CH667649A5 - 2-Substd. amino-benzoxazole and -benzimidazole derivs. prodn. - by reacting prim. amino cpd. with amine in presence of acid catalyst, useful as intermediates e.g. for pharmaceuticals - Google Patents

2-Substd. amino-benzoxazole and -benzimidazole derivs. prodn. - by reacting prim. amino cpd. with amine in presence of acid catalyst, useful as intermediates e.g. for pharmaceuticals Download PDF

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CH667649A5
CH667649A5 CH363586A CH363586A CH667649A5 CH 667649 A5 CH667649 A5 CH 667649A5 CH 363586 A CH363586 A CH 363586A CH 363586 A CH363586 A CH 363586A CH 667649 A5 CH667649 A5 CH 667649A5
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alkyl
formula
amino
amine
substd
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CH363586A
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German (de)
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Frederic Brunner
Laurent Dr Duc
Raffaele Prof Dr Tabacchi
Karl-Josef Dr Boosen
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Lonza Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Prodn. of 2-substd. amino-benzoxazole or -benzimidazole cpds. of formula (I), comprises reacting the prim. amino cpd. (II) with amine R1R2NH (III) in presence of acid catalyst. In (I)-(III) Z = NH or O; R1 = H, alkyl or alkenyl, hydroxyalkyl, or opt. substd. benzyl; R2 is as R1 but not H, or R1 and R2 together complete a heterocycle, opt. contg. additional heteroatoms or substituents; Rn = one or more H, alkyl, halo, NO2, alkoxy, alkoxycarbonyl or one CN. More specifically the catalyst is a 1-4C alkyl or opt. alkyl-substd. phenyl-sulphonic acids, particularly p-toluenesulphonic and methanesulphonic acid. Reaction is in inert solvent, esp. toluene, at 100-200, esp. 140-180 deg. C. (III) is 3-30, pref. 4-20, moles equivalent per mole (II) and the catalyst is 5-100 mole %. USE/ADVANTAGE - (I) are intermediates for pharmaceuticals (e.g. muscle relaxants or antihistamines); light-protection agents and herbicides. This method is simple (only one stage) and provides gooo yields of high quality (I) without use of dangerous reagents.

Description

       

  
 



   BESCHREIBUNG



     2-Aminobenzimidazole    sowie 2-Aminobenzoxazole sind wertvolle Zwischenprodukte für eine grosse Palette von Wirkstoffen für Pharmazeutika aber auch für technische Anwendungen. Vgl. dazu z.B. die Anwendung von Benzoxazolen als Muskelrelaxantien in J. of Pharmaceutical Science, 53, Nr. 5, 1964, S. 538ff. oder als Wirkstoff eines Lichtschutzmittels in der DD-PS 105 993 und von Benzimidazolen als Antihistaminika in J. Med. Chem. 1985. 28, 19341943 oder als Wirkstoffe für Herbicide in der DD-PS 211472.



   Bisher hat es an vorteilhaften Verfahren gemangelt, die genannten Verbindungen einfach, in guter Qualität und Ausbeute herzustellen.



   Aus J. Med. Chem. 1986, Vol 29, Nr. 6 ist es z.B. bekannt, 2-Phenylethylaminobenzimidazol über zwei Stufen aus 2-Hydroxybenzimidazol durch Umsetzung mit Phosphoroxychlorid zum 2-Chlorbenzimidazol und anschliessender Umsetzung dieses Zwischenproduktes mit Phenylethylamin in einer Gesamtausbeute von   41%    herzustellen.



   Neben der schlechten Ausbeute ist vor allem das mit der Verwendung von Phosphoroxychlorid auftretende Entsorgungsproblem der Abgase sowie der Rückstände sehr aufwendig und mit Nachteilen verbunden.



   Für die Herstellung von 2-Aminobenzoxazolen ist bekannt, o-Hydroxyphenylthioharnstoffe, in Gegenwart von Schwermetalloxiden, wie Bleioxide, umzusetzen (Ausbeuten von 45-60%).



