CS269646B1 - Method of new 2,3 -dichlorobenzhydrylamines and their salts preparation - Google Patents
Method of new 2,3 -dichlorobenzhydrylamines and their salts preparation Download PDFInfo
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- CS269646B1 CS269646B1 CS89180A CS18089A CS269646B1 CS 269646 B1 CS269646 B1 CS 269646B1 CS 89180 A CS89180 A CS 89180A CS 18089 A CS18089 A CS 18089A CS 269646 B1 CS269646 B1 CS 269646B1
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- dichlorobenzhydryl
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- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims abstract description 5
- FFEGYZAUBQOAEH-UHFFFAOYSA-N (2,3-dichlorophenyl)-phenylmethanamine Chemical class C=1C=CC(Cl)=C(Cl)C=1C(N)C1=CC=CC=C1 FFEGYZAUBQOAEH-UHFFFAOYSA-N 0.000 title abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000009835 boiling Methods 0.000 claims abstract description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 8
- CUXLOTKXIASOOJ-UHFFFAOYSA-N 1-chloro-2-[chloro-(3-chlorophenyl)methyl]benzene Chemical compound C=1C=CC=C(Cl)C=1C(Cl)C1=CC=CC(Cl)=C1 CUXLOTKXIASOOJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- LWEOFVINMVZGAS-UHFFFAOYSA-N 3-piperazin-1-ylpropan-1-ol Chemical compound OCCCN1CCNCC1 LWEOFVINMVZGAS-UHFFFAOYSA-N 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- YMCKERZFXBJZTG-UHFFFAOYSA-N (2-chlorophenyl)-(3-chlorophenyl)methanamine Chemical compound C=1C=CC=C(Cl)C=1C(N)C1=CC=CC(Cl)=C1 YMCKERZFXBJZTG-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- -1 1- (2,3-Dichlorobenzhydryl) -4- (3-hydroxypropyl) piperazine Chemical compound 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000000202 analgesic effect Effects 0.000 abstract description 3
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000954 anitussive effect Effects 0.000 abstract description 2
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 2
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 2
- 229960003965 antiepileptics Drugs 0.000 abstract description 2
- 229940124584 antitussives Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000812 cholinergic antagonist Substances 0.000 abstract description 2
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 230000002048 spasmolytic effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000007059 acute toxicity Effects 0.000 description 4
- 231100000403 acute toxicity Toxicity 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 3
- 229910001626 barium chloride Inorganic materials 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 210000001198 duodenum Anatomy 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- JYOCLXGPKHQPFD-UHFFFAOYSA-N (2-chlorophenyl)-(3-chlorophenyl)methanol Chemical compound C=1C=CC=C(Cl)C=1C(O)C1=CC=CC(Cl)=C1 JYOCLXGPKHQPFD-UHFFFAOYSA-N 0.000 description 2
- UYUKSGQLYHPHCQ-UHFFFAOYSA-N 1-[(2-chlorophenyl)-(3-chlorophenyl)methyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C(C=1C(=CC=CC=1)Cl)C1=CC=CC(Cl)=C1 UYUKSGQLYHPHCQ-UHFFFAOYSA-N 0.000 description 2
- GKEHZQGLUFPXBD-UHFFFAOYSA-N 2-[4-[(2-chlorophenyl)-(3-chlorophenyl)methyl]piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1C(C=1C(=CC=CC=1)Cl)C1=CC=CC(Cl)=C1 GKEHZQGLUFPXBD-UHFFFAOYSA-N 0.000 description 2
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 229960004266 acetylcholine chloride Drugs 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UBAMBMPJTHYTTK-UHFFFAOYSA-N 1,2-dichloro-3-[chloro(phenyl)methyl]benzene Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(Cl)C1=CC=CC=C1 UBAMBMPJTHYTTK-UHFFFAOYSA-N 0.000 description 1
- YQMFALXYPQOIFE-UHFFFAOYSA-N 1-[(2-chlorophenyl)-(3-chlorophenyl)methyl]azepane Chemical compound ClC1=CC=CC(C(N2CCCCCC2)C=2C(=CC=CC=2)Cl)=C1 YQMFALXYPQOIFE-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Abstract
