium sulfate, and the solvent was removed under reduced pressure.
1-dimethyl-2-hydroxyethyl) -benzamide 1
20.8 g was obtained (97.6% yield).

Further, 120.8 g of this N- (1,1-dimethyl-2-hydroxyethyl) -benzamide was dissolved in 100 ml of thionyl chloride and stirred at room temperature for 2 hours. The reaction solution was crystallized by adding 300 ml of ether and filtered. The filtrate was further crystallized by adding 300 ml of ether, and the crystals were combined, dissolved in 300 ml of water, made alkaline with a 20% aqueous sodium hydroxide solution, extracted with chloroform (300 ml × 3), washed with saturated saline, and washed with magnesium sulfate. , And the solvent was removed under reduced pressure to obtain a white oil. This was distilled to obtain 88.8 g of 2-phenyl-4,4-dimethyl-2-oxazoline (yield: 81.1%).

2964,2928,2888,1650,1450,1352,1320,1304,1060,1024,
968,694 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.37 (6H, s), 4.09 (2H, s), 7.37-7.46 (3H, m), 7.94
(2H, dd, J = 1.5,7.1Hz) Mass spectrum: M / Z (%) 175 (8, M ⁺ ), 160 (100), 145 (24), 132 (3
3), 104 (64), 77 (25) Specific Example 2 72.7 g of thionyl chloride was added to 31.0 g of m-anisic acid under ice cooling, and the mixture was stirred at room temperature overnight. The excess thionyl chloride was distilled off under reduced pressure from the reaction mixture, and then distilled under reduced pressure to obtain 32.0 g of m-anisyl chloride as a colorless oil (yield: 92%).

Next, 2-amino-2-methyl-1-propanol 3
After replacing 3.3 g with argon, 100 ml of anhydrous methylene chloride was added and dissolved, and under stirring and cooling with ice, 100 ml of an anhydrous methylene chloride solution of 31.8 g of m-anisyl chloride was added dropwise.
The mixture was further stirred at room temperature for 2 hours. 100 m of water in the reaction mixture
After addition of l, the mixture was extracted with chloroform (400 ml × 2), the chloroform layer was washed with 50 ml of 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N- (1,1) as a white crystalline solid.
39.6 g of 1-dimethyl-2-hydroxyethyl) -3-methoxybenzamide was obtained.

Further, this N- (1,1-dimethyl-2-hydroxyethyl) -3-methoxybenzamide is converted to thionyl chloride.
6.7 g and stirred at room temperature for 2 hours. 100 ml of ether was added to the reaction mixture to crystallize, and white crystals of 2-
The hydrochloride of (3-methoxyphenyl) -4,4-dimethyl-2-oxazoline was collected by filtration. This 2- (3-methoxyphenyl) -4,4-dimethyl-2-oxazoline hydrochloride was dissolved in 50 ml of water, made alkaline with a 20% aqueous sodium hydroxide solution, and extracted with chloroform (400 ml ×
2), dried over potassium carbonate and sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance. Distill this,
2- (3-methoxyphenyl) -4,4- as a colorless oil
32.2 g of dimethyl-2-oxazoline were obtained (yield 84
%).

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.39 (6H, s), 3.82 (3H, s), 4.09 (2H, s), 6.88-7.71
(4H, m) Mass spectrum: M / Z (%) 205 (48, M ⁺ ), 190 (100), 175 (30), 162
(39), 134 (72), 119 (8), 103 (14), 92 (12), 77
(16) Specific Example 3 To 30.0 g of 3,4-dimethoxybenzoic acid was added 58.8 g of thionyl chloride under ice-cooling, followed by stirring at room temperature overnight. Excessive thionyl chloride was distilled off from the reaction mixture at normal pressure, followed by distillation under reduced pressure to obtain 3,4-dimethoxybenzoic acid chloride 3 as green-white powdery crystals.
0.2 g was obtained (91% yield).

Next, 2-amino-2-methyl-1-propanol 2
After replacing 2.3 g with argon, 50 ml of anhydrous methylene chloride was added and dissolved, and the solution was stirred under ice-cooling, and a solution of 3,4-dimethoxybenzoic acid chloride (25.1 g) in anhydrous methylene chloride (150 ml) was added.
Was added dropwise, and the mixture was further stirred at room temperature for 2 hours. After adding 50 ml of water to the reaction mixture, extraction with chloroform (350 ml ×
2) The chloroform layer was washed with a 5% aqueous sodium hydroxide solution 50
The solution was washed with 50 ml of 5% hydrochloric acid and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless solid substance. Thionyl chloride was added to the N- (1,1-dimethyl-2-hydroxyethyl) -3,4-dimethoxybenzamide, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 200 ml of ether, and the mixture was crystallized to collect 2- (3,4-dimethoxyphenyl) -4,4-dimethyl-2-oxazoline hydrochloride as white crystals by filtration. The white crystals were dissolved in 100 ml of water, made alkaline with a 20% aqueous sodium hydroxide solution, extracted with ether (250 ml × 2), dried over potassium carbonate and magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily substance. Was. This is distilled to give a colorless viscous substance 2
-(3,4-dimethoxyphenyl) -4,4-dimethyl-2-
24.4 g of oxazoline was obtained (83% yield).

2960,2925,2895,2836,1646,1604,1586,1514,1464,1422,
1358,1310,1272,1260,1232,1172,1140,1078,1026,974,7
64,714 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.38 (6H, s), 3.91 (3H, s), 3.93 (3H, s), 4.08 (2H,
s), 6.86 (1H, d, J = 8.3Hz), 7.46 (1H, d, J = 2.0Hz), 7.
53 (1H, dd, J = 8.3, 2.0 Hz) Mass spectrum: M / Z (%) 235 (M ⁺ , 35), 220 (100), 205 (7), 192
(25), 164 (24), 148 (5) Specific Example 4 50 g of thionyl chloride was added to 29.7 g of 3,4,5-trimethoxybenzoic acid under ice-cooling, followed by stirring at room temperature overnight. After distilling off excess thionyl chloride from the reaction mixture, the mixture was distilled under reduced pressure,
3,4,5-Trimethoxybenzoic acid chloride 2 as yellowish white powder
9.1 g was obtained (90% yield).

Next, 2-amino-2-methyl-1-propanol 2
After replacing 2.5 g with argon, 50 ml of anhydrous methylene chloride was added and dissolved, and under stirring and cooling with ice, 2,4 g of 3,4,5-trimethoxybenzoic acid chloride 29.1 g of an anhydrous methylene chloride solution 150
ml was added dropwise, and the mixture was further stirred at room temperature for 2 hours. After adding 50 ml of water to the reaction mixture, the mixture was extracted twice with 250 ml of chloroform (250 ml × 2), and the chloroform layer was washed with 50 ml of a 5% aqueous sodium hydroxide solution, 50 ml of 5% hydrochloric acid and saturated saline. This was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 38.0 g of a yellow solid substance. To this N- (1,1-dimethyl-2-hydroxyethyl) -3,4,5-trimethoxybenzamide was added 45 g of thionyl chloride, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was crystallized by adding 200 ml of ether, and white crystals of 2- (3,4,5-trimethoxyphenyl) -4,4-dimethyl-2-oxazoline hydrochloride were collected by filtration. This was dissolved in 100 ml of water, made alkaline with a 20% aqueous sodium hydroxide solution, and extracted with ether (300 ml).
× 2), dried over potassium carbonate and sodium sulfate, and the solvent was distilled off under reduced pressure to obtain white crystals. This was recrystallized from n-hexane to give 2- (3,4,5-trimethoxyphenyl) -4,4-dimethyl-2-oxazoline 2 as white prism crystals.
6.9 g was obtained (81% yield).

2964,2932,2896,2844,1648,1588,1504,1456,1416,1358,
1230,1126,1092,996,856,722 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.38 (6H, s), 3.88 (3H, s), 3.91 (6H, s), 4.10 (2H,
s), 7.19 (2H, s) Mass spectrum: M / Z (%) 265 (M ⁺ , 47), 250 (100), 235 (6), 222
(18), 194 (17), 178 (10), 150 (5) Next, the compound of the formula III obtained as described above is reacted with an alkyl halide in an organic solvent in the presence of a base. The compound of formula IV is obtained. As the organic solvent used,
Anhydrous tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, ethers such as diethylene glycol dimethyl ether and the like, specific examples of the base,
n-butyllithium, sec-butyllithium, tert-butyllithium and the like. Specific examples of the alkyl halide include propyl iodide, propyl bromide, propyl chloride, butyl iodide, butyl bromide, butyl chloride, Pentyl iodide, pentyl bromide, pentyl chloride, hexyl iodide, hexyl bromide, hexyl chloride, heptyl iodide, heptyl bromide, heptyl chloride, octyl iodide, octyl bromide, octyl chloride, isopropyl iodide, bromide Isopropyl, isobutyl iodide, isobutyl bromide, iodide se
c-butyl, sec-butyl bromide and the like. After the reaction, a compound of the formula IV is obtained by a commonly used general purification technique.

Then, the compound of formula IV is hydrolyzed by the action of an acid,
Let it be a compound of formula V. Specific examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid.
Water or alcohols or a mixed solvent thereof is suitable. The reaction is preferably carried out by heating from room temperature to the boiling point of the solvent used. After the reaction, a compound of the formula V is obtained by combining commonly used general purification techniques such as extraction, drying, evaporation of the solvent and recrystallization.

Then, a compound of formula V is added to an organic solvent such as anhydrous tetrahydrofuran, acetone, dioxane, and dimethylformamide, and a base such as N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and triethylamine is added. Methyl iodide,
By reacting a methylating agent such as dimethyl sulfate,
Methyl ester.

