CS243559B1 - Method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroamidazole preparation - Google Patents
Method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroamidazole preparation Download PDFInfo
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- CS243559B1 CS243559B1 CS842182A CS218284A CS243559B1 CS 243559 B1 CS243559 B1 CS 243559B1 CS 842182 A CS842182 A CS 842182A CS 218284 A CS218284 A CS 218284A CS 243559 B1 CS243559 B1 CS 243559B1
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- methyl
- nitroimidazole
- hydroxypropyl
- chloroform
- nitromethane
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- 238000000034 method Methods 0.000 title abstract description 9
- 238000002360 preparation method Methods 0.000 title description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims abstract description 13
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 7
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 7
- 238000007171 acid catalysis Methods 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- -1 1- (2-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole Chemical compound 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 6
- 238000002955 isolation Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000003960 organic solvent Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- PKHSYECOARTNJZ-UHFFFAOYSA-N (3-chloro-2-hydroxypropyl) hydrogen sulfate Chemical compound ClCC(O)COS(O)(=O)=O PKHSYECOARTNJZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
Vynález popisuje spósob přípravy l-(3- -chlór-2-hydroxypropylJ -2-metyl-5-nitroimodazolu štruktúrneho vzorca I 0^·' N CH;,- (C. CW3 CH-CH Cl I * OH (I) reakciou 2-metyl-4(5J-nitroimidazolu s epichlórhydrínom za katalýzy Lewisovými kyselinami ako je bezvodý AlCls, ZnClz, FeCb, pri teplotách 6 až 60 °C, reakčnom čase 0,5 až 12 h, v prostředí organických rozpúšťadiel ako je aceton, nitrometán alebo octan etylnatý. Popisuje taktiež sposob izolácie produktu pre vedenie syntézy v každom z rozpúšťadiel.The invention discloses a method of preparing 1- (3- -chloro-2-hydroxypropyl-2-methyl-5-nitroimodazole of Formula I 0 ^ N ' CH;, - (C. CW3 CH-CHCl I * OH (I) by reacting 2-methyl-4 (5'-nitroimidazole with epichlorohydrin under Lewis acid catalysis such as anhydrous AlCl 3, ZnCl 2, FeCl 2, at temperatures of 6 to 60 ° C, reaction time of 0.5 up to 12 h, in an organic solvent environment such as acetone, nitromethane or acetate acetate. It also describes the method of product isolation for conducting synthesis in each of the solvents.
Description
Vynález popisuje sposob přípravy titulnej zlúčeniny, ktorá sa dá i zíiážjarnjiť šitru^túr4* nym vzorcom IThe present invention discloses a method of synthesis of the title compound to be the touring zíiážjarnjiť Sitro ^ 4 * nym formula I,
c/£CW-c«, ώ I I 4c / £ C W -c «, ώ II 4
OH Cl (I)OH Cl (I)
Zlúčenina sa využívá v humánnej medicíně na liečbu protozonálnych infekcii. Je popísaná příprava tejto látky reakciou 2-metyl-4 (5 j-nitroimidazolu s epichlórhydrínom v 85 °/o-nej kyselině mravčej s výťažkom 40 % [M. Hoffer, E. Grundberg: J. Med. Chem. 17, 1019 (1974)], ďalej alkyláciou 2-metyl-4 (5) -nitroimidazolu bis (3-chlór-2-hydroxypropyljsulfátom s výtažkem 25 % (USA pat. č. 3 519 637).The compound is used in human medicine for the treatment of protozonal infections. The preparation of this compound is described by reaction of 2-methyl-4- (5'-nitroimidazole with epichlorohydrin in 85% formic acid in a yield of 40% [M. Hoffer, E. Grundberg: J. Med. Chem. 17, 1019 ( 1974)], followed by alkylation of 2-methyl-4 (S) -nitroimidazole with bis (3-chloro-2-hydroxypropyl sulfate) in 25% yield (U.S. Pat. No. 3,519,637).
