CH497381A - 2-aminohalobenzyl amines - Google Patents

2-aminohalobenzyl amines

Info

Publication number
CH497381A
CH497381A CH283469A CH283469A CH497381A CH 497381 A CH497381 A CH 497381A CH 283469 A CH283469 A CH 283469A CH 283469 A CH283469 A CH 283469A CH 497381 A CH497381 A CH 497381A
Authority
CH
Switzerland
Prior art keywords
glycine
acetylamino
methyl
alkyl
melting point
Prior art date
Application number
CH283469A
Other languages
German (de)
Inventor
Gerd Dr Krueger
Ottmar Dr Zipp
Johannes Dr Keck
Josef Dr Nickl
Hans Dr Machleidt
Gerhard Dr Ohnacker
Robert Dr Engelhorn
Sigfrid Dr Pueschmann
Original Assignee
Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Priority claimed from CH743466A external-priority patent/CH493468A/en
Publication of CH497381A publication Critical patent/CH497381A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

(A) Compds. - (I) Hal = Br or Cl - R' = H or Cl - R2 = H, alkyl opt. subst. by OH, O alkyl, or N(alkyl2); alkenyl; cycloalkyl; aryl opt. substd. by halogen, alkyl, O alkyl, NO2, CO2H, or CO2 alkyl; aralkyl opt. subst. by halogen, alkyl, or O-alkyl; pyridyl; or pyridylalkyl - R3 = OH; O alkyl; NH2 opt. substd. by lower alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, alkenyl, dialkylaminoalkyl, aryl, haloaryl, aralkyl, or pyridyl; or an opt. lower alkyl substd., pyrrolidine, piperidine, piperazine, morpholine, or hexamethylene ring. - R4 and R5 = H or acyl - n = 1-3. - (B) Salts of I - Anti-tussives, sedatives and respiratory stimulants, and intermediates for benzodiazepines and benzodiazocines. - N-(5-bromo 2-diacetylaminobenzyl) N-phenyl beta-aminopropionic acid methyl ester.

Description

  

  Verfahren zur Herstellung von neuen 2-Amido-halogen-benzylaminen    Die Erfindung betrifft ein Verfahren zur Herstellung  von neuen 2-Amido-halogen-benzylaminen der Formel  
EMI0001.0000     
    in der Hal ein Chlor- oder Bromatom in 3-, 4-, 5- oder  6-Stellung und R, ein Wasserstoff- oder Halogenatom,  R2 einen geradkettigen oder verzweigten Alkyl- oder  Alkenylrest, einen Hydroxyalkyl-, Alkoxyalkyl-,     Dialkyl-          aminoalkyl-,    Cycloalkyl-, Aryl-, einen durch Halogen,  Alkyl, Alkoxy, Nitro, Carboxy oder Carbalkoxy substi  tuierten Aryl, einen Aralkyl, einen durch Halogen,  Alkyl oder Alkoxy substituierten Aralkyl-, einen     Pyri-          dyl-    oder einen Pyridylalkylrest darstellt,  R:

  , eine freie oder eine durch niederes verzweigtes  oder unverzweigtes Alkyl, Hydroxyalkyl, Alkoxyalkyl,  Cycloalkyl, Alkenyl, Dialkylaminoalkyl, Aryl durch  Halogen substituiertes Aryl, Aralkyl und/oder Pyridyl,  substituierte Aminogruppe oder eine cyclische     Amino-          gruppe    in Form eines gegebenenfalls durch niederes  Alkyl substituierten Pyrrolidin-, Piperidin-, Piperazin-,  Morpholin- oder Hexamethyleniminrings bedeutet,  R, ein Wasserstoffatom oder einen Acylrest und n  eine Zahl von 1-3 bedeuten, sowie von deren physio  logisch verträglichen Salzen mit anorganischen oder orga  nischen Säuren oder Basen.  



  Erfindungsgemäss werden die neuen Verbindungen  durch Umsetzung eines 2-Amido-benzylamins der For  mel  
EMI0001.0007     
    mit einer Verbindung der Formel  H-R3 (III)  hergestellt.  



  Die Umsetzung wird vorzugsweise in Gegenwart  eines säureaktivierenden Mittels, z. B. eines anorgani  schen oder organischen Säurehalogenids, vorteilhafter  weise in einem Lösungsmittel, z. B. Methylenchlorid,  Chloroform, Dioxan oder Tetrahydrofuran, vorzugs  weise in Gegenwart eines säurebindenden Mittels, bei  spielsweise eines tertiären Amins, und gegebenenfalls  bei Temperaturen zwischen -20 C und der Siedetempera  tur des verwendeten Lösungsmittels durchgeführt. Als  Lösungsmittel kann auch ein Überschuss einer Verbin  dung der Formel III dienen.  



  Falls hierbei     R4    und     R5    Wasserstoffatome darstellen,  so ist vorübergehender Schutz der Aminogruppe, bei  spielsweise durch ihre Überführung in eine Schiffsche  Base, vorteilhaft.  



  Die bei den erfindungsgemässen Verfahren verwen  deten Ausgangsverbindungen erhält man durch Um  setzung eines entsprechenden     2-Diacylamino-benzyl-          halogenids    mit einer entsprechenden Aminocarbonsäure  bzw. durch Reduktion einer entsprechenden     2-Nitro-          benzylamino-alkansäure.     



