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Synthesis of cycloalkyl analogues of antergan Wang, Yih Song 1969

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SYNTHESIS OP CYCLOALKYL ANALOGUES OP ANTERGAN  by  YIH SONG WANG B.S.P., The N a t i o n a l Taiwan U n i v e r s i t y , T a i p e i , Taiwan, China, 1964-  A THESIS SUBMITTED IN THE PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF MASTER OF SCIENCE (PHARMACY) i n the D i v i s i o n of P h a r m a c e u t i c a l Chemistry o f the F a c u l t y o f Pharmaceutical Sciences  We a c c e p t t h i s t h e s i s as conforming to" the required  standard  THE UNIVERSITY OF BRITISH COLUMBIA December 1969  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree tha  permission for extensive copying of this thesis  for scholarly purposes may be granted by the Head of my Department or by his representatives.  It is understood that copying or publication  of this thesis for financial gain shall not be allowed without my written permission.  Department The University of British Columbia Vancouver 8, Canada  i ABSTRACT C y c l o a l k y l analogues of Antergan w i t h the b a s i c s t r u c t u r e of  N.N-dimethyl-N'-cycloalkylmethyl-N'-phenylethylenedi-  amlne have been s y n t h e s i z e d In good y i e l d s . was  The  a l k y l group  a b u t y l - , pentyl-, hexyl-, or h e p t y l - r i n g s t r u c t u r e .  The  compounds with the b e n z y l group of Antergan s u b s t i t u t e d by a hydrogen or a methyl group were a l s o s y n t h e s i z e d i n good y i e l d s . The  g e n e r a l r e a c t i o n sequence f o l l o w e d was  to  start  with the a p p r o p r i a t e c y c l o a l k a n e c a r b o x y l l c a c i d and b u i l d to a secondary amine v i a an a c i d c h l o r i d e and an amide. methods (1) were f o l l o w e d and  checked up to t h i s s t e p .  r e a c t i o n sequences were developed s i r e d amine was amine and  d u r i n g t h i s study.  up Leung's  Further The  reacted with c h l o r o a c e t y l c h l o r i d e , dimethyl-  then reduced  to the t e r t i a r y diamine analogues.  The p r e l i m i n a r y a n t i h i s t a m i n e a c t i v i t y of these logues was  de-  ana-  s t u d i e d and compared with t h a t of Diphenhydramine  Hydrochloride analogue was  Standard  Solution.  The  r e l a t i v e a c t i v i t y of each  a l s o determined. S i g n a t u r e of Examiners  11 ACKNOWLEDGEMENT My s i n c e r e g r a t i t u d e i s extended t o my major p r o f e s s o r , Dr. T. H. Brown, f o r p r o f e s s i o n a l guidance,  under-  s t a n d i n g and encouragement d u r i n g the course o f t h i s study. I wish t o express my thanks t o Dr. J . E . H a l l i d a y f o r h i s guidance i n p h a r m a c o l o g i c a l t e s t s , and my s i n c e r e thanks t o Dr. F. S. Abbott f o r advice and c o u n s e l i n g . F i n a n c i a l support by the N a t i o n a l Research C o u n c i l of Canada i s g r a t e f u l l y acknowledged. I am most g r a t e f u l t o f e l l o w graduate students f o r t h e i r f r i e n d s h i p and h e l p f u l a d v i c e .  iii TABLE OF CONTENTS Part  Page  Abstract  .  1  Acknowledgement  i l  L i s t of Tables  vi  L i s t of Figures I.  II. III. IV.  v i i  INTRODUCTION  1  A.  Histamine  1  B.  Analogs  7  C.  A n t i h i s t a m i n e s and R e l a t i o n s h i p between S t r u c t u r e and P h a r m a c o l o g i c a l A c t i v i t y  of Histamine  9  STATEMENT OF PROBLEM  13  ANALYTICAL METHODS  14  EXPERIMENTAL  15  A.  B.  C.  S y n t h e s i s of  N,N-Dimethyl-N'-Phenylethylene-  d i amine  15  1.  c*-Chloroacetanllide  15  2.  o<-Dimethylaminoacetanilide  16  3. N,N-Dlmethyl-N*-Phenylethylenedlamlne S y n t h e s i s o f N.N-Dimethyl-N'-Methyl-N'Phenylethylenedlamlne  18  1.  c<-Chloro-N-Methylacetanllide  18  2.  c<-Dimethylamino-N-Methyl-N-Phenylacetamide.  20  3.  N,N-Dime thyl-N•-Me thyl-N•-Phenyle t h y l e n e diamine...  21  Synthesis of  17  N.N-Dimethyl-N'-Cyclobutylmethyl-  N' -Phenylethylenedlamlne  22  1.  Cyclobutanecarbonyl C h l o r i d e . . .  22  2.  Cyclobutanecarboxanilide  23  iv Part  Page  D.  E.  3.  N-Cyclobutylmethyl-N-Phenylamine  23  4.  o<-Chloro-N-Cyclobutylmethyl-N-Phenylacetamide  25  5.  crt-Dimethylamino-N-Cyclobutylmethyl-NPhenylacetamide  26  6.  N,N-Dimethyl-N•-Cyclobutylmethyl-N*Phenylethylenediamine  27  S y n t h e s i s of N,N-Dimethyl-N'-CyclopentylmethylN*-Phenylethylenediamine  29  1.  Cyclopentanecarbonyl Chloride  29  2.  Cyclopentanecarboxanilide.........  29  3.  N-Cyclopentylmethyl-N-Phenylamine.  30  *K  o<-Chloro-N-Cyclopentylmethyl-NPhenylacetamide  31  5.  oC-Dimethylamino-N-Cyclopentylmethyl-NPhenylacetamide  32  6.  N,N-Dlmethyl-N*-Cyclopentylmethyl-N'Phenylethylenediamlne  33  S y n t h e s i s of N,N-Dimethyl-N'-CyclohexylnethylN'-Phenylethylenediamine  3^-  1.  Cyclohexanecarbonyl C h l o r i d e  3^  2.  Cyclohexanecarboxanilide  35  3.  N-Cyclohexylmethyl-N-Phenylamine  35  4„  crf-Chloro-N-Cyclohexylme t h y l - N Phenylacetamide crf-Dimethylamino-N-Cyclohexylmethyl-NPhenylacetamide  5. 