Ďalšou metodou přípravy je alkylácia 2-metyl-4(5)-nitroimidazolu epichlórhydrínom v prostředí bezvodého nitrobenzénu. Reakcia je katalyzovaná Lewisovou kyselinou — — prakticky bezvodý AICI3 (čs. AO číslo 211414) a má niekolko výhod oproti predchádzajúcim postupom. Ide o skrátenie reakčného času a dosahovanie dobrých výťažkov okolo 40 %.Another method of preparation is alkylation of 2-methyl-4 (S) -nitroimidazole with epichlorohydrin in anhydrous nitrobenzene. The reaction is catalyzed by Lewis acid - practically anhydrous AlCl 3 (ref. AO no. 211414) and has several advantages over the prior art. This is a shortening of reaction time and achieving good yields of around 40%.
Uvedený postup má však jednu vel'kú nevýhodu pre praktické využitie. Nitrobenzén, ktorý sa používá vo velkom množstve ako rozpúšťadlo, je silné toxický.However, this process has one major disadvantage for practical applications. Nitrobenzene, which is used in large quantities as a solvent, is highly toxic.
Uvedené nevýhody odstraňuje spósob přípravy 1- (3-chlór-2-hydroxypropyl) -2-metyl-5-nitroimidazolu štruktúrneho vzorca I °YYThe above disadvantages are overcome by the process for the preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole of structural formula (I)
CH-CH-CHCiCH-CH-CHCl
I i.I i.
OH (I) reakciou 2-metyl-4 (5 )-nitr oimidazolu s epichlórhydrínom za katalýzy Lewisovou kyselinou, ako sú bezvodý AlClj, ZnCla, FeCl3, pri teplotách 6 až 60 °C, reakčnom čase 0,5 až 12 h, ktorý sa uskutočňuje tak, že ako reakčné rozpúšťadlo sa použije aceton alebo nitrometán alebo octan etylnatý.OH (I) by reaction of 2-methyl-4 (S) -nitroimidazole with epichlorohydrin under Lewis acid catalysis such as anhydrous AlCl 3, ZnCl 3, FeCl 3, at temperatures of 6 to 60 ° C, reaction time of 0.5 to 12 h, which The reaction is carried out by using acetone or nitromethane or ethyl acetate as the reaction solvent.
Podstata úspěšnosti alkylácie 2-metyl-4(5j-nitroimidazolu epichlórhydrínom za katalýzy Lewisovou kyselinou je vo výbere vhodného rozpúšťadla, ktoré musí mať dostatočne vysokú dielektrickú konstantu.The essence of the success of alkylation of 2-methyl-4- (5'-nitroimidazole with epichlorohydrin under Lewis acid catalysis is in the choice of a suitable solvent which must have a sufficiently high dielectric constant.
Výhoddu -, tofíto 'vynálezu je náhrada ιοί xiókého^jiitýobénzéjiu fpri alkylácii 2-metyl-4(5)-niťroimidazolu epichlórhydrínom za katalýzy Lewisovou kyselinou acetonom alebo nitrometánom alebo octanom etylnatým.Výhoddu -, tofíto 'invention to replace ιοί xiókého jiitýobénzéjiu ^ f the alkylation of 2-methyl-4 (5) -niťroimidazolu epichlorohydrin under Lewis acid catalysis, acetone or nitromethane or ethyl acetate.
Dielektrické konštanty sú uvedené v ta buíke 1.The dielectric constants are given in Table 1.
Tabulka 1Table 1
Rozpúšťadlo Dielektrická konstanta ε při 20 °C nitrometán 38,20 nitrobenzén 35,96 aceton 21,45Solvent Dielectric constant ε at 20 ° C nitromethane 38.20 nitrobenzene 35.96 acetone 21.45
Postup podl'a vynálezu sa uskutočňuje tak, že sa k suspenzii 1 molu 2-metyl-4(5j-nitroimidazolu v bezvodom acetone, octane etylnatom alebo nitrometáne přidá 0,2 až 2 moly, s výhodou 0,8 až 1,1 mólu Lewisovej kyseliny a ďalej 1 až 5 mólov, s výhodou 1 až 1,5 mólu epichlórhydrínu pri teplote 6 až 60 °C, s výhodou 7 až 9 °C.The process according to the invention is carried out by adding 0.2 to 2 moles, preferably 0.8 to 1.1 moles, to a suspension of 1 mole of 2-methyl-4- (5'-nitroimidazole in anhydrous acetone, ethyl acetate or nitromethane). Lewis acid and further 1 to 5 moles, preferably 1 to 1.5 moles of epichlorohydrin at a temperature of 6 to 60 ° C, preferably 7 to 9 ° C.
