CS211414B1

CS211414B1 - Process for preparing 1- [3-chloro-2-hydroxypropyl] -2-methyl-5-nitroimidazole

Info

Publication number: CS211414B1
Application number: CS729580A
Authority: CS
Inventors: Jozefina Jakubcova; Ladislav David; Alfonz Rybar; Richard Frimm; Augustin Martvon
Original assignee: Jozefina Jakubcova; Ladislav David; Alfonz Rybar; Richard Frimm; Augustin Martvon
Priority date: 1980-10-29
Filing date: 1980-10-29
Publication date: 1982-02-26

Abstract

Vynález sa týká spósobu přípravy zlúčeniny vzorca I, CH2-CH-CH2 71' Óh Cl používanej v humánnej medicíně na liecbu protozoálnych infekcii. Doposial sa táto látka připravovala reakciou 2-metyl-4/5/- -nitroimidazolu s epichlórhydrínom v 85% kyselině mravčej, alebo alkyláciou 2-metyl- -4/5/-nitroimidazolu bis-/3-ehlór-2-hydroxypropyl/sulfátom. Podstatou vynálezu je spósob přípravy zlúčeniny vzorca I reakciou 2-metyl-4/5/-nitroimidazolu s epichlórhydrínom v bezvodom nitrobenzene v přítomnosti Lewisovej kyseliny.The invention relates to a method for preparing a compound of formula I, CH2-CH-CH2 71' Óh Cl used in human medicine for the treatment of protozoal infections. Previously, this substance was prepared by reacting 2-methyl-4/5/- -nitroimidazole with epichlorohydrin in 85% formic acid, or by alkylating 2-methyl- -4/5/-nitroimidazole with bis-(3-echloro-2-hydroxypropyl) sulfate. The essence of the invention is a method for preparing a compound of formula I by reacting 2-methyl-4/5/-nitroimidazole with epichlorohydrin in anhydrous nitrobenzene in the presence of Lewis acid.

Description

1 211414 /1/1 211414/1 /

Vynález sa týká spósobu přípravy zlúČeniny vzorca I, °2n CHo CHyCH-CH? 2 I I 2 OH Cl používanej v humánnej medícíne na liečbu proCozoálnych infekcií. Doposíal sa táto látka při-pravovala reakciou 2-mety1-4/5/-nitroimidazolu s epich1órhydrínom v 85% kyselině mravcej s vý-tažkom 40 % [m. Hoffer, E. Grundberg: J. Med. Chem. 1 7 , 1019, /1974/], alebo alkyláciou 2-me-ty1-4/5/-nitroimídazolu bis-/3-chlór~2-hydroxypropy1/sulfátom s výťaškom 25 % /Amer. patent3 5 1 9 637 / .The invention relates to a process for the preparation of a compound of formula I, 2n CHo CHyCH-CH? 2 I 2 OH Cl used in human mediation for the treatment of Coso infections. In addition, this compound was prepared by reacting 2-methyl-4 S, 5-nitroimidazole with epichlorohydrin in 85% formic acid at a yield of 40% [m. Hoffer, E. Grundberg, J. Med. Chem. 17, 1019, (1974)], or by alkylation of 2-methyl-4- [5-nitroimidazole bis- (3-chloro-2-hydroxypropyl) sulfate with a 25% yield / Amer. patent 3 5 9 637].

Podstatou vynálezu je reakcia 2-mety1-4/5/-nitroimidazolu s epichlorhydrínom za katalý-zy Lewísovou kyselinou v prostředí bezvodeho nitrobenzénu. Ako katalyzátor reakcie - Lewiso-vu kyselinu, možno použiti bezv. chlorid hlinitý, bortrifluorid éterát, bortrifluorid acetát,bezv. chlorid železitý, bezv. chlorid zinočnatý a pod., -s výhodou chlorid hlinitý.SUMMARY OF THE INVENTION The present invention relates to the reaction of 2-methyl-4- [5-nitroimidazole with epichlorohydrin under Lewis acid catalysis in an anhydrous nitrobenzene medium. As the reaction catalyst, the Lewis acid may be used as an acid. aluminum chloride, boron trifluoride etherate, boron trifluoride acetate, anhydrous; ferric chloride; zinc chloride and the like, preferably aluminum chloride.

