JPS58126845A - Preparation of propanol derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a medicine, economically, at a low cost, in an industrial scale, by reacting a specific propanol derivative with optically active glutamic acid. CONSTITUTION:The objective compound is prepared by adding an optically active glutamic acid as an optical resolving agent to dl-1-(2,3,5-trimethyl-4- acetoxyphenoxy)-3-isopropylamino-2-propanol, adding a small amount of methanol to the mixture in benzene or toluene, stirring the mixture at 8-30 deg.C for 24-48hr to effect the reaction, and filtering, concentrating and drying the reaction product. EFFECT:Since the process can be carried out without fractional crystallization nor the dissociation of the resolving agent, the side reactions such as deacetylation reaction, etc. can be prevented.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides optically active l-(2,3,5-)dimethyl-
The present invention relates to a method for producing 4-acetoxyphenoxy)-3-isopropylamino-2-propanol (hereinafter referred to as (1)).

Tff-1-(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol is an important drug with β-blocking action, but it is generally used for various β-blocking activities. It is well known that one blocker shows pharmacological activity and six blockers are inactive. Similar pharmacological results were obtained for (1) above (Table 1).

However, it is technically extremely difficult to selectively produce only the two on an industrial scale, and most β-blockers are
It is commercially available in racemic form.

The purpose of the present invention is to provide a pure pharmaceutical product having pharmacologically active p-form only, and to provide an inexpensive and industrially advantageous manufacturing method thereof.

In general, the optical resolution of dl-amino alcohol is performed using dl-
A commonly used method is to carry out fractional crystallization by utilizing the difference in solubility in a solvent between diastereomeric salts obtained from amino alcohols and other optically active optical resolution agents to achieve the objective.

However, finding an optical resolution agent suitable for dl-amino alcohol is very difficult and requires a lot of trial and error.

Fact 9 The present inventors attempted to optically resolve (1) using optical resolution methods such as L-tartaric acid, L-aspartic acid, and L-malic acid, but the resolution effect in this case was limited in terms of yield, purity, etc. It was extremely inadequate and could not be used industrially.

Based on these facts, the present inventors conducted intensive studies on the optical resolution of (1) and found that optically active (+) could be obtained only when optically active glutamic acid was used as the optical resolving agent. The present invention has now been completed.

The method for obtaining optically active (1) in the present invention will be described below.

I will explain in detail.

(Acquisition method-1) dI-1-(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol per 1 mol about 0.5 to 1.0 mol, preferably 0
．． Add 6 moles of optically active glutamic acid, add a small amount of methanol in benzene or toluene, stir for 24 to 48 hours at a reaction temperature of 8 to 30°C, and filter after the reaction.
When liquid g is concentrated to dryness, optically active 1-(2゜3.5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol is obtained, which can be recrystallized from benzene or isopropanol. High purity optically active 1-(2,3,51-limethyl-4-acetoxyphenoxy)-3-isopropylamino-2-
You can get property tools.

The characteristics of the method shown here are: ■ It does not require a fractional crystallization operation. ■ Therefore, the operation to dissociate the resolving agent can be omitted, so there is no need to worry about side reactions such as deacetylation reactions, and it is suitable for industrial use. It is clear that this is an extremely superior method.

The following are different operating methods.

(Acquisition method-2) About 0.5 to 1.0 mol per dl-1-(2,3,5-)dimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol, preferably 0
．． Add 6 mol of optically active glutamic acid and stir in methanol at a reaction temperature of 5 to 50°C until a homogeneous system is obtained (
7-8 hours). After the reaction, it was concentrated to dryness under reduced pressure, and benzene was added to the dried product to obtain optically active 1-(2°3.5-)dimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol. Extract.

By washing the benzene extract with water, drying, and concentrating under reduced pressure.

Optically active 1-(2,3,5-)dimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol is obtained.

Furthermore, a highly purified product can be obtained by recrystallizing with benzene or inpropertool as shown in Obtaining Method-1.