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

Further, the benzyl position of this methyl ester is radically brominated in an organic solvent. Bromination is achieved by reacting a brominating agent such as N-bromosuccinimide with a catalytic amount of a peroxide such as benzoyl peroxide or by irradiating with light. Examples of the organic solvent used include carbon tetrachloride and the like. The reaction is preferably carried out by heating from room temperature to about the boiling point of the solvent used.

The compound of formula I is obtained by reacting the compound of formula VI obtained as described above as it is or in an organic solvent such as dimethylformamide. Specific examples of compounds of formula A include ammonia, methylamine,
Ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, n-pentylamine,
Examples include isopentylamine, neopentylamine, hexylamine, heptylamine, octylamine, nonylamine, and decylamine. Further, the reaction temperature is preferably from about −20 ° C. to about room temperature. After the reaction, the compound of the formula I can be purified by combining commonly used general purification techniques such as extraction, drying, solvent removal, column chromatography and recrystallization.

This compound of formula I is further optionally demethylated and / or reacted with a compound of formula B. As a method of demethylation, the 4-position is demethylated by reacting an acid in an organic solvent. Specific examples of acids include boron tribromide, boron trichloride, boron trifluoride, aluminum tribromide, aluminum trichloride, Lewis acids such as aluminum trifluoride, or hydroiodic acid, hydrobromic acid, Hydrochloric acid, trifluoroacetic acid and the like. Specific examples of the organic solvent used include anhydrous methylene chloride, anhydrous chloroform, and ethanol. The reaction temperature is 0
A temperature from about ° C to about room temperature is appropriate. After the reaction, the compound of the formula I is obtained by a commonly used purification technique.

The compound of the formula B can be added to N-methylpiperazine or N-phenylpiperazine in an organic solvent according to the target substance in the form of 1-
It is obtained by adding bromo-3-chloropropane, heating the mixture from room temperature to the boiling point of the solvent to be used, and reacting the mixture. After the reaction, the compound of the formula B can be purified by a combination of commonly used purification techniques such as extraction, drying, solvent removal and recrystallization.

The compound of formula B and the compound of formula I obtained as described above are reacted in an organic solvent by heating from room temperature to about the boiling point of the solvent used in the presence of tetra-n-butylammonium iodide and sodium hydroxide. . Examples of the organic solvent used include benzene and the like. After completion of the reaction, the compound of the formula I can be obtained by a combination of commonly used purification techniques such as extraction, drying, solvent removal, and column chromatography.

 Hereinafter, specific examples of the production of the compound of the formula B will be described.

Example 5 To 10.01 g of N-methylpiperazine was added 50 ml of a benzene solution of 7.87 g of 1-bromo-3-chloropropane, and the solution was added at room temperature.
After stirring for an hour, the mixture was heated under reflux for 3 hours. This reaction solution is
After cooling to 2 ° C., extraction with 2N hydrochloric acid (10 ml × 3), 50% aqueous sodium hydroxide solution was added to the hydrochloric acid layer while cooling to make it alkaline, and then extracted with ether (10 ml × 3), and washed with saturated brine ( 10 ml × 2), dried over magnesium sulfate, the solvent was removed under reduced pressure, and the residue was distilled under reduced pressure to obtain 1- (3-
4.00 g of (chloropropyl) -4-methylpiperazine were obtained (46% yield).

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.94 (2H, q, J = 6.7 Hz), 2.27 (3H, s), 2.44-2.51 (10
H, m), 3.58 (2H, t, J = 6.7Hz) Mass spectrum: M / Z (%) 176 (43, M ⁺ ), 113 (100), 98 (21), 71 (2
1), 70 (81), 56 (24), 44 (19), 43 (64), 42 (42) Example 6 A solution of 4.96 g of 1-bromo-3-chloropropane in 10.17 g of N-phenylpiperazine After adding 30 ml and stirring at room temperature for 1 hour, the mixture was heated under reflux for 3 hours. The reaction solution was cooled to 0 ° C., extracted with 2N hydrochloric acid (10 ml × 3), 50% aqueous sodium hydroxide solution was added while cooling the hydrochloric acid layer to make it alkaline, and extracted with ether (10 ml × 3), and saturated. The extract was washed with brine (10 ml × 2), dried over magnesium sulfate, the solvent was removed under reduced pressure, and the residue was distilled under reduced pressure to obtain 1- (3
3.27 g of (-chloropropyl) -4-phenylpiperazine were obtained (4.4% yield).

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 1.97 (2H, q, J = 6.8 Hz), 2.53 (2H, t, J = 7.1 Hz), 2.59
(2H, dd, J = 5.1,5.1Hz), 2.59 (2H, dd, J = 3.3,6.9Hz),
3.19 (2H, dd, J = 5.1,5.1Hz), 3.19 (2H, dd, J = 3.3,6.9H
z), 3.61 (2H, t, J = 6.5Hz), 6.88 (1H, t, J = 7.3Hz), 6.
91 (2H, d, J = 8.5 Hz), 7.25 (2H, dd, J = 7.3, 8.5 Hz) Mass spectrum: M / Z (%) 238 (56, M ⁺ ), 175 (100), 132 (35) ), 105
(32), 98 (16), 88 (11), 77 (19), 70 (40), 56 (1
1), 43 (16), 42 (22) Methods of obtaining compounds of formula I include those of formula VII (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meaning as described above) (hereinafter referred to as the compound of formula VII)
And a method of reacting a compound of the formula A and then reducing the compound in the presence of a hydrochloride of the compound of the formula A.

Specific examples of the reducing agent used include sodium borohydride, sodium cyanoborohydride and the like.
A suitable reaction temperature is about room temperature, and specific examples of the compound of the formula A are the same as those described above. After completion of the reaction, the compound of formula I can be obtained by combining commonly used purification techniques such as extraction, drying, solvent removal, and column chromatography.

 Examples of the production of the compound of the present invention are shown below.

Example 1 2-Phenyl-4,4-dimethyl-2- obtained in Example 1
After replacing 21.03 g of oxazoline with argon, it was dissolved in 360 ml of anhydrous tetrahydrofuran, cooled to -45 ° C, and stirred.
90 ml of a 1.6 M n-butyllithium solution was added and stirred for 2 hours. To this reaction solution, 28.52 g of pentyl iodide was added dropwise at -45 ° C, and the mixture was stirred at -45 ° C for 1 hour and further at room temperature for 20 hours. After completion of the reaction, add 100 ml of water and extract with ether (300 ml ×
2) and the solvent was removed under reduced pressure. 200 ml of 4N hydrochloric acid
And extracted with chloroform (150ml × 2), then 4N
Sodium hydroxide solution 100ml, saturated sodium thiosulfate 1
The extract was washed sequentially with 00 ml and 100 ml of saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was distilled using an oil diffusion pump to obtain 2- (2
-Pentylphenyl) -4,4-dimethyl-2-oxazoline (23.93 g) was obtained (yield: 81.3%).

2960,2928,2864,1646,1462,1348,1306,1050,1036,746,6
94,664 proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.5 Hz), 1.24 to 2.45 (4H, m), 1.37 (6H,
s), 2.45-2.71 (2H, m), 2.93 (1H, dd, J = 5.4, 10.4H
z), 2.93 (1H, dd, J = 7.8, 7.8 Hz), 4.05 (2H, s), 7.14-
7.36 (3H, m), 7.68 (1H, dd, J = 2.1,7.8Hz) Mass spectrum: M / Z (%) 245 (15.M ⁺ ), 202 (100), 148 (14), 131
(13), 117 (10) Next, 600 ml of 6N hydrochloric acid was added to 16.84 g of 2- (2-pentylphenyl) -4,4-dimethyl-2-oxazoline, and the mixture was heated and stirred on an oil bath for 18 hours. After completion of the reaction, the reaction solution was cooled in an ice bath, extracted with ether (300 ml × 3), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was distilled using an oil diffusion pump to obtain 10.06 g of 2-pentylbenzoic acid (yield: 76.0 g).
%).

3350−2500,2956,2928,2860,2648,2552,1692,1602,157
4,1456,1406,1298,1268,746,656 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.90 (3H, t, J = 7.0 Hz), 1.20-1.51 (2H, m), 1.51-1.7
4 (2H, m), 3.02 (1H, dd, J = 7.8,7.8Hz), 3.02 (1H, dd, J
= 5.9,9.7Hz), 7.26 (1H, dd, J = 1.2,7.5,7.8Hz), 7.29
(1H, dd, J = 1.2,7.3Hz), 7.47 (1H, ddd, J = 1.5,7.3,7.5
Hz), 8.37 (1H, dd, J = 1.5, 7.8 Hz) Mass spectrum: M / Z (%) 192 (60, M ⁺ ), 175 (9), 136 (100), 135
(47), 131 (56), 118 (76), 91 (35), 77 (27) 8.25 g of this 2-pentylbenzoic acid and potassium carbonate
280 ml of anhydrous acetone was added to 6.63 g, and the mixture was stirred at room temperature for 15 minutes. Then, 3 ml of methyl iodide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was removed under reduced pressure, water (100 ml) was added to the residue, and the mixture was extracted with ether (100 ml × 3), and washed with saturated saline (100 ml).
The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 8.22 g of methyl 2-pentylbenzoate (92.8 g).
%).

