NL7908669A - PROCESS FOR PREPARING A THERAPEUTICALLY ACTIVE AMINE - Google Patents

Description

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• - YO 869 ^

Title: Method for the preparation of a therapeutically active amine.

The invention relates to a new process for the preparation of 1-s-opylamino-3- / 5-t 2-methoxyethyl-1-enoxy-2-pr-opanol or metoprolol of the formula I and its acid addition salts.

5 Metoprolol is a therapeutically valuable / Ö adrenergic blocking agent. Most of the blocking agents have the drawback that, in addition to the β receptors of the heart, they also block the receptors of the blood vessels and lungs.

Metoprolol, on the other hand, is specific to the heart and thus an important drug in the therapy of heart disease.

The preparation of metoprolol is e.g. known from Swedish patent specification 35 ^ .851, which describes no less than 12 methods for the preparation thereof. These methods are guaranteed to cover all methods of synthesis of the isopropylamino side chain.

The present process, on the other hand, is characterized in that a compound of the formula 2, in which X represents a reactive ester group, is converted into a compound of the formula U with epichlorohydrin of the formula 3, which compound becomes further.

20 reacted with an acid addition salt of isopropylamine to give a compound of the formula. This compound is finally reacted with an alkali metal methoxide or methanol in the presence of an acid catalyst in the final product of the formula I.

The formula scheme of this method is indicated on the formula sheet under A.

The reactive ester group X may be an alkyl or aryl sulfonate group, most preferably a tosylate group, where the compound U

1,2-epoxy-3- (u-tosyloxyethylphenoxy) -propane, a new organic compound of the formula 7; or X is a halogen atom / 908853 "m

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*) -, - -2- preferably a chlorine atom, in which case the compound becomes 5 1-isopropyl-amino-3- / lt- (2-chloroethyl) -phenoxy7-2-propanol, a new organic compound of the formula 6.

The isopropylamino acid addition salt can e.g. isopropylamine-5 hydrochloride of the formula 8 or the isopropylamine-p-toluene-sulfonic acid salt of the formula 9

As an alkali metal methoxide, e.g. potassium or sodium methoride, preferably sodium methoride. Suitable acidic catalysts in the reaction of methanol with a compound of formula III are e.g. dry HCl gas or p-toluenesulfonic acid.

Particularly characteristic of the present preparation method is that the final treatment of the synthesis takes place at the methoxyethyl end of the molecule, i.e. a reaction between compound 5 not an alkali metal methoxide or between compound 5 and methanol in the presence of an acid catalyst. A further characteristic of the invention is furthermore that compound 5 is prepared specifically from compound U by reacting the last substance with an acid addition salt of isopropylamine under neutral conditions. It is further characteristic of the invention that, especially by using the synthesis route described above, the starting materials for a synthesis synthesis are cheap and can be easily obtained, so that the entire synthesis becomes very economical.

The second reaction step in the present process, wherein an acid addition salt of isopropylamine is reacted with a compound. of the formula k is a specific reaction with the epoxide end of the molecule. This specificity is, of course, necessary to prevent the isopropylamine group from reacting with the reactive ester group. This specificity was surprisingly achieved in that it was found that the epoxy group is properly opened already under neutral conditions with acid addition salts of isopropylamine. The reaction can be carried out by combining the starting materials and mixing in an appropriate solvent until the reaction is complete. Preferably, the mixture is boiled to promote this reaction rate.

7908868 -3-

Suitable solvents are e.g. alcohols, such as ethanol or isopropanol.

The final step of the reaction, wherein h.v. sodium methoxid is added with the compound 5, is carried out in advance by boiling in an appropriate solvent, such as methanol, dimethylformamide, dimethyl sulfoxide or a mixture thereof.

For example, in the reaction with acidic catalysts, put the corresponding tosylate derivative with methanol in an appropriate solvent such as methanol at the boiling point of the mixture and in the presence of an acid catalyst. Suitable acidic catalysts are e.g. hydrochloric acid and p-toluenesulfonic acid.

The first stage of the reaction series is carried out by conventional methods, e.g. with the corresponding sodium phenolate derivative and epichlorohydrin in an alcohol, e.g. ethanol, at 20-30 ° C with stirring.

In the present process, it is not necessary to purify the intermediates in order to obtain a pure final product, and the process is thus particularly simple for implementation on a technical scale.

The amine of formula I formed can be easily converted into its acid addition salts by reacting it with an inorganic or organic acid.

The following examples further illustrate the invention.

Example I

A) 1,2-epoxy-3 - (- - tosyloxyethylphenoxy) propane: * 3 2.6 g of sodium were dissolved in 200 cm of absolute ethanol.

26 g of p-toluenesulfonic acid 2- (1-hydroxyphenyl) ethyl ester and 10 g of epichlorohydrin were added and then at ca.