6. F.  1  N,N-Dimethyl-N•-Cyclohexylmethyl-N•Phenylethylenediamine  36 37 39  S y n t h e s i s of N,N-Dimethyl-N*-CycloheptylmethylN' -Phenylethylenediamine  4-0  1.  4-0  Cycloheptanecarboxylic Acid  V Part  V. VI. VII. VIII. IX.  Page 2.  Cycloheptanecarbonyl Chloride  42  3.  Cycloheptanecarboxanilide  42  4.  N-Cycloheptylmethyl-N-Phenylamine  43  5.  <X-Chloro-N-Cycloheptylmethyl-NPhenylacetamide  44  6.  o<-Dimethylamino-N-Cycloheptylmethyl-NPhenylacetaraide  45  7.  N.N-Dimethyl-N -Cycloheptylmethyl-N'Phenylethylenedlamlne  46  1  DISCUSSION OF CHEMISTRY  48  PRELIMINARY ANTIHISTAMINE ACTIVITY STUDIES  63  SUMMARY  68  INFRARED SPECTRA  70 89  LIST OF REFERENCES  Biographical Information  .-  91  vi LIST OP TABLES Table  Page  1.  Histamine Content of T i s s u e s Compared with Heparin Content and the R e l a t i v e M a s t - c e l l Content  2  2.  Mast C e l l Number i n Guinea-pig I n f e r i o r Pulmonary Lobes Before and A f t e r Anaphylaxis  4  3.  Histamine Content i n Guinea-pig I n f e r i o r Pulmonary Lobes Before and A f t e r Anaphylaxis  4  4.  Cycloalkanecarbonyl Chlorides  49  5.  Cycloalkanecarboxanllides  50  6  N-Cycloalkylmethyl-N-Phenylamines  52  7.  C y c l o a l k y l Analogues  52  8.  o<-Chloro-N-(R)-Acetanilides  59  9.  o<-Dime thy lamino-N-(R)-N-Pheny l a c e tamlde  60  0  of Antergan  10.  N.N-Dimethyl-N'-UJ-N' -Phenylethylenedlamlne  61  11.  E f f e c t s of C y c l o a l k y l Analogues of Antergan (MonoHC1 S a l t s ) and Diphenhydramine HCl on Response of I s o l a t e d Guinea-pig Ileum .  64  v  vii L I S T OP  FIGURES  Figure  Page  1.  M a j o r Routes  7  2.  pA V a l u e f o r Mono-HCl S a l t s o f C y c l o a l l c y l Analogues o f Antergan v s . Diphenhydramine HCl  of Histamine Catabolism i n Vivo  2  Infrared  66  Spectrum o f i  3.  ot-Chloroacetanilide  71  4.  ot-Dirnethylaminoacetanilide  72  5.  N,N-Dimethyl-N' - P h e n y l e t h y l e n e d l a m l n e  73  6.  oC-Chloro-N-Methylacetanilide  74  7.  o<-Dimethylamino-N-Methyl-N-Phenylacetamide  75  8.  N,N-Dimethyl-N'-Methyl-N'-Phenylethylenedlamlne....  76  9.  o<-Chloro-N-Cyclobutylmethyl-N-Phenylacetamlde......  77  <*-Dimethylamino-N-Cyclobutylmethyl-NPhenylacetamide  78  N,N-Dlmethyl-N•-Cyclobutylmethyl-N* Phenylethylenedlamlne  79  12.  oC-Chloro-N-Cyclopentylmethyl-N-Phenylacetamide  80  13.  erf-Dime t h y l a m l n o - N - C y c l o p e n t y l m e t h y l - N Phenylacetamide  81  N,N-Dimethyl-N'-Cyclopentylmethyl-N•Phenylethylenedlamlne  82  15.  o<-Chloro-N-Cyclohexylmethyl-N-Phenylacetamide  83  16.  o<-Dimethylamino-N-Cyclohexylmethyl-NPhenylacetamlde  84  10. 11.  14.  17.  N,N-Dlmethyl-N'-Cyclohexylmethyl-N•Phenylethylenedlamlne  85 «  18.  o<-Chloro-N-Cycloheptylmethyl-N-Phenylacetamide  86  19.  o<-Dimethylamino-N-Cycloheptylmethyl-NPhenylacetamide.  87  N,N-Dimethyl-N'-Cycloheptylmethyl-N * Phenylethylenedlamlne  88  20.  PART I INTRODUCTION Leung (1) f i r s t Antergan"  i n 1964.  r e p o r t e d " C y c l o a l k y l Analogues o f  The b e n z y l group o f Antergan was r e p l a c e d  by a c y c l o p r o p y l m e t h y l , a c y c l o b u t y l m e t h y l , a c y c l o p e n t y l m e t h y l , a c y c l o h e x y l m e t h y l o r a c y c l o h e p t y l m e t h y l group, but the y i e l d of  each o f these analogues was very poor.  The purpose o f t h i s  study was t o i n c r e a s e the y i e l d s o f f o u r analogues  (cyclobutyl-  methyl t o c y c l o h e p t y l m e t h y l ) by new s y n t h e t i c methods and make them a v a i l a b l e f o r p h a r m a c o l o g i c a l  i n v e s t i g a t i o n s i n t o the na-  ture of a n t i h l s t a m i n l c receptors.  Two o t h e r compounds w i t h the  b e n z y l group of Antergan r e p l a c e d by a hydrogen o r a methyl group were a l s o s y n t h e s i z e d i n o r d e r t o complete the a n t l h i s t amlnlc a c t i v i t y s t u d i e s f o r a s e r i e s o f these compounds. Antergan, diamine,  N-benzyl-N-phenyl-N*,N'-dimethylethylene-  was the f i r s t  c l i n i c a l l y e f f e c t i v e a n t i h l s t a m i n l c drug  produced i n 19^2. Although  i t caused  a number o f unpleasant  s i d e e f f e c t s such as p o t e n t i a t i n g the reponses t o epinephrine and  the s t i m u l a t i o n o f a d r e n e r g i c nerves  ( 2 ) , the b a s i c Antergan  s t r u c t u r e has served as a model f o r a number of the a n t i h i s t a m i n e drugs i n use today.  I t was hoped i n the present study t h a t by  r e p l a c i n g one phenyl group i n the parent compound w i t h s t r u c t u r e s , a g r a d u a l a l t e r a t i o n i n potency  allcyclic  and o r s e l e c t i v i t y  would be found i n a s e r i e s of these compounds. A. HISTAMINE Histamine  i s k(or 5 ) - ( 2 ' - a m i n o e t h y l ) i m i d a z o l e ,  C^HQN-,  and i s r e p r e s e n t e d s t r u c t u r a l l y by e i t h e r formula I o r I I : H• HC  CH ll C-CH -CH -NH  W N  2  2  HC CH \ II N — C-CHg-CHg-NHg  2  I  II  The imlno hydrogen o f the Imidazole  r i n g i s mobile  and can s h i f t from one n i t r o g e n atom t o the o t h e r w i t h a concomitant  s h i f t of the double bond.  