   Das Verfahren weist, neben der unbefriedigenden Ausbeute durch die Verwendung der bezüglich der Entsorgung problematischen Schwermetallverbindungen, erhebliche Nachteile auf.



   Es bestand daher die Aufgabe, ein Verfahren zu finden, das die genannten Nachteile nicht aufweist und mit dem es möglich ist, 2-Aminobenzimidazole oder 2-Aminobenzoxazole einfach und in guten Ausbeuten und Qualitäten herzustellen.



   Es wurde gefunden, dass die Aufgabe mit einem überraschend einfachen Verfahren gemäss Patentanspruch 1 gelöst werden kann.



   Erfindungsgemäss wird von einer Verbindung der Formel
EMI1.3     
 worin Z eine Iminogruppe der Formel -NH oder Sauerstoff und Rn Wasserstoff, Alkylgruppen, geradkettig oder verzweigt, Halogenatome, Nitrogruppen, Alkoxygruppen, Alkoxycarbonylgruppen oder eine Nitrilgruppe bedeutet, ausgehend mit einem Amin der Formel
R1R2NH worin R1 Wasserstoff, Alkyl oder Alkenyl, geradkettig oder verzweigt, Hydroxyalkyl, Benzyl substituiert oder unsubstituiert bedeutet und R2 Alkyl oder Alkenyl, geradkettig oder verzweigt, Hydroxyalkyl, Benzyl substituiert oder unsubstituiert bedeutet oder R1 und R2 mit dem Stickstoffatom einen Heterocyclus bilden, der gegebenenfalls zusätzliche Heteroatome oder Substituenten enthält, in Gegenwart eines sauren Katalysators zum entsprechend substituierten 2-Aminobenzoxazol bzw. 2-Aminobenzimidazol umgesetzt.



   Als saurer Katalysator werden zweckmässig Sulfonsäuren der Formel  
R3SO3H worin R3 Alkylgruppen mit 1 bis 4 C-Atomen oder Phenyl, gegebenenfalls substituiert mit Alkylgruppen, bedeutet, zweckmässig in Mengen von 5 bis 100 Mol%, eingesetzt. Bevorzugt wird p-Toluolsulfonsäure oder Methansulfonsäure, insbesondere Methansulfonsäure verwendet.



   Die Umsetzung wird vorteilhaft in einem inerten organischen Lösungsmittel, wie Benzol, Xylol oder Toluol, bevorzugt in Toluol durchgeführt.



   Die Reaktionstemperatur wählt man zweckmässig zwischen 100 und 200 C, bevorzugt zwischen   140-    und   180 C.   



   Üblicherweise wird das Amin der Formel    R1R2NH    im Überschuss, bezogen auf das Edukt eingesetzt.



   Bezogen auf 1 Moläquivalent 2-Aminobenzimidazol resp.   2-Aminobenzoxazol    werden zweckmässig 3 bis 30 Mol äquivalente, vorzugsweise 4 bis 20 Moläquivalente Amin eingesetzt.



   Abhängig vom Edukt und der gewählten Reaktionstemperatur kann nach einer Reaktionszeit zwischen 3 und 50 Stunden nach üblichen Methoden aufgearbeitet und das Reaktionsprodukt isoliert und gegebenenfalls gereinigt werden.



   Beispiel 1
In einen 100 ml Stahlautoklaven wurden 1,5   g (11,1    mMol) 2-Aminobenzoxazol, 19,6 g (180 mMol) Benzylamin und 0,53 g (3,5 mMol) Methansulfonsäure in 50 ml Toluol aufgenommen. Das Reaktionsgemisch wurde während 8 Stunden bei 160 C gerührt. Danach wurde abgekühlt. Das überschüssige Amin sowie das Lösungsmittel wurden am Rotavapor abgedampft. Der Rückstand wurde gewaschen mit 50 ml Natronlauge 1 M und anschliessend mit 2 x 50 ml Wasser.