Řešení spadá do oblasti synthesy léčiv. Jeho předmětem je způsob přípravy nových 2,3 -dichlorbenzhydrylaminu vzorce I, kde X značí -CH2CH2-, >NCH3, >N(CH2)2 OH, > N(CH2)3oh a jejích solí. Látky podle řešení jsou meziprodukty přípravy farmakodynamicky účinných sloučenin a jejich soli samy o sobě mají některé použitelné farmakodynamické efekty (např. spasmolytický, hypoglykemický, analgetlcký, antitusický, protikřečový), takže jsou potenciálními léčivy. Způsob přípravy látek podle řešení spočívá v substitučních reakcích 2,3'-dichlorbenzhydrylchloridu s hexamethylenlminem, l-methylpiperazinem, 2-(l- -piperazinyljethanolem a 3-(l-piperazinyl) propanolem, nejlépe ve vroucím dioxanu. Neutralisací basí kyselinami se získají příslušné solí.The solution lies in the field of drug synthesis. His subject is a method of preparation of new 2,3-dichlorobenzhydrylamine of formula Wherein X is -CH2CH2-, > NCH3, > N (CH2) 2 OH,> N (CH 2) 3 OH and its salts. Substances by solutions are intermediates of the preparation pharmacodynamically active compounds and their salts themselves have some useful pharmacodynamic effects (eg spasmolytic, hypoglycemic, analgesic, antitussive, anticonvulsant), so they are potential medicinal. Process for preparing substances according to the invention consists of substitution reactions 2,3'-dichlorobenzhydryl chloride with hexamethylenimine, 1-methylpiperazine, 2- (1- -Piperazinyljet ethanol and 3- (1-piperazinyl) propanol, preferably in boiling dioxane. Neutralization of the acids was obtained appropriate salt.
Description
Vynález se týká způsobu přípravy nových 2,3'-dichlorbenzhydrylaminu obecného vzorce I,The invention relates to a process for the preparation of novel 2,3'-dichlorobenzhydrylamines of the general formula I,
(I) ve kterém X značí -CH2CH2~, χΝΟΗ3, ^C^Cf^OH nebo ^Ν(ΟΗ2)3ΟΗ, a jejich solí s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami.(I) wherein X represents -CH 2 CH 2 -, χ ΝΟΗ 3 , ^ C ^ Cf ^ OH or ^ Ν (ΟΗ 2 ) 3 ΟΗ, and their salts with pharmaceutically acceptable inorganic or organic acids.
Látky vzorce I podle vynálezu jsou meziprodukty syntézy farmakodynamicky účinných látek a jejich soli - samy o sobě - vykazují některé použitelné farmykodynamické efekty (spasmolytlcký, hypoglýkemický, analgetický, antitusický, protikřečový), kte ré z nich činí potenciální léčiva. Dále jsou uvedeny některé látek vzorce I, které byly podávány orálně nebo intravenozně v mg/kg.The compounds of the formula I according to the invention are intermediates in the synthesis of pharmacodynamically active substances and their salts - in themselves - show some useful pharmacodynamic effects (antispasmodic, hypoglycemic, analgesic, antitussive, anticonvulsant) which make them potential drugs. The following are some of the compounds of formula I which have been administered orally or intravenously in mg / kg.
N-(2,3'-0ichlorbenzhydryl)hexamethylenimin byl testován □eho akutní toxicita při i. v. podání LD„ « 100 mg/kg. V i.N- (2,3'-dichlorobenzhydryl) hexamethyleneimine was tested for acute toxicity at i.v. administration of LD 100 <100 mg / kg. V i.
Ov volává látka krátkodobé, hluboké poklesy krevního tlaku normotensních, anestetizovaných krys, v orální dávce 125 mg/kg má mírný analgetický účinek v tzv. peritoneálním testu u myší, kdy bolestivý podnět je navozen intraperitoneální injekcí zředěného roztoku kyseliny octové.Ov calls short-term, deep drops in blood pressure in normotensive, anesthetized rats, at an oral dose of 125 mg / kg has a mild analgesic effect in the so-called peritoneal test in mice, where the painful stimulus is induced by intraperitoneal injection of dilute acetic acid solution.