I I , of histamine c o e x i s t . Histamine  Thus, the two forms,  I t has l i t t l e  I and  therapeutic value.  i s w i d e l y d i s t r i b u t e d i n mammalian t i s s u e s ,  but the c o n c e n t r a t i o n i n a g i v e n organ has s p e c i e s v a r i a t i o n . Much of the t i s s u e histamine i s formed i n mast c e l l s from t i d i n e by enzymatic c e l l granule  (3)«  L-his-  d e c a r b o x y l a t i o n and i t i s h e l d i n the mast The histamine content p e r mast c e l l i s r e a -  sonably constant i n normal t i s s u e  (4).  The mast c e l l s a r e l o -  cated m a i n l y i n c o n n e c t i v e t i s s u e i n r e l a t i o n t o b l o o d v e s s e l s . I n s p e c t i o n o f Table 1 i n d i c a t e s t h a t as good a p a r a l l e l i s m  exists  between histamine and mast c e l l s as between h e p a r i n and mast c e l l s i n these t i s s u e s  (3)« TABLE 1  HISTAMINE CONTENT (jug/g) OF TISSUES COMPARED WITH HEPARIN CONTENT (mg STANDARD HEPARIN/Kg) AND THE RELATIVE MASTCELL CONTENT i TISSUE  HISTAMINE  HEPARIN  MAST CELLS  Rat l i v e r  0.3  0  0  Pig  0.7  0  0  4.5  56-75  +  aorta  O x - l i v e r parenchyma (to be  continued)  3. TISSUE  HISTAMINE  HEPARIN  MAST CELL  10.0  5-65  +  63  ++  100-120  ++  5^0-830  +++  Ox a o r t a subcutaneous t i s s u e  Rat  16.0 20.0  Ox I n f e r i o r vena cava  ko.o  O x - l i v e r capsule  However, the mast c e l l s are not the o n l y c e l l s t a i n i n g histamine.  Histamine  has been found  in platelets  conand  i n b a s o p h i l i c leukocytes; i t i s present i n high concentration i n f e t a l l i v e r and i n the p a r i e t a l r e g i o n of the stomach even though mast c e l l s are v i r t u a l l y nonexlxtent i n these s i t e s ( 4 ) . The b i o l o g i c a l s i g n i f i c a n c e of histamine i n mast c e l l s i s a t p r e s e n t unknown. i s connected  The  r e l e a s e of histamine from mast c e l l s  w i t h the m o r p h o l o g i c a l change of the mast  cell.  Most of the substances known to r e l e a s e histamine, cause damage to the mast c e l l s . i t s own  In a n a p h y l a x i s , although each s p e c i e s has  peculiarities,  there i s l i t t l e  room f o r doubt t h a t most  - a l t h o u g h c e r t a i n l y not a l l - of the histamine r e l e a s e d by gen,  comes from the mast c e l l s .  Mota (5)  investigated antigen-  induced mast c e l l damage and histamine r e l e a s e l n the guinea-pig.  The  l a x i s produced cells and  3)  r e s u l t s of the experiment  intact  showed t h a t anaphy-  a s i g n i f i c a n t r e d u c t i o n i n the number of mast  and i n the histamine content of the l u n g (see T a b l e 2  (5)»  anti-  4. TABLE 2 MAST CELL NUMBER (*) IN GUINEA-PIG INFERIOR PULMONARY LOBES BEFORE AND AFTER ANAPHYLAXIS* BEFORE  AFTER  G.P.  BEFORE  AFTER  1  162  87  12  249  152  2  114  96  13  91  77  3  139  98  14  137  55  4  103  92  15  75  94  5  234  225  16  84  83  6  115  62  17  75  73  7  I69  159  18  197  68  8  92  73  19  191  110  9  115  91  20  88  73  10  93  68  21  171  127  n  90  84  22  55  31  G.P.  (*) The c e l l s were counted under a m a g n i f i c a t i o n of 250X. Each f i g u r e was mean o f 100 f i e l d s . D i f f e r e n c e between the means o f the two lobes h i g h l y s i g n i f i c a n t ( P < 0 . 0 1 ) . TABLE 3 HISTAMINE CONTENT (jug/g) IN GUINEA-PIG INFERIOR PULMONARY LOBES BEFORE AND AFTER ANAPHYLAXIS 1 D i f f e r e n c e between the means of the two l o b e s h i g h l y s i g n i f i c a n t (P< 0.01). BEFORE  AFTER  BEFORE  20  9  29  25  28  12  32  17  11  9  28  18  32  15  40  21  21  11  15  15  !9  17  36  25  26  20  AFTER  I t i s w e l l known t h a t the a n a p h y l a c t i c phenomenon can be c o n s i d e r e d as a sequence of r e a c t i o n s s t a r t i n g by the union of a n t i g e n w i t h a n t i b o d y and h a v i n g as one of i t s many consequences the r e l e a s e of h i s t a m i n e . great volume of r e s e a r c h i n the f i e l d  Notwithstanding a t h e r e i s not yet a com-  prehensive e x p l a n a t i o n f o r the mechanism of histamine r e l e a s e by a n t i g e n i n a n a p h y l a x i s .  In the i n v e s t i g a t i o n of the mech-  anism of histamine r e l e a s e i t was  thought t h a t the study of  i n h i b i t i o n of histamine r e l e a s e by chemical compounds of known p r o p e r t i e s c o u l d p o s s i b l y c o n t r i b u t e t o c l e a r up t h i s F o r i n s t a n c e , the experiments  w i t h phenol  issue.  (5) showed t h a t the  r e l e a s e o f histamine from the mast c e l l by a n t i g e n was  not a  d i r e c t consequence of the a n t i g e n - a n t i b o d y r e a c t i o n but the union of a n t i g e n w i t h antibody o n l y t r i g g e r e d o f f a complex s e r i e s of events l e a d i n g to mast c e l l damage and histamine r e lease.  