   Nach dem Trocknen im Vakuumtrockenschrank erhielt man 2,46 g (99%) 2-Benzylaminobenzoxazol mit einem Gehalt nach DC von grösser als 98%.



   Schmelzpunkt: 111 bis   112"C   
NMR: (DMSO, 200 MHz) 6 in ppm 4,5 (s, -CH2-); 6,95-7,40 (m, arom.)
MS: m/e 224 (M+), 133, 105, 91, 78, 65, 51.



   Beispiel 2
In einem 100 ml Stahlautoklaven wurden 3,0 g (22,5 mMol) 2-Aminobenzimidazol, 30 g (270 mMol) Benzylamin und 1,6 g  (16,65 mMol)  Methansulfonsäure in 50 ml Toluol aufgenommen. Das Reaktionsgemisch wurde während 8 Stunden bei 165 ¯ C gerührt.



   Nach dem Abkühlen wurde am Rotavapor das überschüssige Amin sowie das Lösungsmittel abgedampft.



   Dem Rückstand wurden darauf 5 ml 10% Natrium-bicarbonatlösung zugegeben, worauf das Produkt ausfiel. Anschliessend wurde filtriert, der Filterrückstand mit Wasser gewaschen und getrocknet.



   Es wurden 5,02 g (99,8%) 2-Benzylaminobenzimidazol mit einem Gehalt nach DC von grösser als 98% erhalten.



   Schmelzpunkt: 164 bis 165   C.   



   NMR: (DMSO, 200 MHz) 6 in ppm 4,65 (s, -N-CH2-);   7,10-7,42    (m, arom.)
MS: m/e 224 (M+1), 223 (M+), 222, 207, 206, 146, 132, 119, 118, 106,   105, 91, 65, 39.   



   Beispiel 3
In einem 100 ml Glasgefäss wurden 5,0 g (37,55 mMol) 2-Aminobenzimidazol, 10 g (163,7 mMol) Ethanolamin und 0,216 g (2,25 mMol) Methansulfonsäure in 20 ml Diethylenglykoldimethylether (Diglym) aufgenommen.



   Das Reaktionsgemisch wurde während 48 Stunden bei Rückflusstemperatur (165 "C) gehalten.



   Danach wurde abgekühlt und am Rotavapor der Amin überschuss sowie das Lösungsmittel entfernt.



   Durch Zugabe von wenig Wasser kristallisierte aus dem öligen Rückstand das Produkt aus.



   Dieses wurde darauf filtriert, gewaschen mit Natriumbicarbonatlösung 10% und anschliessend mit Wasser und schliesslich getrocknet.



   Es wurden 5,27 g (79%) 2-Hydroxyethylaminobenzimidazol mit einem Gehalt nach DC von 98% erhalten.



   Schmelzpunkt: 189 bis 190   "C   
NMR: (DMSO, 200 MHz) 6 in ppm 3,35 (t, N-CH2); 3,58 (t, CH2-O); 6,83-7,15 (m, arom.)
MS: m/e 178   (mm'),    177 (M+), 147, 146, 133, 105, 92, 91.



  Beispiele 4-13 Entsprechend Beispiel 1 wurden folgende 2-Aminobenzoxazole hergestellt: Amin Aminobenzoxazol Kataly- Lösungs- Temp. Reaktions- Aus- Schmelz    Rn = H sator mittel "C zeit Std. beute punkt "C    n-Propylamin R1 = H, R2 = n-Propyl MeSO3H* Toluol 160 8 95% 99-100 n-Butylamin R1 = H, R2 = n-Butyl do. do. do. do. 80% 87-88 n-Pentylamin R1 = H, R2 = n-Pentyl do. do. do. do.   88%    87-88 n-Hexylamin R1 = H, R2 = n-Hexyl do. do. do. do. 95% 71-73 n-Octylamin   Rt    = H, R2 = n-Octyl do. do. do. do. 98% 52-53 Allylamin R1 = H, R2 = Allyl do. do. do. do. 96% 52-53 3-Picolin   R1    = H, R2 = 3-Picolyl do. do. do. do. 99% 156-157 Pyrrolidin R1, R2 = Pyrrolidyl do. do. do. do. 97% 136-137 Piperidin   Rl,    R2 = Piperidyl do. do. do. do. 