  Die erhaltenen Verbindungen können mit physio  logisch verträglichen anorganischen oder organischen      Säuren in ihre     Salze    überführt werden. Als Säuren  haben sich beispielsweise Salzsäure, Bromwasserstoff  säure, Schwefelsäure, Phosphorsäure, Milchsäure, Zitro  nensäure, Weinsäure, Maleinsäure als geeignet erwie  sen.  



  Die erfindungsgemäss hergestellten Verbindungen  weisen wertvolle pharmakologische Eigenschaften auf,  sie zeigen insbesondere neben teilweise sedativer und  atemanregender Wirkung eine sehr gute hustenstillende  Wirkung, sie dienen     ferner    als Zwischenprodukte für  pharmazeutisch wertvolle Benzodiazepine und     Benzo-          diazocine.     



  <I>Beispiel 1</I>       N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-gly-          cin-[3-diäthylamino-propyl-(1)-amid].     



  2,0 g     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-me-          thyl-glycin    und 0,7 ml Triäthylamin werden unter Er  wärmen in 100 ml Tetrahydrofuran gelöst, auf -10  C  abgekühlt und unter Rühren mit 0;48 ml     Chlorameisen-          säureäthylester    versetzt. Nach 10 Minuten versetzt man  mit 0,65 g N,N-Diäthyl-1,3-diamino-propan und lässt  auf Raumtemperatur kommen. Nach 1 Stunde dampft  man im Vakuum ein, nimmt in Chloroform auf, wäscht  die Chloroformlösung mit Wasser, verdünntem Ammo  niak und Wasser, trocknet und entfernt das Lösungsmit  tel. Der Rückstand kristallisiert aus Essigester.  



  F. 142-1440 C.  



  Analog Beispiel 1 werden dargestellt:  a)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-niethyl-          glycin-isopropylamid,    Schmelzpunkt: 208  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Isopropylamin,  b)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-cyclohexylamid,     Schmelzpunkt: 178-179  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Cyclohexylamin,  c)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-benzylamid,     Schmelzpunkt:

   142-143  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Benzylamin,  d)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-anilid,     Schmelzpunkt: 167  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Anilin,  e)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-diäthylamid,     Schmelzpunkt: l00  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Diäthylamin.  



  f)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-pyrrolidid,     Schmelzpunkt: 157  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Pyrrolidin.  



  g)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-piperidid,          Schmelzpunkt:    119  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Piperidin.  



  h)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(4-methyl-piperazid),     Schmelzpunkt: 139  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und N-Methyl-piperazin.    i) N-(2     Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-morpholid,          Schmelzpunkt:    118  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Morpholin.  



  j)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(2-hydroxyäthyl-amid),          Schmelzpunkt:    127-128  C,  aus     2-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Äthanolamin.  



  k)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(2-diäthylamino-äthylamid),     Schmelzpunkt: 153-154  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und 2-Diäthylamino-äthylamin.  



  1)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-propylamid,     Schmelzpunkt:<B>171'C,</B>  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Propylamin.  



  m)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-[3-methoxy-propyl-(1)-amid],     Schmelzpunkt: 125  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und 1-Amino-3-methoxy-propan.  



  n)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-allylamid,     Schmelzpunkt: 166  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Allylamin.  



  o)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(p-fluor-anilid),     Schmelzpunkt: 174-175  C,  aus N-(2     Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und p-Fluor-anilin.  



  p)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-[pyridyl-(4)-amid],     Schmelzpunkt: 149-150  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und 4-Amino-pyridin.  



  q)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(N,N-hexamethylen-amid),     Schmelzpunkt: l05  C,  aus N     (2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Hexamethylenimin.  



  r)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-dicyclohexylamid,     Schmelzpunkt: 154  C,  aus N     (2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Dicyclohexylamin.  



  s)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin-(benzyl-isopropyl-amid),     amorph, dünnschichtchromatographisch einheitlich,  RF - 0,4 (SiO2, Chloroform),  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-methyl-          glycin    und Benzyl-isopropyl-amin,  t)     N-(2-Acetylamino-4-brom-benzyl)-N-methyl-          glycin-morpholid,     Schmelzpunkt: 138-140  C,  aus     N-(2-Acetylamino-4-brom-benzyl)-N-methyl-          glycin    und Morpholin,  u) IV     (2-Acetylamino-4-brom-benzyl)-N-methyl-          glycin-benzylamid,     Schmelzpunkt:

       169-171'    C,  aus     N-(2-Acetylamino-4-brom-benzyl)-N-methyl-          glycin    und     Benzylamin,         v)     N-(2-Acetylamino-5-brom-benzyl)-N-methyl-          glycin-morpholid,          Schmelzpunkt:    151-l54  C,  aus     N-(2-Acetylamino-5-brom-benzyl)-N-methyl-          glycin    und Morpholin.  



  w)     N-(2-Acetylamino-5-brom-benzyl)-N-methyl-          glycin-benzylamid,          Schmelzpunkt:    177-178  C,  aus     N-(2-Acetylamino-5-brom-benzyl)-N-methyl-          glycin    und Benzylamin.  



  x)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-äthyl-          glycin-morpholid,     Schmelzpunkt: 138  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-äthyl-          glycin    und Morpholin.  



  y)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-äthyl-          glycin-benzylamid,          Schmelzpunkt:    149  C,  aus N-(2-Acetylamino     -3,5-dibrom-benzyl)-N-äthyl-          glycin    und Benzylamin.  