The  i n h i b i t i o n of the a n a p h y l a c t i c r e l e a s e of histamine  from the mast c e l l s by v a r i o u s m e t a b o l i c i n h i b i t o r s ( i o d o a c e t a t e , chloromercuribenzoate and cyanide e t c . ) and i t s dependence on pH and temperature of  s t r o n g l y . s u g g e s t e d the e x i s t e n c e  an enzymatic mechanism i n t h i s phenomenon (5).  t h a t chymotrypsin  The  fact  i n h i b i t o r s and s u b s t r a t e s i n h i b i t e d the ana-  p h y l a c t i c r e l e a s e of histamine s t r o n g l y i m p l i e d the i n v o l v e ment of an enzymatic trypsin.  Furthermore,  a c t i v i t y s i m i l a r t o that of alpha-chymothe d i s c o v e r y of a h e a t - l a b i l e  factor  i n the t i s s u e s , p r o b a b l y a pro-enzyme t h a t r e q u i r e d c a l c i u m for  i t s a c t i v a t i o n and was  necessary f o r the a n a p h y l a c t i c r e -  l e a s e of h i s t a m i n e , suggested the p a r t i c i p a t i o n of complement i n t h i s phenomenon (5)«  However, i n s p i t e o f o b s e r v a t i o n s i n  f a v o r o f the p a r t i c i p a t i o n o f complement i n a n a p h y l a x i s t h e r e i s not y e t evidence  t h a t complement i s necessary f o r the ana-  p h y l a c t i c r e l e a s e o f histamine from the mast c e l l .  Another  f a c t o r n e c e s s a r y f o r the a n a p h y l a c t i c r e l e a s e o f histamine i s cellular integrity  (5)»  Histamine  r e l e a s e from  Intracellular  p a r t i c l e s c o u l d be demonstrated o n l y when a n t i g e n was a p p l i e d to  i n t a c t c e l l s , b u t n o t when i t was added t o I s o l a t e d  cellular particles.  intra-  Since histamine i s l o c a t e d i n the mast  c e l l g r a n u l e s , the union o f a n t i g e n w i t h antibody on the mast c e l l membrane must t r i g g e r o f f an enzymatic  mechanism a b l e t o  r e l e a s e histamine from I n t r a c e l l u l a r mast c e l l  granules.  T h e r e f o r e , probably both membrane and i n t r a c e l l u l a r  enzymes  were i n v o l v e d i n the a n a p h y l a c t i c r e l e a s e o f histamine the mast c e l l s  from  (5)»  Some of the e s t a b l i s h e d p h a r m a c o l o g i c a l a c t i o n s o f histamine i n c l u d e i n c r e a s e o f c a p i l l a r y p e r m e a b i l i t y , bronc h i o l a r and o t h e r smooth muscle c o n s t r i c t i o n , and s t i m u l a t i o n of  the glands o f e x o c r i n e s e c r e t i o n ( 4 ) . Histamine  i s degraded e i t h e r by o x i d a t i o n o r by  m e t h y l a t i o n such t h a t the p r i n c i p l e e x c r e t i o n products a r e i m i d a z o l e a c e t i c a c i d r i b o s i d e o r 1,4-methylimidazole acid  (6), respectively  (see F i g u r e 1 ) .  acetic  FIGURE 1 MAJOR ROUTES OF HISTAMINE CATABOLISM IN VIVO:  / =  ^GH -CH -NH  HN Diamine oxidase I  2  2  2  ^N Methylation  Histamine  ^CH -CHQ 2  H N ^ N Imidazoleacetaldehyde  1,4-Methylhlstamlne  Aldehyde dehydrogenase  Monoamine oxidase  t ^r^CHg-COOH  ^=^CH -CHO 2  H N ^ N  H  Imidazoleacetlc  acid  3  C  -  N ^  N  1,4-Methylimidazole  Enzymatic synthesis ¥  .N  /  ribose  H  ^  3  C  -  N  acetaldehyde  Aldehyde dehydrogenase  / /  ^z^CHg-COOH N-  N  r-CH -C00H \ r  \ ^  N  1,4-Methylimidazole a c e t i c a c i d  Imidazoleacetlc  acid riboside  B. ANALOGS OF HISTAMINE Most o f the compounds t h a t have h i s t a m i n e - l i k e a c t i v i t i e s c o n t a i n i n t h e i r s t r u c t u r e s the fragments • C - C - C - N :  =N  or  .C-C-C-N. -N*  8. The d e f i n i t i o n compound  of h i s t a r a i n e - l i k e  a c t i v i t y i s that a  causes c o n t r a c t i o n of smooth muscle and l o w e r i n g of  blood p r e s s u r e , t h i s a c t i v i t y i s h i s t a m i n e - l i k e only i f i t i s inhibited  by one of the t y p i c a l a n t i h i s t a m i n e drugs.  I t i s to  be noted here, however, t h a t , a l t h o u g h many o f the histamine analogs possess a c t i v i t i e s resembling those o f histamine, none has y e t been d i s c o v e r e d t h a t antagonizes any of the a c t i v i t i e s of h i s t a m i n e .  The a n t i h i s t a m i n e drugs are not analogs o f h i s t  amine i n a chemical sense. At  f i r s t the s y n t h e t i c analogs were c o n f i n e d t o d e r i -  v a t i v e s of i m i d a z o l e , but i n 19^1 Walter, Hunt and F o s b i n d e r (12) observed t h a t 2 - ( 2 - a m i n o e t h y l ) - p y r i d i n e e x h i b i t e d histamine a c t i v i t y on smooth muscle.  Since then many  typical compounds  not c o n t a i n i n g the i m i d a z o l e r i n g have been found to have phys i o l o g i c a l a c t i v i t i e s resembling h i s t a m i n e . divided into tures ( 7 ) J  The analogs were  seven groups a c c o r d i n g to t h e i r chemical s t r u c I . Imidazole compounds;  I I I . 1 , 2 , 3 - T r l a z o l e compounds;  I I . P y r a z o l e compounds;  IV. 1 , 2 , 4 - T r i a z o l e s ; V. T h i a z o l e  compounds; V I . P y r i d i n e compounds; and V I I . M i s c e l l a n e o u s compounds.  N N I Imidazole  N —R III  II cpds.  NH  Pyrazole  cpds.  1,2,3-Trlazole  cpds.  9.  f>  R  HN — N IV 1,2,4-Triazoles.  T h i a z o l e cpds.  