PL158497B1 - Method of obtaining a salt of //-1-isppropylamino-3-(4-/2-methoxyethyl/phenoxy)-2-propanol in particular tartarate - Google Patents

Abstract

A method of obtaining of /+/-/-1-isopropylamino-3-[4-/2-metoxyethylo/fenoxy]-2-propanol salts, particularly /+/-/-1-isopropylamino-3-[4-/2-metoxyethylo/fenoxy]-2-propanol tartrate in the reaction of 4-/2-metoxyethylo/phenol with molar excess of epichlorhydrine at the temperature of 20-80 degrees C, in the presence of a aqueous solution of inorganic base, where the reaction product is reacted with molar excess of isopropyl amine at boiling temperature, followed by the reaction with L-tartaric acid, characterized in that 4-/2-metoxyethylo/phenol is reacted with 1-3 times as much of molar excess of epichlorhydrine in a monophase system in water, while the reaction of epoxide with 2-5 times as much of molar excess of isopropyl amine is conducted in the medium consisting of reaction products, and where raw /+/-/-1-isoproylamino-3-[4-/2-metoxyethylo/fenoxy]-2-propanol tartrate obtained in the reaction with L-tartaric acid is macerated in 4-8 times as much of excess by weight of acetone for 5-15 hours at room temperature, followed by crystallisation from the aqueous solution of acetone.

Description

REPUBLIC

POLAND

PATENT DESCRIPTION © PL © 158497 © Bl

Application number: 277458

I ⁿ tCl ^5:

C07C 217/32

Patent Office of the Republic of Poland

Date of notification: ² 6.0 ¹ · ¹⁹⁸⁹

Method for the preparation of the salt of (q) -1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol, especially (q) -1-inopropylamine-3] [4- (2-non-zoxyethyl) fnnooxy] tartrate -2-propanol

Application announced:

04.09.1Ł33 BUP 18/89

The grant of the patent was announced on: September 30, 1992, WUP 09/92

The holder of the patent:

Lodz University of Technology, Lodz, PL Rzeszowskie Zakłady Farmaceutyczne

POLFA, Rzeszów, PL

Zakłady Tworzyw Sztucznych “GAMRAT-ERG, Jasło, PL

Inventors:

Jordan Zjawiony, Łódź, PL Eugeniusz Kaczur-Kaczyński, Łódź, PL Kazimierz Witkowski, Łódź, PL Zo / ia Grosman-Zjawiona, Łódź, PL Andrzej Matłok, Jasło, PL

Marian Pepera, Jasło, PL Krzysztof Węgrzyn, Jasło, PL Janina Bałon, Jasło, PL Janina Suśniak, Rzeszów, PL Andrzej Fibiger, Rzeszów, PL Stanisław Zytkik. Rzeszow. PL

58497 Bl

Method for the preparation of the salt / ± / -i-ioopropylaamino-3- [4- (2-methoxyethyl) eenoxy] -2-propanol, especially tartrate (± 1-iropropylamino-3- [4- (O-methoxyethyl) eenoxy] -2-orΌpannIu, by reaction of 4- / 2-metnkspetplo // ennl with a molar excess of epichlorohpdrpnp at a temperature of 20o80 ° C, in the presence of an aqueous solution of an inorganic base, the product of which is reacted with a molar excess of iznpropploaminp at boiling temperature, and then with with L-tartaric acid, characterized in that 4- / 2-methoxspetpl (r // ennl is reacted with a 1-fold molar excess of epichlorohpdrpnp in a single-phase system in an aqueous medium, and the reaction of epoxide with a 2-5-fold molar excess of isopropploamine is carried out in the reaction medium of this reaction, and the crude tartrate (± N -1-iropropylamino-3- [4- (amethoxyethyl) eenoxy] -2-propanol obtained by reaction with L-tartaric acid is macerated with a 4-8-fold excess by weight of acetone in for 5-15 hours at room temperature, and then crystallized from an aqueous solution acetone.

CL

METHOD OF MAKING SALT / - / - 1-ISUPKUPYL-AMIN0-3 [- / 2-METHOXYETHYL0 / PHENOXY] -2-PROPANOL, ESPECIALLY Tartrate / - / - l-ISOPROPYLAMINO-3- [4- / 2-METHOXYETHYL0] -PROPANOL

Claims (2)