   91% 72-73 Morpholin R1, R2 = Morpholinyl do. do. do. do. 94% 95-96 *MeSO3 = Methansulfonsäure   Beispiele 14-28 Entsprechend Beispiel 2 wurden folgende 2-Aminobenzimidazole hergestellt: Amin Aminobenz- Kataly- Lösungs- Temp. Reaktions- Aus- Schmelz imidazol sator mittel   -C    zeit Std. beute punkt   GC    n-Propylamin R1 = H, R2 = n-Propyl MeSO3H Toluol 160 8 79% 143-144 n-Butylamin R1 = H, R2 = n-Butyl do. do. do. do. 85% 150-151 n-Pentylamin R1 = H, R2 = n-Pentyl do. do. do. do. 85% 124-125 n-Hexylamin R1 = H, R2 = n-Hexyl do. do. do. do. 93% 104-105 n-Octylamin   Rl    = H, R2 = n-Octyl do. do. do. do. 84% 135-136 Allylamin R1 = H, R2 = Allyl do. do. do. do. 72% 128-130 2-Chlorbenzyl R1 = H, R2 = Chlorbenzyldo. do. do. do. 65% 181-182 3-Picolin   R1    = H, R2 = 3-Picolyl do. do. do. do. 

   84% 200-201 Pyrrolidin R1, R2 = Pyrrolidyl do. do. do. do. 73% gr. als 300 Piperidin R1, R2 = Piperidyl do. do. do. do. 100% 279-280 Morpholin R1, R2 = Morpholinyl do. do. do. do.



   80% 289-290 l-Methyl-2- R1 = H, R2 = 2-Me- do. Diglyme 165 33 91%   170171    Amino- thyl-2-hydroxyethanol ethyl 3-Amino-   R1    = H, R2 = 3- do. do. do. do. 84% 132-133 propanol Hydroxypropyl 4-Amino- R1 = H, R2 = 4- do. do. do. do. 64% 147-148 butanol Hydroxybutyl 5-Amino- R1 = H, R2 = 5- do. do. do. do. 73% 111-112 pentanol Hydroxypentyl 



  
 



   DESCRIPTION



     2-aminobenzimidazoles and 2-aminobenzoxazoles are valuable intermediates for a wide range of active ingredients for pharmaceuticals but also for technical applications. See e.g. the use of benzoxazoles as muscle relaxants in J. of Pharmaceutical Science, 53, No. 5, 1964, p. 538ff. or as an active ingredient of a light stabilizer in DD-PS 105 993 and of benzimidazoles as antihistamines in J. Med. Chem. 1985. 28, 19341943 or as active ingredients for herbicides in DD-PS 211472.



   So far there has been a lack of advantageous processes for producing the compounds mentioned simply, in good quality and in yield.



   From J. Med. Chem. 1986, Vol 29, No. 6 it is e.g. known to produce 2-phenylethylaminobenzimidazole in two stages from 2-hydroxybenzimidazole by reaction with phosphorus oxychloride to 2-chlorobenzimidazole and subsequent reaction of this intermediate with phenylethylamine in a total yield of 41%.



   In addition to the poor yield, the disposal problem of the exhaust gases and the residues which arises with the use of phosphorus oxychloride is very complex and has disadvantages.



   For the preparation of 2-aminobenzoxazoles it is known to react o-hydroxyphenylthioureas in the presence of heavy metal oxides such as lead oxides (yields of 45-60%).



   In addition to the unsatisfactory yield due to the use of the heavy metal compounds which are problematic with regard to disposal, the process has considerable disadvantages.