2952,2928,2856,1726,1450,1434,1254,1098,1072,748,7
08,664 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.89 (3H, t, J = 6.8 Hz), 1.28-1.47 (4H, m), 1.47-1.6
8 (2H, m), 2.93 (1H, dd, J = 5.7,9.9Hz), 2.93 (1H, dd, J
= 7.0,7.6Hz), 3.88 (3H, s), 7.22 (1H, dd, J = 7.0,7.
6), 7.23 (1H, d, J = 7.6Hz), 7.39 (1H, dd, J = 7.0,7.6H)
z), 7.84 (1H, d, J = 7.6 Hz) Mass spectrum: M / Z (%) 206 (29, M ⁺ ), 175 (52), 131 (100), 119
(45), 118 (56), 91 (45) Further, after replacing 7.64 g of methyl 2-pentylbenzoate and 6.91 g of N-bromosuccinimide with argon, 70 ml of anhydrous carbon tetrachloride was added, and the mixture was heated and stirred on an oil bath. While irradiating with light for 1.5 hours. The reaction solution was cooled in an ice bath, succinimide was filtered off, and the filtrate was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (7.5 cm in diameter; silica gel, 230-400 mesh, 300 g; elution solvent, ethyl acetate: hexane = 1: 10) to give 2- (1-
10.40 g of methyl (bromopentyl) benzoate was obtained (98.6% yield).

2952,2868,1720,1434,1288,1262,1196,1134,1100,1074,
758,712,666 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.90 (3H, t, J = 6.8 Hz), 1.22-1.62 (4H, m), 2.00-2.3
8 (2H, m), 3.91 (3H, s), 6.14 (1H, dd, J = 6.4,8.3Hz),
7.31 (1H, ddd, J = 1.2, 7.8, 7.8 Hz), 7.53 (1H, ddd, J = 1.
7,7.8,8.1Hz), 7.78 (1H, dd, J = 1.2,8.1Hz), 7.83 (1H,
dd, J = 1.2, 7.8 Hz) Mass spectrum: M / Z (%) 286 (1, M ⁺ ), 285 (3), 284 (1, M ⁺ ), 283
(3), 205 (32), 161 (27), 145 (25), 133 (100), 10
5 (39) Then, after 2.85 g of methyl 2- (1-bromopentyl) benzoate was replaced with argon, ethylamine 15m
l was added and stirred at room temperature for 10 hours. The solvent of the reaction solution was removed under reduced pressure, 20 ml of chloroform was added, and the mixture was filtered. The filtrate was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (2.0 cm in diameter; silica gel 110 g, 230-400
Mesh; elution solvent, ethyl acetate: hexane = 1: 5) to give 1.94 g of 3-butyl-2-ethylphthalimidine (89.3% yield).

3536,2956,2928,2864,1688,1618,1468,1440,1414,1378,
1356,1322,1300,1230,768,726,696,620 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.81 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.2 Hz), 0.90−
1.28 (4H, m), 1.82-2.02 (2H, m), 3.19,4.04 (2H, qd, J
= 7.1, 14.2 Hz), 4.63 (1H, t, J = 4.3 Hz), 7.29-7.56 (3
H, m), 7.83 (1H, dd, J = 1.6, 6.8 Hz) Mass spectrum: M / Z (%) 217 (9, M ⁺ ), 161 (57), 160 (79), 132 (10
0), 104 (18), 77 (22) Example 2 After replacing 5.72 g of 2 (1-bromopentyl) benzoic acid methyl ester obtained as an intermediate in Example 1 with argon, 30 ml of n-propylamine was added. Stirred at room temperature for 10 hours. The solvent of the reaction solution was removed under reduced pressure, 50 ml of chloroform was added and the mixture was filtered. The filtrate was removed under reduced pressure to obtain a yellow oily substance.
Flash column chromatography (7.5 cm in diameter;
Silica gel 240 g, 230-400 mesh; elution solvent, ethyl acetate: hexane = 1: 5) to give 4.19 g of 3-butyl-2-propylphthalimidine (yield 90.6%).

3576,2956,2928,2864,1688,1618,1468,1438,1414,1380,
1344,1332,1300,1226,1084,728 696,620 Proton nuclear magnetic resonance spectrum (δppm in CD
Cl ₃ ): 0.80 (3H, t, J = 7.0Hz), 0.95 (3H, t, J = 7.4Hz), 1.13−
1.30 (4H, m), 1.51-1.82 (2H, m), 1.82-2.02 (2H,
m), 3.07 (1H, ddd, J = 5.1,8.6,14.0Hz), 3.95 (1H, ddd,
J = 7.8,8.3,14.0Hz), 4.61 (1H, t, J = 4.3Hz), 7.38-7.
59 (3H, m), 7.83 (1H, dd, J = 0.7, 7.2 Hz) Mass spectrum: M / Z (%) 231 (21, M ⁺ ), 202 (26), 188 (18), 175 (6
1), 146 (58), 132 (100) Example 3 After 8.79 g of 2- (1-bromopentyl) benzoic acid methyl ester obtained as an intermediate in Example 1 was replaced with argon, 45 ml of n-butylamine was added. Stirred at room temperature for 10 hours. The solvent of the reaction solution was removed under reduced pressure, 50 ml of chloroform was added, and the mixture was filtered. The filtrate was removed under reduced pressure to obtain a yellow oily substance.
Flash column chromatography (7.5 cm in diameter;
Silica gel 300 g, 230-400 mesh; elution solvent, ethyl acetate: hexane = 1: 5) to give 5.57 g of 2,3-dibutylphthalimidine (yield 75.7%).

3580,2952,2928,2864,1690,1468,1438,1416,1378,1302,
728,696 proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.80 (3H, t, J = 7.2 Hz), 0.95 (3H, t, J = 7.2 Hz), 1.06-
1.48 (6H, m), 1.48-1.68 (2H, m), 1.82-2.02 (2H,
m), 3.09 (1H, ddd, J = 5.6,8.0,13.5Hz), 4.03 (1H, ddd,
J = 7.8,7.9,13.5Hz), 4.61 (1H, t, J = 4.4Hz), 7.30-7.
56 (3H, m), 8.31 (1H, dd, J = 1.2, 6.4 Hz) Mass spectrum: M / Z (%) 245 (25, M ⁺ ), 202 (20), 188 (100), 146
(79), 132 (41) Example 4 To 5.77 g of methyl 2- (1-bromopentyl) benzoate obtained as an intermediate in Example 1, 20 ml of n-pentylamine was added, and the mixture was stirred at room temperature for 8 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ether (50 ml × 3).
l, then washed with 50 ml of saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (7.5 cm in diameter; 364 g of silica gel, 230-400 mesh; elution solvent, ethyl acetate:
Hexane = 1: 6) to give 4.72 g of 3-butyl-2-pentylphthalimidine (85.4% yield).

2952,2928,2860,1692,1468,1438,1414,1378,1302,752,6
96,620 proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.80 (3H, t, J = 7.1 Hz), 0.89 (3H, t, J = 7.1 Hz), 1.17−
1.49 (8H, m), 1.49-1.73 (2H, m), 1.86-2.05 (2H, m
m), 3.07 (1H, ddd, J = 5.6,8.0,13.9Hz), 4.01 (1H, ddd,
J = 7.9.7.9,13.9Hz), 4.61 (1H, t, J = 4.4Hz), 7.38-7.
56 (3H, m), 7.83 (1H, d, J = 7.1Hz) Mass spectrum: M / Z (%) 259 (20, M ⁺ ), 216 (16), 2
02 (83), 146 (100), 132 (36), 77 (11), 43 (17) Example 5 Methyl 2- (1-bromopentyl) benzoate 5.85 g obtained as an intermediate in Example 1 To the mixture was added 20 ml of n-hexylamine, and the mixture was stirred at room temperature for 8 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ether (50 ml × 3).
l, then washed with 50 ml of saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (diameter 7.5 cm; silica gel 373 g, 230-400 mesh; elution solvent, ethyl acetate:
Hexane = 1: 6) to give 4.87 g of 3-butyl-2-hexylphthalimidine (yield 91.5%).

2952,2928,2860,1690,1468,1438,1414,1378,1302,752,6
96 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.80 (3H, t, J = 7.2Hz), 0.88 (3H, t, J = 7.2Hz), 1.19−
1.47 (10H, m), 1.47-1.73 (2H, m), 1.84-2.07 (2H, m
m), 3.07 (1H, ddd, J = 5.6,8.1,13.8Hz), 4.01 (1H, ddd,
J = 7.8.7.8,13.8Hz), 4.60 (1H, t, J = 4.3Hz), 7.39-7.
53 (3H, m), 7.83 (1H, d, J = 7.2 Hz) Mass spectrum: M / Z (%) 273 (40, M ⁺ ), 230 (31), 216 (100), 202
(25), 146 (97), 132 (42), 104 (12), (77 (11), 4
3 (26) Example 6 To 4.29 g of methyl 2- (1-bromopentyl) benzoate obtained as an intermediate in Example 1, 15 ml of n-heptylamine was added, and the mixture was stirred at room temperature for 8 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ether (50 ml × 3).
l, then washed with 50 ml of saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (diameter 7.5 cm; silica gel 434 g, 230-400 mesh; elution solvent, ethyl acetate:
Hexane = 1: 10) to give 4.28 g of 3-butyl-2-heptylphthalimidine (99.4% yield).