  z)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-butyl-          glycin-morpholid,     Schmelzpunkt: 134  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-butyl-          glycin    und Morpholin.  



  aa)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-butyl-          glycin-benzylamid,     Schmelzpunkt: 106  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-butyl-          glycin    und Benzylamin.  



  bb)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-benzyl-          glycin-morpholid,     Schmelzpunkt: 102  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-benzyl-          glycin    und Morpholin.  



  cc)     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-äthyl-l-          amino-propionsäure-morpholid,     Schmelzpunkt: l15  C,  aus     N-(2-Acetylamino-3,5-dibrom-benzyl)-N-äthyl-          j-amino-propionsäure    und Morpholin.  



  dd)     N-(2-Acetylamino-6-chlor-benzyl)-N-methyl-glycin-          morpholid,     Schmelzpunkt: 166-167  C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-methyl-          glycin    und Morpholin.  



  ee)     N-(2-Acetylamino-6-chlor-benzyl)-N-methyl-          glycin-benzylamid,     Schmelzpunkt:     114-115'    C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-methyl-          glycin    und Benzylamin.  



  ff)     N-(2-Acetylamino-6-chlor-benzyl)-N-äthyl-          glycin-morpholid,     Schmelzpunkt: 141' C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-äthyl-          glycin    und Morpholin.  



  gg)     N-(2-Acetylamino-6-chlor-benzyl)-N-äthyl-          glycin-benzylamid,          Schmelzpunkt:        100-101'    C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-äthyl-          glycin    und Benzylamin.  



  hh)     N-(2-Acetylamino-6-chlor-benzyl)-N-propyl-          glycin-morpholid,     Schmelzpunkt: 154-155  C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-propyl-          glycin    und Morpholin.    ii)     N-(2-Acetylamino-6-chlor-benzyl)-N-isopropyl-          glycin-morpholid,          Schmelzpunkt:    170  C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-isopropyl-          glycin    und Morpholin.  



  jj)     N-(2-Acetylamino-6-chlor-benzyl)-N-butyl-          glycin-morpholid,     Schmelzpunkt:     94--95     C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-butyl-          glycin    und Morpholin.  



  kk)     N-(2-Acetylamino-6-chlor-benzyl)-N-isobutyl-          glycin-morpholid,     Schmelzpunkt: 165-166  C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-isobutyl-          glycin    und Morpholin.  



  11)     N-(2-Acetylamino-6-chlor-benzyl)-N-benzyl-          glycin-morpholid,     Schmelzpunkt: 117-1l8  C,  aus     N-(2-Acetylamino-6-chlor-benzyl)-N-benzyl-          glycin    und Morpholin.  



  mm)     N-(2-Acetylamino-6-chlor-benzyl)-N-phenyl-          glycin-morpholid,     Schmelzpunkt: 166-167  C,  aus N     (2-Acetylamino-6-chlor-benzyl)-N-phenyl-          glycin    und Morpholin.  



  nn)     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin-morpholid,     Schmelzpunkt: 122,5-123  C,  aus     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Morpholin.  



  oo)     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin-isopropylamid,          Schmelzpunkt:    153-155  C,  aus N     (2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Isopropylamin.  



  pp)     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin-benzylamid,     amorph, dünnschichtchromatographisch einheitlich,  RF = 0,75 (SiO2, Chloroform: Methanol = 19: 1),  aus     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Benzylamin.  



  qq)     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin-anilid,     Schmelzpunkt: 142  C,  aus     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Anilin.  



  rr)     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin-diäthylamid,     Schmelzpunkt: 98-l01  C,  aus N     (2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Diäthylamin.  



  ss)     N-Äthyl-N-(2-benzoylamino-3,5-dibrom-benzyl)-          glycinamid,     Schmelzpunkt: 173-174  C,  aus     N-Äthyl-N-(2-benzoylamino-3,5-dibrom-benzyl)-          glycin    und konz. Ammoniak.  



  tt)     N-Äthyl-N-(2-benzoylamino-3,5-dibrom-benzyl)-          glycin-isopropylamid,     Schmelzpunkt: 170-172  C,  aus     N-Äthyl-N-(2-benzoylamino-3,5-dibrom-benzyl)-          glycin    und Isopropylamin.  



  vv)     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycinamid,     Schmelzpunkt: 155-157  C,  aus N     (2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin    und     konz.    Ammoniak.      ww) N     (2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin-isopropylamid,          Schmelzpunkt:    122-124  C,  aus     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin    und Isopropylamin.  



  xx)     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin-cyclohexylamid,     Schmelzpunkt: 190-192  C,  aus     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin    und Cyclohexylamin.  



  yy)     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin-anilid,          Schmelzpunkt:    157-159  C,  aus     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin    und Anilin.  



  zz)     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin-morpholid,     Schmelzpunkt des Hydrochlorids: 215  C (Zers.),  aus     N-(2-Benzoylamino-5-chlor-benzyl)-N-methyl-          glycin    und Morpholin.  



  aaa)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycinamid,     Schmelzpunkt: 131-132  C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und konz. Ammoniak.  



  bbb)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-allylamid,     Schmelzpunkt:<B>97-98'</B> C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und Allylamin.  



  ccc)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-isopropylamid,     Schmelzpunkt: 110-111   C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und Isopropylamin.  



