JPS622595B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the formula () The present invention relates to a novel catechol derivative represented by the formula (in which R represents a hydrogen atom or an alkyl group) and a method for producing the same.

Formula () obtained by reacting the compound represented by formula () of the present invention [hereinafter referred to as compound ()] and isopropylamine Compound represented by [formula (), R has the same meaning as above] [hereinafter referred to as compound ()]
For example, the formula () obtained by reacting allyl halide in the presence of a condensing agent 1-isopropylamino-2-hydroxy-3-(2-allyloxyphenoxy)propane [hereinafter referred to as compound ()] and its acid addition salts are known to have beta-adrenergic nerve blocking effects. It is a remarkable compound as a therapeutic agent for angina pectoris, arrhythmia, etc. That is, an object of the present invention is to provide a novel intermediate compound for producing a compound () having the above-mentioned valuable pharmacological properties or an analogous compound thereof, and a method for producing the same.

Compound () can be easily obtained by reacting the novel compound () produced by the method of the present invention with isopropylamine in an inert solvent or without a solvent. Examples of inert solvents in this case include methanol, ethanol,
Propanol, butanol, dioxane, acetone, dimethylformamide, tetrahydrofuran, etc. are used. Further, since the presence of water promotes this reaction, the above-mentioned solvent can also be used in an appropriate water-containing state. The compound () thus obtained is also a new compound that has not been described in any literature.

Next, compound () can be easily obtained by reacting compound () with allyl halide in the presence of a condensing agent in an inert solvent. Examples of inert solvents in this case include n-butanol, ethyl alcohol, dioxane, dimethylformamide, and tetrahydrofuran. Caustic potash or caustic soda is used as the condensing agent. The reaction proceeds in a short time under mild conditions such as 30° to 100°C, and the compound () having the above-mentioned valuable pharmacological properties can be obtained in good yield.

In the case of the compound of the present invention (), for example, when R is a methyl group or a hydrogen atom, catechol mono(4-methylphenyl) (or phenyl) sulfonate is used as a starting material, and this is reacted with epichlorohydrin in the presence of a deoxidizing agent. can be easily obtained by Suitable deoxidizing agents are the customary alkalis, such as caustic soda, caustic potash or potassium carbonate.
Inert solvents used in this reaction include water, dioxane, tetrahydrofuran, dimethylformamide and acetone. In addition, in the case of a solvent other than the above-mentioned water, the reaction can be carried out more conveniently by using a mixture of an appropriate amount of water. The reaction proceeds easily at a temperature of 5° to 30°C, and if necessary, 30° to 50°C. In order to isolate the compound of the present invention () from the reaction mixture, if necessary, the reaction solution is diluted with water, the precipitated oil is extracted with benzene, for example, and thoroughly washed with water, and the benzene layer is extracted with anhydrous sulfur salt. After drying, benzene is distilled off to obtain a residue. This product can be used directly in the next reaction or, if desired, purified by recrystallization from a suitable solvent such as n-hexane or by distillation under reduced pressure. In the formula (), when R is a methyl group, that is, 1,2-epoxy-
3-[2-(4-Methylphenylsulfonyloxy)-phenoxy]-propane is obtained as crystals and can be recrystallized from n-hexane. In the formula (), when R is a hydrogen atom, that is, 1,2-epoxy-3-[2-(phenylsulfonyloxy)-
Phenoxy]-propane is obtained as a liquid at room temperature.

The synthetic route for the compound () of the present invention is shown in the reaction formula below.

(In the above reaction formula, R represents a hydrogen atom or an alkyl group, and X represents a halogen atom).

In the above reaction formula, the compound () which is the starting material of the present invention is, for example, catechol and 4-methylphenylsulfonyl chloride when R is a methyl group, or catechol and phenylsulfonyl chloride when R is a hydrogen atom. can be easily obtained by reacting them in an inert solvent at a low temperature (-10 to 10°C) in the presence of an acid absorbing agent. In this case, pyridine, triethylamine, etc. are suitable as the deoxidizing agent. Acetone, dioxane, tetrahydrofuran, etc. are used as the solvent. It is convenient to remove some by-product disulfonate by performing purification with dilute alkali and dilute acid before use (see Reference Examples below).

In the conventionally known production method of the above-mentioned pharmacologically valuable compound (for example, British Patent No. 1077603), allyl halide is added to catechol in the presence of a deoxidizing agent such as potassium carbonate, and an inert compound such as acetone is added to catechol. The starting material is catechol monoallyl ether, which is obtained by reacting in a suitable solvent.
In this case, catechol diallyl ether is produced as a by-product. And it is extremely difficult to recover this by-produced catechol diallyl ether as a monoether using normal methods. In the method of the present invention, a certain amount of catechol-di-4-methylphenylsulfonate (or catechol-di-phenylsulfonate) is produced as a by-product depending on the reaction conditions during the production of compound (), but this disulfonate For example, catechol-mono-4-methylphenylsulfonate (or catechol-mono-phenylsulfonate) can be produced by partial hydrolysis by heating (35° to 50°C) in the presence of an alkali such as caustic alkali, alkali carbonate, or calcium hydroxide. Enylsulfonate) [Compound ()] has the advantage of being easily recovered in good yields (see Reference Examples below).