2956,2928,2856,1686,1468,1438,1416,1302,752,696,66
4 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.80 (3H, t, J = 7.2Hz), 0.87 (3H, t, J = 7.1Hz), 1.44-
1.98 (12H, m), 1.53-1.75 (2H, m), 1.90-2.04 (2H,
m), 3.07 (1H, ddd, J = 5.6,8.0,13.4Hz), 4.01 (1H, ddd,
J = 7.6,7.6,13.4Hz), 4.60 (1H, t, J = 4.2Hz), 7.38-7.
56 (3H, m), 7.83 (1H, d, J = 6.8 Hz) Mass spectrum: M / Z (%) 287 (29, M ⁺ ), 244 (24), 230 (790), 202
(21), 146 (100), 132 (25), 77 (5), 43 (4) Example 7 To 4.28 g of methyl 2- (1-bromopentyl) benzoate obtained as an intermediate in Example 1 15 ml of n-octylamine was added and the mixture was stirred at room temperature for 8 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ether (50 ml × 3).
l, then washed with 50 ml of saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (diameter 7.5 cm; silica gel 305 g, 230-400 mesh; elution solvent, ethyl acetate: hexane = 1: 8) to give 2.57 g of 3-butyl-2-octylphthalimidine. Obtained (56% yield).

2952,2924,2856,1688,1468,1438,1416,1378,1302,752,6
96 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.80 (3H, t, J = 7.1Hz), 0.86 (3H, t, J = 7.1Hz), 1.18−
1.42 (14H, m), 1.51-1.71 (2H, m), 1.83-2.05 (2H,
m), 3.07 (1H, ddd, J = 5.4,7.8,14.0Hz), 4.01 (1H, ddd,
J = 7.6,7.6,14.0Hz), 4.60 (1H, t, J = 4.3Hz), 7.38-7.
56 (3H, m), 7.83 (1H, d, J = 7.1 Hz) Mass spectrum: M / Z (%) 301 (30, M ⁺ ), 258 (26), 246 (74), 245 (2
00), 202 (23), 146 (100), 132 (23), 77 (5), 43
(8) Example 8 After replacing 1.10 g of 2-valerylbenzoic acid with argon,
33 ml of 0.8 M methylamine / anhydrous acetonitrile was added and stirred at room temperature overnight. Add methylamine hydrochloride 1.
After adding 80 g and then 0.30 g of sodium borohydride, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was removed under reduced pressure, made acidic by adding water and 5% hydrochloric acid, and then extracted with chloroform (100 ml × 2).
The extract was washed with 20 ml of sodium hydroxide and saturated saline, dried over magnesium sulfate, and removed under reduced pressure to obtain a colorless transparent oily substance. This was subjected to flash column chromatography (silica gel, 230-400 mesh; diameter 4.5 cm, length 20 cm; about 160 g;
Eluent, ethyl acetate: chloroform = 1: 5)
3-butyl-2-methylphthalimidine as a colorless oil
0.68 g was obtained (63% yield).

2952,2928,2864,1694,1620,1470,1426,1396,1266,1102,
1050,728,694 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.82 (3H, t, J = 7.3 Hz), 0.60-1.20 (2H, m), 1.24 (2H,
tt, J = 7.2,7.2Hz), 1.90-2.05 (2H, m), 3.11 (3H, s),
4.49 (1H, dd, J = 4.5,4.5Hz), 7.36-7.60 (3H, m), 7.83
(1H, dd, J = 7.3,1.0Hz) Mass spectrum: M / Z (%) 203 (4, M ⁺ ), 169 (5), 146 (100), 131
(1), 118 (2), 103 (1), 91 (10), 77 (2), 69
(6) Example 9 2- (3-methoxyphenyl) -4,4 obtained in Example 2
After 3.5 g of -dimethyl-2-oxazoline was replaced with argon, it was dissolved in 17 ml of anhydrous tetrahydrofuran, cooled to -45 ° C, and 12 ml of 1.6 M n-butyllithium was added with stirring, followed by stirring for 2 hours. N-Pentyl bromide was added to the reaction mixture at -45 ° C.
2.6 ml of anhydrous tetrahydrofuran solution was added dropwise,
For 1 hour and at room temperature overnight. After the reaction,
30 ml was added, extracted with ether (150 ml × 2), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel: 230-400 mesh, diameter 4.5).
cm x length 20 cm, about 160 g; ethyl acetate: n-hexane = 1: 8)
To give 2- (3-methoxy-2-pentylphenyl) -4,4-dimethyl-2-oxazoline 2.4 as a colorless oil.
1 g was obtained (54% yield).

2956,2928,1648,1580,1462,1438,1348,1294,1256,1220,
1188,1044,968,788,736 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.89 (3H, t, J = 6.8 Hz), 1.37 (6H, s), 1.10-1.65 (6H,
m), 2.89 (1H, dd, J = 5.6, 10.0 Hz), 2.89 (1H, dd, J = 7.
6,7.6Hz), 3.80 (3H, s), 4.05 (2H, s), 6.89 (1H, dd, J
= 1.5,7.8Hz), 7.14 (1H, dd, J = 7.8,7.8Hz), 7.23 (1H,
dd, J = 1.5, 7.8 Hz) Mass spectrum: M / Z (%) 275 (22, M ⁺ ), 260 (2), 246 (11), 232 (1
00), 219 (12), 204 (6), 189 (6), 178 (20), 176
(11), 169 (17), 161 (29), 147 (12), 131 (10), 116
(7), 103 (7), 91 (12) Next, 2- (3-methoxy-2-pentylphenyl)-
7.95 g of 4,4-dimethyl-2-oxazoline in 410 ml of 6N hydrochloric acid
Was added and stirred vigorously, followed by heating and stirring on an oil bath for 14 hours. After the completion of the reaction, the reaction solution was ice-cooled, and the insoluble matter was collected by filtration to obtain 6.60 g of brownish white crystals. This was recrystallized from petroleum ether to obtain 5.54 g of 3-methoxy-2-pentylbenzoic acid as white powdery crystals (83% yield).

3052,2948,2924,2852,2632,1686,1598,1580,1460,1436,
1402,1326,1294,1280,1250,1216,1092,1058,938,756 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.91 (3H, t, J = 6.8Hz), 1.15-1.70 (6H, m), 2.99 (1H,
dd, J = 7.6,7.6Hz), 2.99 (1H, dd, J = 5.4,9.8Hz), 3.85
(3H, s), 7.04 (1H, dd, J = 1.0,8.3Hz), 7.23 (1H, dd, J
= 7.8,8.3Hz), 7.55 (1H, dd, J = 1.0,7.8Hz), 10.0-14.
0 (1H, br, disappears with addition of D ₂ O) mass spectrum: M / Z (%) 222 (60, M +), 165 (100), 152 (11), 135
(8), 121 (7), 91 (8), 77 (10) 65 ml of anhydrous acetone was added to 2.0 g of 3-methoxy-2-pentylbenzoic acid and 1.37 g of potassium carbonate, and the mixture was stirred to dissolve, and then iodized. 0.67 ml of methyl was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was removed under reduced pressure, water (50 ml) was added to the residue, extracted with ether (100 ml × 2), and washed with saturated saline (100 ml).
Drying over magnesium sulfate and removal of the solvent under reduced pressure gave 3.06 g of a pale yellow transparent oily substance. This was subjected to flash column chromatography (silica gel, 230-400 mesh; diameter
4.5 cm × length 15 cm; about 120 g; elution solvent, ethyl acetate: n-hexane = 1: 10) to give 3-methoxy- as a colorless oily substance.
1.90 g of methyl 2-pentylbenzoate was obtained (89% yield).

2952,2920,2860,1726,1582,1460,1436,1278,1256,1096,
1058,752 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.90 (3H, t, J = 6.8 Hz), 1.15 to 1.68 (6H, m), 2.88 (1H,
dd, J = 7.7,7.7Hz), 2.88 (1H, dd, J = 5.4,10.0Hz), 3.88
(3H, s), 3.88 (3H, s), 6.97 (1H, dd, J = 1.2,8.1Hz),
7.19 (1H, dd, J = 7.6,8.1Hz), 7.35 (1H, dd, J = 1.2,7.6H)
z) Mass spectrum: M / Z (%) 226 (23, M ⁺ ), 205 (21), 179 (100), 175
(14), 161 (34), 149 (29), 135 (6), 121 (13), 105
(7), 91 (34) Further, 8 ml of anhydrous carbon tetrachloride was added to 1.66 g of methyl 3-methoxy-2-pentylbenzoate, 1.25 g of N-bromosuccinimide and 85 mg of benzoyl peroxide, followed by purging with argon. Then, the mixture was heated and refluxed on an oil bath for 30 minutes with stirring. The reaction solution was ice-cooled, insolubles were filtered off, and the filtrate was removed under reduced pressure to obtain a yellow oily substance. Flash column chromatography (4.5 cm diameter x
Length 20 cm; silica gel, 230-400 mesh, 160 g; elution solvent, ethyl acetate: hexane = 1: 10), and colorless oily methyl 3-methoxy-2- (1-bromopentyl) benzoate 1.52. g was obtained (68% yield).

2952,2920,2868,1768,1720,1584,1492,1458,1436,1272,
1194,1148,1100,1058,754 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.8 Hz), 0.90-1.60 (4H, m), 2.14-2.5
6 (2H, m), 3.92 (3H, s), 3.95 (3H, s), 5.88 (1H, dd, J
= 6.7,8.4Hz), 7.05 (1H, dd, J = 2.4,6.6Hz), 7.28 (1H,
dd, J = 2.4, 7.6 Hz), 7.31 (1H, dd, J = 6.6, 7.6 Hz), mass spectrum: M / Z (%) 316 (1, M ⁺ ), 315 (3), 314 (1, M ⁺ ), 313
(3), 285 (2), 283 (2), 235 (58), 203 (27), 179
(100), 175 (23), 163 (23), 149 (16), 105 (13), 91
(10), 77 (9) 1.62 g of methyl 3-methoxy-2- (1-bromopentyl) benzoate was cooled to -20 ° C, 7 to 8 ml of methylamine was added, and the mixture was stirred at room temperature for 5 hours. The reaction was left at room temperature to evaporate excess methylamine, then filtered,
The filtrate was removed under reduced pressure to give a yellow oil. This was subjected to flash column chromatography (4.5 cm in diameter × 20 cm in length; silica gel 160 g, 230-400 mesh; elution solvent, ethyl acetate: hexane = 1: 2) to give a colorless oily substance, 3-butyl-4. 867 mg of -methoxy-2-methylphthalimidine was obtained (yield 73%).