  ddd)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-cyclohexylamid,     Schmelzpunkt: 138-139  C,  aus     N-(2-Benzoylamino-6-chlor-benzyl)-N-methyl-          glycin    und Cyclohexylamin.  



  eee)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-benzylamid,     Schmelzpunkt: 141-142  C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und Benzylamin.  



  fff)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-anilid,          Schmelzpunkt:    144-145  C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und Anilin.  



  ggg)     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin-morpholid,     Schmelzpunkt:<B>95-96'</B> C,  aus     N-(2-Benzoylamino-4-chlor-benzyl)-N-methyl-          glycin    und Morpholin.  



  hhh)     &gamma;-[N-(2-Acetylamino-3,5-dibrom-benzyl)-N-          isopropyl]-amino-buttersäure-diäthylamid,     farbloses Öl, dünnschichtchromatographisch  einheitlich aus     &gamma;-[2-(Acetylamino-3,5-dibrom-          benzyl)-N-isopropyl]-amino-buttersäure    und  Diäthylamin.  



  <I>Beispiel 2</I>       N-(2-Amino-6-chlor-benzyl)-N-methyl-glycin-          morpholid.     



  15,0g N-(2-Amino-6-chlor-benzyl)-N-methyl-glycin  und 17,5 g 2 Hydroxy-1-naphthaldehyd werden in 1 1  absol. Äthanol gekocht. Das gebildete Wasser wird    azeotrop abdestilliert, und man gibt entsprechend der destil  lierten Menge neues absol. Äthanol hinzu. Nach 3 Stun  den lässt man abkühlen. Die ausgefallenen gelben Kri  stalle an N - [6 - Chlor - 2 -     (2-hydroxy-1-naphthyliden-          amino)-benzyl]-N-methyl-glycin    werden abgesaugt und  mit Äthanol und Äther gewaschen.  



  Schmelzpunkt: 185-187  C (Zers.).  



  5,9- g     N-[6-Chlor-2-(2-hydroxy-1-naphthyliden-amino)-          benzyl]-N-methyl-glycin    werden in 100 m1 absol. Chlo  roform gelöst. Unter     Stickstoffschutz    und Rühren ver  setzt man bei -10  C mit 2,2 ml Triäthylamin und  1,5 ml Chlorameisensäureäthylester. Nach 20 Minuten  bei -l0  C fügt man 2,7 ml Morpholin hinzu und lässt  1 Stunde bei 20  C und unter     N2    reagieren, Das Reak  tionsgemisch wird im Vakuum vom Lösungsmittel be  freit und zur Abspaltung der Aminoschutzgruppe  11;, Stunden mit 70 ml 0,5n HCl verrührt. Man extra  hiert den regenerierten Hydroxynaphthaldehyd mit  Chloroform.

   Durch Neutralisation der wässrigen Phase  mit 35 ml 1 n NaOH wird das     N-(2-Amino-6-chlor-          benzyl)-N-methyl-glycin-morpholid    ausgefällt. Man saugt  ab und wäscht mit Wasser.  



  Schmelzpunkt: 116-118  C (aus Methanol/Wasser).



  Process for the preparation of new 2-amido-halogen-benzylamines The invention relates to a process for the preparation of new 2-amido-halogen-benzylamines of the formula
EMI0001.0000
    in which Hal is a chlorine or bromine atom in the 3-, 4-, 5- or 6-position and R is a hydrogen or halogen atom, R2 is a straight-chain or branched alkyl or alkenyl radical, a hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl -, Cycloalkyl, aryl, an aryl substituted by halogen, alkyl, alkoxy, nitro, carboxy or carbalkoxy, an aralkyl, an aralkyl substituted by halogen, alkyl or alkoxy, a pyridyl or a pyridylalkyl radical, R :

  , a free or an amino group substituted by lower branched or unbranched alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, alkenyl, dialkylaminoalkyl, aryl substituted by halogen, aralkyl and / or pyridyl, substituted amino group or a cyclic amino group in the form of an optionally substituted by lower alkyl Pyrrolidine, piperidine, piperazine, morpholine or hexamethyleneimine rings, R, a hydrogen atom or an acyl radical and n is a number from 1-3, as well as their physiologically compatible salts with inorganic or organic acids or bases.



  According to the invention, the new compounds by reacting a 2-amido-benzylamine of the formula
EMI0001.0007
    with a compound of the formula H-R3 (III).



  The reaction is preferably carried out in the presence of an acid activating agent, e.g. B. an inorganic rule or organic acid halide, advantageously in a solvent, for. B. methylene chloride, chloroform, dioxane or tetrahydrofuran, preferably carried out in the presence of an acid-binding agent, for example a tertiary amine, and optionally at temperatures between -20 C and the boiling temperature of the solvent used. An excess of a compound of the formula III can also serve as a solvent.



  If R4 and R5 represent hydrogen atoms, temporary protection of the amino group, for example by converting it into a Schiff base, is advantageous.



  The starting compounds used in the process according to the invention are obtained by reacting a corresponding 2-diacylamino-benzyl halide with a corresponding aminocarboxylic acid or by reducing a corresponding 2-nitro-benzylamino-alkanoic acid.



  The compounds obtained can be converted into their salts using physiologically compatible inorganic or organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid have proven to be suitable.



  The compounds prepared according to the invention have valuable pharmacological properties; in addition to partially sedative and breath-stimulating effects, they show, in particular, a very good antitussive effect; they also serve as intermediates for pharmaceutically valuable benzodiazepines and benzodiazocines.



