JPH0977694A - New production of guaiazulene or its derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a guaiazulen or its derivative useful as a precursor for a medicine having an antiinflammatory action in a practically and with a high yield under a mild reaction condition in reduced danger from isopropylazulene-1- carboxylic acid methyl ester as starting raw material. SOLUTION: A 7-isopropylazulene-1-carboxylic acid methyl ester of formula I (Me is methyl; Pri is isopropyl) is reduced to obtain 1-methyl-7-isopropylazulene of formula II, which is alkylated into guaiazulene of formula III (R is a lower alkyl) or its derivative. Or, the compound of formula I is deesterified to obtain 5-isopropylazulene, which is alkylated into 4-alkyl-7-isopropylazulene. The 4- alkyl-7-isopropylazulene is formylated into a 1-formyl-4-alkyl-7-isopropylazulene of formula IV, which is reduced to obtain the guaiazulene of formula III or its derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a guaiazulene derivative useful as a precursor of a drug having an anti-inflammatory effect.

[0002]

2. Description of the Related Art A compound obtained by introducing a water-soluble sodium sulfonate group into guaizulene has antiallergic action, antiinflammatory action, tissue regeneration action and the like, and is widely used especially as a drug (antiulcer drug). This guaiazulene production method is currently produced by 1) dehydrogenation of natural products, but the supply amount is limited. In addition, 2) a method based on a diaddition reaction of methylfulvene and pyrrolidine with a dienamine is known (Journal Americ).
an Chemical Society, 251 19
1979). In this synthetic step, expensive m-chloroperbenzoic acid is used, and the reaction time is as long as 48 hours, and inconveniences such as danger remain, which is not a realistic synthetic method. Also, 3) a synthesis method using dihydrolinalool as a raw material has been reported (Tetrahedron let)
ters No. 8 533-536 1975),
The reaction conditions for the aldol condensation in the reaction step are 19
It must be set to a high temperature of 0 ° C, and since sulfur is used in the dehydrogenation reaction in the final stage, a large amount of malodorous hydrogen sulfide is generated, so this is also not a practical synthesis. .

[0003]

Therefore, the object of the present invention is to solve the above-mentioned problems of the prior art, to reduce the risk, and to show the formula (3) in a practical and high yield under mild reaction conditions. Another object of the present invention is to provide a method capable of producing guaizulene or a derivative thereof.

[0004]

Means for Solving the Problems As a result of various efforts made by the present inventors to solve the above problems, guaizulene or its derivative using 7-isopropylazulene-1-carboxylic acid methyl ester as a starting material Has developed a new synthetic route for. That is, the present invention has the general formula (1)

Embedded image (In the formula, Me represents a methino group, and Pri represents an isopropyl group), and 7-isopropylazulene-1-carboxylic acid methyl ester represented by the formula (2) is reduced.

Embedded image (In the formula, Me and Pri are the same as the above), 1-methyl-7-isopropylazulene is obtained, and then this compound is alkylated to obtain the formula (3).

Embedded image (In the formula, R represents a lower alkyl group, Me and Pri are the same as the above), and a method for producing guaiazulene or a derivative thereof.

2. Formula (1)

[Chemical 12] (In the formula, Me represents a methino group and Pri represents an isopropyl group), and 7-isopropylazulene-1-carboxylic acid methyl ester represented by the formula (4) is deesterified.

Embedded image (In the formula, Pri is the same as above), 5-isopropylazulene is obtained, and then the compound is alkylated to obtain the compound of the formula (5)

Embedded image (Wherein R represents a lower alkyl group, and Pri is the same as above), 4-alkyl-7-isopropylazulene is obtained, and then the compound (5) is formylated to give formula (6).

[Chemical 15] (Wherein R represents a lower alkyl group, and Pri is the same as above), 1-formyl-4-alkyl-7-isopropylazulene is obtained, and then the compound (6) is reduced. Expression (3)

Embedded image (In the formula, R represents a lower alkyl group, Me and Pri are the same as the above), and a method for producing guaiazulene or a derivative thereof.