2952,2920,2864,1694,1604,1492,1456,1424,1396,1274,
1082,746 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.77 (3H, t, J = 7.2 Hz), 0.50-1.00 (2H, m), 1.18 (2H,
tt, J = 7.3, 7.3 Hz), 1.82-2.05 (1H, m), 2.16-2.38 (1
H, m), 3.07 (3H, s), 3.89 (3H, s), 4.56 (1H, dd, J = 3.
7,3.7Hz), 7.00 (1H, dd, J = 2.4,6.6Hz), 7.39 (1H, dd, J
= 6.6,7.6Hz), 7.43 (1H, dd, J = 2.4,7.6Hz) Mass spectrum: M / Z (%) 233 (3, M ⁺ ), 176 (100), 161 (7), 133
(7), 105 (6), 91 (4), 77 (4) Example 10 After replacing 970 mg of 3-butyl-4-methoxy-2-methylphthalimidine obtained in Example 9 with argon, anhydrous chloride was performed. 10 ml of methylene was added to dissolve the mixture, and a 0.8 M solution of boron tribromide in methylene chloride was added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 50 ml of ice water and extracted with methylene chloride (10
0 ml × 3), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid substance. This was recrystallized from a mixed solvent of benzene and n-hexane to obtain 812 mg of white needles of 3-butyl-4-hydroxy-2-methylphthalimidine (89% yield).

3084,2952,2928,2860,1658,1606,1480,1446,1410,1378,
1334,1296,1066,748,678 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.79 (3H, t, J = 7.2 Hz), 0.60-1.00 (2H, m), 1.21 (2H,
tt, J = 7.2.7.2Hz), 1.90−2.10 (1H, m), 2.30−2.52 (1
H, m), 3.12 (3H, s), 4.68 (1H, dd, J = 3.5,3.5Hz), 7.03
(1H, dd, J = 8.0,1.0Hz), 7.25 (1H, dd, J = 7.6,8.0Hz),
7.38 (1H, dd, J = 1.0,7.6Hz), 8.12 (1H, bs, disappears with addition of D ₂ O) mass spectrum: M / Z (%) 219 (5, M +), 162 (100), 147 (1), 134
(2), 119 (1), 107 (4), 105 (2), 91 (1), 77
(3) Example 11 2- (3,4-dimethoxyphenyl)-obtained in Example 3
15.0 g of 4,4-dimethyl-2-oxazoline was replaced with argon, 120 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature.After dissolution, 48 ml of 1.6 M n-butyllithium was added with stirring at −45 ° C. Stir for 2 hours. A solution of 15 ml of n-pentyl iodide in 18 ml of anhydrous tetrahydrofuran was added to the reaction solution at -45 ° C, and the mixture was stirred at -45 ° C for 1 hour and further at room temperature overnight. This is heated under reflux for 2 hours,
After adding 100 ml to terminate the reaction, extraction with ether (3
00ml × 2), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oil. This was subjected to flash column chromatography (silica gel 230-4).
00 mesh; 6.5cm in diameter x 20cm in length; about 300g; ethyl acetate: n
-Hexane = 1: 4) to give 2- (3,4-dimethoxy-2-pentylphenyl) -4,4-dimethyl- as a colorless oil.
16.08 g of 2-oxazoline was obtained (83% yield).

2956,2928,2850,1644,1596.1574,1490,1454,1418,1348,
1288,1226,1190,1094,1064,1022,972,808,722 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.89 (3H, t, J = 7.1 Hz), 1.36 (6H, s), 1.10-1.60 (6H,
m), 2.99 (1H, dd, J = 7.3,7.3Hz), 2.99 (1H, dd, J = 5.9,
9.8Hz), 3.80 (3H, s), 3.88 (3H, s), 4.03 (2H, s), 6.7
4 (1H, d, J = 8.7Hz), 7.44 (1H, d, J = 8.7Hz) Mass spectrum: M / Z (%) 305 (34, M ⁺ ), 290 (17), 276 (22), 262 (1
00), 249 (13), 233 (32), 218 (11), 204 (19), 190
(22), 176 (32), 161 (43), 146 (9), 131 (11), 116
(12) To 9.07 g of 3,4-dimethoxy-2-pentylphenyloxazoline was added 420 ml of 4.5N hydrochloric acid, and with vigorous stirring,
The mixture was heated and refluxed on an oil bath for 16 hours. The reaction solution was cooled on ice, and the precipitate was collected by filtration to obtain a brown white solid. This was dissolved in 210 ml of anhydrous acetone, 5.6 ml of methyl iodide and 12.3 g of potassium carbonate were added, and the mixture was stirred at room temperature overnight. Then
After removing the solvent of the reaction solution under reduced pressure, ether and water were added, and the mixture was extracted with ether (300 ml × 2), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. . This was subjected to flash column chromatography (silica gel 230-400 mesh, about 300 g;
6.5 cm x length 20 cm; elution solvent, ethyl acetate: n-hexane =
1: 8) to give 6.38 g of 3,4-dimethoxy-2-pentylbenzoic acid methyl ester as a colorless insoluble substance (yield: 81).
%).

2948,2856,1720,1594,1574,1488,1452,1434,1418,1284,
1264,1222,1212,1188,1152,1102,1078,1034,990,792,75
0 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.90 (3H, t, J = 6.8 Hz), 1.20-1.70 (6H, m), 2.98 (1H,
dd, J = 7.3, 7.3 Hz), 2.98 (1H, dd, J = 6.1, 9.5 Hz), 3.81
(3H, s), 3.85 (3H, s), 3.90 (3H, s), 6.77 (1H, d, J =
8.8 Hz), 7.68 (1H, d, J = 8.8 Hz) Mass spectrum: M / Z (%) 266 (100, M ⁺ ), 235 (93), 209 (79), 194
(20), 191 (40), 179 (18), 163 (10), 151 (24), 149
(14), 136 (9), 121 (6), 105 (8), 91 (15) 3,4-dimethoxy-2-pentylbenzoic acid methyl ester 3.00 g, N-bromosuccinimide 2.11 g and benzoyl peroxide After adding and dissolving 20 ml of anhydrous carbon tetrachloride to 143 mg, the atmosphere was replaced with argon, and the mixture was heated to reflux on an oil bath with stirring for 40 minutes. The reaction solution was ice-cooled, insolubles were filtered off, and the filtrate was removed under reduced pressure to obtain a yellow oily substance. Use flash column chromatography (silica gel 230-400 mesh, approx.
160 g; diameter 4.5 cm × length 20 cm; elution solvent, ethyl acetate: n-hexane = 1: 10) to give a colorless oily substance, methyl 3,4-dimethoxy-2- (1-bromobenzyl) -benzoate. 3.65 g of the ester was obtained (94% yield).

2948,2868,1714,1592,1488,1452,1432,1274,1228,1190,
1148,1080,1034,752 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.87 (3H, t, J = 6.8Hz), 1.10-1.60 (4H, m), 2.10-2.6
0 (2H, m), 3.88 (3H, s), 3.91 (3H, s), 3.99 (3H, s),
6.11 (1H, dd, J = 6.8,8.3Hz), 6.84 (1H, d, J = 8.7Hz),
7.56 (1H, d, J = 8.7 Hz) Mass spectrum: M / Z (%) 346 (5, M ⁺ ), 345 (5), 344 (5, M ⁺ ), 343
(4), 265 (94), 250 (15), 233 (51), 221 (18), 209
(100), 205 (44), 193 (95), 175 (13), 165 (12), 16
3 (12), 149 (12), 105 (10), 91 (12), 77 (11) 3.91 g of 3,4-dimethoxy-2- (1-bromopentyl) -benzoic acid methyl ester at -20 ° C After cooling and adding 12 ml of methylamine, the mixture was stirred at -10 ° C overnight. The reaction was left at room temperature to evaporate excess methylamine,
Chloroform insolubles were filtered off, and the filtrate was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel, 230-400 mesh; diameter 4.5 cm x length 20).
cm; about 160 g; elution solvent, ethyl acetate: n-hexane = 1: 1)
To give 1.93 g of 3-butyl-4,5-dimethoxy-2-methylphthalimidine as a colorless oil (yield 87).
%).

2950,2932,2868,1690,1620,1498,1484,1426,1396,1272,
1220,1082,1066,742 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.79 (3H, t, J = 7.2 Hz), 0.55-1.00 (2H, m), 1.21 (2H,
tt, J = 7.3,7.3Hz), 1.85-2.32 (2H, m), 3.05 (3H, s),
3.90 (3H, s), 3.93 (3H, s), 4.60 (1H, dd, J = 3.7,3.7H
z), 7.00 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.3 Hz) Mass spectrum: M / Z (%) 263 (6, M ⁺ ), 206 (100), 191 ( 2), 169 (4
2), 162 (5), 135 (9), 134 (8), 105 (13), 77 (1
2) Example 12 15.0 g of 2- (3,4,5-trimethoxyphenyl) -4,4-dimethyl-2-oxazoline obtained in Example 4 was replaced with argon, 105 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature. After dissolving, the mixture was cooled to −35 ° C.
42 ml of butyllithium was added and stirred for 2 hours. To this reaction solution, a solution of n-pentyl iodide (8.9 ml) in anhydrous tetrahydrofuran (20 ml) was added at -35 ° C, and the mixture was stirred at -35 ° C for 1 hour, then the cooling bath was removed, and the mixture was stirred at room temperature overnight. Water 10
0 ml was added, extracted with ether (300 ml × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This is subjected to column chromatography (silica gel, 230-400 mesh, about 300 g;
6.5 cm in diameter, 20 cm in length; 0.3 kg / cm ² ; ethyl acetate: n-hexane = 1: 3), fractionated 70 ml each, and combined the 10th to 22nd fractions to obtain a colorless oily substance. 2- (3,4,5-
17.46 g of trimethoxy-2-pentylphenyl) -4,4-dimethyl-2-oxazoline was obtained (yield 92%).

