JPH11302216A - Production of dialkoxy-substituted indanone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a dialkoxy-substituted indanone derivative by acylating a specific alkoxybenzene with a specified acid halide, capable of obtaining the derivative having a strong acetylcholine esterase- inhibiting action and useful as an intermediate for synthesizing an Alzheimer's disease medicine in shorter processes using inexpensive general reagents. SOLUTION: This method for producing the dialkoxy-substituted indanone derivative of formula IV (R1 and R2 are each methyl, ethyl or the like) (for example, 5,6-dimethoxy-1-indanone) comprises acylating (A) a dialkoxybenzene of formula I with (B) a propionic acid halide of formula II (X and Y are each a halogen) in the presence of (C) aluminum chloride as a catalyst and subsequently cyclizing the obtained compound of formula III in the presence of an acid catalyst. The acylation reaction is carried out in a solvent such as nitrobenzene, and the cyclization reaction is preferably performed in the presence of concentrated sulfuric acid at 60-80 deg.C for 2-5 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has a strong acetylcholinesterase inhibitory activity and is commercially available in the United States and the like as a remedy for Alzheimer's disease.

Embedded image (Wherein Ph represents a phenyl group), which is a synthetic intermediate of the compound of the following formula (2):

Embedded image The present invention relates to a novel method for producing a dialkoxy-substituted indanone derivative represented by the formula:

[0002]

2. Description of the Related Art Various methods have been reported as methods for synthesizing dialkoxy-substituted indanone derivatives represented by the formula (2). That is, as a typical method, a condensation reaction of dialkoxybenzaldehyde and malonic acid,
Dialkoxyphenylpropionic acid obtained by subsequent hydrogenation reaction (3)

Embedded image A method for cyclization via is reported.

[0003] Among them, as a method via an acid halide, for example, when both R1 and R2 are methyl groups, compound (3) is converted into 3- (3,4-dimethoxyphenyl) propionyl chloride with phosphorus pentachloride, There is an example in which an intramolecular Friedel-Crafts-acylation reaction is performed using aluminum chloride as a catalyst. (J. Chem. Soc., 91 , 1080
(1907))

As another method, diphosphorus pentoxide (J. Chem. Soc., 91 , 1080 (1907)) and polyphosphoric acid (Chem. Ber., 102 , 3656 (1967)) are added to compound (3). , Hydrofluoric acid (J. Am. Chem. Soc., 71 , 1092 (1949)), or a mixture of diphosphorus pentoxide and methanesulfonic acid (Heterocycle)
s, 43 , 127 (1996)), and a method of cyclization by the action of a dehydrating agent or a strong acid.

On the other hand, a method for producing compound (2) using dialkoxybenzene as a starting material is represented by the following formula (4)

Embedded image (Wherein, Tf represents a trifluoromethanesulfonyl group) (Tetrahedoron Lett., 3
7 , 4199 (1996)). However, the yield of this reaction is not satisfactory at 42%, and the trifluoromethanesulfonic anhydride used in this reaction is an expensive reagent, and has high reactivity and requires careful handling. is there.

[0006]

According to the above-mentioned production method, at least three steps must be performed to obtain the desired compound (2) from, for example, dialkoxybenzaldehyde. Also, considering mass production,
Special equipment is required to perform the hydrogenation reaction.

In order to obtain compound (2) from dialkoxybenzene according to the production method described below, trifluoromethanesulfonic acid, which is expensive and requires careful handling, is used. Various difficulties are expected.

[0008]

In view of the above problems,
As a result of various studies, the present inventors have found that a method for producing the desired dialkoxy-substituted indanone derivative (2) by a more practical method using a less expensive and less common reagent in a shorter process. I found it. The present invention is the following invention which has this as a gist.

The following equation (5)

Embedded image (Wherein, R 1 and R 2 may be the same or different and each represents an alkyl group such as a methyl group or an ethyl group,
Or together, they form -O- (CH2) 1-2-O- and the like. ) And the following formula (6)

Embedded image (Wherein, X and Y each independently represent a halogen atom.) The acylation reaction of a propionic halide represented by the following formula (7) is carried out using aluminum chloride as a catalyst.

Embedded image (Wherein R1, R2 and Y have the same meanings as described above) by cyclizing a compound using an acid catalyst to produce a dialkoxy-substituted indanone derivative.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the manufacturing method of the present invention, X, Y
Examples of the halogen atom represented by are a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom or a bromine atom is preferable.

When both R1 and R2 are methyl groups, 1,2-dimethoxybenzene used as a raw material is a known compound and can be easily obtained.

When both X and Y are chlorine atoms, 3-chloropropionyl chloride used as a raw material is a known compound and can be easily obtained.

In order to obtain the compound (7) from the compound (5) and the compound (6), a Friedel-Crafts acylation reaction may be carried out using aluminum chloride in a solvent such as nitrobenzene, carbon disulfide or dichloromethane. . Compound (2) is obtained from compound (7) in the presence of a strong acid such as concentrated sulfuric acid, polyphosphoric acid or hydrofluoric acid at room temperature to 100 ° C.
The reaction may be carried out at 60 ° C., preferably 60 to 80 ° C. for 2 to 5 hours in the presence of concentrated sulfuric acid.

On the other hand, a Friedel-Crafts acylation reaction is carried out without using a solvent by using an excess amount of the compound (5), and the compound (7) is successively added to the compound (2).
You can also get

This reaction is carried out by removing the hydrogen chloride from the compound (7).