As the lower alkyl group in the present invention,
An alkyl group having 1 to 5 carbon atoms, particularly 1 to 3 carbon atoms is preferable. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a pentyl group.

The present invention will be described in detail below. The starting material of the present invention, 2-methyl-7-isopropylazulene-1-carboxylic acid methyl ester, is 3-alkoxycarbonyl-7-isopropyl-2H represented by the formula (7).
Prepared by reacting cyclohepta [b] furan-2-one with acetone in the presence of a secondary amine.

Embedded image (In the formula, Me and Pri are the same as above.) In this case, the amine used is preferably a dialkylamine, particularly diethylamine. In this method, the temperature is set to 40 ° C. or below the boiling point of the solvent, and the reaction is preferably carried out for several hours to several tens of hours.

The above 3-alkoxycarbonyl-7
-Isopropyl-2H-cyclohepta [b] furan-2
The -one is a 2-chloro-5-isopropyltropolone synthesized by the method found by the present inventors (Japanese Patent Publication No.
-53681) or γ-tsuyapurisin, which is easily synthesized by an existing method. (Tetrahedro
n, 27 , 3359, 1971)

Hereinafter, the case where the alkyl group is methyl will be described as an example. There are roughly two methods for obtaining guaiazulene or its derivative, which is the initial target product, from 7-isopropylazulene-1-carboxylic acid methyl ester thus obtained.

First, the first method will be described. By reducing the ester of 7-isopropylazulene-1-carboxylic acid methyl ester with a reducing agent, 1-methyl-
7-isopropylazulene is obtained. The reducing agent used at this time is preferably diisobutylaluminum hydride. As another method, there is a method in which the 7-isopropylazulene-1-carboxylic acid methyl ester is reacted with iodotrimethylsilane, subsequently reduced with trichlorosilane and a tertiary amine, and then hydrolyzed.

Next, 1-methyl-7-isopropylazulene can be methylated to produce the guaiazulene derivative which is the object of the present invention. A known method may be used for the methylation method. Preferred examples include a method using methyllithium and a method using a Grignard reagent such as CH3MgCl. As a method using methyl lithium, there is a method of Hafner et al. (K. Hafner and H. Weldes, Li.
ebigs Ann. , 606, 90, 1957). In this method, the reaction temperature is from −20 ° C. to room temperature, particularly preferably room temperature, and methyllithium used is 1-methyl-7-
The amount is 2 to 10 times, preferably 3 times the mol of isopropylazulene.

During the methylation according to the method of Hafner et al., A dihydro body is first produced. By dehydrogenating the dihydro body, 1,4-dimethyl-7 is obtained.
-Isopropylazulene (also known as guaiazulene) is obtained in high yield. The dehydrogenation reaction can proceed in the presence of an oxidizing agent such as chloranil, o-chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone, but chloranil is most preferred. The reaction temperature is usually from -20 ° C to room temperature, preferably room temperature. Further, it is preferable to use the oxidizer in a two-fold molar amount with respect to the substrate.

Next, the second method will be described. 7-Isopropylazulene-1-carboxylic acid methyl ester is deesterified to prepare 5-isopropylazulene. A preferable deesterification reaction is, for example, a method in which 7-isopropylazulene-1-carboxylic acid methyl ester is hydrolyzed with alkali and then decarboxylated using trichloroacetic acid or the like.

The 5-isopropylazulene thus obtained is methylated by a method similar to the above-mentioned first method to obtain 4-alkyl-7-isopropylazulene.

The 4-alkyl-7-isopropylazulene is then formylated. A known method can be used for this formylation. Specifically, there are a method of reacting with dimethylformamide in the presence of phosphorus oxychloride and a method of reacting with trifluoroacetic acid in the presence of hexamethyleneteramine.