2960,2928,2864,1644,1596,1572,1494,1454,1400,1356,
1268,1196,1126,1088,1044,1026,980 Proton nuclear magnetic resonance spectrum: 0.89 (3H, t, J = 7.0Hz), 1.38 (6H, s), 1.05-1.55 (6H,
m), 2.86 (2H, dd, J = 7.6,7.6Hz, dd, J = 5.6,10.0Hz), 3.
85 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.06 (2H, s),
7.01 (1H, s) Mass spectrum: M / Z (%) 335 (45, M ⁺ ), 320 (27), 306 (19), 292 (1
00), 279 (14), 263 (21), 236 (9), 222 (20), 206
(47), 191 (25), 176 (6), 161 (7), 131 (6) Next, 2- (3,4,5-trimethoxy-2-pentylphenyl) -4,4-dimethyl- 9.84 g of 2-oxazoline 4.
410 ml of 5N hydrochloric acid was added, and the mixture was heated and refluxed on an oil bath for 15 hours with vigorous stirring. The reaction solution was cooled on ice and extracted with ether (30
0 ml × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 7.3 g of brown oily substance.
I got This was dissolved in 210 ml of anhydrous acetone, 5.5 ml of methyl iodide and 12.16 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature overnight. After the solvent of the reaction solution was removed under reduced pressure, ether and water were added, and the mixture was extracted with ether (300 m
1 × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 300 g; diameter 6.5 cm × length 20 cm;
Ethyl acetate: n-hexane = 1: 8; 0.3 kg / cm ² )
The twelfth to twentieth fractions were collected by fractionation, and 6.21 g of a colorless oily methyl ester of 3,4,5-trimethoxy-2-pentylbenzoic acid methyl ester was obtained (71%).

2948,2856,1724,1596,1574,1494,1454,1432,1402,1338,
1224,1168,1126,1094,1058,1032,996,990,762,750 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.91 (3H, t, J = 6.8 Hz), 1.10-1.55 (6H, m), 2.87 (2H,
dd, J = 7.1,7.1Hz, dd, J = 5.9,9.5Hz), 3.86 (3H, s), 3.8
7 (3H, s), 3.88 (3H, s), 3.91 (3H, s), 7.20 (1H, s) Mass spectrum: M / Z (%) 296 (40, M ⁺ ), 265 (9), 239 (100), 224
(13), 209 (5), 194 (3), 181 (9), 179 (9), 164
(3), 149 (3) 1.54 g of methyl 3,4,5-trimethoxy-2-pentylbenzoate, 1.04 g of N-bromosuccinimide and 142 mg of benzyl peroxide were dissolved by adding 20 ml of anhydrous carbon tetrachloride. Thereafter, the atmosphere was replaced with argon, and the mixture was heated and refluxed on an oil bath with stirring for 50 minutes. The reaction solution was ice-cooled, insolubles were filtered off, and the filtrate was removed under reduced pressure to give 3,4,5-trimethoxy-2-yellow oil.
(1-Bromopentyl) -benzoic acid methyl ester was obtained.

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 7.0 Hz), 1.10-1.55 (4H, m), 2.10-2.5
5 (2H, m), 3.89 (3H, s), 3.91 (6H, s), 4.03 (3H, s),
5.94 (1H, dd, J = 6.6,8.5Hz), 7.04 (1H, s) 3,4,5-trimethoxy-2- (1-bromopentyl)
-Methyl benzoate was cooled to -20 ° C, 7-8 ml of methylamine was added, and the mixture was stirred at -10 ° C overnight. After allowing the reaction to stand at room temperature to evaporate excess methylamine,
The insoluble matter in chloroform was filtered, and the filtrate was distilled off under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 160 g;
cm, length 20 cm; ethyl acetate: n-hexane = 1: 1; 0.3 kg / c
m ² ) and fractionated in 60 ml aliquots and combined the 13th to 20th fractions to give a colorless oil, 3-butyl-4,5,6
1.20 g of trimethoxy-2-methylphthalimidine was obtained (77% yield).

2950,2932,2860,1694,1618,1478,1418,1396,1336,1226,
1194,1130,1098,1034,764 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.80 (3H, t, J = 7.2 Hz), 0.52-1.00 (2H, m), 1.21 (2H,
tt, J = 7.3,7.3Hz), 1.80-2.30 (2H, m), 3.06 (3H, s),
3.90 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 4.54 (1H, d
d, J = 3.7, 3.7 Hz), 7.13 (1H, s) Mass spectrum: M / Z (%) 293 (9, M ⁺ ), 262 (2), 236 (100), 221
(2), 206 (10), 203 (5), 192 (3), 178 (2), 175
(3) Example 13 2- (3-methoxyphenyl) -4,4 obtained in Example 2
-Dimethyl-2-oxazoline (20.2 g) was replaced with argon, anhydrous tetrahydrofuran (105 ml) was added, and the mixture was stirred and dissolved at room temperature to sufficiently dissolve, then cooled to -45 ° C and stirred under 1.6 M
74 ml of butyllithium was added, and the mixture was stirred at -45 ° C for 2 hours.
To this reaction solution was added a solution of 19.4 ml of n-heptyl iodide in anhydrous tetrahydrofuran (25 ml) at -45 ° C, and the mixture was stirred at -45 ° C for 1 hour, and then stirred at room temperature overnight. Water 10
After adding 0 ml to terminate the reaction, extraction with ether (300
ml × 2), and the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was applied to a flash column chromatograph (silica gel 230-400 mesh, about 320 g; diameter 7 cm, length 20 cm; ethyl acetate: n-hexane = 1: 8; 0.3 kg / cm ² ), and fractionated in 70 ml portions. The 13th to 18th fractions were combined to give 15.35 g of 2- (3-methoxy-2-heptylphenyl) -4,4-dimethyl-2-oxazoline as a colorless oil (yield 51%).

2956,2924,2852,1648,1580,1462,1438,1348,1298,1260,
1220,1188,1044,972,790,736 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.8 Hz), 1.38 (6H, s), 1.15-1.60 (10
H, m), 2.89 (2H, dd, J = 7.8,7.8Hz, dd, J = 5.9,9.8Hz),
3.81 (3H, s), 4.06 (2H, s), 6.90 (1H, dd, J = 1.5,7.8H
z), 7.14 (1H, dd, J = 7.8,7.8Hz), 7.22 (1H, dd, J = 1.5,
7.8Hz) Mass spectrum: M / Z (%) 303 (32, M ⁺ ), 288 (5), 274 (5), 272
(5), 246 (11), 232 (100), 219 (20), 204 (4), 17
8 (10), 176 (11), 161 (15), 146 (12), 131 (4), 11
6 (7), 103 (4), 91 (6) Next, 2- (3-methoxy-2-pentylphenyl)
4.5N hydrochloric acid 5 in 11,11 g of -4,4-dimethyl-2-oxazoline
20 ml was added, and the mixture was heated and refluxed on an oil bath for 15 hours with vigorous stirring. The reaction solution was cooled with ice, insolubles were filtered off, the filtrate was distilled off under reduced pressure, and recrystallized from n-hexane to give white fine needles.
4.28 g of -methoxy-2-heptylbenzoic acid was obtained (yield 4
7%).

3300-2500,2952,2920,2852,1698,1596,1580,1460,140
0,1284,1262,1102,1052,926,750 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 7.1 Hz), 1.10-1.70 (10H, m), 2.99 (2
H, dd, J = 7.7,7.7Hz, dd, J = 5.9,9.5Hz), 3.85 (3H, s),
7.03 (1H, dd, J = 1.2,8.1Hz), 7.22 (1H, dd, J = 7.8,8.1H)
z), 7.52 (1H, dd, J = 1.2, 7.8 Hz), 8.0-12.0 (1H, br, D ₂
Mass spectrum M / Z (%) 250 (37, M ⁺ ), 205 (4), 165 (100), 152
(13), 135 (7), 121 (8), 91 (7) 180 ml of anhydrous acetone was added to 6.39 g of 3-methoxy-2-heptyl-benzoic acid and 10.6 g of anhydrous potassium carbonate to dissolve, and then the mixture was stirred at room temperature. 4.8 ml of methyl iodide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure, and the residue was diluted with 100 ml of water.
And extracted with ether (300 ml × 2), washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 160 g;
cm × length 20 cm; ethyl acetate: n-hexane 91:20; 0.3 kg / c
m ² ) and fractionated in 70 ml aliquots to combine the third to sixth fractions to give a colorless oil, 3-methoxy-2-
5.66 g of heptyl benzoic acid methyl ester was obtained (yield 84
%).

