DK154072B - Process for preparing 1-isopropylamino-3-(4-(2- methoxyethyl)phenoxy)-2-propanol or acid addition salts thereof - Google Patents

Description

in

DK 154072 B

The invention relates to a novel process for the preparation of 1-isopropylamino-3- (4 - * (2-methoxyethyl) phenoxy) -2-propanol or metoprolol of formula I

OH CH3 '

CH₂O - CH₂ - CH7 .J / nY. 0 - CH2 - CH -CH2 - NH - CH1

2 2 \ 2/2 2 ch3 or addition salts thereof.

The compound is a therapeutically valuable so-called β-receptor blocking agent. Most β-receptor blocking agents have the disadvantage that, in addition to the β-receptors of the heart, they also block the β-receptors in blood vessels and lungs.

The compound in question, on the other hand, is heart-specific and is therefore an important drug in cardiac therapy.

The preparation of the subject compound is known, for example, from Swedish Patent Specification No. 354,851, wherein 10 discloses 12 analogous methods for the preparation thereof.

These methods have in common that they are all referred to a method for synthesizing the isopropylaminoside chain.

The process according to the invention is peculiar.

15, the characterizing part of claim 1. A compound of formula II

X - CH2 - CH2 ~ \ 0 / ° Na II

wherein X represents a reactive ester residue may be reacted with epichlorohydrin of formula III

/ ° \

Cl - CH2 - CH - CH2 τιι

for a compound of formula IV

X 'CH2' - CH2 - CH · iv

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2

which is then reacted according to the invention with an acid addition salt of isopropylamine to a compound of formula V

OH CH3

X - CH2 - cH2YQVo - CH2 - CH - CH2 - NHCH V

and this compound is finally reacted with alkali metal methoxide or with methanol in the presence of an acidic catalyst to a final product of formula I.

The process can be described by the following formula: 0 \ C1-CH2 -CH-CHO

Δ 1 O

X - CH2 - CH2 - ^^ - ONa -> X ~ CH2-CH2 - ^^ - O-CH2-CH-CH2

II IV

OH. & Θ ch3 ^ ° H T3 NaOCH3 -> X-CH2-CH2 - ^ (JV O-CH2-CH-CH2-NH-CH --->

* or H + and CH-DH

ch3 3

V

OH CH3

CH30-CH2-CH2-O) V O-CH2-CH-CH2-NH-CH

CH3

The reactive ester residue X may be an alkyl or arylsulfonate group, advantageously a tosyl group, the compound IV being 1,2-epoxy-3- (4-tosyloxyethylphenoxy) propane which is a novel organic compound having

DK 154072B

0 3

formula VII

CH3 +) D-CH2-CH2 ^ D) D-CH2-CH-CH2 VII

or X is a halogen atom, advantageously a chlorine atom, the compound V! is 1-isopropylamino-3- (4- (2-chloroethyl) phenoxy) -2-propanol which is a novel organic compound of formula VI

OH CH3

Cl-CH2 ~ CH2 - ^^ n-O-CH2-CH-CH2-NH-CH VI

CH3

The isopropylamine acid addition salt may e.g. may be isopropylamino hydrochloride of the formula CH 2 O 3 X 00 CHNI-LC 1 or it may be, for example, isopropylamine p-toluenesulfonic acid salt of the formula CH

For example, the alkali metal methoxides may be potassium or sodium methoxide, especially sodium methoxide. When reacting methanol with compounds of formula V, e.g. dry HCl gas or p-toluenesulfonic acid suitable acid catalysts.

The process of the invention may be particularly peculiar in that the last part of the synthesis chain is attributed to the methoxyethyl end of the molecule, i.e. the reaction between the compound V and sodium methoxide or between the process.

DK 154072 B

4 the binding ice V and methanol in the presence of an acidic catalyst. Further, particularly peculiar to the process of the invention, it may be that Compound V is specifically prepared from Compound IV by reaction of the latter compound under neutral conditions with an isopropyl-amino acid addition salt. Furthermore, it may be peculiar to the process that explicitly using the synthesis reactions described above, the raw materials for the synthesis of the final product are cheap and readily available, and therefore the entire synthesis is economical.

The reaction of the acid addition salt of the isopropylamine with a compound of formula IV is a specific invention in which the acid addition salt of the isopropylamine reacts with a compound of formula IV is a specific reaction with the epoxide end of the molecule. Of course, the reaction is specific to prevent the isopropylamine group from reacting with the reactive ester residue. This specificity is surprisingly obtained in that it appears that the epoxide group of the molecule is properly opened or altered under neutral conditions with acidic addition salts of isopropylamine. The reaction can be carried out by combining the starting materials and mixing them in a suitable solvent until the reaction is complete. For acceleration, it is advantageous to boil the reaction mixture. Suitable solvents are, for example, alcohols such as ethanol and isopropanol.