Reakčná zmes sa nechá reagovat pri tejto teplote 0,5 až 12 h, s výhodou 1 až 1,5 h. Po ukončení reakcie sa zmes vyleje do studenej vody (0 až 5 °C) a odfiltruje sa nezreagovaná vstupná surovina.The reaction mixture is allowed to react at this temperature for 0.5 to 12 h, preferably 1 to 1.5 h. After completion of the reaction, the mixture was poured into cold water (0-5 ° C) and the unreacted feedstock was filtered off.
V případe použitia acetónu sa zmes opatrné neutralizuje vodným roztokom NLUOH do pH = 6,0 až 6,5 tak, aby pri použití AICI3 ako alkylačného katalyzátora nevypadol hydroxid hlinitý. Neutralizácia sa robí v přítomnosti chloroformu. Po oddělení sa vodná vrstva ešte dalej extrahuje chlóroformom.If acetone is used, the mixture is carefully neutralized with an aqueous solution of NLUOH to a pH of 6.0 to 6.5 so that aluminum hydroxide does not fall out when using AlCl 3 as the alkylation catalyst. Neutralization is carried out in the presence of chloroform. After separation, the aqueous layer was further extracted with chloroform.
Spojené chloroformové vrstvy sa extrahujú zriedenou kyselinou sírovou alebo chlorovodíkovou. Kyselinová (vodná) vrstva sa opat v přítomnosti chloroformu neutralizuje vodným roztokom čpavku na pH — 7,0 až 7,5, vodná vrstva sa extrahuje ďalšou porclou chloroformu a chloroformové vrstvy sa spoja. Chloroform sa odstráni na vákuovej odparke pri maximálnej teplote do 40 °C a získá sa surový produkt (I), ktorý sa kryštalizuje z etylacetátu.The combined chloroform layers are extracted with dilute sulfuric acid or hydrochloric acid. The acidic (aqueous) layer is neutralized in the presence of chloroform to an aqueous ammonia solution to a pH of 7.0-7.5, the aqueous layer is extracted with another portion of chloroform, and the chloroform layers are combined. The chloroform is removed in a vacuum evaporator at a maximum temperature of up to 40 ° C to give the crude product (I) which is crystallized from ethyl acetate.
V případe použitia nitrometánu ako rozpúšťadla sa po odfiltrovaní nezreagovaného 2-metyl-4 (5)-nitroimidazolu reakčná zmes nechá rozvrstvit. Nitrometánová vrstva sa potom extrahuje zriedenou kyselinou chlorovodíkovou. Kyselinová (vodná vrstva) sa ďalej neutralizuje v přítomnosti chloroformu vodným roztokom čpavku na pH 7,0 až 7,5.If nitromethane is used as the solvent, the reaction mixture is allowed to stratify after filtering off unreacted 2-methyl-4 (S) -nitroimidazole. The nitromethane layer was then extracted with dilute hydrochloric acid. The acidic (aqueous layer) is further neutralized in the presence of chloroform with an aqueous ammonia solution to a pH of 7.0 to 7.5.
Vodná vrstva sa dalej extrahuje ďalšou dávkou chloroformu. Chloroformové vrstvy sa spoja a na vákuovej odparke sa odstráni chloroform pri teplote maximálně 40 “C. Surový produkt sa kryštalizuje z etylacetátu.The aqueous layer was further extracted with another portion of chloroform. Combine the chloroform layers and remove the chloroform at a maximum temperature of 40 ° C on a vacuum evaporator. The crude product was crystallized from ethyl acetate.
V dalšom je priebeh vynálezu popísaný v príkladoch bez toho, aby sa na tieto obmedzoval.In the following, the invention is described in the examples without being limited thereto.