The formyl group of the formyl compound is reduced with a reducing agent to obtain 1,4-dimethyl-7-isopropylazulene (8). The reducing agent used at this time is preferably diisobutylaluminum hydride. In addition, as a reduction method, there is also a method in which lithium aluminum hydride is once used as an alcohol and then hydrogenated in the presence of palladium.

[0017]

According to the present invention, the formula (3)

Embedded image (In the formula, R, Me, and Pri are the same as the above), and guaiazulene or its derivative could be adjusted with good yield under mild conditions with low risk.

The present invention will be described in detail below with reference to preparation examples and examples, but the present invention is not limited thereto.

Preparation Example 1 Synthesis of 7-isopropylazulen-1-carboxylic acid methyl ester: 3-methoxycarbonyl-5-isopropyl-2H-cyclohepta [b] furan-2-one (3
0.8 g 0: 125 mol of diethylamine (50
Acetaldehyde (60 ml) was slowly added while the suspension (0 ml) was cooled with ice water. Next, the reaction solution was heated under reflux in an oil bath for 3 hours. After cooling, the solvent was distilled off under reduced pressure, and the obtained oily substance was separated by silica gel column chromatography. The reddish-purple oil obtained from the first fraction eluted with benzene was dissolved in benzene, charged on an alumina column and allowed to stand for 6 hours, then eluted with benzene and the 7th-isopropylazulene-1 was obtained from the first red-purple fraction. -Carboxylic acid methyl ester was obtained. (21.4 g 0.0093 mol, yield 75%) ¹ H-NMR (200 MHz, CDCl 3) δPPM: 1.43 (6 H, d, J = 6.9 Hz, iPr-CH
3) 3.24 (1H, sept, J = 6.9Hz, iPr-
CH) 3.96 (3H, s, COOCH3) 7.20 (1H, d, J = 4.2Hz, H-3) 7.41 (1H, dd, J = 10.2 and 10.
2Hz, H-5) 7.76 (1H, br.d, J = 10.2Hz.H-
6) 8.33 (1H, d, J = 4.2Hz.H-2) 8.35 (1H, d, J = 10.2Hz, H-4) 9.76 (1H, d, J = 1. 8Hz, H-8)

[0019]

Example 1 a) Synthesis of 7-isopropyl-1-methylazulene: 5
In a 00 ml three-necked flask, 7-isopropylazulene-1-carboxylic acid methyl ester (2.04 g · 8.9) was added.
4 mmol), and under an argon atmosphere, ether (1
20 ml) was added and the mixture was cooled to −78 ° C. with stirring, and diisobutylaluminum hydride (hexane solution 0.
87 ml of 93M: 80.5 mmol) was slowly added dropwise. The color of the solution changed from purple to blue during the dropping. The mixture was stirred as it was for 1 hour, and the temperature was raised to room temperature. After stirring was continued for further 12 hours, the mixture was cooled to 0 ° C. and ethanol (20 ml) was added. The temperature was raised to room temperature, and the reaction solution was poured into a 10% sulfuric acid aqueous solution. Subsequently, the mixture was extracted with n-hexane, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained blue oil was applied to a short column (alumina, n-hexane), and 1-methyl-7-isopropylazulene (1.58 g, 8.55 mmol / yield 96%) as a blue oil was obtained from the first fraction. Obtained. ¹ H-NMR (200 MHz, CDCl 3) δPPM: 1.39 (3 H, d, J = 6.9 Hz, iPr-CH
3) 2.70 (3H, s, 1-CH3) 3.12 (1H, sept, J = 6.9Hz, iPr-
CH3) 7.02 (1H, dd, J = 10Hz, H-5) 7.23 (1H, d, J = 3.7Hz, H-3) 7.49 (br.d, J = 10.0Hz, H-5) 7.73 (1h, d, J = 3.7Hz, H-2) 8.16 (1H, d, J = 10.0Hz, H-4) 8.21 (1H, d, J = 1.6 Hz)