P y r i d i n e cpds,  R = D e r i v a t i v e s of 2-aminoethyl group. A number o f the compounds mimic histamine i t s e f f e c t s w h i l e others may possess activities.  only one of histamine's  G e n e r a l l y a l l of the analogs  a r e l e s s a c t i v e than  the parent h i s t a m i n e , b u t there a r e two e x c e p t i o n s . histamine  I n a l l of  N-Methyl-  and N N-dlmethylhistamine are more a c t i v e than B  hist-  amine as s t i m u l a n t s of g a s t r i c s e c r e t i o n i n the dog ( 7 ) . As l a r g e r numbers of compounds have been made and tested  (210 analogs  l i s t e d i n L i t . (7))» i t has become i n c r e a s -  i n g l y d i f f i c u l t t o formulate  any g e n e r a l r u l e r e l a t i n g s t r u c -  ture t o h i s t a m i n e - l i k e a c t i v i t y . is  About a l l t h a t can be s a i d  t h a t compounds p o s s e s s i n g a p p r e c i a b l e h i s t a m i n e - l i k e a c t i -  vity  c o n s i s t o f small n i t r o g e n - h e t e r o c y c l i c aromatic  r i n g s to  which are a t t a c h e d 2-aminoethyl s i d e c h a i n s . C. ANTIHISTAMINES AND RELATIONSHIP BETWEEN STRUCTURE AND PHARMACOLOGICAL ACTIVITY A n t i h i s t a m i n e s a r e drugs w i t h the a b i l i t y t o a n t a gonize  i n v a r y i n g degree most, b u t n o t a l l , of the pharmaco-  l o g i c a c t i o n s of histamine group of p h a r m a c o l o g i c a l occupying  (8).  They f a l l  i n t o that large  a n t a g o n i s t s t h a t appear to a c t by  the " r e c e p t o r s i t e " on the e f f e c t o r c e l l s t o the ex-  10. e l u s i o n of the a g o n i s t . r e c e p t o r without act  Apparently  they bind with the histamine  i n i t i a t i n g a response.  Most a n t i h i s t a m i n e s  as c o m p e t i t i v e a n t a g o n i s t s to h i s t a m i n e . A n t i h i s t a m i n e s have found wide t h e r a p e u t i c a p p l i c a -  t i o n , c h i e f l y f o r the symptomatic c o n t r o l of a l l e r g i c d i s e a s e s , due to t h e i r h i g h degree of e f f e c t i v e n e s s a f t e r o r a l tration.  adminis-  I t i s e v i d e n t from t h e i r mechanism of a c t i o n and the  e t i o l o g y o f a l l e r g i c d i s e a s e s t h a t the a n t i h i s t a m i n e drugs i n no sense achieve a cure of the p a t i e n t ' s a l l e r g y  (9)»  After  the a d m i n i s t r a t i o n o f a t h e r a p e u t i c dose, temporary b l o c k of the e f f e c t s of histamine 2 to 12 hours, is  i s obtained  f o r p e r i o d s v a r y i n g from  a f t e r which time r e a d m l n i s t r a t l o n of the drug  necessary. A n t i h i s t a m i n e s were a b l e t o i n h i b i t the a n a p h y l a c t i c  mast c e l l damage and histamine  r e l e a s e induced  by a n t i g e n .  Mota (5) showed t h a t p r e v i o u s c o n t a c t of s e n s i t i z e d or r a t t i s s u e s w i t h a n t i h i s t a m i n e s prevents and mast c e l l damage induced  guinea-pig  histamine  by l a t e r c o n t a c t with  release  antigen.  The a c t u a l mechanism of the i n h i b i t o r y e f f e c t of a n t i h i s t a m i n e s on the a n a p h y l a c t i c mast c e l l damage and histamine no y e t known.  Probably  release i s  the i n h i b i t i o n was due t o the r e l e a s e  by the a n t i h i s t a m i n e of a l a r g e p r o p o r t i o n of the a v a i l a b l e t i s s u e histamine,  and t h e r e f o r e the r e s i d u e l e f t  by a n t i g e n was c o n s i d e r a b l y d i m i n i s h e d . t h a t a n t i h i s t a m i n e molecules to  f o r release  I t i s also possible  i n a c r i t i c a l c o n c e n t r a t i o n near  t h a t r e q u i r e d f o r histamine  r e l e a s e become a t t a c h e d  t o the  mast c e l l membrane and i n t e r f e r e w i t h the a n t i g e n - a n t i b o d y r e action.  A l t e r n a t i v e l y they may i n h i b i t the enzymatic system  '11. r e q u i r e d i n the a n a p h y l a c t i c r e a c t i o n . amine r e l e a s e i n a n a p h y l a x i s  The  i n h i b i t i o n of  by a n t i h i s t a m i n e s may  hist-  help to  ex-  p l a i n the p r o t e c t i v e e f f e c t of these drugs i n a n a p h y l a x i s .  In  some cases, a t l e a s t , the p r o t e c t i o n may  be due  more to  t i o n of c e l l u l a r damage than to c o m p e t i t i o n a t r e c e p t o r  inhibisite.  As most m e d i c i n a l s , agents used as a n t i h i s t a m i n e s ssess a d d i t i o n a l p h a r m a c o l o g i c a l  activities  po-  (sedative-hypnotic,  anticholinergic, antiserotonin, antitussive, l o c a l anesthetic, and  anti-emetic)  f o r the dryness  (9)»  The  parasympatholytic  of the mouth experienced  action  accounts  by some p a t i e n t s .  C e r t a i n a n t i h i s t a m i n e s can p o t e n t i a t e the c a r d i o v a s c u l a r a c t i o n of n o r e p i n e p h r i n e .  T h i s has been a t t r i b u t e d to i n h i b i t i o n of  uptake of n o r e p i n e p h r i n e  by v a r i o u s t i s s u e s , r e s u l t i n g i n an  i n c r e a s e d amount of unbound drug i n the plasma r e a c t i n g w i t h the a c t i v e r e c e p t o r s i t e s  (8).  