Příklad 1Example 1
K suspenzii 120 g acetonu a 12,7 g (0,1 molu) 2-metyl-4(5)-nitroimidazolu sa za miešania přidá 13,3 g (0,1 molu) bezvodého A1CÍ3 pri teplote 18 °C počas 30 min. Reakčná zmes sa ochladí na 5 až 10 °C a pomaly sa prikvapkáva 9,3 g (0,1 molu) epichlórhydrínu. Po 90 min miešania pri teplote okolo 8 °C sa zmes vyleje do 100 ml ladovej vody a odfiltruje sa nezreagovaný 2-metyl-4 (5 j-nitroimidazol (4,5 až 5,5 g). Táto nezreagovaná surovina sa vymyje studenou vodou, vysuší, dalej sa rozpustí v etanole za horúca, rafinuje s aktívnym uhlím a nechá vykrystalizovat. Takto regenerovaný 2-metyl-4 (5 j-nitroimidazol je možné použit na alkyláciu a celkové výtažky sa tým zvýšia o cca 20 %.To a suspension of 120 g of acetone and 12.7 g (0.1 mol) of 2-methyl-4 (S) -nitroimidazole was added with stirring 13.3 g (0.1 mol) of anhydrous AlCl 3 at 18 ° C for 30 min. . The reaction mixture was cooled to 5-10 ° C and 9.3 g (0.1 mol) of epichlorohydrin was slowly added dropwise. After stirring at about 8 ° C for 90 minutes, the mixture is poured into 100 ml of ice water and filtered off unreacted 2-methyl-4 (5'-nitroimidazole (4.5-5.5 g). This unreacted raw material is washed with cold water. The thus-recovered 2-methyl-4 (5'-nitroimidazole can be used for the alkylation and the overall yields thus increased by about 20%), dried, further dissolved in hot ethanol, refined with activated carbon and allowed to crystallize.
Do filtrátu sa přidá 40 ml chloroformu a opatrné sa zneutralizuje s 1 až 5 ml koncentrovaného roztoku amoniaku na pH — = 6,0 až 6,5. (Nesmie vypadnut hydroxid hlinitý.) Chloroformová vrstva sa oddělí a vodná vrstva sa extrahuje 3 X 30 ml chloroformu. Chloroformové vrstvy sa spoja a extrahujú sa 3 X 10 ml 9 N H2SO4. Vodná kyselinová vrstva sa zmieša s 200 ml chloroformu a za miešania a chladenia (18 až 20 °C) sa neutralizuje s vodným roztokom čpavku do pH = 7,0 až 7,5.40 ml of chloroform are added to the filtrate and carefully neutralized with 1 to 5 ml of concentrated ammonia solution to pH = 6.0 to 6.5. The aluminum layer was separated and the aqueous layer was extracted with 3 X 30 mL of chloroform. Combine the chloroform layers and extract with 3 X 10 mL 9 N H 2 SO 4. The aqueous acid layer was mixed with 200 ml of chloroform and neutralized with an aqueous ammonia solution to pH = 7.0 to 7.5 with stirring and cooling (18-20 ° C).
Chloroformová vrstva sa oddělí a vodná vrstva sa extrahuje s 2 X 20 ml chloroformu. Chloroformové vrstvy sa spoja, vysušia bezvodým CaCh a rozpúšťadlo sa odpaří na vákuovej odparke pri maximálnej teplote 40 °C. K destilačnému zvyšku (10 g olejovej kvapaliny) sa přidá 10 g etylacetátu a za miešania sa zmes podchladí na teplotu —10 až 0 °C.The chloroform layer was separated and the aqueous layer was extracted with 2 X 20 mL of chloroform. The chloroform layers were combined, dried over anhydrous CaCl 2, and the solvent was evaporated in a vacuum evaporator at a maximum temperature of 40 ° C. To the distillation residue (10 g of an oily liquid) was added 10 g of ethyl acetate and the mixture was cooled to -10 ° C to 0 ° C with stirring.
Vypadnutý kryštál l-(3-chlór-2-hydroxypropyl j-2-metyl-5-nitroimidazolu sa odsaje a vysuší na vákuovej sušiarni pri teplote maximálně 40 °C. Získá sa 9,0 g produktu (40,9 % na teóriu) o teplote topenia 83,5 až 87 °C.The precipitated 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole crystal is filtered off with suction and dried in a vacuum oven at a maximum of 40 ° C to give 9.0 g of product (40.9% of theory). mp 83.5-87 ° C.