l-(2,3'-Dichlorbenzhydryl)-4-methylpiperazin byl testován ve formě bis(hydrogenmaleinátu). Akutní toxicita u myší LDgc je 326 mg/kg orálně a 40 mg/kg i. v. V. orální dávce 40 mg/kg signifikantně snižuje hladinu krevního cukru (hypoglýkemický účinek). V orálních dávkách 25 až 40 mg/kg působí protizánětlivě v testu kaolinového zánětu krysí tlapy. Působí spasmolyticky na izolovaném krysím duodenu v koncentracích 1 až 10 mg/1, a to jak vůči acetylcholinovým kontrakcím, tak i proti kontrakcím ba ry ume hlor i dovým.1- (2,3'-Dichlorobenzhydryl) -4-methylpiperazine was tested as bis (hydrogen maleate). The acute toxicity in LD gc mice is 326 mg / kg orally and 40 mg / kg iv in the V. oral dose of 40 mg / kg significantly reduces blood sugar (hypoglycemic effect). At oral doses of 25 to 40 mg / kg, it has an anti-inflammatory effect in the rat paw kaolinitis test. It acts spasmolytically on isolated rat duodenum in concentrations of 1 to 10 mg / l, both against acetylcholine contractions and against barium chloride contractions.
l-(2,3'-0ichlorbenzhydryl)-4-(2-hydroxyethyl)piperazin byl testován jako dihy drochlorid. Akutní toxicita u myší LDg0 je 245 mg/kg orálně a 30 mg/kg i tu maximálního elektrošoku u myší má látka mírný protektivní účinek vůči křečovým projevům (chráněno 30 % myší) v dávce 50 mg/kg orálně (tato dávka plně chrání myši proti hynutí). V i dávce 6 mg/kg vyvolává krátkodobé a hluboké poklesy krevního tlaku u normotensních, anestetizovaných krys. Působí spasmolyticky na izolovaném krysím duodenu v koncentracích 1 až 10 mg/1, a to jak vůči acetylcholinovým, tak i baryumchloridovým spasmům. V orální dávce 30 mg/kg působí antitusticky u morčat : snižuje počet záchvatů kašle, vyvolávaného aerosolem roztoku kyseliny citrónové, na 50 %. Při orálním podání dávky 30 mg/kg vyvolává mírnou hypoglykemii u krys (za 2 h snížení hladiny cukru o 20 %).1- (2,3'-dichlorobenzhydryl) -4- (2-hydroxyethyl) piperazine was tested as the dihydrochloride. Acute toxicity in LD g0 mice is 245 mg / kg orally and 30 mg / kg even in maximal electroshock in mice has a mild protective effect against seizures (protected by 30% of mice) at a dose of 50 mg / kg orally (this dose fully protects mice against death). At a dose of 6 mg / kg, it causes short-term and profound decreases in blood pressure in normotensive, anesthetized rats. It acts spasmolytically on isolated rat duodenum in concentrations of 1 to 10 mg / l, both against acetylcholine and barium chloride spasms. At an oral dose of 30 mg / kg, it has an antitustic effect in guinea pigs: it reduces the number of cough attacks caused by the aerosol of citric acid solution to 50%. When administered orally at a dose of 30 mg / kg, it causes mild hypoglycaemia in rats (20% reduction in sugar levels in 2 hours).
l-(2,3x-Oichlorbenzhydryl)-4-(3-hydroxypropyl)piperazin byl testován jako maleinát. Akutní toxicita u myší LD50 je 326 mg/kg orálně a 30 mg/kg i. v. V i. v. dávce 6 mg/kg vyvolává krátkodobé a hluboké poklesy krevního tlaku u normotensních, anestetizovaných krys. Podobně jako předchozí látky působí spasmolyticky vůči acetylcholinu i chloridu barnatému na izolovaném krysím duodenu. V dávkách 10 až 30 mg/kg snižuje signifikantně hladinu krevního cukru u krys. V orální dávce 30 mg/kg působí z 26 % antltueicky u morčat (kašel vyvolávaný aerosolem roztoku kyseliny citrónové).1- (2,3 x -chlorobenzhydryl) -4- (3-hydroxypropyl) piperazine was tested as the maleate. The acute toxicity in LD 50 mice is 326 mg / kg orally and 30 mg / kg iv in an iv dose of 6 mg / kg causes short-term and profound decreases in blood pressure in normotensive, anesthetized rats. Like the previous substances, it has a spasmolytic effect on acetylcholine and barium chloride on isolated rat duodenum. At doses of 10 to 30 mg / kg, it significantly lowers blood sugar in rats. At an oral dose of 30 mg / kg, 26% is antifungal in guinea pigs (cough caused by an aerosol of citric acid solution).