The characteristics of the division method shown in acquisition method-2 are as follows: Acquisition method-1
Similar to the method shown in , ■ the fractional crystallization operation can be omitted;
This eliminates the need for a dissociation operation and eliminates the deacetylation reaction.

This can be said to be an extremely excellent optical separation method.

The thus obtained optically active, especially A'-1-(2,3
,5-trimethyl-4-acetoxyphenoxy)-3-
As shown in Table 1, there are 6 isopropylamino-2-propatools.

It has higher pharmacological activity compared to 8-propanol, and 2.5 times higher pharmacological activity than propranolol, making it very useful.

The present invention will be described below with reference to Examples.

Example 1 dl-1-(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol 5.0gL Glutamic acid 1.42g Benzene 40ml and methanol 1.0+al 100ml
1Pour into an Erlenmeyer flask, keep at 25°C, and start stirring.

After 24 hours, stirring was stopped, and the reaction solution 9 was filtered to remove insoluble matter.

The filtrate was washed with 51 portions of water and then dried over magnesium sulfate.

When concentrated under reduced pressure, [α] back -6,60 1-1-
(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatool is 2.
Obtained in an amount of 26 g (yield 90.2%).

32.3 ml of benzene was added to the obtained crystals, stirred at room temperature for 7 hours, filtered after completion, and concentrated the filtrate under reduced pressure to obtain 1-1- of [α]Ki-9,25 (c-5 ethanol).
(2,3,5-)dimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol (optical purity 97.2%ee) was obtained in an amount of 1.25g (yield 50%).
) was obtained. mp, 114-115°C Optical purity was determined by the following method.

(HPLC analysis conditions) Column: ff1-10-camphorsulfonic acid saturated Lic
hrosorb D 10L (10μm) 4ma+
φX 25cm Mobile phase 1-pentanol in dichloromethane 0.2% e-10-camphorsulfonic acid 0.00
22M content flow rate: 0.6 ml/in Detector = SP low 1232 nm Column temperature: 20-25°C #-1-(2,3,5- ) riftyl-4-acetoxyphenoxo)-3-isopropylamino-2-
The optical purity of propatool was determined.

In addition, as a result of fractionating only the β-isomer under the above analysis conditions, 1-1(2,3,5-)dimethyl-4-acetoquinphenoxy)-3-isopropylamino-2- with optical purity of 100% was found.
The [alpha] of the propatool was -9,52 (c=5 ethanol) mp, 114-115°C.

Example 2 #-1-(2,3,5-)tumethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol 5. OgD-Glutamine #&1.42g 40ml of benzene and 1.01ml of methanol are placed in a 100ml Erlenmeyer flask, kept at 25°C, and stirring is started.

After 24 hours, stirring was stopped, and the first reaction solution was filtered to remove insoluble matter.

The filtrate was washed with 51 portions of water and then dried over magnesium sulfate.

Vacuum concentrated water and [α] sauce +6.50 d-1-(
2,3,5-trimethyl-4-acetoxyphenoxy)
-3-isopropylamino-2-propatool is 2.2
5g (yield 9o%) was obtained.

32.2 ml of benzene was added to the obtained crystals, stirred at room temperature for 7 hours, filtered after completion, and the filtrate was concentrated under reduced pressure to give d- of (α]?+9.23 (c=5 ethanol)
1-(2,3,5-trimester-4.-acetoxyphenoxy)-3-isopropylamino-2-propanol (optical purity 97%ee) was obtained in 1.23 g (yield 49.2%). It was done. gap, 114-115℃
Optical purity was determined by the method shown below.

(HPLC analysis conditions) Column: d-10-camphorsulfonic acid saturated Lic
hrosorb D-1OL (+0,17 va)
4tgtm φ×25cs Mobile phase Ni dichloromethane Sole 0.2% d-10-camphorsulfone #0.0022M Containing flow rate: 0.6ml/mi
n Detector: 5PD-1232n+* Ram temperature: 20-25°C d-i (2,3,5-)dimethyl-4-acetoxyfluoride obtained by the reversed phase ion pair chromatography method shown above Noquin)-3-isopropylamino-2-
The optical purity of propatool was determined.