2950,2928,2852,1728,1582,1462,1436,1266,1100,1062,
752 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.8 Hz), 1.10-1.60 (10H, m), 2.88 (2
H, dd, J = 7.7,7.7Hz, dd, J = 5.9,9.8Hz), 3.83 (3H, s),
3.84 (3H, s), 6.97 (1H, dd, J = 1.0,7.8Hz), 7.18 (1H, d
d, J = 7.8, 7.8 Hz), 7.35 (1H, dd, J = 1.0, 7.8 Hz) Mass spectrum: M / Z (%) 264 (44, M ⁺ ), 233 (23), 205 (4), 179 (1
00), 166 (8), 161 (32), 149 (20), 121 (10), 91 (2
0) 3-methoxy-2-heptylbenzoic acid methyl ester
After adding and dissolving 73 ml of anhydrous carbon tetrachloride to 5.09 g, 3.77 g of N-bromosuccinimide and 256 ml of benzoyl peroxide, the mixture was purged with argon and heated to reflux for 50 minutes while stirring on an oil bath. The reaction solution was ice-cooled, insolubles were filtered off, and the filtrate was evaporated under reduced pressure to obtain a yellow oily substance, 3-methoxy-2- (1-bromoheptyl) -benzoic acid methyl ester. Further, 15 ml of n-hexylamine was added and dissolved therein, followed by stirring at room temperature overnight. 70 ml of 10% hydrochloric acid was added to the reaction solution, and the mixture was extracted with ether (200 ml × 2). The ether layer was washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a brown oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 160 g;
cm x length 20 cm; ethyl acetate: n-hexane = 1: 8; 0.3 kg / c
m ² ) and fractionated in 70 ml aliquots to combine the twelfth through twentieth fractions, yielding 4-methoxy-
4.97 g of 2,3-dihexylphthalimidine was obtained (78% yield).

2952,2928,2586,1694,1604,1492,1462,1412,1270,1084,
748 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.81 (3H, t, J = 7.1 Hz), 0.88 (3H, t, J = 7.3 Hz), 0.45-
1.70 (16H, m), 1.75-2.00 (1H, m), 2.10-2.40 (1H,
m), 3.04 (1H, ddd, J = 5.3,7.8,14.2Hz), 3.99 (1H, ddd,
J = 7.8,7.8,13.9Hz), 4.68 (1H, dd, J = 3.8,3.8Hz), 6.9
8 (1H, dd, J = 1.8,7.0Hz), 7.39 (1H, dd, J = 7.0,7.6H
z), 7.44 (1H, dd, J = 1.8, 7.6 Hz) Mass spectrum: M / Z (%) 331 (12, M ⁺ ), 260 (9), 246 (100), 176
(38), 162 (14), 132 (3), 105 (3) Example 14 2- (3,4,5-trimethoxyphenyl) -4,4-dimethyl-2- obtained in Example 4 20.0 g of oxazoline was replaced with argon, 140 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred and dissolved at room temperature, cooled to -35 ° C, and stirred at 1.6 Mn-
56.5 ml of butyllithium was added and stirred for 2 hours. To this reaction solution was added a solution of n-heptyl iodide (14.8 ml) in anhydrous tetrahydrofuran (25 ml) at -35 ° C, and the mixture was stirred at -35 ° C for 1 hour, and then the cooling bath was removed, followed by stirring at room temperature overnight. Water in the reaction solution
100 ml was added, extracted with ether (300 ml × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This is subjected to column chromatography (silica gel 230-400 mesh, approx. 320
g; diameter 7.0 cm × length 20 cm; 0.3 kg / cm ² ; ethyl acetate: n-hexane = 1: 4), fractionate 70 ml each, and combine the 9th to 18th fractions to form a colorless oil 2- (3,4,5)
-Trimethoxy-2-heptylphenyl) -4,4-dimethyl-2-oxazoline was obtained in an amount of 25.29 g (yield 92%).

2956,2928,2852,1644,1594,1572,1494,1454,1402,1356,
1268,1196,1126,1092,1026,980,920,856 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.8 Hz), 1.37 (6H, s), 1.10-1.57 (10
H, m), 2.86 (2H, dd, J = 7.7,7.7Hz, dd, J = 5.9,9.8Hz),
3.86 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 7.01 (1H,
s) Mass spectrum: M / Z (%) 363 (42, M ⁺ ), 348 (26), 334 (4), 332
(7), 306 (17), 292 (100), 279 (23), 264 (19), 23
6 (11), 222 (18), 206 (36), 191 (17), 176 (5), 16
1 (4) Next, 24.7 g of 2- (3,4,5-trimethoxy-2-heptylphenyl) -4,4-dimethyl-2-oxazoline was added to 44.7 g.
960 ml of 5N hydrochloric acid was added, and the mixture was heated and refluxed on an oil bath for 15 hours with vigorous stirring. The reaction solution was returned to room temperature, extracted with ether (500 ml × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a brown oily substance. After dissolving this in 480 ml of anhydrous acetone,
12.7 ml of methyl iodide and 28.2 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature overnight. After the solvent of the reaction solution was removed under reduced pressure, ether and water were added, and the mixture was extracted with ether (30
0 ml × 2), the ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 160 g; diameter 4.5 cm × length 20 cm;
Ethyl acetate: n-hexane = 1: 10; 0.3 kg / cm ² )
The 6th to 9th fractions were collected by fractionation in ml to give 8.05 g of 3,4,5-trimethoxy-2-heptylbenzoic acid methyl ester as a colorless oil (yield 37%).

2950,2928,2852,1724,1596,1574,1492,1454,1432,1402,
1338,1222,1204,1126,1058,996,914,858,780 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.88 (3H, t, J = 7.1Hz), 1.10-1.60 (10H, m), 2.86 (2H, dd, J = 7.6,7.6Hz, dd, J = 5.9,9.3Hz), 3.86 (3H, s), 3.87 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 7.19 (1H, s) ) Mass spectrum: M / Z (%) 324 (42, M ⁺ ), 293 (9), 265 (6), 239 (1
00), 224 (10), 221 (4), 209 (4), 181 (6), 179
(6), 164 (2), 149 (2) 78 ml of anhydrous carbon tetrachloride was added to 6.77 g of 3,4,5-trimethoxy-2-heptylbenzoic acid methyl ester, 4.09 g of N-bromosuccinimide and 556 mg of benzoyl peroxide. After addition and dissolution, the atmosphere was replaced with argon, and the mixture was heated and refluxed for 1 hour on an oil bath with stirring. The reaction solution was cooled on ice, insolubles were filtered off, and the filtrate was evaporated under reduced pressure to give 3,4,5-trimethoxy-2 as a yellow oil.
-(1-Bromoheptyl) -benzoic acid methyl ester was obtained. Further, 15 ml of n-hexylamine was added and dissolved therein, followed by stirring at room temperature overnight. 10% hydrochloric acid
70 ml was added, and the mixture was extracted with ether (200 ml × 2). The ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a brown oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, about 160 g; diameter 4.5 cm × length 20 cm; ethyl acetate: n-hexane = 1: 8; 0.3 kg / cm ² ). Take the 16th to 29th fractions and combine them into a colorless oil
4,5-trimethoxy-2,3-dihexylphthalimidine 5.
34 g were obtained (65% yield).

2950,2928,2856,1692,1616,1478,1424,1406,1336,1224,
1194,1112,1038,764 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.81 (3H, t, J = 6.8 Hz), 0.88 (3H, t, J = 7.1 Hz), 0.45-
1.40 (13H, m), 1.45-1.70 (2H, m), 1.80-2.25 (3H,
m), 3.02 (1H, ddd, J = 5.1,7.9,14.2Hz), 3.90 (3H, s),
3.91 (3H, s), 3.95 (1H, ddd, J = 7.8,7.8,13.9Hz), 3.97
(3H, s), 4.64 (1H, dd, J = 3.5,3.5Hz), 7.13 (1H, s) Mass spectrum: M / Z (%) 391 (8, M ⁺ ), 320 (5), 306 ( 100), 236 (1
9), 222 (7) Example 15 To 42.32 g of methyl 2- (1-bromopentyl) benzoate obtained as an intermediate in Example 1, 400 m of dimethylformamide was added.
l, and 123.15 g of potassium iodide was added with stirring. Then, about 200 ml of liquid ammonia was added from a bomb and stirred for 8 hours. After the reaction, extraction with ether (200 ml
× 3), extraction with ethyl acetate (200 ml × 2), washing with a saturated aqueous solution of sodium thiosulfate and brine, drying over magnesium sulfate, and removing the solvent under reduced pressure to obtain a brown oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, 486 g; ethyl acetate: hexane =
1: 2), fractionated 200 ml each, and combined the 7th to 22nd fractions to obtain 19.50 g of pale yellow crystals. This was recrystallized from hexane to give 3-butylphthalimidine 1
8.50 g was obtained (66.0% yield).

3192,3076,2952,2928,2864,1688,1614,1470,1360,766,7
46,732 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.90 (3H, t, J = 6.8 Hz), 1.23-1.56 (4H, m), 1.56-1.7
7 (1H, m), 1.85-2.08 (1H, m), 4.62 (1H, dd, J = 4.4,5.
1Hz), 7.12 (1H, br), 7.45-7.60 (3H, m), 7.85 (1H, d
d, J = 1.0, 7.3 Hz) Mass spectrum: M / Z (%) 189 (65, M ⁺ ), 146 (9), 133 (100), 104
(50), 77 (67), 76 (14), 51 (17) Next, 9.39 g of 3-butylphthalimidine, 8.71 of 1- (3-chloropropyl) -4-methylpiperazine obtained in Specific Example 5 g and tetra n-butylammonium iodide 3.6
6 g of benzene 75 ml and 50% aqueous sodium hydroxide solution 78
Then, the mixture was heated and refluxed for 5 hours. The reaction solution was cooled to 0 ° C. and extracted with benzene (20 ml × 2), the benzene layer was extracted with 2N hydrochloric acid (30 ml × 3), the hydrochloric acid layer was made alkaline with 5% sodium hydroxide, and then extracted with ether (30 ml ×). 3), washed with water (10 ml × 3), dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 9.54 g of an oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, 3
66; methanol).
The 15th fraction was merged to give 3-butyl-2- [3
-(N-methylpiperazyl) propyl] phthalimidine
9.21 g was obtained (56.4% yield).