Patent claim A process for preparing / - / - 1-isopropylamino-3- | _4- / 2-methoxyethyl 1 o / ίenoksyj -2-propanol, in particular in and ⁿ oate 1 ^- isopropylamino-3- ^ 4/2-meeoks ^ t ^ lo / ^f enoksyy- -firopiano ^{2 1 u,} by reacting 4- / 2-metoksyeeylo / phenol with a molar excess of epichlorohydrin in turn tempera 20 80 ° C in the presence of an aqueous inorganic base solution, which is then reacted with a molar excess lzopΓopl- oamίny at the boiling point and then with L-tartaric acid, characterized in that 4- / 2-methoxyytyl / phenol is reacted with a 1-3-fold molar nodule of epichlorohydrin in a monophasic system in an aqueous medium, and the reaction of epoxide with a 2-S-stage molar excess of lsopropyl-Gamiπy is carried out in the environment of the reactants of this reaction, and the crude tartrate / - / - 1 -isoprope ¹ amino- ³ - [ ⁴ - / 2-methoxye obtained by reaction with L-tartaric acid ^{ty 1} o / f tt-ks ^y J - ² - ^p oat- ¹ u is macerated with ⁴ - O-steps in excess acetone by weight for 5-15 hours at room temperature, then Then it crystallizes from an aqueous acetone solution. ^The invention relates to a method for the production of salt / - / - Ι- ^ οργο ¹ ^ lommino-3 - ^^ - / 2ne ^t oxyetho / Tenoxy-2-propanol, especially tartrate ^/ - / - l / ¹ z- ^p ror ^l] oamlno- ³ - [4- / ^{2-methoxy-yl t /} Aenolksy] ^ propanol ^who rice ^j es ^{t y} as used] ¹ .ek cardiac named Me ^ prolol. There is known, from the patents of Germany No. 2 106 209, Swedish truck 368 004 and the United States of America Ammeyka No. 3 928 601, a method of producing the hydrochloride (- / - i-opooropylommino-3-.) // Z-methoxyethyl.oHenox /] - ^ Lara ^ phenol which ^ lego reacting ⁴ - / 2-methoxy ^ lo / phenol of 30 kt ^ obiym excess with roll epichlorahydrynp in the presence of piperidine as each is 1 ise ra, and the production ^background above reaction postoci mixtures ^y 1 ^{, 2-} epokkyi ^- - [p- (2-me tpsye tylo) ( ^p ) propos i. Ctiloro ( ³ ) [ ⁴ - (2-methoxyethyl) f ^ no ^k s ^y j - ^ propane u [e ^j subjected to reai cj ^ ^{y and} z izprop benzyl amine ^e in the outoklaw agent or wyodΓ ^ę BNI-t ^l of this mixture ^{1 1,2} -epoxy-3- ^[4-methoxy ^ lo? ' ^ phenoxy] ^p ^^ you calls ^SIU after ocz ^ zczeniu by destylocji ^yellow żniowe ^p r ^j into c ^t śπten ^and 0.46 mi After, the reaction of lzorΓory-oaiιiną in ou ^ oklawie at 100 ° C for 12 hours, and otm ^ an ¹ as a result of ^t e ^j re ° <t: ji ^{/ 2} -l - \ - iso ^p rop ^y loam ito-3-j \ -22-mt ^t o ^k s ^y e ^{ty 1} o / ^/ enox ^y J - ^^ opanol is separated from the post-reaction mechanine in the form of hydrochloride. The disadvantage of these methods is the use of large, 15-30 times excess of toxic epichlorohydrin or carrying out reoccurrence with volatile isor izopy-oamiπ in an autoclave under high pressure and at high temperature, which makes it dangerous and difficult to implement in terms of technology. fiefdom. Japanese Patent pote ^ pink # 57 169 448 1 of European patent specification No. ^{50 885} jeyt Known ^y y ^p oyób preparation ^h1 OΓowod c-r ^k u ^ ^^ A opropylommino- ³ - ^4- - / ^2-y inetoks et ^y lo / ^ phenoxy] - ^ propane ^ (box ^g ai c ^{± p} reacting ⁴ - yl ^// -metoksyp ^t / u fet- ¹ ghost epichloro dr ^ ^ ¹ ^ will wipe of any simi ^k of this reaction ¹ Μρ (° 3 ^ 33 jri - ^ - methoxye tyło / ^ ηο ^ ^ρ] -propane is reacted with a 10kΓOt molar excess of isorΓ-rylaminp in the presence of kata1rza-OΓΰw such as triethylogi, aluminum chloride or ferric chloride, and - tΓZ-NANP by ^t than real <cj ^and / - ² ~ l laminated ozoiorp ^{11 3} - ^{4- / 2-methoxy me you lo / ¹ phenoxy] - ^ propanol. isolated the ^ę hnia mieyronίtp of the reaction in the form of a hydrochloride . This yroyobit uses a large, 10- ^ nadmiarηι excess of volatile isopropploaminp and catalysts, which in the post-reaction mixture are troublesome and difficult to remove impurities. From the Polish description of this rottt-144 036 discloses a process for the product ^ 1 izppn present py1oamino- ³ / ^[4 - ^{/ 2} 1 ^e-yl methoxy / fenoksyj - ^ propan ^ relying on no ^one white ^{background, e 4} - / 2-me ^t o p ^{y k} e because ^you / phenol is subjected to reokcji 2-iΓotnym nodmiorem molar eoichlorohpdryny system 497 dwufo158 brown mixture in an organic solvent immiscible with water, preferably toluene, and an aqueous solution of an inorganic base such as alkali or alkaline earth metal hydroxide at a temperature of 20-80 ° C, and the crude product of this reaction is treated with a 2-3 fold molar excess of isopropylamine in an organic solvent, preferably isopropanol, in the presence of catalytic amounts of isopropylamine hydrochloride. The product of this reaction is then converted into the L-tartaric acid salt. In this process, flammable solvents are used: toluene and isopropanol, and the use of isopropanol, due to the possibility of its formation of peroxides, is particularly dangerous on an industrial scale. An additional disadvantage is the use of a catalyst in the reaction with isopropylamine, which, after completion of the reaction, contaminates the product, reducing its quality. 