  <I> Example 1 </I> N- (2-Acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- [3-diethylamino-propyl- (1) -amide].



  2.0 g of N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine and 0.7 ml of triethylamine are dissolved in 100 ml of tetrahydrofuran under He warm, cooled to -10 C and below Stirring mixed with 0.58 ml of ethyl chloroformate. After 10 minutes, 0.65 g of N, N-diethyl-1,3-diamino-propane is added and the mixture is allowed to come to room temperature. After 1 hour it is evaporated in vacuo, taken up in chloroform, the chloroform solution is washed with water, dilute ammonia and water, dried and the solvent is removed. The residue crystallizes from ethyl acetate.



  F. 142-1440 C.



  The following are shown analogously to Example 1: a) N- (2-acetylamino-3,5-dibromobenzyl) -N-niethyl-glycine-isopropylamide, melting point: 208 ° C., from N- (2-acetylamino-3,5-dibromo -benzyl) -N-methyl-glycine and isopropylamine, b) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-cyclohexylamide, melting point: 178-179 C, from N- (2nd -Acetylamino-3,5-dibromobenzyl) -N-methyl-glycine and cyclohexylamine, c) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-benzylamide, melting point:

   142-143 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N-methylglycine and benzylamine, d) N- (2-acetylamino-3,5-dibromobenzyl) -N- methylglycine anilide, melting point: 167 ° C., from N- (2-acetylamino-3,5-dibromobenzyl) -N-methylglycine and aniline, e) N- (2-acetylamino-3,5-dibromo -benzyl) -N-methyl-glycine diethylamide, melting point: 100 ° C., from N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine and diethylamine.



  f) N- (2-acetylamino-3,5-dibromobenzyl) -N-methylglycine-pyrrolidide, melting point: 157 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- methylglycine and pyrrolidine.



  g) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-piperidide, melting point: 119 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- methylglycine and piperidine.



  h) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- (4-methyl-piperazid), melting point: 139 ° C., from N- (2-acetylamino-3,5-dibromo -benzyl) -N-methyl-glycine and N-methyl-piperazine. i) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-morpholide, melting point: 118 ° C., from N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl - glycine and morpholine.



  j) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- (2-hydroxyethyl-amide), melting point: 127-128 ° C., from 2- (2-acetylamino-3,5 -dibromobenzyl) -N-methylglycine and ethanolamine.



  k) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- (2-diethylamino-ethylamide), melting point: 153-154 ° C., from N- (2-acetylamino-3,5 -dibromobenzyl) -N-methylglycine and 2-diethylamino-ethylamine.



  1) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-propylamide, melting point: 171'C, from N- (2-acetylamino-3,5 -dibromobenzyl) -N-methylglycine and propylamine.



  m) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- [3-methoxy-propyl- (1) -amide], melting point: 125 C, from N- (2-acetylamino -3,5-dibromo-benzyl) -N-methyl-glycine and 1-amino-3-methoxy-propane.



  n) N- (2-Acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-allylamide, melting point: 166 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- methyl glycine and allylamine.



  o) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- (p-fluoro-anilide), melting point: 174-175 C, from N- (2 acetylamino-3,5- dibromobenzyl) -N-methyl-glycine and p-fluoro-aniline.



  p) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- [pyridyl- (4) -amide], melting point: 149-150 ° C, from N- (2-acetylamino-3 , 5-dibromo-benzyl) -N-methyl-glycine and 4-amino-pyridine.



  q) N- (2-Acetylamino-3,5-dibromobenzyl) -N-methyl-glycine- (N, N-hexamethylene-amide), melting point: 105 C, from N (2-acetylamino-3,5- dibromobenzyl) -N-methylglycine and hexamethyleneimine.



  r) N- (2-acetylamino-3,5-dibromobenzyl) -N-methyl-glycine-dicyclohexylamide, melting point: 154 ° C., from N (2-acetylamino-3,5-dibromobenzyl) -N-methyl - glycine and dicyclohexylamine.



  s) N- (2-acetylamino-3,5-dibromobenzyl) -N-methylglycine- (benzyl-isopropyl-amide), amorphous, uniformly by thin-layer chromatography, RF - 0.4 (SiO2, chloroform), from N - (2-Acetylamino-3,5-dibromobenzyl) -N-methyl-glycine and benzyl-isopropyl-amine, t) N- (2-acetylamino-4-bromo-benzyl) -N-methyl-glycine-morpholide , Melting point: 138-140 C, from N- (2-acetylamino-4-bromobenzyl) -N-methylglycine and morpholine, u) IV (2-acetylamino-4-bromobenzyl) -N-methyl- glycine benzylamide, melting point:

       169-171 'C, from N- (2-acetylamino-4-bromo-benzyl) -N-methyl-glycine and benzylamine, v) N- (2-acetylamino-5-bromo-benzyl) -N-methyl-glycine -morpholide, melting point: 151-154 ° C., from N- (2-acetylamino-5-bromobenzyl) -N-methylglycine and morpholine.



  w) N- (2-acetylamino-5-bromo-benzyl) -N-methyl-glycine-benzylamide, melting point: 177-178 C, from N- (2-acetylamino-5-bromobenzyl) -N-methyl- glycine and benzylamine.



  x) N- (2-acetylamino-3,5-dibromobenzyl) -N-ethyl-glycine-morpholide, melting point: 138 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- ethyl glycine and morpholine.



