JPS6344733B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Fields The present invention is directed to β-Thuyaprisin (Hinokitiol), which is used in hair growth and growth agents, therapeutic agents for alveolar pyorrhea, toothpastes, basic cosmetics, etc., as it has antibacterial and antifungal effects and cell activating effects. ). Hinokitiol is also attracting attention as an ingredient in whitening cosmetics due to its ability to inhibit melanin pigment production. It is also used as an insect repellent for clothing and as a stain repellent for lumber. Prior Art β-Thujaplicin (hinokitiol) was originally extracted from the essential oil of the heartwood of Taiwanese cypress trees.
However, in recent years, as the demand has increased, an inexpensive synthesis method has been desired. Therefore, 1-isopropylcyclopenta-1,
Addition reaction of 3-diene and dihaloketene, 1
Synthesize an -isopropylcyclopenta-1,3-dienedihaloketene adduct, and use the obtained dihaloketene adduct with a lower carboxylic acid (having 1 to 3 carbon atoms) and its alkali metal salt to produce β-thujaplicin. A method for producing β-thujaplicin has been invented (Japanese Patent Publication No. 33901/1989). Problems to be solved by the invention However, 1-isopropylcyclopentane-
The method of synthesizing β-thujaplicin by addition reaction of 1,3-diene and dihaloketene requires that the process of synthesizing the raw material 1-isopropylcyclopent-1,3-diene from cyclopentadiene is not always easy. There were some inconveniences. As a result of intensive studies, the present inventors have invented a method for synthesizing β-thujaplicin that is simple and has a high yield. Means for Solving the Problems In other words, the present invention was developed as a result of intensive research into a synthetic method with simple synthesis reaction and high yield in view of the shortcomings of the prior art. -Thujaplicin is synthesized by oxidizing 3-isopropylcycloheptanone of formula (7) to produce 4-isopropyl of formula (8)-
Step of obtaining 1,2-cycloheptanedione.