   The object was therefore to find a process which does not have the disadvantages mentioned and with which it is possible to prepare 2-aminobenzimidazoles or 2-aminobenzoxazoles simply and in good yields and qualities.



   It has been found that the object can be achieved with a surprisingly simple method according to claim 1.



   According to the invention, a compound of the formula
EMI1.3
 wherein Z is an imino group of the formula -NH or oxygen and Rn is hydrogen, alkyl groups, straight-chain or branched, halogen atoms, nitro groups, alkoxy groups, alkoxycarbonyl groups or a nitrile group, starting with an amine of the formula
R1R2NH in which R1 denotes hydrogen, alkyl or alkenyl, straight-chain or branched, hydroxyalkyl, benzyl substituted or unsubstituted and R2 denotes alkyl or alkenyl, straight-chain or branched, hydroxyalkyl, benzyl substituted or unsubstituted or R1 and R2 form a heterocycle with the nitrogen atom, which if appropriate contains additional heteroatoms or substituents, in the presence of an acid catalyst to give the correspondingly substituted 2-aminobenzoxazole or 2-aminobenzimidazole.



   Sulfonic acids of the formula are expediently used as the acid catalyst
R3SO3H in which R3 denotes alkyl groups with 1 to 4 carbon atoms or phenyl, optionally substituted with alkyl groups, advantageously in amounts of 5 to 100 mol%. P-Toluenesulfonic acid or methanesulfonic acid, in particular methanesulfonic acid, is preferably used.



   The reaction is advantageously carried out in an inert organic solvent, such as benzene, xylene or toluene, preferably in toluene.



   The reaction temperature is advantageously chosen between 100 and 200 C, preferably between 140 and 180 C.



   The amine of the formula R1R2NH is usually used in excess, based on the starting material.



   Based on 1 mol equivalent of 2-aminobenzimidazole resp. 2-aminobenzoxazole is advantageously 3 to 30 mol equivalents, preferably 4 to 20 mol equivalents, of amine.



   Depending on the starting material and the selected reaction temperature, after a reaction time of between 3 and 50 hours, it can be worked up by customary methods and the reaction product isolated and optionally purified.



   example 1
1.5 g (11.1 mmol) of 2-aminobenzoxazole, 19.6 g (180 mmol) of benzylamine and 0.53 g (3.5 mmol) of methanesulfonic acid in 50 ml of toluene were taken up in a 100 ml steel autoclave. The reaction mixture was stirred at 160 C for 8 hours. It was then cooled. The excess amine and the solvent were evaporated off on a Rotavapor. The residue was washed with 50 ml of 1 M sodium hydroxide solution and then with 2 x 50 ml of water.



   After drying in a vacuum drying cabinet, 2.46 g (99%) of 2-benzylaminobenzoxazole were obtained with a DC content of greater than 98%.



   Melting point: 111 to 112 "C
NMR: (DMSO, 200 MHz) 6 in ppm 4.5 (s, -CH2-); 6.95-7.40 (m, aroma.)
MS: m / e 224 (M +), 133, 105, 91, 78, 65, 51.



   Example 2
3.0 g (22.5 mmol) of 2-aminobenzimidazole, 30 g (270 mmol) of benzylamine and 1.6 g (16.65 mmol) of methanesulfonic acid in 50 ml of toluene were taken up in a 100 ml steel autoclave. The reaction mixture was stirred at 165 ° C. for 8 hours.



   After cooling, the excess amine and the solvent were evaporated off on a Rotavapor.



   5 ml of 10% sodium bicarbonate solution were then added to the residue, whereupon the product precipitated. It was then filtered, the filter residue washed with water and dried.



   5.02 g (99.8%) of 2-benzylaminobenzimidazole with a DC content of greater than 98% were obtained.



   Melting point: 164 to 165 C.



   NMR: (DMSO, 200 MHz) 6 in ppm 4.65 (s, -N-CH2-); 7.10-7.42 (m, aroma)
MS: m / e 224 (M + 1), 223 (M +), 222, 207, 206, 146, 132, 119, 118, 106, 105, 91, 65, 39.