The last reaction step, in which case, for example, sodium methoxide is reacted with the compound V, is advantageously carried out by boiling in a suitable solvent such as methanol, dimethylformamide, dimethylsulfoxide or a mixture thereof.

The reaction is carried out with acid catalysis, e.g. corresponding tosylate derivatives with methanol in a suitable solvent such as methanol at the boiling point of the mixture in the presence of an acidic catalyst. Suitable acid catalysts are e.g. hydrochloric or p-toluenesulfonic acid.

The first step of the reaction scheme is carried out by

DK 154072 B

5 ventional methods, e.g. from the corresponding sodium phenolate derivative and epichlorohydrin in alcohol, e.g. ethanol, at 20-30 ° C with stirring.

By the process of the invention, it is not necessary to isolate and purify the intermediates to obtain a pure final product, and thus the process is simple, even on an industrial scale.

The resulting amine I can be readily transferred to acidic addition salts by reaction thereof with inorganic or organic acids.

The following examples illustrate the procedure.

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Example 1.

a) 1,2-Epoxy-3- (4-tosyloxyethylphenoxy) propane (preproduct).

Dissolve 2.6 g of sodium in 200 ml of absolute ethanol.

26 g of p-toluenesulfonic acid 2- (4-hydroxyphenyl) ethyl ester 5 and 10 g of epichlorohydrin are added and stirred for 25 hours at ca. 25 ° C. The mixture is poured into water and the product is extracted with methylene chloride which is dried over sodium sulfate. The solvent is distilled off in vacuo to give 1,2-epoxy-3- (4-tosyloxyethylphenoxy) propane as an oil.

b) 1-Isopropylamino-3- (4-tosyloxyethylphenoxy) -2-propanol hydrochloride.

The oil from the previous step is dissolved in ethanol and 11 g of isopropylamine hydrochloride is added and boiled for 10 hours.

The solvent is evaporated to give 1-isopropylamino-3- (4-tosyloxyethylphenoxy) -2-propanol hydrochloride.

c) 1-Isopropylamino-3- (4- (2-methoxyethyl) phenoxy) -2-propanol.

The residue from the previous step is dissolved in lithanol and 50 ml of 30 M sodium methoxide in methanol and 30 ml of dimethylformamide are added. The mixture is boiled for 20 hours and the solvent is evaporated. The residue is collected in water and the product is extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness. The evaporation residue consists of metoprolol base, which after recrystallization of, for example, heptane has sap. 45 ° C.

Of this, tartrate is made in tartaric acid acetone. The mp of the metoprolol tar funnel is 120 ° C.

Example 2.

Proceed as in Example I, but with the difference that an equivalent amount of 4- (2-chloroethyl) phenol is used instead of 4-hydroxyphenylethanol tosylate.

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Example 5

1-isopropylamino-5- (4- (2-methoxyethyl) phenoxyl, y) -2β-propanol.

1-isopropylamino-3- (4-tosyloxyethylphenoxy) -2-propanol hydrochloride; prepared according to Example 1, point b), dissolved in methanol. The resulting solution is acidified with hydrogen chloride gas and boiled for 20 hours, the methanol is evaporated and the residue is dissolved in water, the Yand solution is washed with toluene and made alkaline with sodium hydroxide. The product is extracted with chloroform, dried with sodium sulfate and the chloroform evaporated. The first is metoprolol base which is converted to tartrate in tartaric acid acetone. One resulting tartrate has m.p.

120 ° C.

Claims (5)

A process for the preparation of 1-isopropylamino-3- (4- (2-methoxyethyl) phenoxy) -2-propanol of formula I GH CH3 ch3d-ch2-ch2 - ^^ - o -ch2-ch-ch2 -nh-ch in ch 3 or pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula. IV D X-CH 2 -CH 2 O-CH 2 -CH-CH 2 IV wherein X is a reactive ester residue such as an alkyl or arylsulfonate group or a halogen atom is reacted with an isopropylaminic acid addition salt to a compound of formula V □ H CH 3 X-CH 2 -CH 2 Wherein X has the same meaning as above, after which this compound is reacted with an alkali metal methoxide or with methanol in the presence of an acidic catalyst for a compound of formula I. The process according to claim 1, characterized in that the isopropylamic acid addition salt is a hydrochloride, the formula of the compound being CH 2 - 3- (CHNhLCl CH 3) or a p-toluenesulfonic acid salt, the compound of the compound being DK 154072 B ch 3 © O li / ^ \ ........................... "/ CHNH3 ° -f, - <Q) -CH3 ch3. 0 * * V Process according to claim 1, characterized in that the isopropylamine acid addition salt is reacted under neutral conditions with a compound of formula IT to a compound of formula V. Process according to claim 1, characterized in that a compound of formula Y is reacted with an alkali methoxide, preferably sodium methoxide, to a compound of formula I Process according to claim 1, characterized in that a compound of formula V is reacted with methanol in the presence of an acidic catalyst.