Embedded image Or a compound of the following formula (9) obtained by elimination of chloride ion from compound (7)

Embedded image Can be considered to be proceeding via the compound of

In the present invention, when attention is paid to the synthesis process, that is, a method of introducing a substituent into a benzene ring, in a conventional production method, the reaction is carried out in the order of alkylation and acylation. This is because, generally, when an acyl group is introduced, the electron density of the benzene ring decreases, and the alkylation reaction becomes difficult. However, in this reaction, the alkylation reaction was successfully performed after the acylation, and the present production method was completed. In this regard, the present invention is an extremely novel synthesis technique.

Further, the present invention uses an inexpensive and easily available compound such as dialkoxybenzene and propionic acid halide as starting materials and uses only industrially common reagents such as aluminum chloride, concentrated sulfuric acid, and polyphosphoric acid to shorten the time. This is an extremely practical synthesis method that can obtain the desired dialkoxy-substituted indanone derivative in a high yield in the process, and is applicable to mass production.

[0018]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1 Production of 3-chloro-3 ', 4'-dimethoxypropiophenone 16.0 g of aluminum chloride was added to 18 mL of dichloromethane.
Was suspended. There, 13.3 g of 3-chloropropionyl chloride and 13.2-dimethoxybenzene 13.
8 g was added dropwise, and after stirring at room temperature for 1 hour, the reaction solution was poured into ice water and extracted with dichloromethane. After drying over anhydrous sodium sulfate, dichloromethane was distilled off under reduced pressure to obtain 23.0 g of a solid product.

1H-NMR (CDCl3) δ (ppm) = 3.43 (2H, t, J =
6.83 Hz), 3.93 (2H, t, J = 6.83 Hz), 3.94 (3H, s), 3.9
6 (3H, s), 6.91 (1H, d, J = 8.46 Hz), 7.53 (1H, d, J = 2.
03 Hz), 7.58 (1H, dd, J = 2.03, 8.46 Hz) IR (KBr) 1651
cm-1

Example 2 Production of 5,6-dimethoxy-1-indanone 3.0 g of 3-chloro-3 ', 4'-dimethoxypropiophenone obtained in Example 1 was dissolved in 9 ml of trifluoroacetic acid. And stirred at 75 ° C. for 27 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure and the residue was purified by silica gel chromatography to obtain 0.5 g (20%) of a white to slightly yellow solid product having a melting point of 119 to 120 ° C. The resulting solid is Heterocycl
es, 43 , 127 (1996).
It almost coincided with 0 ° C.

1H-NMR (CDCl3) δ (ppm) = 2.68 (2H, m), 3.06
(2H, m), 3.91 (3H, s), 3.97 (3H, s), 6.90 (1H, s), 7.19 (1
H, s) IR (KBr) 1700 cm-1

Example 3 Production of 5,6-dimethoxy-1-indanone 3.0 g of 3-chloro-3 ′, 4′-dimethoxypropiophenone obtained in Example 1 was dissolved in 10 ml of polyphosphoric acid. Stirred at 60 ° C. for 3 hours. After cooling to room temperature, ice water was poured into the reaction solution, and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 1.0 g (40%) of a solid product. Melting point of this product, 1H
-NMR and IR data were as above.

Example 4 Production of 5,6-dimethoxy-1-indanone 20.0 g of 3-chloro-3 ′, 4′-dimethoxypropiophenone obtained in Example 2 was dissolved in 60 ml of concentrated sulfuric acid.
Stirred at 70 ° C. for 2-5 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure to obtain 11.8 g (70%) of a crude product. acetone/
Recrystallized from n-hexane to give a white to pale yellow solid product 1
0.5 g (63%) was obtained. The melting point, 1H-NMR and IR data were the same as above.

Example 5 Production of 5,6-dimethoxy-1-indanone (2) 200.0 g of 3-chloro-3 ′, 4′-dimethoxypropiophenone obtained in Example 2 was added to 520 ml of concentrated sulfuric acid. Dissolve and stir at 70 ° C. for 2-5 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure to obtain 126.1 g (75%) of a crude product.
Recrystallization from acetone / n-hexane gave 113.5 g (68%) of a white to pale yellow solid product. The melting point, 1H-NMR and IR data were the same as above.

Example 6 Production of 5,6-dimethoxy-1-indanone (2) 1.16 g of aluminum chloride was suspended in 5 ml of 1,2-dimethoxybenzene. 1.00 g of 3-chloropropionyl chloride was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. Thereafter, 15 ml of concentrated sulfuric acid was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium hydroxide solution and water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 0.6 g (40%) of a solid product. The melting point, 1H-NMR and IR data were the same as above.

[0027]

According to the present invention, an indanone derivative (2), which is an intermediate for the synthesis of a therapeutic drug for Alzheimer's disease having an acetylcholinesterase inhibitory action, can be produced in a short process simply and inexpensively.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Teruo Kosugi 48 Hagiwara, Toyama City, Toyama Fukuju Pharmaceutical Co., Ltd.

Claims (1)

[Claims] [Claim 1] The following formula: (Wherein, R 1 and R 2 may be the same or different and each represents an alkyl group such as a methyl group or an ethyl group,
Or together, they form -O- (CH2) 1-2-O- and the like. ) And a dialkoxybenzene represented by the following formula: (Wherein X and Y each independently represent a halogen atom.) The acylation reaction of a propionic halide represented by the formula (1) is carried out using aluminum chloride as a catalyst, and the following formula is obtained. (Wherein R1, R2 and Y have the same meanings as described above) by cyclization using an acid catalyst to give the following formula: A method for producing a dialkoxy-substituted indanone derivative represented by the formula: