FI58909C - REFERENCE FOR THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVATING OF 1-ISOPROPYLAMINO-3- (4- (2-METHOXYETHYL) -PHENOXY) -2-PROPANOL OCH DESS SYRAADDITIONSSALTER - Google Patents

Description

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Patent Meddelat ^ ^ (S1) Kv.ik.3 / »nt.a.3 C 07 C 93/06 FINLAND —FINLAND (21) NM * ttltalwmu« -P> t * n «* etaln * 78361 * 6 (22 ) H ^ wntapUvt —Anaeknkipdat 29-11.78 (23) Start cloud — Glkighttsdag 29-11-78 (41) Interpreters | ulkiMkil - Bllvlt offuntllg 30-05-80 rurnM. I. r »kl.MrlhftllltU,, 44) NBitMki ^ —βη i- hmilJwtalMii pvm. -

Patent- and registerstyrelMn 'An »ök * n uttagd och utUkrfftun pubiicurad 30-01. Ö1 (32) (33) (31) Requested ecu month * —Buglrd priorltut (71) Farmos-Yhtyma Oy, PO Box 1 * 25, 20101 Turku 10, Finland-Finland (FI) (72) Soini Kanerva Huhta, Kempele, Arto Johannes Karjalainen, Oulu, Suomi-Finland (FI) (5l *) Method for the preparation of therapeutically active 1-isopropylamino-3- [1 * - (2-methoxyethyl) -phenoxy] -2-propanol and its acid addition salts - Förfarande för framställning av den The present invention relates to a novel process for the preparation of 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy "and the following invention: 1 - Isopropylamino-3-Z1- (2-methoxyethyl) -phenoxy-2-propanol and acid syrup ] -2-propanol or metoprolol of the formula / -?? F f3

CH30 - CH2 - CH2- (0/0 “OH2 - CH - CH2 - NH - CH I

'-' CH3 and its acid addition salts »

Metoprolol is therapeutically valuable in the so-called 0-receptor blocker. The disadvantage of most β-receptors is that they block not only cardiac β-receptors but also vascular and lung 0-receptors. Metoprolol, on the other hand, is a heart-specific and thus important drug in the treatment of heart disease.

-2- 58909

The preparation of metoprolol is known, for example, from Swedish Patent No. 354,851, which describes 12 analogous methods for its preparation.

What these methods have in common is that they all address the functions involved in synthesizing the isopropylamino side chain.

The process of the invention is characterized in that the compound of formula

X - ch2 - ch2 ^ 2> o - CH2 - cfi ^ - CH2 IV

wherein X is a reactive ester residue such as an alkyl or aryl sulfonate group or a halogen tower, is reacted with an acid addition salt of isopropylamine under neutral conditions to give a compound of formula

X - CH2 - CH2_ / Q V-0 - CH2 - CH -CH2 - NH -ch V

'-' ch3 wherein X is as defined above and which compound is then reacted with methanol in the presence of an alkali metal methoxide or acid catalyst to give a compound of formula I.

58909

The method of the reaction formulas is as follows: _ / 0 / / 7T \ ci-ch2 ch-ch2 / CT \ / ° \ X-CH2-CH2 - ^ (^ J VoNa ΠΙ_ ^ X-CH2-CH2 CH 2

II IV

ch3 © O nch- nh3y CH3 i — v OH CH3 NaOCH3 -> X-CH2-CHj / Q Vo-ch2-ch-ch2-nh-ch ---------

'-' CH3 or H + and CH3OH

V

/ —— V OH CH3

CH30-CH2-CH2 / Q Vo-CH2-CH-CH2-NH-CH

ch3 wherein Y is, for example, a halogen or tosyloxy group.

The reactive ester residue X may be an alkyl or aryl sulfonate group, preferably a tosylate group, wherein the compound IV is 1,2-epoxy-3- (4-tosyloxyethylphenoxy) propane, which is a novel organic compound having the formula

ΛϋτΛϋ 77ä \ A

CH2 / (^) V-S- ° -cH2-cH2 - ^ (^) \ -0-0Η2-0Η-0η2 VII

or it may be a halogen atom, preferably a chlorine atom, wherein the compound V is 1-isopropylamino-3- [4- (2-chloroethyl) -phenoxy] -2-propanol, which is a novel organic compound having the formula CH3

ci-ch2-ch2- / Q Vo-CH2-CH-CH2-NH-CH VI

'- * ch3

The acid addition salt of isopropylamine may be, for example, isopropylamine hydrochloride of the formula

CH3 © O

xchnh3ci αζ -4- 58909 or it may be, for example, a salt of isopropylamine and p-toluenesulphonic acid having the formula “3 Θ © A / - \

Nchnh3 ch3 o '- *

The alkali metal methoxide may be, for example, potassium and sodium methoxide, preferably sodium methoxide. When methanol reacts with a compound of formula V, suitable acid catalysts include, for example, dry HCl gas or p-toluenesulfonic acid.

A very characteristic feature of the process according to the invention is that the last function of the synthetic chain takes place at the methoxyethyl end of the backbone molecule, i.e. the reaction between compound V and sodium methoxide in the presence of an acid catalyst. A very characteristic feature of the process according to the invention is that compound V is prepared specifically from compound IV by reacting the latter compound with the acid addition salt of isopropylamine under neutral conditions. It is a further feature of the invention that, precisely with the synthetic reactions described above, the starting materials for the synthesis of metoprolol are inexpensive and readily available, and thus the whole synthetic process is economical.

The first reaction step of the process according to the invention, in which the acid addition salt of isopropylamine reacts with a compound of formula IV, is a specific reaction with the epoxide end of the molecule. Specificity is, of course, necessary because the isopropylamine group does not react with the reactive ester residue. This specificity was surprisingly achieved when the epoxy group of the molecule was found to open properly under already neutral conditions with the acid addition salts of isopropylamine. The reaction can be carried out by combining the starting materials and stirring in a suitable solvent until the reaction is complete.

To speed up the reaction, it is preferable to boil the reaction mixture. Suitable solvents are, for example, alcohols, such as ethanol or isopropanol.

The second step of the reaction, in which e.g. sodium methoxide is reacted with compound V, is preferably carried out by boiling in a suitable solvent such as methanol, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

-5- 58909

When the reaction is carried out acid-catalytically, for example, the corresponding tosylate derivative is reacted with methanol in a suitable solvent, such as methanol, at the boiling point of the reaction mixture in the presence of an acid catalyst. Suitable acid catalysts are, for example, hydrochloric acid or p-toluenesulfonic acid.

The starting material of the first step of the process according to the invention (formula IV) is obtained by conventional methods, for example from the corresponding sodium phenolate derivative and epichlorohydrin in an alcohol, e.g. ethanol, with stirring at 20-30 ° C.

In the process according to the invention, the intermediates need to be isolated and not purified in order to obtain a pure end product, and thus the process is also simple on an industrial scale.

The amine I formed can be easily converted into an acid addition salt by reacting it with inorganic or organic acids.

The invention is further illustrated by the following examples:

Example 1 a) 1,2-Epoxy-3- (4-tosyloxyethylphenoxy) -propane 2.6 g of sodium are dissolved in 200 ml of absolute ethanol. 26 g of p-toluenesulfonic acid 2- (4-hydroxyphenyl) ethyl ester and 10 g of epi-chlorohydrin are added, and the mixture is stirred for 25 hours at about 25 ° C. The mixture is poured into water and the product is extracted into methylene chloride, which is dried over sodium sulfate. The solvent is evaporated 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 obtained in the previous step is dissolved in ethanol and 11 g of isopropylaraine hydrochloride are added and the mixture is boiled for 10 hours. The solvent is evaporated to give 1-isopropylamino-3- (4-tosyloxyethyl-phenoxy) -2-propanol hydrochloride.

~ 6 ~ 58909 c) 1-Isopropylamino-3- [4- (2-methoxyethyl) -phenoxy] -2-propanol

The evaporation residue from the previous step is dissolved in methanol and 50 ml of 30% sodium methoxide in methanol and 30 ml of dimethylformamide are added.

The mixture is boiled for 20 hours and the solvent is evaporated off. The residue is slurried in water and the product is extracted into chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness. The evaporation residue is from metoprolol broth. For example, crystallization from heptane gives 12.8 g of product (54% yield based on 2- (4-hydroxy-phenyl) -ethyl ester of p-toluenesulfonic acid), m.p. is 45 ° C. This is made into tartrate in tartaric acetone. Metoprolol tartrate m.p. is about 120 ° C.

Example 2

The procedure described in Example 1 is followed, except that an equivalent amount of 4- (2-chloroethyl) phenol is used instead of 4-hydroxyphenylethanol ethylate. The total yield of metoprolol base is 42%.

Example 3 1-Isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol.

1-Isopropylamino-3- (4-tosyloxyethylphenoxy) -2-propanol hydrochloride, prepared in the same manner as in Example 1 b), is dissolved in methanol. The resulting solution is acidified with hydrogen chloride gas and boiled for 20 hours. The methanol is evaporated off and the residue is dissolved in water. The aqueous solution is washed with toluene and made alkaline with sodium hydroxide. The product is extracted into chloroform, dried over sodium sulfate and the chloroform is evaporated off. The residue is from metoprolol base (total yield 45% based on 4-hydroxyphenylethanol ethylate), which is tartrated in tartaric acetone. The resulting metoprolol tartrate m.p. is about 120 ° C.

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Claims (4)

58909 A process for the preparation of therapeutically valuable 1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol of the formula / -V OHH3 CH3O-CH2-CH2 - [(^)] - CH2-1H-CH2-NH-CH1 VV CH3 and its pharmaceutically acceptable acid addition salts, characterized in that the compound of the formula / P \ _ Λ XCH2CH2- / Vo-CH2-CH-CH2 IV wherein X is a reactive ester residue , such as, for example, an alkyl or aryl sulfonate group or a halogen atom, is reacted with an acid addition salt of isopropylamine under neutral conditions to give a compound of the formula / -v OH CH3 X-CH2-CHo - / ^ y o-ch, -ch-ch, - nh-ch V Jh, wherein X is as defined above, and the compound of which is then reacted with methanol in the presence of an alkali metal methoxide or acid catalyst to give a compound of formula I which is, if desired, converted into acid addition salts by conventional methods. Process according to Claim 1, characterized in that the acid addition salt of isopropylamine is the hydrochloride or the p-toluenesulfonic acid salt. Process according to Claim 1, characterized in that the compound of the formula V is reacted with sodium methoxide to give the compound of the formula I. Process according to Claim 1, characterized in that the compound of the formula V is reacted with methanol in the presence of HCl gas or p-toluenesulfonic acid.