  y) N- (2-acetylamino-3,5-dibromobenzyl) -N-ethyl-glycine-benzylamide, melting point: 149 C, from N- (2-acetylamino -3,5-dibromobenzyl) -N- ethyl glycine and benzylamine.



  z) N- (2-acetylamino-3,5-dibromobenzyl) -N-butylglycine-morpholide, melting point: 134 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- butylglycine and morpholine.



  aa) N- (2-acetylamino-3,5-dibromobenzyl) -N-butylglycine-benzylamide, melting point: 106 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- butylglycine and benzylamine.



  bb) N- (2-acetylamino-3,5-dibromobenzyl) -N-benzylglycine-morpholide, melting point: 102 C, from N- (2-acetylamino-3,5-dibromobenzyl) -N- benzylglycine and morpholine.



  cc) N- (2-Acetylamino-3,5-dibromobenzyl) -N-ethyl-1-aminopropionic acid morpholide, melting point: 115 ° C., from N- (2-acetylamino-3,5-dibromobenzyl ) -N-ethyl-j-aminopropionic acid and morpholine.



  dd) N- (2-acetylamino-6-chlorobenzyl) -N-methyl-glycine morpholide, melting point: 166-167 C, from N- (2-acetylamino-6-chlorobenzyl) -N-methyl- glycine and morpholine.



  ee) N- (2-acetylamino-6-chloro-benzyl) -N-methyl-glycine-benzylamide, melting point: 114-115 ° C, from N- (2-acetylamino-6-chloro-benzyl) -N-methyl - glycine and benzylamine.



  ff) N- (2-acetylamino-6-chlorobenzyl) -N-ethylglycine-morpholide, melting point: 141 ° C, from N- (2-acetylamino-6-chlorobenzyl) -N-ethylglycine and morpholine.



  gg) N- (2-Acetylamino-6-chlorobenzyl) -N-ethyl-glycine-benzylamide, melting point: 100-101 ° C, from N- (2-acetylamino-6-chlorobenzyl) -N-ethyl - glycine and benzylamine.



  hh) N- (2-acetylamino-6-chloro-benzyl) -N-propyl-glycine-morpholide, melting point: 154-155 C, from N- (2-acetylamino-6-chloro-benzyl) -N-propyl- glycine and morpholine. ii) N- (2-acetylamino-6-chloro-benzyl) -N-isopropyl-glycine-morpholide, melting point: 170 ° C., from N- (2-acetylamino-6-chloro-benzyl) -N-isopropyl-glycine and Morpholine.



  jj) N- (2-acetylamino-6-chlorobenzyl) -N-butylglycine-morpholide, melting point: 94-95 ° C., from N- (2-acetylamino-6-chlorobenzyl) -N-butyl - glycine and morpholine.



  kk) N- (2-Acetylamino-6-chlorobenzyl) -N-isobutylglycine-morpholide, melting point: 165-166 C, from N- (2-Acetylamino-6-chlorobenzyl) -N-isobutyl- glycine and morpholine.



  11) N- (2-Acetylamino-6-chlorobenzyl) -N-benzyl-glycine-morpholide, melting point: 117-1l8 C, from N- (2-acetylamino-6-chlorobenzyl) -N-benzyl- glycine and morpholine.



  mm) N- (2-acetylamino-6-chloro-benzyl) -N-phenyl-glycine-morpholide, melting point: 166-167 ° C., from N (2-acetylamino-6-chloro-benzyl) -N-phenyl-glycine and morpholine.



  nn) N- (2-Benzoylamino-6-chlorobenzyl) -N-methyl-glycine-morpholide, melting point: 122.5-123 C, from N- (2-benzoylamino-6-chlorobenzyl) -N- methylglycine and morpholine.



  oo) N- (2-benzoylamino-6-chloro-benzyl) -N-methyl-glycine-isopropylamide, melting point: 153-155 ° C., from N (2-benzoylamino-6-chloro-benzyl) -N-methyl-glycine and isopropylamine.



  pp) N- (2-Benzoylamino-6-chlorobenzyl) -N-methyl-glycine-benzylamide, amorphous, uniform by thin-layer chromatography, RF = 0.75 (SiO2, chloroform: methanol = 19: 1), from N- ( 2-benzoylamino-6-chloro-benzyl) -N-methyl-glycine and benzylamine.



  qq) N- (2-Benzoylamino-6-chloro-benzyl) -N-methyl-glycine anilide, melting point: 142 C, from N- (2-benzoylamino-6-chloro-benzyl) -N-methyl-glycine and Aniline.



  rr) N- (2-Benzoylamino-6-chlorobenzyl) -N-methyl-glycine-diethylamide, melting point: 98-101 ° C., from N (2-benzoylamino-6-chloro-benzyl) -N-methyl-glycine and diethylamine.



  ss) N-ethyl-N- (2-benzoylamino-3,5-dibromobenzyl) -glycine amide, melting point: 173-174 ° C, from N-ethyl-N- (2-benzoylamino-3,5-dibromobenzyl ) - glycine and conc. Ammonia.



  tt) N-ethyl-N- (2-benzoylamino-3,5-dibromobenzyl) -glycine-isopropylamide, melting point: 170-172 ° C., from N-ethyl-N- (2-benzoylamino-3,5-dibromo -benzyl) - glycine and isopropylamine.