Příklad 2Example 2
K suspenzii 12,7 g (0,1 molu) 2-metyl-4(5j-nitroimidazolu v 120 g acetonu sa pri teplote 18 až 20 °C přidá 15,4 g (0,095 mólu) bezvodého chloridu železitého počas 30 min. Potom sa zmes ochladí na 4 až 8 °C a pomaly sa přidá 18,6 g (0,2 móluj epichlórhydrínu. Po ukončení pridávania sa zmes mieša 6 h pri teplote do 10 °C. Potom sa reakčná zmes vyleje do 100 ml Tadovej vody a odsaje sa nezreagovaný 2-metyl-4(5j-nitroimidazol.To a suspension of 12.7 g (0.1 mol) of 2-methyl-4- (5'-nitroimidazole in 120 g of acetone at 18-20 ° C) was added 15.4 g (0.095 mol) of anhydrous ferric chloride over 30 min. The mixture is cooled to 4-8 ° C and 18.6 g (0.2 mol of epichlorohydrin) are added slowly. After the addition is complete, the mixture is stirred at a temperature of up to 10 ° C for 6 h, then poured into 100 ml of ice water. unreacted 2-methyl-4 (5'-nitroimidazole) is filtered off with suction.
Ďalšia izolácia je rovnaká ako je popísané v příklade 1. Získá sa 5,1 g l-(3-chlór-2-hydroxypropyl j -2-mety 1-5-nitroimidazolu (23,2 % na teóriu) o teplote topenia 84 až 86,5 °C.Further isolation is the same as described in Example 1. 5.1 g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (23.2% of theory), m.p. 86.5 ° C.
Příklad 3Example 3
K suspenzii 120 g acetonu a 12,7 g (0,1 móluj 2-metyl-4(5)-nitroimidazolu sa pri teplote 18 až 20 °C počas 20 min přidá 13,6 gramov (0,1 móluj bezvodého chloridu zinočnatého. Potom sa dávkuje 13,9 g (0,15 móluj epichlórhydrínu pri teplote 7 až 10°C. Po nadávkovaní celého množstva sa reakčná zmes mieša pri tejto teplote ešte 5 h a vyleje sa do 100 ml ladovej vody. Vypadnutý nezreagovaný 2-metyl-4(5j-nitroimidazol (7,4 g) sa odsaje a regeneruje podfa postupu v příklade 1. Filtrát sa spracuje izolačným postupom popísaným v příklade 1.To a suspension of 120 g of acetone and 12.7 g (0.1 mol of 2-methyl-4 (S) -nitroimidazole) at 18-20 ° C is added, over a period of 20 min, 13.6 g (0.1 mol of anhydrous zinc chloride). 13.9 g (0.15 mol) of epichlorohydrin are then metered in at a temperature of 7 to 10 [deg.] C. After the addition is complete, the reaction mixture is stirred at this temperature for 5 h and poured into 100 ml of ice water. (5'-Nitroimidazole (7.4 g) was aspirated and recovered according to the procedure of Example 1. The filtrate was treated according to the isolation procedure described in Example 1.
Získá sa 5 g (22,7 % na teóriu] l-(3-chlór-2-hydroxypropyl) -2-metyl-5-nitr oimidazolu o teplote topenia 84,5 až 87 °C.5 g (22.7% of theory) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole are obtained, m.p. 84.5-87 ° C.
Příklad 4Example 4
K suspenzii 120 g nitrometánu a 12,7 g (0,1 móluj 2-metyl-4(5)-nitroimidazolu sa pomaly přidá 13,3 g (0,1 móluj bezvodého AlCb pri 15 až 20 °C počas 30 min. Potom sa pomaly dávkuje 9,3 g epichlórhydrínu (0,1 móluj pri 7 až 9 °C počas 60 min. Pri tejto teplote sa zmes zmieša dalších 90 min. Reakčná zmes sa vyleje do 100 ml 1'adovej vody a odfiltruje sa 5,2 g nezreagovaného 2-metyl-4(5)-nitroimidazolu, ktorý sa regeneruje podfa příkladu 1.To a suspension of 120 g of nitromethane and 12.7 g (0.1 mol of 2-methyl-4 (S) -nitroimidazole) was slowly added 13.3 g (0.1 mol of anhydrous AlCl 3 at 15-20 ° C over 30 min.). 9.3 g of epichlorohydrin (0.1 mol at 7 to 9 ° C for 60 min) are slowly added. At this temperature, the mixture is stirred for a further 90 min. The reaction mixture is poured into 100 ml of ice-cold water and filtered off g of unreacted 2-methyl-4 (S) -nitroimidazole which is regenerated according to Example 1.