Postup podlá vynálezu sa uskutočňuje tak, že sa k suspenzii' 1 molu 2-mety1-4/5/-nitroimi-dazolu v bezvodom nitrobenzéne přidá 0,1 až 3 moly, s výhodou 0,9 až 1 mol, Lewisovej kyseli-ny a ďalej sa přidá 1 až 6 molov, s výhodou 1 až 2 moly, epich1órhydrinu pri teplote -10 až+70 °C, s výhodou 5 °C až 10 °C. Reakčná zmes sa nechá reagovat pri uvedenej teplote 0,1 až10 h 8 výhodou 0,1 až 1,5 h.The process of the invention is carried out by adding 0.1 to 3 mol, preferably 0.9 to 1 mol, of Lewis acid to a suspension of 1 mol of 2-methyl-4 (5H-nitro-imidazole in anhydrous nitrobenzene). and further adding 1 to 6 moles, preferably 1 to 2 moles, of epichlorohydrin at a temperature of -10 to + 70 ° C, preferably 5 ° C to 10 ° C. The reaction mixture is reacted at said temperature for 0.1 to 10 hours, preferably 0.1 to 1.5 hours.

Po skončení reakcie sa reakčná zmes vyleje do zriedenej minerálnej kyseliny, s výhodou20 aŽ 40% kyseliny sírovej, ktorá sa potom neutralizuje vodným roztokem čpavku na pH 6,5 až7,5. Roztok extrahuje organickým rozpúšiadlom?napr. dichlórmetánom, chloroformom, benzénom,etylacetátom a pod. Získané extrakty sa zahustia, s výhodou vákuovo a surový produkt sa pre-kryštalizuje z etylacetátu. Výhodou tohto postupu oproti predchádzajúcim postupom je značné skrátenie reakeného Ča-su, .nižsie energetické náklady, zjednodušenie izolácie a vyššíe výtažky reakcie. V ďalšom je priebeh vynálezu popísaný v príkladoch bez toho, že by sa na tieto." óbmedzo- val. Příklad 1After completion of the reaction, the reaction mixture is poured into diluted mineral acid, preferably 20 to 40% sulfuric acid, which is then neutralized with an aqueous ammonia solution to a pH of 6.5 to 7.5. The solution is extracted with an organic solvent e.g. dichloromethane, chloroform, benzene, ethyl acetate and the like. The extracts obtained are concentrated, preferably in vacuo, and the crude product is recrystallized from ethyl acetate. The advantage of this process over previous processes is the considerable shortening of the reaction time, the lower energy cost, the simplification of the isolation and the higher reaction yields. In the following, the process of the invention is described in the Examples without being exemplified.

Do 100 ml bezvodeho nítrobenzénu sa za míešania přidá 12,7 g /0,1 mol/ 2-mety 1-4/5/-nitroiraidazolu. Ku vzníklej suspenzii sa potom přidá pri teplote 15 až 20 °C 13,3 g /0,1 mol /bezvodeho chloridu hlinitého. Po 0,5 h miešanía se k reakčnej zmesi pri teplote 7 až 10 °Cza míešania prikvapká 9,25 g /0,1 mol/ epich1órhydrinu, Po 1 h míešania sa reakčná zmesvyleje na predom připravenu· zmes ladu a konc. kyseliny sírovej v pomere 2:1. Nitrobenzénovávrstva sa oddělí a extrahuje sa ešte raz 20% kyselinou sírovou. Extrakty kyseliny sírovejsa spojá a premyjú 2 rázy toluénom.12.7 g (0.1 mol) of 2-methyl-4 S -n-nitroiraidazole are added to 100 ml of anhydrous benzobenzene with stirring. 13.3 g (0.1 mol) of anhydrous aluminum chloride are then added to the resulting suspension at 15-20 ° C. After stirring for 0.5 h, 9.25 g (0.1 mol) of epichlorohydrin is added dropwise to the reaction mixture at 7-10 ° C and after stirring for 1 h, the reaction mixture is poured into a pre-prepared mixture of ice and conc. 2: 1 sulfuric acid. The nitrobenzene layer was separated and extracted once more with 20% sulfuric acid. The sulfuric acid extracts are combined and washed with 2 times toluene.

