JPH0776591A - Phosphonic acid diester derivative - Google Patents

Abstract

PURPOSE:To obtain the novel derivative, having excellent hypolipemic and hypoglycemic actions and useful as a therapeutic agent for hyperlipemia or cataract for treating and preventing the hyperlipemia or diabetes. CONSTITUTION:This phosphonic acid diester derivative is expressed by formula I (R<1>, R<2> and R<3> are each H, a lower alkyl, a lower alkoxy, a phenyl-lower alkoxy or a halogen; R<4> is H or hydroxyl; R<5> is a lower alkyl), e.g. diethyl 4-[3-(5-fluoro-2-hydroxyphenyl)1,3-dioxopropyl]benzylphosphonate. The derivative expressed by formula I is obtained by reacting equimolar amounts of a compound expressed by formula II with an acid halide expressed by formula III (X is halogen) in the presence of an excess amount of a deacidifying agent such as pyridine in an inert solvent such as dichloromethane at 0 deg.C to ambient temperature for 1-12 hr and rearranging the resultant ester derivative expressed by formula IV with 1-3 equiv. base (preferably an alkali metallic hydroxide) in a solvent such as pyridine or collidine at ambient temperature to 100 deg.C for about 0.5-4hr.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel phosphonic acid diester derivative.

[0002]

2. Description of the Related Art The phosphonic acid diester derivative of the present invention is a novel compound which has not been published in the literature.

[0003]

DISCLOSURE OF THE INVENTION The present invention aims to provide a compound useful as a pharmaceutical as described below.

[0004]

According to the present invention, there is provided a phosphonic acid diester derivative represented by the following general formula (1).

[0005]

[Chemical 2]

[Wherein R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group,
A phenyl lower alkoxy group or a halogen atom, R ⁴ represents a hydrogen atom or a hydroxyl group, and R ⁵ represents a lower alkyl group. Specific examples of the groups of the general formula (1) include the following groups.

That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy and 6-phenylhexyloxy groups.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The phosphonate diester derivative of the present invention represented by the above general formula (1) has an excellent lipid-lowering action and hypoglycemic action, and is highly effective as a therapeutic agent for hyperlipidemia and a therapeutic agent for cataracts. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as cholesterolemia, hypertriglyceridemia, hyperphospholipidemia, and hyperfree fatty acidemia, and for the treatment and prevention of diabetes.

Hereinafter, the phosphonic acid diester derivative represented by the above general formula (1) of the present invention can be produced by various methods. A specific example is shown in the following reaction process formula.

[0013]

[Chemical 3]

[Wherein R ¹ , R ² , R ³ and R ⁵ are the same as defined above. X represents a halogen atom. ] The reaction of the compound (2) shown in the above reaction process formula-1 with the acid halide (3) is carried out by using dichloromethane, chloroform,
1,2-dichloroethane, tetrahydrofuran (TH
It is carried out in the presence of a deoxidizing agent such as pyridine, collidine, lutidine, N, N-dimethylaniline and triethylamine in an inert solvent such as F). The acid halide (3) is preferably used in an approximately equimolar amount with respect to the compound (2), and the deoxidizing agent is generally used in an excessive amount. The reaction is performed under the temperature condition of 0 ° C. to room temperature for 1 to 12 hours.

Subsequently, the compound (1a) of the present invention can be obtained by subjecting the obtained ester form (4) to a rearrangement reaction. The rearrangement reaction is carried out by treating the ester form (4) with 1 to 3 equivalents of a base in a solvent such as pyridine, collidine or lutidine. As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferable, and the reaction temperature may be room temperature to 100 ° C. and the reaction time may be 0.5 to 4 hours.

[0016]

[Chemical 4]

[Wherein R ¹ , R ² , R ³ , R ⁵ and X are the same as defined above. R and R'are the same or different and each represents a lower alkyl group. ] The reaction of the acid halide (3) and the amine (5) shown in the above reaction process formula-2 is performed in an inert solvent in the presence of a deoxidizing agent. In the above, examples of the inert solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether, chain ethers such as diethyl ether, 1,2-dimethoxyethane, THF, and 1,4-dioxane. Examples thereof include cyclic ethers, ketones such as acetone, methyl ethyl ketone and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Preferred examples of the deoxidizing agent include tertiary amines such as triethylamine, pyridine and 4-dimethylaminopyridine. In the above reaction, the amine (5) is the acid halide (3)
On the other hand, it is preferable to use an equimolar amount to a small excess amount, and the deoxidizing agent is generally used in an equimolar amount to an excessive amount. The reaction is
Usually, it is completed in about 0.5 to 10 hours within a temperature range of 0 ° C. to the reflux temperature of the solvent.