   Example 3
5.0 g (37.55 mmol) of 2-aminobenzimidazole, 10 g (163.7 mmol) of ethanolamine and 0.216 g (2.25 mmol) of methanesulfonic acid in 20 ml of diethylene glycol dimethyl ether (Diglym) were taken up in a 100 ml glass vessel.



   The reaction mixture was kept at reflux temperature (165 ° C.) for 48 hours.



   The mixture was then cooled and the amine excess and the solvent were removed on a Rotavapor.



   The product crystallized from the oily residue by adding a little water.



   This was then filtered, washed with sodium bicarbonate solution 10% and then with water and finally dried.



   5.27 g (79%) of 2-hydroxyethylaminobenzimidazole were obtained with a DC content of 98%.



   Melting point: 189 to 190 "C
NMR: (DMSO, 200 MHz) 6 in ppm 3.35 (t, N-CH2); 3.58 (t, CH2-O); 6.83-7.15 (m, aroma)
MS: m / e 178 (mm '), 177 (M +), 147, 146, 133, 105, 92, 91.



  Examples 4-13 The following 2-aminobenzoxazoles were prepared in accordance with Example 1: amine aminobenzoxazole catalyze-solution temp. Reaction-off melt Rn = H sator medium "C time hour prey point" C n-propylamine R1 = H, R2 = n-propyl MeSO3H * toluene 160 8 95% 99-100 n-butylamine R1 = H, R2 = n-butyl do. do. do. do. 80% 87-88 n-pentylamine R1 = H, R2 = n-pentyl do. do. do. do. 88% 87-88 n-hexylamine R1 = H, R2 = n-hexyl do. do. do. do. 95% 71-73 n-octylamine Rt = H, R2 = n-octyl do. do. do. do. 98% 52-53 allylamine R1 = H, R2 = allyl do. do. do. do. 96% 52-53 3-Picolin R1 = H, R2 = 3-Picolyl do. do. do. do. 99% 156-157 pyrrolidine R1, R2 = pyrrolidyl do. do. do. do. 97% 136-137 piperidine R1, R2 = piperidyl do. do. do. do.

   91% 72-73 morpholine R1, R2 = morpholinyl do. do. do. do. 94% 95-96 * MeSO3 = methanesulfonic acid Examples 14-28 The following 2-aminobenzimidazoles were prepared in accordance with Example 2: amine aminobenz-cataly- solution temp. Propylamine R1 = H, R2 = n-propyl MeSO3H toluene 160 8 79% 143-144 n-butylamine R1 = H, R2 = n-butyl do. do. do. do. 85% 150-151 n-pentylamine R1 = H, R2 = n-pentyl do. do. do. do. 85% 124-125 n-hexylamine R1 = H, R2 = n-hexyl do. do. do. do. 93% 104-105 n-octylamine Rl = H, R2 = n-octyl do. do. do. do. 84% 135-136 allylamine R1 = H, R2 = allyl do. do. do. do. 72% 128-130 2-chlorobenzyl R1 = H, R2 = chlorobenzyldo. do. do. do. 65% 181-182 3-Picolin R1 = H, R2 = 3-Picolyl do. do. do. do.

   84% 200-201 pyrrolidine R1, R2 = pyrrolidyl do. do. do. do. 73% gr. Than 300 piperidine R1, R2 = piperidyl do. do. do. do. 100% 279-280 morpholine R1, R2 = morpholinyl do. do. do. do.