Thus, there may  when a n t i h i s t a m i n e s are a d m i n i s t e r e d amine oxidase  inhibiting  From a chemical  be a  hazard  to p a t i e n t s t a k i n g mono-  drugs. s t a n d p o i n t , a l l of the compounds  h i b i t i n g a high degree of a n t i h l s t a m i n l c a c t i v i t y , with a few e x c e p t i o n s ,  are d e r i v e d from a common s t r u c t u r a l  R  2  R  (as b e n z y l ) ,  c y c l i c , or h e t e r o c y c l i c - m e t h y l ; X i s =N-  (diamine  ( a m i n o a l k y l e t h e r ) , o r =CH-  q u e n t l y a -CH -CH - group but, 2  2  p a r t of a c y c l i c r i n g ; R^ and  only formula:  5  R^ and R^ are commonly a r y l , a r y l - m e t h y l  =C-0-  ex-  ( a l k y l a m i n e ) ; R^  hetero-  derivative), i s most f r e -  i n s e v e r a l cases, t h i s group i s R,- are u s u a l l y methyl groups, but,  12. considered  with nitrogen,  can be p a r t o f a h e t e r o c y c l i c r i n g .  I t i s once apparent t h a t the core of t h i s s t r u c t u r e i s a substituted and  ethylamine, -CH2-CH2-N=, a l s o present  i n histamine}  i t may be presumed t h a t i t i s t h i s p o r t i o n o f the mole-  cule t h a t competes w i t h histamine f o r c e l l  receptors.  13. PART I I STATEMENT OF PROBLEM The y i e l d s of each of " C y c l o a l k y l Analogues of Antergan" r e p o r t e d by Leung (1) were v e r y poor.  Attempts were t o  be made t o i n c r e a s e the y i e l d s of these compounds by new t h e t i c methods.  The presence of an u n s a t u r a t e d  syn-  r i n g attached  to the n i t r o g e n conforms t o the r e q u i r e d s t r u c t u r e f o r a n t i histaminic  activity. Two r e l a t e d compounds w i t h the b e n z y l group of An-  tergan s u b s t i t u t e d by a hydrogen or- a methyl group were a l s o to be s y n t h e s i z e d .  14. FART I I I ANALYTICAL METHODS M e l t i n g p o i n t s were determined u s i n g 640.6-H ThomasHoover M e l t i n g P o i n t Apparatus (Arthur H. Thomas Co., P h i l a d e l p h i a , PA., U.S.A.). were r e p o r t e d  A l l m e l t i n g p o i n t s and b o i l i n g  points  uncorrected.  A Beckman IR 10 I n f r a r e d Spectrophotometer (Beckman Instruments, Inc., F u l l e r t o n , C a l i f o r n i a , U.S.A.) was used to obtain infrared  spectra.  Carbon, hydrogen, n i t r o g e n , c h l o r i n e and i o d i n e det e r m i n a t i o n s were performed by A l f r e d Bernhardt t i s c h e s Laboratorium, Im Max - Planck forschung,  Mlkroanaly-  I n s t i t u t f u r Kohlen-  433 Mulheim (Ruhr), West Germany.  PART IV EXPERIMENTAL A.  S y n t h e s i s of 1.  N,N-Dimethyl-N*-Phenylethylenediamine:  rX-Chloroacetanlllde : To a 0 . 5 - l i t e r three-necked f l a s k equipped with a  r e f l u x condenser ( c a r r y i n g a d r y i n g t u b e ) , a side arm f o r s e t t i n g a thermometer (range from -100 p i n g f u n n e l (125  m l . ) , and a mechanical s t i r r e r was  d r i e d e t h e r (250 ml.) The s o l u t i o n was  added a  (93 S»» 1 mole, A.C.S. reagent) i n sodium-  s o l u t i o n of a n i l i n e  to reach - 5  to 50°C.) and a drop-  (Note: h e r e a f t e r r e f e r r e d as d r y e t h e r ) .  s t i r r e d over an i c e - s a l t bath f o r 30 minutes  to - 1 0 ° C .  Chloroacetyl chloride  mole, A l d r i c h Chemical Co.) was  (56.5  S»»  °»5  added dropwise to the v i g o r o u s -  l y s t i r r e d s o l u t i o n from the d r o p p i n g f u n n e l a t such a r a t e as to keep the temperature of the r e a c t i o n not h i g h e r than A f t e r the a d d i t i o n was  complete, s t i r r i n g was  f o r another hour and the mixture was mantle f o r one hour.  c o n t i n u e d a t 0°C.  then r e f l u x e d on a h e a t i n g  The mixture was poured i n t o a beaker^and  washed w i t h 100 ml. of water.  HC1  s o l u t i o n and 100 ml. of d i s t i l l e d  The white product which p r e c i p i t a t e d was  t e r e d and the l a y e r s were s e p a r a t e d . d r i e d over anhydrous  0°C.  sodium  suction  The e t h e r e a l l a y e r  filwas  s u l f a t e and reduced i n volume to  r e c o v e r more of the a n i l i d e product i n a t o t a l y i e l d of 84.7 ( 0 . 5 mole, 100#).  The a n i l i d e was  g.  r e c r y s t a l l i z e d from 60%  e t h a n o l and melted a t 1 3 4 . 5 - 1 3 5 . 5 ° C . . I n f r a r e d spectrum of the s o l i d amide l n KBr showed a s t r o n g C-0  s t r e t c h i n g band a t 1675  cm.""^, and the C-H  vibra-  16. t i o n a l s t r e t c h i n g f o r an a l i p h a t i c hydrocarbon a t 2970 and 2920 cm.~^; a l s o the absence of N-H 3370 cm.~^  at  cm.~^  stretching for aniline  and 3440 cm. ^ and the presence of C - C l s t r e t c h -1  a t 770  ing  cm. Anal.  8.261'Cl, 2.  20.90.  proved the a n i l i d e s t r u c t u r e  (Figure  3).  f o r CgHgONCl: C, 56.64; H, 4 . 7 6 ;  Calcd.  Found: C, 5 6 . 5 3 ? H, 4 . 8 5 $ N, 8 . 2 8 ; C l , 2 1 . 1 0 .  c<-Dlmethylaminoacetanilide: (32 ml., approx. 