JPS6126902B2 - - Google Patents

Description

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

Formula () obtained by reacting a compound represented by formula () of the present invention [hereinafter abbreviated as compound ()] with, for example, an allyl halide in the presence of a condensing agent. 1-isopropylamino-2-hydroxy-3-(2-allyloxyphenoxy)propane and its acid addition salts [hereinafter abbreviated as compound ()] 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 precursor compound and a method for producing the same, which are useful for producing a compound having the above-mentioned valuable pharmacological properties or an analog thereof.

A pharmacologically valuable compound () can be easily produced by reacting the compound () provided by the method of the present invention with an allyl halide in the presence of a condensing agent such as a neutral alkali, if necessary in a solvent inert to the reaction. can be obtained. Suitable condensing agents in this case include caustic potash and caustic soda, and examples of solvents include methanol, ethanol, propanol, butanol, dioxane, dimethylformamide, and tetrahydrofuran. The reaction conditions for producing compound () are 30
The process can be carried out in a short time under mild conditions such as 100°C to 100°C, and compound (2) can be obtained in good yield.

The compound of the present invention (), for example, when R is a methyl group or a water atom, is prepared by reacting catechol mono 4-methylphenyl (or phenyl) sulfonate with epichlorohydrin in the presence of an alkali, for example in water, using catechol mono 4-methylphenyl (or phenyl) sulfonate as a starting material. -[2-
It can be easily produced by obtaining (4-methylphenyl (or phenyl)sulfonyloxy)-phenoxy]-1,2-epoxypropane [hereinafter abbreviated as compound ()] and then reacting this compound with isopropylamine.

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 () of the present invention and its precursor compound () are not described in literature, and the compound ()
For example, if R is a megatyl group, catechol and p
- It can be easily obtained by reacting with toluenesulfonyl chloride in an inert solvent in the presence of a deoxidizing agent at low temperature (-10° to 5°C). In this case, pyridine, triethylamine, etc. are suitable as the deoxidizing agent. Acetone, dioxane, tetradrofuran, etc. are used as the solvent. Compound () can be easily obtained by reacting Compound () with epichlorohydrin as a deoxidizing agent in the presence of, for example, a caustic alkali in water or an inert solvent at 0°C to room temperature. The compound () of the present invention is a compound
It can be easily obtained by reacting () with isopropylamine. In this case, the presence of a small amount of water has the effect of accelerating the reaction. The isopropylamine can be reacted with an excess of solvent or, if necessary, in an inert solvent such as methanol, ethanol, dioxane and tetrahydrofuran. The reaction proceeds at a temperature of 0°C to room temperature, but if necessary, it can be further accelerated by heating to about 40°C. In order to isolate the compound () of the present invention from the reaction mixture, excess isopropylamine, for example, is distilled off and recovered from the reaction completed solution, and a crude product is obtained as a residue, which is dissolved in, for example, benzene, and extracted with dilute hydrochloric acid. If necessary, the diluted hydrochloric acid extract is treated with decolorizing charcoal, then neutralized while cooling with diluted caustic soda solution, made alkaline, extracted the precipitated oil with benzene, dried with boron sulfur, and distilled off the benzene. Obtain purified products. Furthermore, if necessary, a highly purified product can be obtained by recrystallizing from n-hexane, for example. The compounds () of the present invention can be converted into salt addition salts by conventional methods, if necessary. For example, the hydrochloride salt can be isolated as flaky crystals from an aqueous solution. It can also be purified as a free base by neutralizing it with an alkali when cold. EXAMPLES The present invention will be specifically explained below by showing examples and reference examples for synthesis of starting compounds.

Example 1 2.5 ml of water, 25 ml of isopropylamine and 1,
2-Epoxy-3-[2-(4-methylphenylsulfonyloxy)-phenoxy]-propane 5
g (0.015 mol) and stirred at 15-20°C for 1 hour. Then, the mixture was stirred at room temperature for 6 hours and then at 40°C for 2 hours to complete the reaction.

Excess isopropylamine is distilled off under reduced pressure.
Crude 1-isopropylamino-2- as a residue
Hydroxy-3-[2-(4-methylphenylsulfonyloxy)-phenoxy)-phenoxy]
- Got propane. When left overnight, it crystallized. The melting point of this product was 65-75°C. yield
5.8g, yield 97.9%.

The crude product was dissolved in benzene, extracted with dilute hydrochloric acid,
0.2 g of decolorizing charcoal was added to the dilute hydrochloric acid extraction solution and filtered. The filtrate was cooled to 5 to 10°C, neutralized (alkaline) by adding dilute caustic soda solution, and the precipitated oil was extracted with benzene. After drying with borax, the benzene was distilled off to obtain a purified product. I got it. The melting point of this thing is 75~
It was 78℃. Furthermore, the melting point of the product recrystallized from n-hexane was 81-82°C.

Elemental analysis results C (%) H (%) N (%)
S (%) Analytical value 60.16 6.53 3.97 8.38 Calculated value 60.13 6.64 3.69 8.44 (as C ₁₉ H ₂₅ NO ₅ S) Infrared absorption spectrum (potassium bromide tablet method, cm ^-1 ) 2980, 2940, 2820, 1600, 1500, 1460, 1380,
1300, 1290, 1260, 1200, 1170, 1120, 1100,
1060, 880, 820, 780, 720, 660.