In addition, as a result of fractionating only the d-isomer under the above analysis conditions, we found that cl-1-(2,3,5-)dimethyl-4 with optical purity of 100%
-acetoquinphenoxy)-3-isopropylamino-
2-Proper tool's (α) crab is +9.52 (c=5
ethanol) +wp, +14-115°C.

Example 3 i/7-1- (2,3,5-trimethyl-4-acetoxyphenoquine) -3-isopropylamino-2-propatol 5.0 g L-glutamic acid 1.42 g
Pour 10 ml of I/L into a 100 ml Erlenmeyer flask, maintain at 30°C, and stir.

After 6 hours, the system becomes homogeneous, so stop stirring and add 50% of 1 reaction solution.
``Concentrate under reduced pressure below c.

Add 761benzene to the resulting residue and heat at 20-25°C.
After stirring for 2 hours, it was filtered and the filtrate was concentrated to dryness to give (α)%F-6,4 of ff-1-(2,3
,5-trimethyl-4-acetoxyphenoxy)-3-
2.0g of isopropylamino-2-propatool
(yield 80%).

i4 Add 28.6++1 benzene to the obtained crystals,
After stirring for a period of time, it is filtered and the filtrate is concentrated under reduced pressure.
[7 pieces -9,23 (C=5 ethanol) 7! -1
-(2,3,5-1-limethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol (optical purity 97%ee) was obtained in an amount of 1.1 g (yield 44%). mp, 114-115°C Optical purity was determined according to Example 1.

Example 4 dl-1-(2,3,5-)tumethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propatol 45 g L-glutamic acid 10.7 g Methanol 90 ml Pour 1 into 200+ ml Erlenmeyer flask for 1 reaction Stirring was started while keeping the temperature at 50°C. After stirring at 50°C for 1 hour, it was cooled to room temperature. After stirring for 2 hours, one reaction solution was concentrated under reduced pressure. Benzene 6801 was added to the obtained residue, and the mixture was stirred at 50°C for 1 hour. Stir at ℃ for 2 hours, filter after stirring,
The filtrate is concentrated to dryness.

44.8 ml of methanol and 3.2 g of L-glutamic acid were added to 22.4 g of the obtained crystals, stirred at 50° C. for 30 minutes, and then cooled to room temperature.

After stirring for 2 hours, the three reaction solutions were concentrated under reduced pressure, 700 ml of benzene was added to the resulting residue, stirred at 20-25°C for 2 hours, filtered after stirring, washed the filtrate with water, dried, and concentrated under reduced pressure. [α] C-7,84 (c-5 ethanol)
13.6 g (yield: 60.4%) of f-1-(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-=propatool was obtained.

The obtained crystals were added to 89.6 ml of isopropanol and stirred at 20°C for 7 hours.

After the stirring path r, the mixture was filtered to obtain 9.56 g of crystals. When this crystal is purified by recrystallization with isopropanol 481, mp,
1-1-(2,3,5-)dimethyl-4=acetoxyphenoxy)-3-isopropylamino-2- of 114-115℃ [α] tube-9,34 (c=5 ethanol)
8.1 g (yield 98.1%) of propatool (optical purity 98.1%) was obtained.

Optical purity was determined according to Example 1.

(Margin below)

Claims (1)

[Claims] (1) dl-1-(2,3,5-)dimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-
It is characterized by allowing optically active glutamic acid to act on propatool. Method for producing optically active i(2,3,5-trimethyl-4-acetoxyphenoxy)-3-isopropylamino-2-propanol (2) Optically active glutamic acid is L-(+)-glutamic acid, and optically active #-1-(2,3,5-trimethyl-4-acetoxyphenoxy)-3 -isopropylamino-2-
The manufacturing method according to claim 1, which is a proprietary tool.