0.48 mole) was trapped  Dimethylamine from a dimethylamine  c y l i n d e r by an acetone-dry i c e bath i n t o  a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a mechanical rer,  N,  and two  s i d e arms f o r s e t t i n g a d r o p p i n g f u n n e l  a thermometer (range from - 1 0 0 condenser  stir-  (500 m l . ) ,  to 50°C.) and an acetone-dry i c e  (carrying a drying tube).  < X - C h l o r o a c e t a n i l i d e (40 g.,  0 . 2 3 6 mole) was d i s s o l v e d by the a i d of heat i n 400 ml. o f abs o l u t e methanol. ( 1 0 )  and the s o l u t i o n was p l a c e d i n the d r o p p i n g  funnel.  s o l u t i o n was  The a n i l i d e  then added dropwise to the  v i g o r o u s l y s t i r r e d l i q u i d dimethylamine a t such a r a t e as t o keep the temperature o f the r e a c t i o n not h i g h e r than A f t e r the a d d i t i o n was  -2°C.  complete, the acetone-dry i c e bath  r e p l a c e d by an i c e - s a l t b a t h and the r e a c t i o n mixture was red  c o n t i n u o u s l y a t -2 to - 1 0 ° C .  o v e r n i g h t a t room temperature. mine HCl s a l t was  filtered  A f t e r t h i s time, the white a-  o f f and the s o l v e n t methanol was r e In o r d e r to get r i d of  dimethylamine HCl s a l t which had d i s s o l v e d i n methanol,  c o n c e n t r a t e d r e s i d u e was ter  stir-  f o r a t l e a s t 3 hours and then  duced i n volume by f l a s h e v a p o r a t i o n . the  was  d i s p e r s e d i n 200 ml. of d i s t i l l e d  and then e x t r a c t e d w i t h two 200 ml. p o r t i o n s of s o l v e n t  the wa-  17. ether. sodium  The combined e t h e r e a l e x t r a c t was d r i e d over s u l f a t e and then reduced i n volume.  anhydrous  The r e s i d u e was  f r a c t i o n a t e d under reduced p r e s s u r e t o y i e l d  3 9 . 5 g» ( 0 . 2 2 2  mole, 9k%) o4-dimethylaminoacetanlllde b.p. 124°C.  (1.4  mm.).  I n f r a r e d spectrum i n d i c a t e d the presence o f d i m e t h y l amino group a t 2840 cm."" , 2800 cm." , and 2750 c m . 1  1  s t r e t c h i n g f o r R-N(CH-j) ), and the absence 2  band a t 770 cm."  -1  (C-H  of C-Cl s t r e t c h i n g  (Figure 4 ) .  1  P r e p a r a t i o n of Methyl Iodide D e r i v a t i v e : The t e r t i a r y amine ( 0 . 5 g.) was mixed with methyl iodide  (2 m l . ) ; i f no immediate r e a c t i o n o c c u r r e d , i t was  heated on a steam-bath gent had evaporated.  f o r 15 minutes o r u n t i l the excess r e a The o<-dimethylaminoacetanillde methyl  i o d i d e s a l t was r e c r y s t a l l i z e d from a b s o l u t e methanol;  m.p.  212. 5 - 2 1 3 . 5 ° C . Anal.  Calcd.  N, 8 . 7 5 ; I . 3 9 . 6 3 .  f o r C ^ H ^ O N g l i C, 4 1 . 2 6 ; H, 5 . 3 6 ;  Found: C, 4 1 . 4 4 ; H, 5 . 4 5 ; N, 8 . 9 5 ; I .  39.75. 3.  N.N-Dlmethyl-N'-Phenylethylenedlamlne: 400 ml. o f d r y e t h e r was p l a c e d i n a 0 . 5 - l i t e r t h r e e -  necked f l a s k equipped w i t h a d r o p p i n g f u n n e l (125 m l . ) , a r e f l u x condenser  ( d r y i n g t u b e ) , and a mechanical s t i r r e r . L i -  thium aluminum hydride ( 1 0 . 7 g.» 0.28 mole) was added t o the e t h e r , and was g e n t l y r e f l u x e d w i t h s t i r r i n g f o r 4 hours.  A  s o l u t i o n of <x*-dimethylaminoacetanilide (25 g., 0.14 mole) i n dry e t h e r (50 ml.) was p l a c e d i n the d r o p p i n g f u n n e l , and added to the L i A l H ^ s o l u t i o n a t such a r a t e as to m a i n t a i n g e n t l e  18. reflux.  -After the a d d i t i o n was  complete, the mixture was  stir-  red and r e f l u x e d f o r 4 days. A f t e r t h i s time, the h e a t i n g mantle was r e p l a c e d by an i c e bath and 45 ml. of water was  s l o w l y added to the v i g o -  r o u s l y s t i r r e d mixture i n the f l a s k to decompose the excess hydride.  S t i r r i n g was  a d d i t i o n was  complete.  continued f o r 30 minutes a f t e r the water S u f f i c i e n t 40$ NaOH s o l u t i o n was  to cause a c l e a r s e p a r a t i o n of the e t h e r e a l l a y e r . was  The mixture  c e n t r i f u g e d and the e t h e r l a y e r was d r i e d over  sodium  sulfate.  The s o l v e n t was  (0.75  anhydrous  removed by f l a s h e v a p o r a t i o n  to y i e l d 21 g. (0.128 mole, 91.3/0 ethylenediamine b.p. 81°C.  added  N,N-dimethyl-N -phenyl1  mm.).  I n f r a r e d spectrum i n d i c a t e d complete r e d u c t i o n by the absence of the c a r b o n y l a b s o r p t i o n band a t I69O cm. the s h i f t of the N-H  \  s t r e t c h i n g v i b r a t i o n t o 3400 cm."  and by 1  (Figure  5). Methyl Iodide D e r i v a t i v e 1 The iodide  t e r t i a r y amine (0.5  g«) was mixed w i t h methyl  (2 ml.) and worked up as d e s c r i b e d f o r the o<-dimethyl-  a m i n o a c e t a n l l i d e methyl i o d i d e d e r i v a t i v e .  N,N-Dimethyl-N'-  Phenylethylenediamine methyl i o d i d e s a l t was  recrystallized  from a b s o l u t e e t h a n o l and melted a t 179.7-180.5°C.. Anal.  9.15f B.  I, 4 1 . 4 4 .  S y n t h e s i s of diamine :  Calcd.  for C^H^Ngl*  C, 4 3 . l 4 j H, 6.27;  Foundt C, 4 3 . 0 7 ; H, 6.38;  N, 9.22;  I, 4 1 . 5 8 .  