Kyselinový roztok sa potom neutralizuje vodným roztokom čpavku na pH 7,5. Vylúčený pro-dukt sa potom extrahuje etylacetátom. Etylacetátový roztok sa zahustí za vakua do sucha. Pev-ný zbytok sa suspenduje v dichlórmetáne, nezreagovaný 2-mety1-4/5/-nitroimidazol sa odsajea filtrát sa zahustí do sucha. K zbytku sa přidá rovnaké hmotnostně množstvo etylacetátu aza míešania a chladenia vykrystalizuje 1-/3-ch1ór-2-hydroxypropy1/-2-mety1-5-nitroimidazo1, oThe acid solution is then neutralized with aqueous ammonia solution to pH 7.5. The precipitate was then extracted with ethyl acetate. The ethyl acetate solution was concentrated to dryness in vacuo. The solid residue is suspended in dichloromethane, the unreacted 2-methyl-4 (5 H -nitroimidazole is suctioned off) and the filtrate is concentrated to dryness. The same amount of ethyl acetate was added to the residue, and 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole was crystallized for mixing and cooling.

ktorý sa odsaje a vysuší. Získá sa 9,5 g, to je 45,5 % produktu s teplotou topenia 84 až 87 C 211414 2 Příklad 2 K suspenzii 12,7 g /0,1 mól/ 2-mety1-4/5/-nitroimidazolu v 150 ml nítrobenzénu sa priizbovej teplote přidá 15,4 g /0,095 mol/ bezvodého chloridu železitého. Po 0,5 h miešaniasa k reakčnej zmesi přidá 13,9 /0,15 mol/ epichlórhydrínu pri teplote 5 až 10 °C. Po 6 h pritejto teplote sa reakčná zmes v-yleje za miešania a chladenia do 40% kyseliny sírovej. Nitro-benzénová vrstva sa oddělí a vytrepe sa ešte raz 40% kyselinou sírovou.which is filtered off with suction and dried. 9.5 g (45.5% of product) are obtained, m.p. 84-87 ° C. 211414 2 Example 2 To a suspension of 12.7 g (0.1 mol) of 2-methyl-4, 5-nitroimidazole in 150 ml. trobenzene, 15.4 g (0.095 mol) of anhydrous ferric chloride are added at room temperature. After stirring for 0.5 h, 13.9 / 0.15 mol / epichlorohydrin is added to the reaction mixture at 5-10 ° C. After 6 h at this temperature, the reaction mixture is stirred with stirring and cooling into 40% sulfuric acid. The nitro-benzene layer is separated and shaken once more with 40% sulfuric acid.

Extrakty kyseliny sírovej sa. spoja, premyjú 2 rázy toluénom a zneutralizujú sa vodnýmroztokom čpavku na pH 7 až 7,5. Vylúčený produkt sa vyextrahuje dichlórmetánom a dichlorme-tán sa oddestiluje. Zbytok sa rozpustí v rovnakom hmotnostnom množstve etylacetátu a za mie-šania a chladenia vykrystalizuje 1-/3-chlór-2-hydroxypropy1/-2-mety1-5-nitroimidazol, ktorýsa odsaje a vysuší. Získá sa 4,7 g, to je 21,5 %. Příklad 3 K suspenzii 38,1 g /0,3 mol/ 2-mety1-4/5/-nitroimidazolu v 200 ml bezvodého nitrobenzé-nu sa pri teplote 5 až 20 QC za miešania přidá 40,4 g /0,285 mol/ bortrifluorid éterátu. Po-tom sa k reakčnej zmesi za miešania pri teplote 0 až 10 °C přidá 55,5 g /0,6 mól/ epichlór-hydrínu a zmes sa nechá miešač pri uvedenej teplote 2 h. K reakčnej zmesi sa potom přidáza chladenia 150 ml 20% kyseliny sírovej a po dókladnom premiešaní sa nitrobenzénová vrstvaoddělí a znovu sa extrahuje 20% kyselinou sírovou, kyselinové extrakty sa spojá, premyjú to-luénom a neutralizuji! sa vodným roztokom čpavku na pH 7 až 7,5.Sulfuric acid extracts are. they are combined, washed with 2 times toluene and neutralized with aqueous ammonia solution to pH 7 to 7.5. The precipitated product is extracted with dichloromethane and the dichloromethane is distilled off. The residue is dissolved in the same amount of ethyl acetate and 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole crystallizes under stirring and cooling, which is filtered off with suction and dried. 4.7 g (21.5%) are obtained. EXAMPLE 3 40.4 g (0.285 mol) boron trifluoride is added to a suspension of 38.1 g (0.3 mol) of 2-methyl-4- [5-nitroimidazole in 200 ml of anhydrous nitrobenzene at 5 to 20 DEG C. with stirring. ether. Thereafter, 55.5 g (0.6 mol) of epichlorohydrin was added to the reaction mixture with stirring at 0 to 10 ° C, and the mixture was left to stir at this temperature for 2 hours. 20% sulfuric acid and after thorough mixing the nitrobenzene layer is separated and extracted again with 20% sulfuric acid, the acid extracts are combined, washed with toluene and neutralized! with an aqueous ammonia solution to pH 7 to 7.5.

Vylúčený produkt sa extrahuje dichlórmetánom a získaný extrakt sa zahustí·. Zbytok sa'rozpustí v etylacetáte a kryštalizáciou sa získá prvý kryštál. Zahuštěním matečného luhu akryštalizáciou sa získá druhý kryštál, ktorý sa spojí s prvým. Spojené kryštály sa vysusia,pričom sa získá 14,0 g 1-/3-chlór-2-hydroxypropy1/-2-mety1-5-nitroimidazol, to je 21 % s tep-lotou topenia 84 až 86 °C. Příklad 4 K suspenzii 12,7 g /0,1 mol/ 2-mety1-4/5/-nitroimidazolu v 100 ml bezvodého nitrobenzé-nu sa pri teplote 15 °C přidá 13,6 g /0,1 mól/ bezvodého chloridu zinočnatého a po 0,5 hpri teplote 7 až 10 °C sa prikvapká 13,9 g /0,15 mól/ epichlórhydrínu. Pri tejto teplote sareakčná zmes mieša 4 h a potom sa vyleje do 20% kyseliny sírovej. Po oddělení nítrobenzénusa tento extrahuje ešte raz 20% kyselinou sírovou.The precipitated product is extracted with dichloromethane and the extract obtained is concentrated. The residue was dissolved in ethyl acetate and crystallized to give the first crystal. Concentration of the mother liquor by crystallization yields a second crystal which is combined with the first. The combined crystals were dried to give 14.0 g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, i.e. 21%, mp 84-86 ° C. EXAMPLE 4 To a suspension of 12.7 g (0.1 mol) of 2-methyl-4H-nitroimidazole in 100 ml of anhydrous nitrobenzene was added 13.6 g (0.1 mol) of anhydrous chloride at 15 ° C. zinc and 13.9 g (0.15 mol) of epichlorohydrin are added dropwise at 0.5 to 10 ° C. At this temperature, the reaction mixture is stirred for 4 h and then poured into 20% sulfuric acid. After separation of the benzobenzene, it is extracted once more with 20% sulfuric acid.

Kyselinové vrstvy sa spoja, premyjú toluénom a neutralizujú sa 10 N roztokom NaOH na pH7,5. Neutrálna zmes sa extrahuje dichlórmetánom. Dichlórraetán sa vakuovo oddestiluje, k desti-lačnérau zvyšku sa přidá rovnaké hmotnostně množstvo etylacetátu a nechá sa krystalizovat.Vypadnutý kryštál sa odsaje a vysuší. Získá sa 4,5 g, to je 20 % 1-/3-chlór-2-hydroxypropy1/--2-metyl-5-nitroimidazolu s teplotou topenia 84 až 87 °C. Příklad 5The acid layers were combined, washed with toluene and neutralized with 10 N NaOH solution to pH 7.5. The neutral mixture was extracted with dichloromethane. Dichlorraethane is distilled off under vacuum, an equal amount of ethyl acetate is added to the distillation residue and crystallized. The precipitated crystal is filtered off with suction and dried. 4.5 g (20%) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole are obtained, m.p. 84-87 ° C. Example 5

Reakcia sa uskutoční ako v příklade 1 s odlišnou izoláciou. Po 1 h miešani sa reakčnázmes· vyleje do ladovej vody a mieša sa ešte 10 min, potom sa vypadnutý kryštál odsaje a pre-myje toluénom. Je to nezreagovaný 2-metyl-4/5/-nitroimidazol 70 až 80 % a anorganické soli.The reaction is carried out as in Example 1 with different isolation. After stirring for 1 h, the reaction mixture was poured into ice water and stirred for 10 min, then the precipitated crystal was filtered off with suction and washed with toluene. It is unreacted 2-methyl-4 H 5 -nitroimidazole 70-80% and inorganic salts.

Nitrobenzénová vrstva sa oddeli a extrahuje 2 rázy HC1 : lad —1:1· Extrakty sa spoja apremyjú 2 rázy toluénom. Ku kyselinovému extraktu sa přidá chloroform a neutralizuje sa vod-ným čpavkom pri teplote do 20 °C na pH 7,5. Chloroformová vrstva sa potom oddělí a vodný roz-tok sa extrahuje ešte raz chloroformora.The nitrobenzene layer was separated and extracted 2 times with HCl: ice-1: 1. The extracts were combined and washed with toluene for 2 hours. Chloroform was added to the acidic extract and neutralized to pH 7.5 with aqueous ammonia at up to 20 ° C. The chloroform layer was then separated and the aqueous solution was extracted once more with chloroform.

Claims

The chloroform is dried and concentrated in vacuo to dryness. The same amount of ethyl acetate was added to the residue and, with stirring and cooling, 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroiraidazole was crystallized and filtered off with suction and dried. 13.4 g (64.2%) of the product are obtained, m.p. 86-89 ° C. SUBJECT OF THE INVENTION

A process for preparing 1- [3-chloro-2-hydroxypropyl] -2-methyl-5-nitroimidazole of formula I

CHo-CH-CH 2 O 2 OH Cl by reacting 2-methyl-4/5-nitroiraidazole with epichlorohydrin characterized in that the reaction is carried out in anhydrous nitrobenzene in the presence of a Lewis acid at -10 to + 70 ° C for 0.1 to 1.0 hours using 0.1 to 3 moles of Lewis acid and 1 to 6 molepichlorohydrin per 1 mol of 2-methyl-4 (5 H -nitroimidazole).

2. A process according to claim 1, wherein the Lewis acid is aluminum anhydride.

3. A process as claimed in claim 1, wherein 0.9 to 1 mol of Lewis acid is used per 1 mol of 2-methyl-4, 5'-nitroimidazole.

4. A process according to claim 1, wherein 1 to 3 moles of epichlorohydrin are used per 1 mol of 2-methyl-4, 5'-nitro-irasidazole.

5. Process according to claim 1, 2, 3 and 4, characterized in that the reaction is carried out at a temperature of 0 to 20 ° C. Severografia. n. p., race 7. Most