B) Synthesis of 1,4-dimethyl-7-isopropylazulene: 1-methyl-7-isopropylazulene (1.07 g: 5.81) in a 300 ml three-necked flask.
mmol), and under an argon atmosphere, ether (25
ml) was added and stirred. Methyl lithium (1.
14 ml of 09M diethyl ether solution: 15.1 mm
ol) was added. When the stirring was continued as it was, the color of the solution became gradually lighter. After 6 hours, the reaction solution was cooled to −78 ° C., and ethanol (3.4 ml) was added dropwise. Then, the temperature was raised to 0 ° C., and chloranil (2.86 g: 11.6 mm
ol) was slowly added and stirred overnight. After adding n-hexane and leaving it for 2-3 hours, the reaction solution was added with 5%: Na.
It was added to the aqueous OH solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The concentrate was subjected to column chromatography (alumina, n-hexane), the first fraction was taken, the solvent was distilled off, and separation was carried out by reverse phase high performance liquid chromatography (ODS, 70% acetonitrile). An initially colorless fraction 1 and subsequently obtained blue fraction 2 were obtained, from fraction 2 being a blue oil, 1,4-dimethyl-7-isopropylazulene (guaiazulene) (668 m: 3. 37 mmol / yield 58%) was obtained. ¹ H-NMR (200 MHz, CDCl3) δPPM: 1.40 (6H, J = 6.9 Hz, iPr-CH3) 1.40 (6H, J = 6.9 Hz, iPr-CH3) 2.71 (s, 1) -CH3) 2.87 (s, 4-CH3) 3.12 (1H, sept, J = 6.9 Hz, iPr-
CH3) 7.04 (1H, d, J = 10.6Hz, H-5) 7.26 (1H, dd, J = 3.8Hz, H-3) 7.45 (1H, dd, J = 10. 6 and 1.9
Hz, H-6) 7.66 (1H, J = 3.8Hz.H-2) 8.24 (1H, J = 1.9Hz, H-8)

[0021]

Example 2 Synthesis of 5-isopropylazulene: a) 7-isopropylazulene-1-carboxylic acid methyl ester (34.5 g: 0.151 mol) in ethanol (700 ml) was dissolved in potassium hydroxide (50 g) in water ( A solution dissolved in 50 ml) was added. This solution was heated under reflux for 5 hours, and after confirming that the hydrolysis reaction was completed,
Added to water (3500 ml). The solution was acidified with hydrochloric acid and then left overnight, and the precipitated carboxylic acid was separated by filtration and collected. Then, it was washed with water and thoroughly dried with a vacuum desiccator to obtain 7-isopropylazulen-1-carboxylic acid (29.
12 g: 0.135 mol / yield 89.9%) was obtained.
This carboxylic acid (20 g: 0.093 mol) was dissolved in benzene (500 ml), and trichloroacetic acid (3.0
g) was added and the mixture was heated under reflux for 10 hours. After confirming that there were no unreacted substances by thin layer chromatography, the solution was transferred to a separating funnel, washed three times with water, dried and the solution was distilled off to obtain a dark green oily substance. The oil was purified using alumina column chromatography, eluting with hexane, to give a blue oil of 5-isopropylazulene (12.67 g 0.
0744 mol yield 80%) was obtained.

B) Synthesis of 7-isopropyl-4-methylazulene: 5-isopropylazulene (600 mg, 3.52 mmol) was placed in a 100 ml three-necked flask, ether (20 ml) was added under an argon atmosphere and the mixture was not stirred. At room temperature, methyllithium (1.09 M diethyl ether solution 14 ml: 15.1 mmol) was added, and the same treatment as in Example 1a) was carried out, followed by reverse phase high performance liquid chromatography (ODS, 70% CH3CN). The first colorless fraction 1 was followed by blue fractions 2 to 4-methyl-7-isopropylazulene (379 mg: 2.04
(mmol / yield 58%) was obtained. ¹ H-NMR (200 MHz, CDCl3) δPPM: 1.39 (6H, J = 6.9 Hz, iPr-CH3) 2.92 (s, 4-CH3) 3.11 (1H, sept, J = 6.9 Hz) , IPr-
CH) 7.16 (1H, d, J = 10.6Hz, H-5) 7.35 (2H, dd, J = 3.9 and 3.9H).
z, H-1, 3) 7.51 (1H, dd, J = 10.6 and 2.0
Hz, H-6) 7.85 (1H, J = 3.9Hz, H-2) 8.36 (1H, J = 2.0Hz, H-8)