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.81 (3H, t, J = 7.2 Hz), 1.21-1.38 (4H, m), 1.89 (2H,
q, J = 7.3Hz), 1.87−2.05 (2H, m), 2.26 (3H, s), 2.37
(2H, t, J = 7.3Hz), 2.26-2.44 (8H, m), 3.16 (1H, ddd,
J = 6.1,8.0,14.2Hz), 4.04 (1H, ddd, J = 6.6,7.5,14.2H
z), 4.62 (1H, t, J = 12,4 Hz), 7.40-7.53 (3H, m), 7.82
(1H, d, J = 6.8Hz) Mass spectrum: M / Z (%) 329 (20, M ⁺ ), 273 (18), 259 (60), 230 (2
7), 228 (27), 146 (18), 127 (33), 113 (60), 97 (1
9), 72 (28), 70 (100), 43 (30), 42 (25) Example 16 2.37 g of 3-butylphthalimidine obtained as an intermediate in Example 15 and 1 obtained in Example 6 -(3-chloropropyl)
To 2.98 g of 4-phenylpiperazine and 0.93 g of tetrabutylammonium iodide, 50 ml of benzene and 50 ml of a 50% aqueous sodium hydroxide solution were added, and the mixture was heated under reflux for 5 hours. The reaction solution was cooled to 0 ° C., extracted with benzene (20 ml × 2), the benzene layer was extracted with 2N hydrochloric acid (20 ml × 3), and the hydrochloric acid layer was made alkaline by adding 50% sodium hydroxide while cooling. Extract with ether (20ml × 3), wash with water (10ml ×
3), dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain an oily substance. This was subjected to flash column chromatography (silica gel 230-400 mesh, 185 g; methanol).
Then, fractions of 100 to 100 ml were collected, and the 8th to 27th fractions were combined to obtain 3.39 g of 3-butyl-2- [3- (N-phenylpiperazyl) propyl] phthalimidine (yield 69.4). %).

Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.80 (3H, t, J = 7.2 Hz), 0.85-1.32 (4H, m), 1.78-2.0
2 (4H, m), 2.46 (2H, t, J = 7.3Hz), 2.56-2.62 (4H, m
m), 3.05-3.22 (1H, m), 3.14-3.19 (4H, m), 4.06 (1
H, ddd, J = 6.8,7.8,14.6Hz), 4.64 (1H, t, J = 4.3Hz), 6.
83-6.92 (3H, m), 7.20-7.28 (2H, m), 7.42-7.52 (3
H, m), 7.83 (1H, d, J = 7.8 Hz) Mass spectrum: M / Z (%) 391 (28, M ⁺ ), 259 (100), 230 (28), 228
(24), 175 (43), 146 (28), 132 (28), 105 (26), 104
(23), 70 (65), 56 (22) Example 17 3-methoxy-2- (1) obtained as an intermediate in Example 9
-Bromopentyl) -benzoic acid methyl ester (14.07 g) was added and dissolved in anhydrous dimethylformamide (170 ml).
37.05 g of potassium iodide was added, and the mixture was stirred at room temperature for 1 hour.
Then, about 50 ml of liquid ammonia was added and the mixture was stirred for 16 hours. After completion of the reaction, the excess ammonia was removed by reducing the pressure with a water-jet pump under stirring, 500 ml of water was added, extracted with ether (400 ml × 2), washed with water, dried over magnesium sulfate,
The solvent was removed under reduced pressure to give a yellow oil. This was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give colorless prism crystals of 3-butyl-4-methoxyphthalimidine 3.
12 g was obtained (31.9% yield).

3200,3076,2948,2916,2852,1688,1602,1492,1464,1444,
1362,1268,1168,1146,1054,912,804,754,664 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 6.8Hz), 1.10-1.45 (4H, m), 1.45-1.7
5 (1H, m), 2.05-2.30 (1H, m), 3.90 (3H, s), 4.66 (1
H, dd, J = 3.2,8.1Hz), 6.85 (1H, br), 6.95-7.05 (1H,
m), 7.35-7.50 (2H, m) Mass spectrum: M / Z (%) 219 (96, M ⁺ ), 186 (6), 163 (100), 147
(28) 132 (34), 119 (27), 105 (15), 92 (11), 77 (1
7) Example 18 The 3-butyl-4-methoxyphthalimidine obtained in Example 17 was replaced with 200 mg of argon, dissolved in 2 ml of anhydrous methylene chloride, and then dissolved under ice cooling with 0.8 M boron tribromide / methylene chloride. 2.4 ml of the solution was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and the white precipitate was collected by filtration to obtain 166 mg of 3-butyl-4-hydroxyphthalimidine as white powdery crystals (yield: 8).
9%).

3276,3088,2948,2860,1678,1644,1604,1476,1418,1332,
1284,1160,972,804,746,664,614,568 Proton nuclear magnetic resonance spectrum (δppm in CDCl ₃ ): 0.88 (3H, t, J = 7.1Hz), 1.00-1.45 (4H, m), 1.65-1.8
5 (1H, m), 2.05-2.30 (1H, m), 4.68 (1H, dd, J = 3.4, 7.
0Hz), 6.96 (1H, dd, J = 1.5,7.3Hz), 7.23 (1H, dd, J = 1.
5,7.6Hz), 7.30 (1H, dd, J = 7.3,7.6Hz) Mass spectrum: M / Z (%) 205 (4, M ⁺ ), 174 (7), 148 (100), 120
(6) The compound of the present invention has a blood viscosity lowering effect and is useful as a pharmaceutical. This will be described with reference to experimental examples.

Experimental Example Male Wistar rats (10-12
Week) under ether anesthesia, blood was collected from the abdominal aorta,
1 ml of blood with 40% EDTA · 2K (saline) as anticoagulant
Per microliter, and centrifuged (3000 rpm, 4
C. for 5 min) to separate into a supernatant and a red blood cell layer. The supernatant was further centrifuged (3000 rpm, 4 ° C., 15 min), and the supernatant was used as plasma.

The erythrocyte layer is obtained by combining several animals, measuring the hematocrit value (hereinafter referred to as HT value), and further diluting with plasma to obtain HT.
The value was adjusted to 45% and subjected to measurement of blood viscosity.

In 1 ml of blood for measurement, the compound obtained in Example was added to a final concentration of 4.8.
It was dissolved in 50% ethanol-physiological saline so as to have a concentration of × 10 ^-4 M, added with 50 μl, and incubated at 37 ° C. for 60 minutes. Next, 0.5 ml of the incubated blood was collected, and the viscosity was measured at a shear rate of 7.5 S- ¹ using a viscosity meter.
The degree of decrease in blood viscosity was calculated from the following equation.

A: Blood viscosity when the compound obtained in the example is not contained B: Blood viscosity when the compound obtained in the example is added The results are shown in Table 1.

From the results shown in Table 1, the compounds obtained in the examples were confirmed to have a blood viscosity lowering effect.

The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers. The administration form is not particularly limited and may be appropriately selected and used as needed. Examples thereof include oral preparations such as tablets, capsules and granules, and parenteral preparations such as injections and suppositories. Oral preparations such as tablets, capsules, granules and the like are produced according to a conventional method. Tablets are produced by mixing and shaping the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc and gum arabic. Capsules contain the compound of the present invention. It is manufactured by mixing with an active pharmaceutical filler or diluent and filling the mixture into a hard gelatin capsule, a soft gelatin capsule or the like. Syrup preparations and elixirs are prepared by mixing the compound of the present invention with sweeteners such as sucrose, preservatives such as methyl and propylparabens, coloring agents, flavoring agents, fragrances and adjuvants.

Parenteral preparations are manufactured according to a conventional method, and are generally used as diluents such as distilled water for injection, physiological saline, dextrose aqueous solution,
Propylene glycol or the like can be used. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Also, from the viewpoint of stability, this parenteral preparation can be frozen after filling in an ampoule or the like, removing water by a usual freeze-drying technique, and re-preparing a liquid preparation from the freeze-dried product immediately before use.

Examples of other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are produced according to a conventional method.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-50-154293 (JP, A) JP-A-62-190162 (JP, A) Org. Chem. , 44 (9), (1979), p. 1519-33 J.C. Org. Chem. , 43 (19), (1978), p. 3719-23

Claims (1)

(57) [Claims] 1. A compound of the general formula I [Wherein, R ₁ and R _{2 each} represent a hydrogen atom, a hydroxyl group or a methoxy group, R ₃ and R _{4 each} represent a hydrogen atom or a methoxy group, and R ₅ represents a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. , N-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group,
Or n-decyl group, and R ₆ is a hydrogen atom, a methyl group,
Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl Group, n-decyl group or formula II (In the formula, R ₇ represents a methyl group or a phenyl group.) However, R ₁ , R ₂ , R ₃ and R ₄ are commonly a hydrogen atom, R ₅ is a methyl group, R ₆ is a hydrogen atom, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group or n -When it is a decyl group, R ₁ , R ₂ , R ₃ and R ₄ are commonly a hydrogen atom, R ₅ is an ethyl group, an n-propyl group or an isopropyl group, and R ₆ is a methyl group In the case, R ₁ , R ₂ , R ₃ , R ₄ and R ₆ are commonly a hydrogen atom,
Except when R ₅ is an n-butyl group. ] The novel phthalide derivative represented by these.