  vv) N- (2-benzoylamino-5-chloro-benzyl) -N-methyl-glycine amide, melting point: 155-157 ° C., from N (2-benzoylamino-5-chloro-benzyl) -N-methyl-glycine and conc . Ammonia. ww) N (2-benzoylamino-5-chlorobenzyl) -N-methyl-glycine-isopropylamide, melting point: 122-124 ° C., from N- (2-benzoylamino-5-chloro-benzyl) -N-methyl-glycine and isopropylamine.



  xx) N- (2-Benzoylamino-5-chlorobenzyl) -N-methyl-glycine-cyclohexylamide, melting point: 190-192 C, from N- (2-Benzoylamino-5-chlorobenzyl) -N-methyl- glycine and cyclohexylamine.



  yy) N- (2-Benzoylamino-5-chlorobenzyl) -N-methyl-glycine-anilide, melting point: 157-159 C, from N- (2-benzoylamino-5-chlorobenzyl) -N-methyl- glycine and aniline.



  zz) N- (2-Benzoylamino-5-chlorobenzyl) -N-methyl-glycine-morpholide, melting point of the hydrochloride: 215 C (decomp.), from N- (2-Benzoylamino-5-chlorobenzyl) - N-methylglycine and morpholine.



  aaa) N- (2-benzoylamino-4-chloro-benzyl) -N-methyl-glycine amide, melting point: 131-132 ° C., from N- (2-benzoylamino-4-chloro-benzyl) -N-methyl-glycine and conc. Ammonia.



  bbb) N- (2-benzoylamino-4-chloro-benzyl) -N-methyl-glycine-allylamide, melting point: 97-98 'C, from N- (2-benzoylamino-4-chloro -benzyl) -N-methylglycine and allylamine.



  ccc) N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl-glycine-isopropylamide, melting point: 110-111 C, from N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl- glycine and isopropylamine.



  ddd) N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl-glycine-cyclohexylamide, melting point: 138-139 C, from N- (2-benzoylamino-6-chlorobenzyl) -N-methyl- glycine and cyclohexylamine.



  eee) N- (2-Benzoylamino-4-chloro-benzyl) -N-methyl-glycine-benzylamide, melting point: 141-142 C, from N- (2-Benzoylamino-4-chloro-benzyl) -N-methyl- glycine and benzylamine.



  fff) N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl-glycine-anilide, melting point: 144-145 C, from N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl- glycine and aniline.



  ggg) N- (2-Benzoylamino-4-chlorobenzyl) -N-methyl-glycine-morpholide, melting point: 95-96 'C, from N- (2-benzoylamino-4-chloro -benzyl) -N-methylglycine and morpholine.



  hhh) γ - [N- (2-Acetylamino-3,5-dibromobenzyl) -N-isopropyl] -amino-butyric acid diethylamide, colorless oil, uniformly obtained by thin layer chromatography from γ - [2- (acetylamino-3, 5-dibromobenzyl) -N-isopropyl] -amino-butyric acid and diethylamine.



  <I> Example 2 </I> N- (2-amino-6-chlorobenzyl) -N-methyl-glycine morpholide.



  15.0 g of N- (2-amino-6-chlorobenzyl) -N-methyl-glycine and 17.5 g of 2-hydroxy-1-naphthaldehyde are absolute in 1 1. Boiled ethanol. The water formed is distilled off azeotropically, and new absol is given according to the amount of distilled water. Add ethanol. After 3 hours it is allowed to cool down. The precipitated yellow crystals of N - [6 - chlorine - 2 - (2-hydroxy-1-naphthylidene-amino) -benzyl] -N-methyl-glycine are filtered off with suction and washed with ethanol and ether.



  Melting point: 185-187 C (dec.).



  5.9 g of N- [6-chloro-2- (2-hydroxy-1-naphthylidene-amino) benzyl] -N-methyl-glycine are absolute in 100 ml. Chloroform dissolved. Under nitrogen protection and stirring, 2.2 ml of triethylamine and 1.5 ml of ethyl chloroformate are added at -10 C. After 20 minutes at −10 ° C., 2.7 ml of morpholine are added and allowed to react for 1 hour at 20 ° C. and under N2. The reaction mixture is freed from the solvent in vacuo and the amino protective group is split off 11 ;, hours with 70 ml of 0 , Stirred 5N HCl. The regenerated hydroxynaphthaldehyde is extracted with chloroform.

   The N- (2-amino-6-chlorobenzyl) -N-methyl-glycine-morpholide is precipitated by neutralizing the aqueous phase with 35 ml of 1N NaOH. It is suctioned off and washed with water.



  Melting point: 116-118 C (from methanol / water).