【formula】

[Formula] By brominating 4-isopropyl-1,2-cycloheptanedione of formula (8), 3,7-dibromo-4-isopropyl-1,2 of formula (9) is obtained.
-Process of obtaining cycloheptanedione. A step of obtaining β-thujaplicin by dehydrobrominating 3,7-dibromo-4-isopropyl-1,2-cycloheptanedione of formula (9). This is a method for synthesizing β-thujaplicin consisting of. Specifically, 3-isopropylcycloheptanone is oxidized using selenium dioxide (SeO ₂ ) as an oxidizing agent to obtain 4-isopropyl-1,2-cycloheptanedione. However, the oxidizing agent is not limited to selenium dioxide, and any other oxidizing method may be used. Next, 4-isopropyl-1,2-cycloheptanedione is brominated to obtain 3,7-dibromo-4-isopropyl-1,2-cycloheptanedione. As the brominated compound, phenyltrimethylammoniem tribromide is preferred, but any chemical agent that causes bromination may be used. Then, 3,7-dibromo-4-isopropyl-1,2-cycloheptanedione is dehydrobrominated to obtain β-thujaplicin. As the chemical agent for this dehydrobromination reaction, lithium carbonate is preferable, but any chemical agent can be used as long as it causes dehydrobromination. EXAMPLES The present invention will be described in detail below with reference to specific examples. Example (a) 3-isopropylcycloheptanone (7) 123 mg
Dissolve it in 0.8ml of 95% ethanol, add 177mg of selenium dioxide (SeO ₂ ), seal it tightly, and incubate at 90℃ for 2 hours.
Stir for a time, selenium oxidation (selenium
(oxidation) After cooling, the reaction solution is filtered and diluted with ether. Next, the ether layer was washed with brine, and the solvent was distilled off under reduced pressure to obtain crude 4-isopropyl-1,2-cycloheptanedione (8). (b) Add 10 ml of crude 4-isopropyl-1,2-cycloheptanedione (8) obtained in (a) to tetrahydrofuran.
Dissolve phenyltrimethylammonium in
Add 752 mg of tribromide and stir for 1 hour and 45 minutes at room temperature for bromination. After the reaction, pour into 0.1N (normal) aqueous sodium thiosulfate solution and extract with ether. The ether layer was sequentially washed with water and saturated brine, and the solvent was distilled off under reduced pressure to obtain crude 3,7-dibromo-4-
Isopropyl-1,2-cycloheptanedione
We get (9). (c) Dissolve the crude 3,7-dibromo-4-isopropyl-1,2-cycloheptanedione (9) obtained in (b) in 4 ml of dimethylformamide, add 160 mg of anhydrous lithium carbonate and 160 mg of lithium chloride,
Stir for 45 minutes at °C for dehydrobromination. After the reaction, dilute with ether and remove the ether layer by
% aqueous sodium hydroxide solution. The extracted aqueous alkali solution was made acidic with hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed successively with water and a saturated aqueous solution, and the solvent was distilled off under reduced pressure. The residue was diluted with ether, washed with water and saturated brine, and the solvent was distilled off under reduced pressure to obtain 80 mg of crude β-thujaburicin (hinokitiol) (1). The crude yield from 3-isopropylcycloheptanone (7) was 61.0% in three steps. This crude β-thujaplicin (hinokitiol) (1)
When the sample was developed with benzene on a phosphoric acid-impregnated filter paper and colored with iron chloride (2000), almost a single spot was observed that matched the sample of hinokitiol. In addition, NMR and
The IR spectrum matched that of the standard β-thujaplicin (hinokitiol). Although there are various methods for synthesizing 3-isopropylcycloheptanone as a raw material, the present inventors have discovered that the following method provides a good yield. Synthesis method 1 (a) Dissolve 3.00 g of 2-isopropylphenol (2) in 15 ml of ethanol, and dissolve Raney nickel (W-
2) 0.5 ml was added, hydrogen was pressurized to 50 Kg/cm ² using an autoclave, and the mixture was reduced at 100° C. for 4 hours. After cooling, the reaction solution was filtered, diluted with ether, washed successively with 5% aqueous sodium hydroxide solution, water, and saturated brine, and the solvent was distilled off under reduced pressure to obtain crude 2-
Isopropylcyclohexanol (3) is obtained. (b) Dissolve the entire amount of crude 2-isopropylcyclohexanol (3) obtained in (a) in 23 ml of glacial acetic acid, cool on ice, add aqueous sodium hypochlorite solution (10% available chlorine) while stirring, and add 0. Oxidation was performed by stirring at °C for 1.5 h. After the reaction, the mixture was diluted with water and extracted with ether. The ether layer was washed successively with an aqueous sodium bicarbonate solution, an aqueous sodium bisulfite solution, water, and saturated brine, and the solvent was distilled off under reduced pressure to obtain an oily substance. This oily substance was distilled under reduced pressure to obtain 3.012 g of 2-isopropylcyclohexanone (4). 2-isopropylphenol (2) in two steps
The yield was 97.5%. (c) 2-isopropylcyclohexanone (4) 362mg
Dissolve in 3.6 ml of ethanol, cool on ice, and add 1.65 ml of acetone cyanohydrin and 107 mg of potassium carbonate.
was added and stirred at 0°C for 18 hours. After the reaction (cyanohydrination), it was diluted with ether, washed sequentially with water and saturated brine, and the solvent was distilled off under reduced pressure. The resulting oily substance was subjected to silica gel flash column chromatography [solvent: ethyl acetate/n- Hexane (1:8)]
400 mg of 1-hydroxy-2-isopropylcyclohexanecarbonitrile (5a) and (5b)
I got it. The yields of (5a) and (5b) are 340mg and 60mg, respectively.
It is. From the NMR spectrum (5a), (5b)
was confirmed to be an isomer with the structural formula shown in the drawing. The combined yield of (5a) and (5b) is 92.6%. (d) 1-hydroxy-2-isopropylcyclohexanecarbonitrile (5a) and (5b) 288 mg
Dissolve in 3 ml of glacial acetic acid, add 30 mg of platinum oxide,
Hydrogen was pressurized to 3.5 Kg/cm ² and reduced for 17 hours. Filter platinum oxide to obtain 1-aminomethyl-2