The obtained amide (6) can be converted to the compound (1b) of the present invention by reacting it with an acetophenone derivative (7) in the presence of a base. Examples of the base include hydrocarbon lithium salts such as n-butyllithium and phenyllithium, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide, which are equivalent to the acetophenone derivative (7). It is preferable to use a molar amount to a small excess amount.
The reaction is carried out in an inert solvent such as THF or diethyl ether,
It is completed in about 5 to 15 hours under the temperature condition of −78 ° C. to room temperature.

The target compound in each of the above steps can be easily isolated and purified by a conventional separation means. Examples of such means include adsorption chromatography, preparative thin layer chromatography, recrystallization, solvent extraction and the like.

[0020]

EXAMPLES In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as Examples.

[0021]

Example 1 Preparation of diethyl 4- [3- (5-fluoro-2-hydroxyphenyl) -1,3-dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
Chloride (19.0 g) was dissolved in dry dichloromethane (65 ml), and 5'-fluoro-2 'was added to this solution with stirring under ice cooling.
-Hydroxyacetophenone 10 g pyridine (65 m
l) The solution was slowly added dropwise. After stirring at room temperature for 10 hours, 100 ml of water was added and the mixture was extracted with chloroform. Chloroform layer is 10% hydrochloric acid 100 ml, water 100
After sequentially washing with ml, it was dried with anhydrous sodium sulfate,
It was concentrated under reduced pressure. Next, the residue was dissolved in 65 ml of pyridine, 5.4 g of potassium hydroxide was added, and the mixture was stirred at 50 ° C. for 2 hours. After the reaction was completed, 200 ml of 10% hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with chloroform. The chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-n-hexane to give 15.7 g of yellow crystals of the desired compound.
Got Table 1 shows the structure and physical properties of the obtained compound.

[0022]

Examples 2 to 11 In the same manner as in Example 1, the compounds shown in Table 1 were synthesized. The structure and physical properties of the obtained compound are also shown in Table 1.

[0023]

Example 12 Diethyl 4- [3- (4-chlorophenyl) -1.3
Preparation of -dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
Chloride 74.4 g was dissolved in dry dichloromethane 250 ml, and N, O-dimethylhydroxylamine.hydrochloride 25 g of pyridine 500 ml was added to this solution under ice-cooling stirring.
The solution was slowly added dropwise. After stirring at room temperature for 2 hours, 200 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was mixed with 200 ml of saturated aqueous sodium hydrogen carbonate solution, 200 ml of 10% hydrochloric acid, and 200 ml of saturated saline solution.
The mixture was washed successively with ml, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 48 g of an oily crude product of diethyl 4-[(N-methoxy-N-methyl) carbamoyl] benzylphosphonate.

¹ H-NMR [δ: ppm (CDC
l ₃ )] 1.24 (t, J = 7.1, 6H), 3.19 (d, J
= 21.9, 2H), 3.36 (s, 3H), 3.54
(S, 3H), 4.0-4.1 (m, 4H), 7.35.
(Dd, J = 7.9, 2.1, 2H), 7.65 (d,
J = 7.9, 2H).

Next, 4'-chloroacetophenone 3.9
g was dissolved in 25 ml of anhydrous THF, and 19 ml of a 1.55 Mn-butyllithium hexane solution was slowly added dropwise to this solution under cooling with stirring at −78 ° C. 1 at -78 ° C
After stirring for an hour, subsequently 7.9 g of the compound obtained above
After slowly adding dropwise a solution of 20 ml of anhydrous THF at -78 ° C, the mixture was gradually returned to room temperature and stirred at room temperature for 12 hours. 50 ml of 10% hydrochloric acid was added to the reaction mixture,
It was extracted with chloroform. The chloroform layer was washed with 100 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 1).
Purified in 1), recrystallized from diethyl ether,
500 mg of colorless crystals of the target compound were obtained. The structure and physical properties of the obtained compound are also shown in Table 1.

[0026]

[Table 1]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Chieko Nawa 4-4 Ebisu-Maehigashi, Minamihama, Narahama-cho, Narato-cho, Tokushima Prefecture

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ , R ² and R ³ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group or a halogen atom, R ⁴ is a hydrogen atom or a hydroxyl group, and R ⁵ is Each is a lower alkyl group. ] The phosphonic acid diester derivative represented by these.