   80% 289-290 l-methyl-2- R1 = H, R2 = 2-medo. Diglyme 165 33 91% 170171 aminoethyl-2-hydroxyethanol ethyl 3-amino- R1 = H, R2 = 3- do. do. do. do. 84% 132-133 propanol hydroxypropyl 4-amino- R1 = H, R2 = 4- do. do. do. do. 64% 147-148 butanol hydroxybutyl 5-amino- R1 = H, R2 = 5- do. do. do. do. 73% 111-112 pentanol hydroxypentyl

Claims (8)

PATENTANSPRÜCHE 1. Verfahren zur Herstellung von Verbindungen der Formel EMI1.1 worin Z eine Iminogruppe der Formel -NH oder Sauerstoff, Rl Wasserstoff, Alkyl oder Alkenyl, geradkettig oder verzweigt, Hydroxyalkyl, Benzyl substituiert oder unsubstituiert und R2 Alkyl oder Alkenyl, geradkettig oder verzweigt, Hydroxyalkyl, Benzyl substituiert oder unsubstituiert bedeutet oder R1 und R2 mit dem Stickstoffatom einen Heterocyclus bilden, der gegebenenfalls zusätzliche Heteroatome oder Substituenten enthält und Rn Wasserstoff, Alkylgruppen, geradkettig oder verzweigt, Halogenatome, Nitrogruppen, Alkoxygruppen, Alkoxycarbonylgruppen oder eine Nitrilgruppe bedeutet, dadurch gekennzeichnet, dass man eine Verbindung der Formel EMI1.2 worin Z und Rn die genannte Bedeutung haben,  PATENT CLAIMS 1. Process for the preparation of compounds of the formula EMI1.1  wherein Z is an imino group of the formula -NH or oxygen, R1 is hydrogen, alkyl or alkenyl, straight-chain or branched, hydroxyalkyl, benzyl substituted or unsubstituted and R2 is alkyl or alkenyl, straight-chain or branched, hydroxyalkyl, benzyl substituted or unsubstituted or R1 and R2 are the nitrogen atom form a heterocycle, which optionally contains additional heteroatoms or substituents and Rn denotes hydrogen, alkyl groups, straight-chain or branched, halogen atoms, nitro groups, alkoxy groups, alkoxycarbonyl groups or a nitrile group, characterized in that a compound of the formula EMI1.2  where Z and Rn have the meaning given, mit einem Amin der Formel R1R2NH wonn R1 und R2 die genannte Bedeutung haben, in Gegenwart eines sauren Katalysators umsetzt.  with an amine of the formula R1R2NH wonn R1 and R2 have the meaning given, in the presence of an acid catalyst. 2. Verfahren nach Patentanspruch 1, dadurch gekennzeichnet, dass als saure Katalysatoren Sulfonsäuren der Formel R3SO3H wonn R3 Alkyl mit 1 bis 4 C-Atomen oder Phenyl, gegebenenfalls substituiert mit Alkylgruppen bedeutet, eingesetzt wird.  2. The method according to claim 1, characterized in that the acidic catalysts are sulfonic acids of the formula R3SO3H is R3 alkyl with 1 to 4 carbon atoms or phenyl, optionally substituted with alkyl groups. 3. Verfahren nach Patentanspruch 2, dadurch gekennzeichnet, dass als Sulfonsäure p-Toluolsulfonsäure oder Methansulfonsäure verwendet wird.  3. The method according to claim 2, characterized in that p-toluenesulfonic acid or methanesulfonic acid is used as the sulfonic acid. 4. Verfahren nach Patentansprüchen 1, 2 und 3, dadurch gekennzeichnet, dass die Umsetzung in einem inerten organischen Lösungsmittel durchgeführt wird.  4. The method according to claims 1, 2 and 3, characterized in that the reaction is carried out in an inert organic solvent.   5. Verfahren nach Patentansprüchen 1, 2, 3 und 4, dadurch gekennzeichnet, dass in Toluol als Lösungsmittel gearbeitet wird.  5. The method according to claims 1, 2, 3 and 4, characterized in that the solvent is worked in toluene. 6. Verfahren nach Patentansprüchen 1, 2, 3, 4 und 5, dadurch gekennzeichnet, dass die Umsetzung bei Temperaturen zwischen 100 und 200 C durchgeführt wird.  6. The method according to claims 1, 2, 3, 4 and 5, characterized in that the reaction is carried out at temperatures between 100 and 200 C. 7. Verfahren nach Patentansprüchen 1, 2, 3, 4, 5 und 6, dadurch gekennzeichnet, dass bezogen auf 1 Moläquivalent Edukt das Amin der Formel R1R2NH in einer Menge von 3 bis 30 Moläquivalenten eingesetzt wird.  7. The method according to claims 1, 2, 3, 4, 5 and 6, characterized in that the amine of the formula based on 1 molar equivalent of starting material R1R2NH is used in an amount of 3 to 30 molar equivalents. 8. Verfahren nach Patentansprüchen 1 2 3 4 5 6 und 7, dadurch gekennzeichnet, dass der saure Katalysator in Mengen von 5 bis 100 Mol% eingesetzt wird.  8. The method according to claims 1 2 3 4 5 6 and 7, characterized in that the acid catalyst is used in amounts of 5 to 100 mol%.
CH363586A 1986-09-10 1986-09-10 2-Substd. amino-benzoxazole and -benzimidazole derivs. prodn. - by reacting prim. amino cpd. with amine in presence of acid catalyst, useful as intermediates e.g. for pharmaceuticals CH667649A5 (en)