Filtrát sa nechá rozvrstvit a nitrometanová vrstva sa extrahuje s 3 X 25 ml zriedenej HCl (1: 1). Vodná (kyselinová vrstva] sa extrahuje s 2 X 25 ml toluénu a destiluje vodnou parou. Vychladnutá vodná vrstva zbavená zvyškou nitrometánu a toluénu sa neutralizuje za přítomnosti 25 ml CHCb s cca 23 ml vodného roztoku čpavku na pH = = 7,5. Po oddělení vrstiev sa vodná vrstva extrahuje dalšími 2 X 20 ml chloroformu. Chloroformové vrstvy sa spoja a vysušia s bezvodým CaCl2. Chloroform sa odpaří na vákuovej odparke pri teplote 40 °C. K destilačnému zvyšku (9,5 g olejovitej kvapaliny) sa přidá 9,5 g etylacetátu a podchladí sa na —10 až 0 °C za stálého miešania. Získá sa takto opakovanou kryštalizáciou 8,5 g 1- (3-chlór-2-hydroxypropyl j -2-metyl-5-nitroimidazolu (38,6 % na teóriu) o teplote topenia 84 až 87 ’C.The filtrate was allowed to stratify and the nitromethane layer was extracted with 3 X 25 mL dilute HCl (1: 1). The aqueous (acidic layer) was extracted with 2 X 25 mL of toluene and distilled with steam, and the cooled aqueous layer devoid of residual nitromethane and toluene was neutralized in the presence of 25 mL of CHCl 3 with about 23 mL of aqueous ammonia solution to pH = 7.5. The aqueous layer was extracted with an additional 2 X 20 mL of chloroform, the chloroform layers were combined and dried with anhydrous CaCl 2, the chloroform was evaporated in a vacuum evaporator at 40 ° C. To the distillation residue (9.5 g oily liquid) 9.5 g of ethyl acetate and cooled to -10 to 0 ° C with stirring to give 8.5 g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (38.6% by weight). theory), m.p. 84-87 ° C.
Příklad 5Example 5
K suspenzi 120 g octanu etylnatého a 12,7 gramov (0,1 móluj 2-metyl-4(5)-nitroimidazolu sa za miešania přidá 13,3 g (0,1 móluj bezvodého AlCb pri teplote 18 °C počas 30 minút. Reakčná zmes sa ochladí na 5 až 10 °C a pomaly sa prikvapkáva 9,3 g (0,1 móluj epichlórhydrínu. Reakcia je ukončená po 90 min miešania pri teplote okolo 8 °C.To a suspension of 120 g of ethyl acetate and 12.7 grams (0.1 mole of 2-methyl-4 (S) -nitroimidazole) was added, with stirring, 13.3 g (0.1 mole of anhydrous AlCl 3 at 18 ° C over 30 minutes). The reaction mixture is cooled to 5-10 ° C and 9.3 g (0.1 mol of epichlorohydrin) is slowly added dropwise. The reaction is complete after stirring for 90 minutes at a temperature of about 8 ° C.
Izolácia produktu sa urobí postupom popísaným v příklade 4. Získá sa 9,1 g l-(3-chlór-2-hydr oxypropylj -2-metyl-5-nitroimi8 dazolu (41,1 % na teóriu) o teplote topenia 84 až 87 °C.Isolation of the product was carried out as described in Example 4. 9.1 g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole (41.1% of theory), m.p. C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS842182A CS243559B1 (en) | 1984-03-27 | 1984-03-27 | Method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroamidazole preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS842182A CS243559B1 (en) | 1984-03-27 | 1984-03-27 | Method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroamidazole preparation |
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| Publication Number | Publication Date |
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| CS218284A1 CS218284A1 (en) | 1985-09-17 |
| CS243559B1 true CS243559B1 (en) | 1986-06-12 |
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| CS842182A CS243559B1 (en) | 1984-03-27 | 1984-03-27 | Method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroamidazole preparation |
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| Country | Link |
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