Stirred at 25 ° C. The resulting mixture was poured into water and the product extracted with methylene chloride and dried with sodium sulfate. The solvent was distilled off in vacuo to give the 1,2-epaxy-3- (tosyloxyethylphenoxy) propane in the form of an oil, b) 1-isopropylamino-3- (H-tosyloxyethylphenoxy) -2-propanohydrochlo-35 rider • V! I · '··; = 1 ΐί ♦ «* η y —it—

The oil obtained in the previous step was dissolved in ethanol and 11 g of isopropylamine hydrochloride was added, followed by boiling for 10 hours. The solvent was then distilled off, yielding the 1-isopropylamino-3- (li-tosylo: methylethylphenaxy) -2-pro- Panol hydrochloride was obtained.

c) 1-sopr-opylamino-3- (5- (2-methoxyethyl) -phenoxyl-2-propanol):

The distillation residue obtained in the previous step was dissolved

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in methanol and 50 cm 3 of 30% sodium methO 3 d.de in methanol and 30 cm-3 of dimethylformamide. This mixture was boiled for 20 hours and the solvent was distilled off. The residue was triturated with. water and this product is extracted with chloroform. The chloroform extract was washed with water, dried with sodium sulfate, and evaporated to dryness. The residue was the metoprolol base, which after recrystallization. from e.g. heptane had a melting point of 15 h-5 ° C. The tartrate was made from this base by adding tartaric acid in acetone. The melting point of metoprolol tartrate is about 120 ° C.

Example II

Example. I became. repeated with the difference that an equivalent amount of 1- (2-chloroethyl) -phenol was used instead of U-by-hydroxyphenylethanol tosylate.

Example III

1-sopropylamino-3- A- (2-methoxyethyl) -f enoxy7-2-propanol.

1-isopropylamino-3- (14-tosylo3cyethylphenoxy) -2-propanol hydrochloride, obtained according to Example 1 b), was dissolved in methanol. The resulting solution was acidified with gaseous HCl and boiled for 20 hours. The methanol was distilled off and the residue dissolved in water. The resulting aqueous solution was washed with toluene and made alkaline with caustic soda. The resulting product was extracted with chlorofom, this chloroform dried with sodium sulfate and the chloroform distilled off. The residue was the metoprolol base, which was converted to its tartrate with tartaric acid in acetone, which had a melting point of about 120 ° C.

7908669

Claims (9)

A process for the "preparation of the therapeutically valuable 1-isopropylamino-3-A- (2-methoxyethyl) -phenoxy-2-propanol of the formula I and its pharmaceutically suitable acid addition compositions, characterized, that a compound of the formula! +, wherein X represents a reactive ester group, eg an alkyl or aryl sulfonate group or a halogen atom, is reacted with an opylamino acid addition salt to form a compound of the formula 5, wherein X as described above has been obtained, then this compound is treated with a 2-potassium methoxide or with methanol in the presence of an acid catalyst to convert a compound of the formula 1. Process according to claim 1, characterized in that the iscropylamine acid addition salt is the hydrochloride or the p-toluene sulfonic acid salt thereof. Method according to claim 1, characterized in that. one ispropylamine acid addition salt is reacted under neutral conditions with a compound of the formula 1 * until a compound of the formula 5 * is formed. 1 *. Process according to claim 1, characterized in that a compound with. formula 5 reacts with an alkali methoxide, preferably sodium methoxide, until a compound of formula 1 is formed. 5. Process according to claim 1, characterized in that a compound of the formula 5 is reacted with methanol in the presence of an acid catalyst. Compounds useful as intermediates in the preparation of metoprolol according to claim 1, characterized by the formula 5 of the formula sheet, wherein X has the meaning shown above. Compounds according to claim 6, usable as intermediates in the preparation of metoprolol, characterized in that it is 1-isopropylamino-3 - /% - (2-chloroethyl) -tenoxff-2-propanol of the formula 6 or 1-Isopropylamino-3- (H-tosyloxyethylphenoxy) -2-propsole of the formula 7. 7. Q 3 S> 5 I. * t * r OH CH30-CH2-CH2 - <^ y Q-CH2-CH-CH2-NH-CH. ch3 2 ....... 3 x - CH2 - ch2 - (^) “0Na C1 - ch2 - CH -Nch2 b 0 X - CH2 - ch ^ o - CH2 - CH - CH2 ^ OH CH3 X-CH2- CH2 ^ Q-CH2-iH-CH2-4 3 OH CH3 ci-ch2-ch2 - (^) - o-ch2-: h-ch2-nh-ch CH3 o:. 7 _. _ 0 CH3 "^^) 'I''CH2 CH2 ~ \ J) ~ 0-ch2 ~ CH-CH2 • Ï 9 0 3 \ 00 3 ^ © 0 II / s ~> \ chnh3ci chnh3 0-s- ^) Vch3 CH ^ s' 'W \ -' 3 CH3 0 179 0 8 6 6 9 ". # p 'Pa.rmos-Yht'VTiia Ov 4> r' A α / \ C1-CH2-CH-.CH2 3 X-CH2-CH2 ^^^ ypNa - »2 Q ___ x-ch2-ch2 ^> - 0-CH2-CH-CH2 ι * CH Θ Ö "; ch-nh3y qh ch ch3 1 'J v X“ CH2 "CH2 \ W / q'ch2" CH "CH2" NH "CH 5 CH3 t NaOChL --2 - ± Or. H + 8Π CH30H KJ 'I 7908659 /' Farmos-Yhtyma Oy