CS 269646 BlCS 269646 Bl
Látky vzorce I podle vynálezu jsou přístupné substitučními reakcemi 2,3'-dichlorbenzhydryIchloridu s aminy obecného vzorce II (II), ve kterém X značí totéž jako ve vzorci I. Reakce se provedou s výhodou ve vroucím dioxanu nebo ve vroucí směsi dioxanu a chloroformu. Výchozí 2,3- dichlorbenzhydry1chlorid je látkou novou a její příprava je popsána v 1. příkladu. Aminy vzorce li, s výjimkou jediného (literatura citována v příkladu), jsou přístupné komerčně. Uvedenými reakcemi se získají olejovlté báze vzorce I, které se převedou neutralizačními reakcemi a farmaceuticky nezávadnými anorganickými nebo organickými kyselinami na příslušné krystalické soli, což je rovněž součástí vynálezu, všechny látky v příkladech popsané jsou nové? jejich identita byla zajištěna analytickými i spektrálními metodami. Dále uvedené příklady, které uvádějí více podrobností, jsou samozřejmě jen znázorněním možností tohoto vynálezu.The compounds of the formula I according to the invention are accessible by substitution reactions of 2,3'-dichlorobenzhydryl chloride with amines of the formula II (II) in which X is the same as in the formula I. The reactions are preferably carried out in boiling dioxane or in a boiling mixture of dioxane and chloroform. The starting 2,3-dichlorobenzhydryl chloride is a novel substance and its preparation is described in Example 1. Amines of formula II, with the exception of one (literature cited in the example), are commercially available. Said reactions give oily yellow bases of the formula I, which are converted by neutralization reactions and pharmaceutically acceptable inorganic or organic acids into the corresponding crystalline salts, which is also part of the invention, all the substances described in the examples being new. their identity was ensured by analytical and spectral methods. The following examples, which provide more details, are, of course, merely illustrative of the possibilities of the present invention.
Příklad 1Example 1
1-(2,3'-D ich iorbenzhydry1Jhexamethylen imin1- (2,3'-Dichlorobenzhydryl] hexamethylene imine
Směs 9,0 g 2,3'-dichlorbenzhydryIchloridu, 16,5 g hexamethyleniminu a 30 ml dioxanu se vaří 11 h pod zpětným chladičem. Po ochlazení se zředí 5% roztokem hydroxidu sodného a extrahuje se etherem. Z organické vrstvy se basický produkt převede do zředěné kyseliny chlorovodíkové, vodná vrstva se z&lkalizuje vodným amoniakem a žádaná báze se izoluje extrakcí etherem. Zpracováním extraktu se získá 4,4 g (40 %) žádané olejovlté báze. Ta se neutralizuje chlorovodíkem ve směsi ethanolu a etheru) získá se krystalický hydrochlorid, t. t. 188 až 191 °C (ethanol-ether).A mixture of 9.0 g of 2,3'-dichlorobenzhydryl chloride, 16.5 g of hexamethyleneimine and 30 ml of dioxane was refluxed for 11 h. After cooling, it is diluted with 5% sodium hydroxide solution and extracted with ether. The basic product was converted from the organic layer to dilute hydrochloric acid, the aqueous layer was basified with aqueous ammonia and the desired base was isolated by extraction with ether. Work-up of the extract gave 4.4 g (40%) of the desired oily yellow base. This was neutralized with hydrogen chloride in a mixture of ethanol and ether) to give a crystalline hydrochloride, m.p. 188-191 ° C (ethanol-ether).