2aden known methods provide receivable / - / - l-isopropylamino-3- [4- / 2-methoxyeth ^yl o / -phenoxy] - ^2-propanol, TCR ^{k y k} of the reaction ^and Wasem now Lw ^{and y} m by ^p EHV ^iłby produ ińruanu ^/ - ^{/ -l-isopropylamino-3} - ^{[4- / 2-methoxyethyl} / fenoksyj - ^2-propanol purely ^TARGET pharmaceutical use, and attempts to purification of the drug did not give so far, the expected effect. A method a ^s twarzan ^and Sou ^{/ - /} - ^l - zo ^and ro ^{p p} y ^l OAM mono- ^{and 3} - [4- ^/ 2-methoxyethyl / ^y j ^{phenoxy-2-pΓOpanolu,} especially tartrate ^{/ - /} - ^l - ^and mono- ^and zopropyloam ³ - [4- / ^{2-methoxyethyl} / ^phenoxy] -2-propanol ₁ by reacting 4- / 2-methoxyethyl / phenol with a molar excess of epichlorohydrin at a temperature of 20 00 ° C in the presence of an aqueous base inorganic acid, the product of which is reacted with a molar excess of isopropylamine at the boiling point and then with L-tartaric acid, the invention is characterized in that 4- (2-methoxyethyl) phenol is reacted with a 1 to 3-fold molar excess of epichlorohydrin in a single phase in the aqueous medium, the reaction of an epoxide of 2 - 5 fold molar excess of isopropylamine is carried out in the reactants of the reaction, and obtained by reaction with L-tartaric acid crude tartrate ^{/ - /} - ^l - ^and zopropy ^l QAM ^and mono- ³ - [i - ^ - ^ me ^ t ^ ksye ofencksy] - ² - ^{p l} ropano triturated with t ^{o 4} - ⁸ m ^s fivefold excess acetone in a weight rainbow 5 - 15 hours at room temperature and then crystallized from an aqueous acetone solution. FIG ^crib own preferences ^{S g l} brea Azkue allow Zyman o ^ ^ ^ wine nu ^{/ - /} - ^l - ^{yl and} zoprop QAM ^and no-3- [i4 ^- 2-methoxyethyl / -phenoxy] -2-propanol pharmaceutical grade. The invention eliminates the use of flammable and explosive solvents both in the reaction with epichlorohydrin and in the reaction with isopropylamine, as well as the use of catalysts in the reaction with isopropylamine, which contaminate the product of this reaction. The method according to the invention is illustrated by the following example without limiting its scope. Example. A solution of 0.53 kg of sodium hydroxide in 3.2 L of water, 8 kg of 4- (2-methoxyethyl) phenol and 1.23 L of epichlorohydrin was placed in the reaction flask which was heated with stirring at 55 ° C for 3 hours. After cooling the contents of the flask, the organic layer was separated and washed 4 times with 0.25 l of water, and then the residual epichlorohydrin was evaporated under reduced pressure. The obtained epoxide in the amount of 0.854 kg was mixed with 1.06 L of isopropylamine and then refluxed under heating for 0 hours. After completion of the reaction the excess is distilled off and the resulting lzopropyloaminyl ^{/ - /} - ^l - ^{yl and} zoprop oamino- ³ - ^{[4- /} 2-methoxy ^{you s} e lo ^/ Ferio ^k s ^y] -2-propano ^l Uośc ^{1 1.13 kg} was dissolved in 1.2 l of acetone, then 0.288 kg of tartaric acid in 4.8 l of acetone was added to the solution, and the reaction mixture was left for several hours for crystallization. The precipitated crude tartrate ^{/ i / il-yl} iaoprop onminoi3- ^{[^^ /} 2-Mett ^^ ^; ^ e ^{backward /} fenok ^ ^y ^^] ^ propane ^ filtered and washed with 0.6 1 of acetone. After drying, 1.176 kg of product was obtained, which was macerated with 12.5 liters of acetone. Maceration was carried out with stirring for 12 hours at room temperature. After removal of acetone by filtration the product was crystallized from 7 1 of acetone and 72 ml of water ^s. Mano will wipe ^{y 0,} 9 ^{28 g} k idnianu / ^- / - ^^ ^ opropyloar mono- ³ - ^[4- / 2-mtto zytty ^{k l} o / ftno'r; Live 4 150 497 -2-propanol of purity: melting point 121.5 - 122.5 ° C, pH of a 10% aqueous solution = FW 46 / standard predicts pH = 6 - 7 /, active substance content 100.3¾ / standard predicts 99 0 - 101.0%; thin-layer chromium TLC of the product in a chlorophyll solution. one spot with saturated ammonia confirmed the pharmacopoeia purity of the product. Department of Publishing of the UP RP. Circulation of 90 copies