Examples of the present invention and reference examples for synthesizing starting compounds will be described below.

Example 1 70 ml of tetrahydrofuran, 90 ml of water, and 4.8 g (0.120 mol) of caustic soda were mixed and stirred to dissolve. Add 28.9 g (0.109 mol) of catechol-mono-4-methylphenyl sulfonate to this.
Stir at 10° to 15°C to dissolve. Then, 20g (0.216 mol) of epichlorohydrin was added at 5° to 10°C.
It was added dropwise over 30 minutes. The mixture was then stirred at 5° to 10°C for 1 hour, then at 20 to 25°C for 6 hours, and left at room temperature overnight to complete the reaction.

200 ml of water was added to the reaction solution, and the precipitated oil was extracted with 80 ml of benzene. The benzene extract was washed three times with 120 ml of water, and the benzene solution was dried over anhydrous copper salt. The benzene was distilled off under reduced pressure, and the residue was 1,2-epoxy-3-[2-(4-methylphenate). Enylsulfonyloxy)-phenoxy]-propane was obtained. Yield: 33 g, yield 94.2% (based on catechol-mono-4-methylphenyl sulfonate). When left overnight, it crystallized. The melting point of this crude product was 70° to 75°C. The melting point of the product recrystallized from n-hexane was 77° to 79°C.

Elemental analysis results C (%) H (%) S (%) Analytical value 59.32 4.09 9.86 Calculated value 59.98 5.03 10.00 (as C ₁₆ H ₁₆ O ₅ S).

Infrared absorption spectrum measurement results, (KBr tablet method, absorption peak: cm ^-1 ) 3050, 2920, 1610, 1500, 1460, 1370, 1290,
1260, 1200, 1190, 1170, 1110, 1100, 1050,
1030, 880, 820, 770, 720, 660.

Example 2 60 ml of dioxane, 50 ml of water and 2.5 ml of caustic soda
g (0.062 mol) was dissolved by stirring. In this, 15g of catechol-mono-phenyl sulfonate
(0.060 mol) dissolved in 10 ml of dioxane.
The mixture was added and stirred at 10° to 15°C for 10 minutes. Next, 11 g (0.119 mol) of epichlorohydrin was added to 5°~
The dropwise addition took 30 minutes at 10°C. Another 5°~10
The mixture was stirred at 15°C for 1 hour, then at 15°C to 20°C for 8 hours, and left at room temperature overnight to complete the reaction. 150 ml of water was added to the reaction solution, and the precipitated oil was extracted by adding 80 ml of benzene. Wash the benzene extraction part three times with 100 ml of water,
After drying the benzene solution with anhydrous glass salt, the benzene was distilled off under reduced pressure, and the residue was 1,2-epoxy-3-[2-(phenylsulfonyloxy)-
Phenoxy]-propane was obtained. Yield 16.3 g, yield 88.7% (based on catechol-mono-phenyl sulfonate). This material was a viscous liquid at room temperature.

Elemental analysis results C (%) H (%) S (%) Analysis value 58.73 4.53 10.42 Calculated value 58.81 4.60 10.46 (as C ₁₅ H ₁₄ O ₅ S) Infrared absorption spectrum measurement results (liquid film method, absorption peak: cm ^{- 1} ) 3060, 3000, 2930, 2880, 1610, 1590, 1500,
1460, 1380, 1290, 1260, 1200, 1165, 1110,
1100, 1030, 920, 880, 820, 765, 740, 700,
680.

Example 3 Mix 140 ml of water, 3.4 g (0.085 mol) of caustic soda, and 20 g (0.075 mol) of catechol-mono-4-methylphenylsulfonate, and heat at 10° to 15°C.
Stir to dissolve. Next, 21 g (0.227 mol) of epichlorohydrin was added to this at 10° to 15°C for 30 minutes.
It took several minutes to drip. The reaction was completed by further stirring at 10° to 15°C for 7 hours and then at room temperature (23° to 25°C) for 7 hours. 70 ml of benzene was added to extract the oil, and the benzene extracted portion was washed twice with 100 ml of water to separate the liquid. After drying with anhydrous salt water, the benzene was distilled off under reduced pressure and the crude 1,2- Epoxy-3-[2-(4-methylphenylsulfonyloxy)-phenoxy]-propane was obtained.

Yield 22g, yield 90.7% (based on catechol mono-
methyl phenyl sulfonate). This was distilled under reduced pressure to obtain a purified product. Boiling point 230°~235°C/0.4mmHg
obs. When the crystals obtained in Example 1 were seeded in this and left to stand, it eventually became crystals. When recrystallized from n-hexane, the melting point was 77° to 79°C.