Example 2 3 ml water, 30 ml isopropylamine and 1,2
8.0 g (0.026 mol) of -epoxy-3-(2-phenylsulfonyloxyphenoxy)propane was mixed and dissolved by stirring at 15 to 20°C for 1 hour. Then, the mixture was stirred at room temperature for 3 hours and then at 40°C for 2 hours to complete the reaction. The reaction solution is treated in the same manner as described in Example 1 to obtain 1-isopropylamino-2-hydroxy-3-(2-phenylsulfonyloxyphenoxy)-propane.

Yield 9.0g, yield 94.7%. viscous liquid.

This was treated with dilute hydrochloric acid and an alkali in the same manner as described in Example 1, and further recrystallized from n-hexane, and the melting point was 91° to 92°.

Elemental analysis results C (%) H (%) N (%)
S (%) Analytical value 59.10 6.44 3.75 8.70 Calculated value 59.16 6.34 3.83 8.77 (as C ₁₈ H ₂₃ NO ₅ S) Infrared absorption spectrum (liquid film method, cm ^-1 ) 2980-2880, 1610, 1510, 1460, 1380, 1300,
1270, 1200, 1170, 1120, 1100, 1050, 940,
880, 820, 780-740, 710.690.

Example 3 Ethyl alcohol 50ml, 1,2-epoxy-3
25 g (0.078 mol) of -[2-methylphenylsulfonyloxy-phenoxy]-propane and 2 ml of water were stirred and dissolved. To this, 11.5 g (0.195 mol) of isopropylamine was added dropwise at 15° to 20°C, and the mixture was stirred at the same temperature for 2 hours and at 75° to 78°C for 5 hours. Ethyl alcohol and excess isopropylamine were then distilled off under reduced pressure, leaving a residue of crude 1-isopropylamino-2-hydroxy-
3-[2-(4-methylphenylsulfonyloxy)-phenoxy]propane was obtained. Dissolve this crude product in dilute hydrochloric acid consisting of 10 g of concentrated hydrochloric acid and 100 ml of water, extract and remove insoluble matter with benzene, decolorize the hydrochloric acid soluble portion with activated carbon, and then neutralize with dilute caustic soda when cool (alkaline). The precipitated oil was extracted with benzene, dried over sulfur salt, and then the benzene was distilled off to obtain 19.6 g of a purified product. Yield 69.5%. The melting point of this product was 75° to 81°C. Furthermore, the melting point of the product recrystallized from n-hexane was 81° to 82°C.

Reference Example 1 Mix 140 ml of water, 3.4 g (0.085 mol) of caustic soda, and 20 g (0.075 mol) of catechol mono-4-methylphenyl sulfonate and stir at 10 to 15°C to remove most of the catechol mono-4-methylphenyl. The sulfonate was dissolved. 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 10-15° C. for 7 hours and then at room temperature for 7 hours. Benzene was added to extract the oil, and the benzene extract was washed twice with 100 ml of water, separated, and dried over anhydrous salt water. The benzene was distilled off under reduced pressure, and the residue was crude 1,2-epoxy. 3-[2-
(4-Methylphenylsulfonyloxy)-phenoxy]-propane was obtained. Yield 22g, Yield 90.7
%. This was distilled under reduced pressure to obtain a purified product. boiling point'
230°~235°C/0.4mmHg abs・. When this was allowed to cool, it became crystals, which were recrystallized from n-hexane and had a melting point of 77° to 79°C.

Elemental analysis results C (%) H (%) S (%) Analytical value 59.32 4.90 9.86 Calculated value 59.98 5.03 10.00 (as C ₁₆ H ₁₆ O ₅ S) Infrared absorption spectrum (potassium bromide tablet method, cm ^-1 ) 3050 , 2920, 1600, 1500, 1460, 1370, 1290,
1265, 1200, 1190, 1170, 1110, 1100, 1060,
1030, 880, 820, 770, 720, 660.

Reference example 2 160 ml of water, 3.4 g (0.085 mol) of caustic soda and 18.8 g of catechol monophenylsulfonate
(0.076 mol) was mixed and stirred at 10-15°C to dissolve. Next, add 21g of epichlorohydrin to this.
(0.227 mol) was added dropwise at 10-15°C over 30 minutes. The mixture was continuously stirred at 10 to 15°C for 7 hours and then at room temperature for 7 hours to complete the reaction. Reference example 1 below
The reaction solution was treated in the same manner as described in , to obtain crude 1,2-epoxy-3-(2-phenylsulfonyloxyphenoxy)-propane. yield
22.2g, yield 95.2%. This product was distilled under reduced pressure to obtain a purified product. Boiling point 209-213℃/0.3mmHg abs.

Elemental analysis results C (%) H (%) S (%) Analytical 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 (liquid film method, 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.

Claims (1)

[Claims] 1 Formula () [In formula (), R represents a hydrogen atom or an alkyl group] An isopropylamine derivative represented by the following. 2 expression() [In the formula (), R represents a hydrogen atom or an alkyl group] A formula characterized by reacting an epoxypropane derivative represented by the following with isopropylamine:
() A method for producing an isopropylamine derivative represented by the formula (in parentheses, R has the same meaning as above).