Potřebný výchozí 2,3'~dichlorbenzhydryIchlorid se připraví z 2,3'- dichlorbenzhydrolu (Faith Η. E. et al., 3. Am. chem. Soc. 77, 543 (1955) tímto způsobem:The required starting 2,3'-dichlorobenzhydryl chloride is prepared from 2,3'-dichlorobenzhydrol (Faith A. E. et al., 3. Am. Chem. Soc. 77, 543 (1955) as follows:
Směs 20 g 2,3'-dichlorbenzhydrolu, 40 ml toluenu a io g thionyIchloridu se míchá a vaří 2,5 h pod zpětným chladičem. Po stání přes noc se směs zpracuje destilací, □ako produkt se získá 18,3 g (85 %) oleje vroucího při 104 až 106 °C/66 pa.A mixture of 20 g of 2,3'-dichlorobenzhydrol, 40 ml of toluene and 10 g of thionyl chloride is stirred and refluxed for 2.5 h. After standing overnight, the mixture is worked up by distillation, yielding 18.3 g (85%) of an oil boiling at 104 DEG-106 DEG C./66 pa as product.
příklad 2 l-(2,3'- DichIorbenzhydryl)-4-methylpiperazinExample 2 1- (2,3'-Dichlorobenzhydryl) -4-methylpiperazine
Podobnou reakcí 8,0 g 2,3'-dichlorbenzhydryIchloridu s 13,0 g 1-methylpiperazinu ve vroucí směsi 20 ml chloroformu a 10 ml dioxanu (24 h varu) se získá 9,4 g (95 %) olejovité žádané báze. Neutralizací chlorovodíkem v ethanolu poskytuje krystalický dihydrochlorid, t. t. 252 až 255 °C (ethanol). Bis-(hydrogenmaleinát), t. t. 108 až 110 °C (ethanol-ether).A similar reaction of 8.0 g of 2,3'-dichlorobenzhydryl chloride with 13.0 g of 1-methylpiperazine in a boiling mixture of 20 ml of chloroform and 10 ml of dioxane (boiling time) gave 9.4 g (95%) of the oily desired base. Neutralization with hydrogen chloride in ethanol gives crystalline dihydrochloride, mp 252-255 ° C (ethanol). Bis- (hydrogen maleate), m.p. 108-110 ° C (ethanol ether).
Příklad 3Example 3
1-(2,3'-DichIorbenzhydryl)-4-(2-hydroxyethyl)piperazin .1- (2,3'-Dichlorobenzhydryl) -4- (2-hydroxyethyl) piperazine.
Podobnou reakcí 9,2 g 2,3'-dichlorbenzhydryIchloridu a 18 g 2-(l-piperazinyl) ethanolu ve 30 ml vroucího dioxanu (23 h) se získá 10,6 g (86 %) olejovité báze. . Neutralizací chlorovodíkem ve směsi ethanolu a etheru poskytuje krystalický dihydrochlorid, t. t. 221,5 až 222,5 °C (ethanol-ether).A similar reaction of 9.2 g of 2,3'-dichlorobenzhydryl chloride and 18 g of 2- (1-piperazinyl) ethanol in 30 ml of boiling dioxane (23 h) gave 10.6 g (86%) of an oily base. . Neutralization with hydrogen chloride in a mixture of ethanol and ether gives crystalline dihydrochloride, m.p. 221.5-222.5 ° C (ethanol-ether).
Příklad 4 nch3,Example 4 nch 3 ,
CS 268646 BlCS 268646 Bl
U obecného vzorce I,In general formula I,
X neboX or
N(CH2)30H, a je-N (CH 2 ) 3 OH, and is
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS89180A CS269646B1 (en) | 1989-01-10 | 1989-01-10 | Method of new 2,3 -dichlorobenzhydrylamines and their salts preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS89180A CS269646B1 (en) | 1989-01-10 | 1989-01-10 | Method of new 2,3 -dichlorobenzhydrylamines and their salts preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS18089A1 CS18089A1 (en) | 1989-09-12 |
| CS269646B1 true CS269646B1 (en) | 1990-04-11 |
Family
ID=5333511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS89180A CS269646B1 (en) | 1989-01-10 | 1989-01-10 | Method of new 2,3 -dichlorobenzhydrylamines and their salts preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS269646B1 (en) |
-
1989
- 1989-01-10 CS CS89180A patent/CS269646B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS18089A1 (en) | 1989-09-12 |
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