Reference example 1 Acetone 120ml, catechol 15g (0.136 mol)
and 15 g (0.148 mol) of triethylamine
Mix and dissolve at ~-10°C. To this was added 26.0 g (0.136 mol) of 4-methylphenylsulfonyl chloride (p-toluenesulfonyl chloride) over a period of about 1 hour while stirring at 0° to -10°C. The mixture was further stirred at 0° to -10°C for 5 hours. The reaction solution was filtered, and the crystals were washed with cold acetone. The enyl sulfonate was isolated as an insoluble substance. Yield: 7 g, melting point: 163 DEG -165 DEG C. (See Reference Example 2 below).

The acetone solution and the acetone washing solution were combined and the acetone was distilled off under reduced pressure, and the residue was discharged into 200 ml of water and extracted with 100 ml of benzene. The benzene extracted portion was washed three times with 70 ml of water, dried over anhydrous salt water, and then benzene was distilled off to obtain catechol-mono-4-methylphenylsulfonate as a residue. Yield 28.9g, yield 80.3% (based on catechol). The melting point of this crude product was 75° to 84°C. Although it can be used as it is as the raw material described in Example 1 or Example 3, it is preferable to use it after purifying it as follows. That is, to a solution of 300 ml of water, 4.8 g of caustic soda, and 0.2 g of sodium sulfite, add 28.9 g of the above crude catechol-mono-4-methylphenylsulfonate, stir at 10° to 15°C for about 30 minutes, and dissolve a small amount. The undissolved catechol-di-4-methylphenyl sulfonate was removed by filtration.
The solution was gradually dropped into dilute hydrochloric acid consisting of 300 ml of water and 12 g of concentrated hydrochloric acid while stirring at 10° to 15°C, and the precipitated crystals were filtered, washed with water, and dried to obtain purified catechol-mono-4-methylphenylsulfonate. Ta. Yield 26.3g, yield 91.0% (based on crude product). melting point
91.5°～93℃.

Reference Example 2 Catechol-di-4 by-produced in Reference Example 1
Partial hydrolysis of -methyl phenyl sulfonate was carried out as follows to recover catechol-mono-4-methyl phenyl sulfonate.

10 g (0.023 mol) of catechol-di-4-methylphenyl sulfonate in 50 ml of methyl alcohol.
To this solution, add a solution of 2.7 g (0.048 mol) of caustic potassium dissolved in 15 ml of methanol at 30° to 35°C.
The dropwise addition took 20 minutes. Stir at 40-45℃ for about 1 hour. Then, drain into 370 ml of water, filter the insoluble part, add 4 to 5 drops of sodium hyposulfite solution, and neutralize (weakly) by adding dilute hydrochloric acid prepared by dissolving 6 g of concentrated hydrochloric acid in 20 ml of water at 10° to 15°C. acidic). The crystals precipitated by cooling and standing were filtered, washed with water, and dried to obtain catechol-mono-4-methylphenyl sulfonate. Yield: 4.6 g, yield: 73.0% (based on catechol-di-4-methylphenyl sulfonate). Melting point: 91° to 93°C.

Reference example 3 Acetone 100ml, catechol 25g (0.227mol)
and 25 g (0.247 mol) of triethylamine
Stir at ~5°C. Add 40 g (0.227 mol) of phenylsulfonyl chloride to this at -5° to 5°C.
It took one hour to drip the solution. Further -5°~5°C
I stirred it for 5 hours. This reaction was carried out in a reaction vessel purged with nitrogen. Crystals precipitated after passing through the reaction solution (mainly triethylamine hydrochloride)
and washed with acetone. The liquid and the acetone washing solution were combined, and the acetone was distilled off under reduced pressure. The residue was discharged into 300 ml of water and stirred well. The oil was extracted with 100 ml of benzene, and the benzene extracted part was washed three times with 100 ml of water. . After drying the benzene solution with anhydrous sulfur salt, the benzene was distilled off under reduced pressure.
Crude catechol-mono-phenyl sulfonate was obtained as a residue. Yield: 42g. Yield 73.9% (based on catechol).

25 g of this crude product was dissolved in an equimolar amount of dilute caustic soda while cold, insoluble matter (mainly catechol-di-phenylsulfonate) was removed by filtration, and the alkali-soluble portion was discharged in cold dilute hydrochloric acid to precipitate. The resulting oil was extracted with benzene, and the benzene extracted portion was washed with water, dried over anhydrous sulfur salt, and then benzene was thoroughly distilled off under reduced pressure. Purified catechol-mono-phenyl sulfonate was obtained as a residue. Yield 17g Melting point 62°~65
It was warm at ℃.

Claims (1)

[Claims] 1 Formula () A catechol derivative represented by the formula (in the formula (), R represents a hydrogen atom or an alkyl group). 2 formula () Formula () characterized by reacting a catechol derivative represented by [Formula (), in which R represents a hydrogen atom or an alkyl group] with epichlorohydrin in an inert solvent in the presence of an acid absorbing agent. A method for producing a catechol derivative represented by the formula (in which R has the same meaning as above).