- An acetic acid solution of isopropylcyclohexanol (6) was obtained. (e) Add 2 ml of glacial acetic acid to the acetic acid solution of 1-aminomethyl-2-isopropylcyclohexanol (6) obtained in (d), cool on ice, and dissolve 1.78 g of sodium nitrite in 8 ml of purified water while stirring. Add the aqueous solution, stir at 0℃ for 3 hours, and then at room temperature for 17 hours.
I stirred the time. After the reaction, the mixture was diluted with dichloromethane, the organic layer was washed successively with water, an aqueous sodium bicarbonate solution, and saturated brine, and the solvent was distilled off under reduced pressure to obtain an oily substance (ring expansion reaction). This oily substance was purified by silica gel flash column chromatography, and 200 mg of 3-
Isopropylcycloheptanone (7) was obtained. The yield is 75.3% in two steps from 1-hydroxy-2-isopropylcyclohexanecarbonitrile (5a, 5b). The compounds obtained in each experiment were isolated and purified, and their NMR and IR spectra were measured to confirm that they had the structural formula shown in the drawing. Synthesis method 2 (a) 27.24g of 2-isopropylphenol (2) to 300g
75.9 g of potassium carbonate dissolved in ml of acetone,
63 g of dimethyl sulfate was added, and the mixture was heated under reflux for 17 hours (methylation). After cooling, the reaction solution was filtered and the solvent was distilled off under reduced pressure. A 20% aqueous sodium hydroxide solution was added to the residue, and the mixture was stirred on a 60°C hot bath for 2 hours. After cooling, the organic layer was extracted with ether, washed with water and saturated brine, and the solvent was distilled off under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 2-isopropyl-1-methoxybenzene (10). Obtained 28.29g. Yield: 94.2% (b) 3.00 g of 2-isopropyl-1-methoxybenzene (10) was added to 70 ml of liquid ammonia at -50°C.
A solution dissolved in 60 ml of tetrahydrofuran was added, and further 6 ml of t-butyl alcohol and 982 mg of lithium pieces were added, followed by stirring at -50°C to -40°C for 5 hours (reduction reaction). After the reaction, 7 g of ammonium chloride was added, diluted with an appropriate amount of ether, and allowed to stand until the temperature reached room temperature. The reaction mixture was poured into water, extracted with ether,
The organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure to obtain crude 2-isopropyl-1-methoxy-1,4-cyclohexadiene (11). (c) To the entire amount of crude 2-isopropyl-1-methoxy-1,4-cyclohexadiene obtained in (b), 3.5 ml of glacial acetic acid and 1.5 ml of purified water were added, and the mixture was stirred at 50°C for 10 minutes for hydrolysis. After cooling, dichloromethane was added, and the organic layer was washed successively with water, aqueous sodium bicarbonate solution, and saturated brine, and the solvent was distilled off under reduced pressure to give crude 6-isopropyl-3-cyclohexenone (12a) and crude 2-
Isopropyl-3-cyclohexenone (12b)
A total of 2.901 g of the mixture was obtained. (d) Crude 6-isopropyl-3-cyclohexenone (12a) obtained in (c) and crude 2-isopropyl-
From a mixture of 3-cyclohexenone (12b)
Weigh out 290 mg, dissolve in 4 ml of ethanol, cool on ice, add 1 ml of glacial acetic acid, and potassium cyanide 912.
mg was added thereto, and the mixture was stirred at 0°C for 112 hours and further at room temperature for 6 hours. After reaction (cyanohydrination), dilute with water,
Extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure to obtain an oily substance. This oily substance was subjected to silica gel flash column chromatography [solvent: ethyl acetate-n
-hexane (1:10)] to obtain a total of 270 mg of a mixture of 1-hydroxy-6-isopropyl-3-cyclohexenecarbonitrile (13a) and 1-hydroxy-2-isopropyl-3-cyclohexenecarbonitrile (13b). Obtained. 2-isopropyl-1-methoxybenzene (10)
The yield is 81.8% in three steps. (e) Dissolve 330 mg of a mixture of hydroxy-6-isopropyl-3-cyclohexenecarbonitrile (13a) and 1-hydroxy-2-isopropyl-3-cyclohexenecarbonitrile (13b) in 3 ml of glacial acetic acid, and add 30 mg of platinum oxide. Hydrogen was pressurized to 3.5 Kg/cm ² and reduced for 15 hours. After the reaction, the catalyst was filtered and 1-aminomethyl-2
- An acetic acid solution of isopropylcyclohexanol (6) was obtained. (f) Add 3 acetic acids to the acetic acid solution of 1-aminomethyl-2-isopropylcyclohexanol (6) obtained in (e).
ml and cooled on ice, and while stirring, added a solution of 2.07 g of sodium nitrite dissolved in 8 ml of purified water, stirred for 2.5 hours while cooling on ice, and further stirred at room temperature for 15 hours. After the reaction (ring expansion reaction), dichloromethane was added and the organic layer was diluted with water, sodium hydrogen carbonate aqueous solution,
The mixture was washed successively with saturated brine, and the solvent was distilled off under reduced pressure to obtain an oily substance. This oily substance was purified by silica gel flash column chromatography, and 232 mg of 3-
Isopropylcycloheptanone (7) was obtained.
The yield is 76.3% in two steps from (13a, 13b). Effects As described above, the method for synthesizing β-thujaplicin (hinokitiol) according to the present invention has an extremely high yield, easy synthesis operations, and simple equipment compared to conventional methods. It's over.

[Brief explanation of drawings]

FIG. 1 is a reaction diagram schematically showing the synthesis method according to the present invention, and FIG. 2 is a reaction diagram schematically showing the method for synthesizing 3-isopropylcycloheptanone used in the synthesis of the present invention.

Claims (1)

[Claims] 1. Each of the following steps: 4-isopropyl- of formula (8) by oxidizing 3-isopropylcycloheptanone of formula (7)
Step of obtaining 1,2-cycloheptanedione. [Formula] [Formula] By brominating 4-isopropyl-1,2-cycloheptanedione of formula (8), 3,7-dibromo-4-isopropyl-1,2 of formula (9) is produced.
-Process of obtaining cycloheptanedione. A step of obtaining β-thujaplicin by dehydrobrominating 3,7-dibromo-4-isopropyl-1,2-cycloheptanedione of formula (9). A method for synthesizing β-thujaplicin consisting of.