SK155898A3 - Method for the synthesis of (r)- or (s)-metipranolol - Google Patents

Method for the synthesis of (r)- or (s)-metipranolol Download PDF

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SK155898A3
SK155898A3 SK155898A SK155898A SK155898A3 SK 155898 A3 SK155898 A3 SK 155898A3 SK 155898 A SK155898 A SK 155898A SK 155898 A SK155898 A SK 155898A SK 155898 A3 SK155898 A3 SK 155898A3
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metipranolol
synthesis
solvent
acetoxy
reaction mixture
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SK155898A
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SK283258B6 (en
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Dusan Pavlovic
Bohumil Proksa
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Slovakofarma As
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Abstract

Disclosed is a synthesis of (R)- or (S)-metipranolol, in which 4-O-acetyl-2,3,5-trimethylhydroquinolone reacts with (R)- or (S)-epichlorhydrine in the solvent or without a solvent in the presence of non-aqueous alkali metal carbonate. When the reaction finishes the inorganic salts are removed, the organic layer is thickened, the residual is re-crystallised in the organic solvent. The prepared (R)- or (S)-1-(4-acetoxy-2,3,5- trimethylphenoxy)-2,3-epoxypropane reacts with isopropylamine in the solvent or without the solvent. When the reaction finishes the mixture is thickened to dry and the resulting product (R)- or (S)-metipranolol is re-crystallised in the suitable solvent.

Description

Spôsob syntézy (R)- alebo (S)-MetipranololuMethod for the synthesis of (R) - or (S) -Metipranolol

Oblasť technikyTechnical field

Predmet vynálezu spadá do oblasti syntézy opticky aktívnych foriem Metipranololu, ktorý sa používa ako účinná látka v oblasti perorálnych a parenterálnych adrenolytík s vysokým špecifickým beta-lytickým účinkom.The present invention is in the field of the synthesis of optically active forms of Metipranolol, which is used as an active ingredient in the field of oral and parenteral adrenolytics with high specific beta-lytic activity.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Opticky aktívne formy Metipranololu, u ktorých sa predpokladá výraznejší farmakodynamický účinok, sa podľa čs. patentu 152096 pripravujú štiepením racemátu v prostredí alkanolu pôsobením opticky aktívnej kyseliny. Vylúčená soľ jedného enantioméru sa oddelí a prečistí frakčnou kryštalizáciou; z kryštalizačných lúhov sa kryštalizáciou získa druhý enantiomér Metipranololu. Delenie racemického metipranololu na jednotlivé enantioméri cez diastereoizomérne soli je predmetom aj japonského patenttf JP 58126845.The optically active forms of Metipranolol, which are believed to have a more pronounced pharmacodynamic effect, are according to U.S. Pat. No. 152096 are prepared by resolution of the racemate in an alkanol environment by treatment with an optically active acid. The separated salt of one enantiomer is separated and purified by fractional crystallization; the second enantiomer of Metipranolol is crystallized from the crystallization liquors. Separation of racemic metipranolol into individual enantiomers via diastereomeric salts is also the subject of Japanese patent JP 58126845.

Podstata vynálezuSUMMARY OF THE INVENTION

Vynález rieši spôsob syntézy opticky aktívnych foriem Metipranololu t.j. (R)- alebo (S)-l-(4-acetoxy-2,3,5-trimetylfenoxy)-3-izopropylamino-2propanolu vzorca (S)-Ia(R)-I.The invention provides a process for the synthesis of optically active forms of Metipranolol, i. (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -3-isopropylamino-2-propanol of formula (S) -Ia (R) -1.

(R)-I(R) -I

(S)-I(ARE YOU

Podľa predloženého vynálezu (R)- alebo (S)-Metipranolol sa syntetizuje tak, žeAccording to the present invention, (R) - or (S) -Metipranolol is synthesized such that

4-O-acetyl-2,3,5-trimetylhydrochinón reaguje s (R)- alebo (S)epichlórhydrínom v rozpúšťadle, s výhodou v acetóne, alebo bez rozpúšťadla, za prítomnosti bezvodého uhličitanu alkalického kovu. Po skončení reakcie sa anorganické soli odstránia napr. filtráciou alebo násobnou extrakciou vodou . Organická vrstva sa potom zahustí a prečistí kryštalizáciou z organického rozpúšťadla, s výhodou z etanolu. Takto pripravený (R)- alebo (S)-l-(4-acetoxy-2,3,5-trimetylfenoxy)-2,3-epoxypropán (R)-II alebo (S)-II reaguje s izopropylamínom v rozpúšťadle, s výhodou v etanole, alebo bez rozpúšťadla pri teplote 30 až 85 °C. Po skončení reakcie sa reakčná zmes zahustí do sucha a výsledný produkt sa kryštalizuje4-O-Acetyl-2,3,5-trimethylhydroquinone is reacted with (R) - or (S) epichlorohydrin in a solvent, preferably acetone, or without a solvent, in the presence of anhydrous alkali metal carbonate. Upon completion of the reaction, the inorganic salts are removed e.g. filtration or multiple extraction with water. The organic layer is then concentrated and purified by crystallization from an organic solvent, preferably ethanol. The (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane (R) -II or (S) -II thus prepared is reacted with isopropylamine in a solvent, preferably in ethanol or without solvent at a temperature of 30 to 85 ° C. After completion of the reaction, the reaction mixture is concentrated to dryness and the resulting product is crystallized

(R)-II (S)-II z organického rozpúšťadla s výhodou z toluénu, alebo z alifatického alkoholu s počtom uhlíkov C-l až C-3.(R) -II (S) -II from an organic solvent, preferably toluene, or an aliphatic alcohol having a carbon number of C-1 to C-3.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Spôsob syntézy podľa vynálezu je v dalšom objasnený v príkladoch, ktoré tento spôsob neobmedzujú.The synthetic process of the invention is further illustrated by the following non-limiting examples.

Príklad 1Example 1

Zmieša sa 20 ml (R)- alebo (S)-epichlórhydrínu, 5g 4-O-acetyl-2,3,5-trimetylhydrochinónu, 5g bezvodého K2CO3 a zmes sa zahrieva pod spätným chladičom 5 hodín. Reakčná zmes sa ochladí, extrahuje sa 2 x 50 ml vody, organická vrstva sa zahustí do sucha, zvyšok sa rozpustí v 20 ml toluénu, roztok sa extrahuje 2 x 20ml vody, toluénová vrstva sa oddelí a rozpúšťadlo sa oddestiluje. K zvyšku sa pridá 20 ml etanolu a 10 ml izopropylamínu, zmes sa zahrieva 2 h pri teplote varu, potom sa zahustí do sucha a zvyšok sa kryštalizuje z toluénu. Po oddelení kryštálov a ich vysušení sa získa l,7g (R)alebo (S)-metipranololu vysokej optickej čistoty (ee = 99.0 %, stanovené kapilárnou zónovou elektroforézou za podmienok: kapilára 40 Čm x 0.05 mm, mM trietanolamín/acetátový tlmivý roztok pH 5.70,20 mM karboxymetyl-βcyklodextrín, teplota 17 °C, 20 kV).20 ml of (R) - or (S) -epichlorohydrin, 5 g of 4-O-acetyl-2,3,5-trimethylhydroquinone, 5 g of anhydrous K 2 CO 3 are added and the mixture is heated under reflux for 5 hours. The reaction mixture is cooled, extracted with 2 x 50 ml of water, the organic layer is concentrated to dryness, the residue is dissolved in 20 ml of toluene, the solution is extracted with 2 x 20 ml of water, the toluene layer is separated and the solvent is distilled off. 20 ml of ethanol and 10 ml of isopropylamine are added to the residue, the mixture is heated at reflux for 2 hours, then concentrated to dryness and the residue is crystallized from toluene. After separating the crystals and drying them, 1.7g of (R) or (S) -metipranolol of high optical purity (ee = 99.0%, determined by capillary zone electrophoresis under the conditions of a capillary of 40 µm x 0.05 mm, mM triethanolamine / acetate buffer pH 5.70.20 mM carboxymethyl-β-cyclodextrin, 17 ° C, 20 kV).

Príklad 2Example 2

Zmes 20ml (R)- alebo (S)-epichlórhydrínu, llg 4-O'-acetoxy-2,3,5-trimetylhydrochinónu, 12g bezvodého K2CO3 v 100mi acetónu sa zahrieva 6 h pri teplote varu rozpúšťadla. Po skončení reakcie sa tuhý podiel odfiltruje, filtrát sa zahustí do sucha, k zvyšku sa pridá 14 ml etanolu a 14ml izopropylamínu a zmes sa refluxuje 2 h. Potom sa roztok zahustí a zvyšok sa kryštalizuje z toluénu. Týmto spôsobom sa získa 5.6 g vlhkého, po vysušení do konštantnej hmotnosti je 3,9 g (R)- alebo (S)-Metipranololu vysokej optickej čistoty (ee = 99.0%, stanovené postupom uvedeným v príklade 1).A mixture of 20 ml of (R) - or (S) -epichlorohydrin, 11 g of 4-O-acetoxy-2,3,5-trimethylhydroquinone, 12 g of anhydrous K 2 CO 3 in 100 ml of acetone is heated at the boiling point of the solvent for 6 hours. After completion of the reaction, the solid is filtered off, the filtrate is concentrated to dryness, 14 ml of ethanol and 14 ml of isopropylamine are added to the residue, and the mixture is refluxed for 2 hours. The solution was concentrated and the residue was crystallized from toluene. 5.6 g wet are obtained, after drying to constant weight 3.9 g of (R) - or (S) -Metipranolol of high optical purity (ee = 99.0%, determined by the procedure of Example 1).

-*τ [a]20,D = + 5.8, resp. -5.8° (c = 1, metanol).- * τ [a] 20, D = + 5.8, resp. -5.8 ° (c = 1, methanol).

Príklad 3Example 3

Zmes 20ml (R)- alebo (S)-epichlórhydrínu, llg 4-O-acetoxy-2,3,5-trimetylhydrochinónu, 12g bezvodého K2CO3 v lOOml acetónu sa zahrieva 6 h pri teplote varu rozpúšťadla, potom sa tuhý podiel odfiltruje filtrát sa zahustí do sucha. Zvyšok sa kryštalizuje z etanolu (12ml). K vlhkému (R)- alebo (S)-l-(4acetoxy^SzS-trimetylfenoxy^S-epoxypropánu sa pridá 12ml etanolu a 12ml izopropylamínu, zmes sa refluxuje 2 h, rozpúšťadlá sa oddestilujú a zvyšok sa kryštalizuje z toluénu.A mixture of 20 ml of (R) - or (S) -epichlorohydrin, 11 g of 4-O-acetoxy-2,3,5-trimethylhydroquinone, 12 g of anhydrous K 2 CO 3 in 100 ml of acetone is heated for 6 hours at the boiling point of the solvent. thicken to dryness. The residue was crystallized from ethanol (12ml). To the wet (R) - or (S) -1- (4acetoxy-5S-trimethylphenoxy-4-epoxypropane) was added 12 ml of ethanol and 12 ml of isopropylamine, the mixture was refluxed for 2 h, the solvents were distilled off and the residue was crystallized from toluene.

Týmto postupom sa získa 4g (R)- alebo (S)-metipranololu.4g of (R) - or (S) -metipranolol is obtained.

Priemyselná využiteľnosťIndustrial usability

Vynález je využiteľný pri výrobe farmaceutických substancií.The invention is useful in the manufacture of pharmaceutical substances.

„r"r

II

V-IN-

Claims (7)

1. Spôsob syntézy (R)- alebo (S)-Metipranololu vzorca (R)-I alebo (S)-I (R)-I (S)-I vyznačujúci sa tým, že 4-0-acetoxy-2,3,5-trimetylhydrochinón, uhličitan alkalického kovu a (R)- alebo (S)-epichlórhydrín reagujú v prítomnosti alebo bez prítomnosti organického rozpúšťadla pri teplote varu reakčnej zmesi po dobu 3 až 6 hodín, z reakčnej zmesi sa odstránia anorganické soli, organická vrstva sa zahustí, zvyšok sa kryštalizuje z etanolu, vykryštalizovaný (R)alebo (S)-l-(4-acetoxy-2,3,5-trimetylfenoxy)-2,3-epoxypropán v organickom rozpúšťadle alebo bez organického rozpúšťadla reaguje s izopropylamínom pri teplote 30 až 85°C, reakčná zmes sa zahustí a zvyšok sa prékryštalizuje z organického rozpúšťadla.Process for the synthesis of (R) - or (S) -Metipranolol of formula (R) -I or (S) -I (R) -I (S) -I, characterized in that 4-O-acetoxy-2,3 , 5-trimethylhydroquinone, alkali metal carbonate and (R) - or (S) -epichlorohydrin react in the presence or absence of an organic solvent at the boiling point of the reaction mixture for 3 to 6 hours, removing the inorganic salts from the reaction mixture, concentrated, crystallized from ethanol, crystallized (R) or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) -2,3-epoxypropane in an organic solvent or without an organic solvent with isopropylamine at temperature 30-85 ° C, the reaction mixture is concentrated and the residue is recrystallized from an organic solvent. 2. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že ako uhličitan alkalického kovu sa použije uhličitan draselný.Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that potassium carbonate is used as the alkali metal carbonate. I »I » 3. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že ako rozpúšťadlo pre reakciu 4-O-acetoxy-2,3,5trimetylhydrochinónu, bezvodého uhličitan alkalického kovu a (R)- alebo (S)-epichlórhydrínu sa použije alifatický ketón s počtom uhlíkov C-3 až C-6.Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that, as a solvent for the reaction of 4-O-acetoxy-2,3,5-trimethylhydroquinone, anhydrous alkali metal carbonate and (R) - or (S). -epichlorohydrin is used an aliphatic ketone having a carbon number of C-3 to C-6. 4. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že anorganické soli sa z reakčnej zmesi odstránia extrakciou vodou,Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that the inorganic salts are removed from the reaction mixture by extraction with water, -Γ organická vrstva sa zahustí do sucha, zvyšok sa rozpustí v toluéne, roztok sa extrahuje vodou.The organic layer is concentrated to dryness, the residue is dissolved in toluene, the solution is extracted with water. 5. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že anorganické soli sa z reakčnej zmesi odstránia filtráciou.Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that the inorganic salts are removed from the reaction mixture by filtration. 6. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že ako rozpúšťadlo sa pri reakcii (R)- alebo (S)-l-(4-acetoxy-2,3,5trimetylfenoxy)-2,3-epoxypropánu a izopropylamínu sa použije alifatický alkohol s počtom uhlíkov C-l až C-3.Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) - Of 2,3-epoxypropane and isopropylamine, an aliphatic alcohol having a carbon number of C1 to C-3 is used. 7. Spôsob syntézy (R)- alebo (S)-Metipranololu podľa nároku 1 vyznačujúci sa tým, že ako organické rozpúšťadlo na prekryštalizáciu (R)- alebo (S)-l-(4acetoxy-2,3,5-trimetylfenoxy)- 3- izopropylamino-2-propanolu sa použije toluén, alifatický alkohol s počtom uhlíkov C-l až C-3, alebo ich zmes.Process for the synthesis of (R) - or (S) -Metipranolol according to claim 1, characterized in that (R) - or (S) -1- (4-acetoxy-2,3,5-trimethylphenoxy) - 3-isopropylamino-2-propanol used is toluene, an aliphatic alcohol having a carbon number of C1 to C-3, or a mixture thereof.
SK1558-98A 1998-11-12 1998-11-12 Method for the synthesis of (R)- or (S)-metipranolol SK283258B6 (en)

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