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung von neuen 2-Amido- halogen-benzylaminen der Formel EMI0004.0063 in der Hal ein Chlor- oder Bromatom in 3-, 4-, 5- oder 6-Stellung und R, ein Wasserstoff- oder Halogenatom bedeuten, R2 einen geradkettigen oder verzweigten Alkyl- oder Alkenylrest, einen Hydroxyalkyl-, Alkoxyalkyl-, Dialkylaminoalkyl-, Cycloalkyl-, Aryl-, einen durch Halogen, Alkyl, Alkoxy, Nitro, Carboxy oder Carbalk- oxy substituierten Aryl-, einen Aralkyl-, einen durch Halogen, Alkyl oder Alkoxy substituierten Aralkyl-, einen Pyridyl- oder einen Pyridylalkylrest darstellt, PATENT CLAIM Process for the production of new 2-amido-halogen-benzylamines of the formula EMI0004.0063 in which Hal is a chlorine or bromine atom in the 3-, 4-, 5- or 6-position and R is a hydrogen or halogen atom, R2 is a straight-chain or branched alkyl or alkenyl radical, a hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl , Cycloalkyl, aryl, an aryl substituted by halogen, alkyl, alkoxy, nitro, carboxy or carbalkoxy, an aralkyl, an aralkyl substituted by halogen, alkyl or alkoxy, a pyridyl or a pyridylalkyl radical, R3 eine freie oder eine durch niederes verzweigtes oder unverzweigtes Alkyl, Hydroxyalkyl, Alkoxyalkyl, Cyclo- alkyl, Alkenyl, Dialkylaminoalkyl, Aryl, durch Halogen substituiertes Aryl, Aralkyl und/oder Pyridyl substituierte Aminogruppe oder eine cyclische Aminogruppe in Form eines gegebenenfalls durch niederes Alkyl substituierten Pyrrolidin-, Piperidin-, Piperazin-, Morpholin- oder Hexamethyleniminrings bedeutet, R.4 ein Wasserstoffatom oder einen Acylrest und n eine Zahl von 1-3 darstellen, sowie von deren physiologisch verträglichen Salzen mit anorganischen oder organischen Säuren oder Basen, dadurch gekenn zeichnet, R3 is a free or an amino group substituted by lower branched or unbranched alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, alkenyl, dialkylaminoalkyl, aryl, halogen-substituted aryl, aralkyl and / or pyridyl or a cyclic amino group in the form of an optionally substituted by lower alkyl Pyrrolidine, piperidine, piperazine, morpholine or hexamethyleneimine rings, R.4 represents a hydrogen atom or an acyl radical and n represents a number from 1-3, as well as their physiologically acceptable salts with inorganic or organic acids or bases, marked thereby , dass ein 2-Amido-benzylamin der Formel EMI0004.0074 mit einer Verbindung der Formel H-R3 (III) in Gegenwart eines säureaktivierenden Mittels umge setzt wird. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass die Umsetzung in einem inerten Lösungs mittel und bei Temperaturen zwischen -20 C und der Siedetemperatur des verwendeten Lösungsmittels durch geführt wird. 2. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass die Umsetzung in Gegenwart eines säure bindenden Mitteis durchgeführt wird. 3. that a 2-amido-benzylamine of the formula EMI0004.0074 is reacted with a compound of the formula H-R3 (III) in the presence of an acid-activating agent. SUBClaims 1. The method according to claim, characterized in that the reaction is carried out in an inert solvent medium and at temperatures between -20 C and the boiling point of the solvent used. 2. The method according to claim, characterized in that the reaction is carried out in the presence of an acid-binding agent. 3. Verfahren nach Patentanspruch, dadurch gekenn zeichnet, dass eine erhaltene basische Verbindung mit Säure in ihr Säureadditionssalz überführt wird. <I>Anmerkung des</I> Eidg. <I>Amtes für geistiges Eigentum:</I> Sollten Teile der Beschreibung mit der im Patentanspruch gegebenen Definition der Erfindung nicht in Einklang stehen, so sei daran erinnert, dass gemäss Art. 51 des Patentgesetzes der Patentanspruch für den sachlichen Geltungs bereich des Patentes massgebend ist. Process according to claim, characterized in that a basic compound obtained is converted into its acid addition salt with acid. <I> Note from the </I> Federal <I> Office for Intellectual Property: </I> If parts of the description are inconsistent with the definition of the invention given in the claim, it should be remembered that according to Art. 51 of the Patent Act, the claim is decisive for the material scope of the patent.
CH283469A 1965-06-08 1966-05-24 2-aminohalobenzyl amines CH497381A (en)

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DET0028754 1965-06-08
CH743466A CH493468A (en) 1965-06-08 1966-05-24 Process for the preparation of new 2-amido-halogen-benzylamines

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CH497381A true CH497381A (en) 1970-10-15

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CH283169A CH487122A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-amido-5-halogenobenzylamino) alkanoic acids, their esters, amides and / or salts
CH283469A CH497381A (en) 1965-06-08 1966-05-24 2-aminohalobenzyl amines
CH283269A CH487843A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-Amidohalogenbenzylamino) alkanoic acids, their esters, amides and / or salts
CH283369A CH487844A (en) 1965-06-08 1966-05-24 Process for the preparation of new 2-amido-halogenobenzylamines
CH283069A CH487121A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-aminohalogenbenzylamino) -alkanoic acids, their esters, amides and / or salts

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CH283169A CH487122A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-amido-5-halogenobenzylamino) alkanoic acids, their esters, amides and / or salts

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CH283269A CH487843A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-Amidohalogenbenzylamino) alkanoic acids, their esters, amides and / or salts
CH283369A CH487844A (en) 1965-06-08 1966-05-24 Process for the preparation of new 2-amido-halogenobenzylamines
CH283069A CH487121A (en) 1965-06-08 1966-05-24 Process for the preparation of new w- (2-aminohalogenbenzylamino) -alkanoic acids, their esters, amides and / or salts

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CH487844A (en) 1970-03-31
CH487121A (en) 1970-03-15
CH487843A (en) 1970-03-31

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