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CH363586A CH667649A5 (en) 1986-09-10 1986-09-10 2-Substd. amino-benzoxazole and -benzimidazole derivs. prodn. - by reacting prim. amino cpd. with amine in presence of acid catalyst, useful as intermediates e.g. for pharmaceuticals

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2643264A1 (en) * 1989-02-20 1990-08-24 Rhone Poulenc Sante TRIFLUOROMETHOXY-5 BENZIMIDAZOLAMINE-2, PROCESS FOR ITS PREPARATION AND MEDICINES CONTAINING IT
US5260447A (en) * 1991-02-15 1993-11-09 Sankyo Company, Limited Polyhydroxycyclopentane derivatives, their preparation and their therapeutic use
EP0657451A2 (en) * 1993-10-26 1995-06-14 Boehringer Ingelheim Pharmaceuticals Inc. Pyrrolidine derivatives inhibitors of leukotriene biosynthesis
CN106565631A (en) * 2016-11-09 2017-04-19 温州大学 Method for synthesizing substituent miscellaneous aromatic amine through reaction between miscellaneous aromatic amine and amine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2643264A1 (en) * 1989-02-20 1990-08-24 Rhone Poulenc Sante TRIFLUOROMETHOXY-5 BENZIMIDAZOLAMINE-2, PROCESS FOR ITS PREPARATION AND MEDICINES CONTAINING IT
EP0384812A1 (en) * 1989-02-20 1990-08-29 Rhone-Poulenc Sante 5-Trifluoromethoxy-2-aminobenzimidazole, process for its preparation and medicaments containing same
US5260447A (en) * 1991-02-15 1993-11-09 Sankyo Company, Limited Polyhydroxycyclopentane derivatives, their preparation and their therapeutic use
EP0657451A2 (en) * 1993-10-26 1995-06-14 Boehringer Ingelheim Pharmaceuticals Inc. Pyrrolidine derivatives inhibitors of leukotriene biosynthesis
EP0657451A3 (en) * 1993-10-26 1996-03-06 Boehringer Ingelheim Pharma Pyrrolidine derivatives inhibitors of leukotriene biosynthesis.
US5594008A (en) * 1993-10-26 1997-01-14 Boehringer Ingelheim Pharmaceuticals, Inc. Pyrrolidine derivatives inhibitors of leukotriene biosynthesis
CN106565631A (en) * 2016-11-09 2017-04-19 温州大学 Method for synthesizing substituent miscellaneous aromatic amine through reaction between miscellaneous aromatic amine and amine
CN106565631B (en) * 2016-11-09 2018-11-30 温州大学 A kind of method that heteroaryl amine reacts synthesis substitution heteroaryl amine with amine

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