C) 1-formyl-7-isopropyl-4
Synthesis of -methyl-7-isopropylazulene: 50 ml
4-Methyl-7-isopropylazulene (398 mg, 2.16 mmol) was placed in a round-bottomed flask, 3 ml of dimethylformamide was added, and the mixture was stirred in an ice bath and phosphorus oxychloride (499 mg, 3.26 mmo cooled in advance in an ice bath.
A dimethylformamide solution (1 ml) of 1) was added dropwise. The purple solution turned orange as it was added dropwise.
Reversed phase high performance liquid chromatography (70% after 1.5 hours)
When the reaction was confirmed with (acetonitrile), unreacted substances could not be detected, so the reaction solution was added to water. When a 2M potassium hydroxide aqueous solution was added dropwise to this, a precipitate was deposited. When PH12 was reached, the dropping was stopped and the mixture was left for a while. This is extracted with benzene, washed with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was removed and subjected to reverse phase high performance liquid chromatography (70% acetonitrile) to give 1-formyl-4-methyl-7 as a purple oil.
-Isopropylazulene (357 mg: 78% yield) was obtained. ¹ H-NMR (200 MHz, CDCl 3) δPPM: 1.39 (6 H, d, J = 6.9 Hz, iPr-CH
3) 3.15 (1H, s, J = 6.9Hz, iPr-CH
3) 3.20 (s, 8-CH3) 7.23 (1H, dd, J = 4.5Hz, H-3) 7.50 (1H, d, J = 2.1Hz, H-4) 8. 41 (1H, d, J = 4.5 Hz, H-2) 10.68 (1H, s, 1-CHO)

D) Synthesis of 1,4-dimethyl-7-isopropylazulene (guaiazulene): 1-formyl-7-isopropyl-4-methylazulene (300 mg: 1.41 mmol) was placed in a 100 ml three-necked flask,
Ether (15 ml) was added and stirred under an argon atmosphere. After cooling to -78 ° C, diisobutylaluminum hydride (0.93M hexane solution 9.1 ml: 8.48).
mmol) was slowly added dropwise. Thereafter, the same treatment as in Example 1a) was performed to obtain 1,4 as a blue oily substance.
-Dimethyl-7-isopropylazulene (guaiazulene) 205 mg: 03 mmol / yield 73%) was obtained.

Claims (2)

[Claims] (1) Formula (1) (In the formula, Me represents a methyl group, and Pri represents an isopropyl point), 7-isobromopyrazulene-1-carboxylic acid methyl ester represented by the formula (2) (Wherein Me and Pri are the same as above), 1-methyl-7-isopropylazulene is obtained, and the compound is then alkylated. (In the formula, R represents a lower alkyl group, Me and Pri are the same as the above), and a method for producing guaiazulene or a derivative thereof. 2. Formula (1): (In the formula, Me represents a methino group and Pri represents an isopropyl group), and 7-isopropylazulene-1-carboxylic acid methyl ester represented by the formula (4): (Wherein Pri is the same as above), 5-isopropylazulene is obtained, and then the compound is alkylated to obtain the compound of the formula (5) (Wherein R represents a lower alkyl group, and Pri is the same as above), 4-alkyl-7-isopropylazulene is obtained, and then the compound (5) is formylated to give formula (6) ] (Wherein R represents a lower alkyl group, and Pri is the same as above), 1-formyl-4-alkyl-7-isopropylazulene is obtained, and then the compound (6) is reduced. Equation (3) (In the formula, R represents a lower alkyl group, Me and Pri are the same as the above), and a method for producing guaiazulene or a derivative thereof.