N,N-Dlmethyl-N*-Methyl-N*-Phenylethylene' ' ~~~  1. c<-Chloro-N-MethyIacetanllide1  N,  ,  19. To a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a r e f l u x condenser  ( d r y i n g tube), a side arm f o r s e t t i n g a t h e r -  mometer (range from -100 t o 50°C.) and a d r o p p i n g f u n n e l (125 ml.), and a mechanical s t i r r e r was p l a c e d a s o l u t i o n o f Nmethylaniline  (70 g., O.65 mole, Eastman Organic Chemicals)  i n d r y e t h e r (300 m l . ) .  The s o l u t i o n was s t i r r e d over an i c e -  s a l t bath f o r 30 minutes t o reach - 5 to - 1 0 ° C . (37.3 g«> 0.33 mole) was added dropwise  chloride  Chloroacetyl i n t o the v i -  g o r o u s l y s t i r r e d s o l u t i o n from the dropping f u n n e l a t such a r a t e as t o keep the temperature than 0 ° C .  o f the r e a c t i o n not h i g h e r  A f t e r the a d d i t i o n was complete,  s t i r r i n g was con-  t i n u e d a t 0°C. f o r 2 hours and the mixture was then r e f l u x e d A f t e r t h i s time, 50 ml. of  on a h e a t i n g mantle f o r one hour.  3% HCl s o l u t i o n was added and r e f l u x l n g was continued w i t h s t i r r i n g f o r 30 minutes.  The white amine HCl s a l t was f i l t e r e d  o f f and the l a y e r s were.separated.  The e t h e r e a l l a y e r was f u r -  t h e r washed w i t h 50 ml. of 5% HCl s o l u t i o n and two 50 ml. port i o n s of water and then d r i e d over anhydrous The  sodium  sulfate.  s o l v e n t was removed by f l a s h e v a p o r a t i o n t o o b t a i n crude  s o l i d product which was r e c r y s t a l l i z e d from n-hexane  (technical  grade) to y i e l d 60 g. (O.326 mole, 100$) c*-chloro-N-methyla c e t a n i l i d e m.p. 67.8-68.8°C.. I n f r a r e d spectrum showed the absence o f N-H i n g v i b r a t i o n band a t 3^40 cm. \ c a r b o n y l a b s o r p t i o n a t 1700 cm. 800  cm."" ( F i g u r e 1  Anal.  stretch-  and the presence o f a s t r o n g and C - C l s t r e t c h i n g band a t  1  6). Calcd.  f o r C H 0NCl» C, 58.86; H, 5.50; N, Q  1n  20. 7 . 6 3 ; 2.  Cl, 1 9 . 3 0 .  Found* C, 5 9 . 0 5 ; H,  5.64;  N, 7 . 7 6 ;  o<--Dlmethylamlno-N~Methyl-N-Phenylacetamide t' Dimethylamine  from a dimethylamine  ( 3 0 ml., approx.  0.45  mole) was  trapped  c y l i n d e r by an acetone-dry i c e bath i n t o  a 0 . 5 - l i t e r three-necked f l a s k equipped with a mechanical r e r , and two  s i d e arms f o r s e t t i n g a d r o p p i n g f u n n e l ( 5 0 0 m l . ) ,  a thermometer (range from -100  to 5 0 ° C ) ,  i c e condenser with d r y i n g tubes.  and an acetone-dry  A s o l u t i o n of c < - c h l o r o - N -  methylacetanllide  (40.4  methanol (10) was  p l a c e d i n t o the d r o p p i n g f u n n e l and was  dropwise  stir-  g., 0.22  mole) i n 4 0 0 ml. of a b s o l u t e  to the v i g o r o u s l y s t i r r e d l i q u i d dimethylamine  such a r a t e as to keep the temperature h i g h e r than - 2 ° C .  a c t i o n mixture was  at  o f the r e a c t i o n not  A f t e r the a d d i t i o n was  tone-dry i c e bath was  added  complete,  the ace-  r e p l a c e d by an i c e - s a l t bath and the r e -  s t i r r e d c o n t i n u o u s l y f o r a t l e a s t 3 hours  a t -2 to -10°C. and then o v e r n i g h t a t room temperature.  After  t h i s time, the white amine HCl s a l t was  the  s o l v e n t methanol was  f i l t e r e d o f f and  reduced i n volume by f l a s h e v a p o r a t i o n .  In o r d e r to get r i d of the dimethylamine d i s s o l v e d i n methanol,  HCl s a l t which had  the c o n c e n t r a t e d r e s i d u e was d i s p e r s e d  i n 200 ml. of d i s t i l l e d water and then e x t r a c t e d w i t h two ml. p o r t i o n s of s o l v e n t e t h e r . was  The  200  combined e t h e r e a l e x t r a c t  d r i e d over anhydrous sodium s u l f a t e .  moved by f l a s h e v a p o r a t i o n to y i e l d 38.1  The s o l v e n t was g. (O.I98 mole,  %) otr-dimethylamino-N-methyl-N-phenylacetamide  b.p«  re90.5  106°C. ( 0 . 3  mm.). The i n f r a r e d spectrum  i n d i c a t e d the presence of a  Cl,  21. d i m e t h y l a m i n o g r o u p a t 2880 cm. (C-H  stretching vibration  C-Cl  s t r e t c h i n g b a n d a t 800  2840 cm.  and  1  f o r R - N ( C H ) ) , and 3  cm.  the  2  The  tertiary  (2 ml.)  and  amlnoacetanilide  absence  amine ( 0 . 5  worked up  g«)  was  mixed w i t h  as d e s c r i b e d f o r the  methyl i o d i d e d e r i v a t i v e .  The  of  from a b s o l u t e  ethanol  and  then  methyl  c*-dimethyl-  <x-dimethylamino  N - m e t h y l - N - p h e n y l a c e t a m i d e m e t h y l i o d i d e s a l t was lized  cm.  7).  (Figure  1  2?80  Iodide D e r i v a t i v e t  Methyl  Iodide  \  recrystal-  e t h y l a c e t a t e ; m.p.  148.8-  150.0°C. Anal. 8.38;  I,  3.  Calcd.  37.97.  for C  Found* C,  H  1 2  2  5.80;  43.21; H,  N,  8.21;  I,  38.20.  8  dropping  funnel  (125  ml.),  a reflux  a m e c h a n i c a l s t i r r e r was  t h i u m aluminum h y d r i d e ether,  and  was  (7.9  placed g«»  0.2  gently refluxed with  flask  equipped with  condenser 320  ml.  of dry  m o l e ) was stirring  0.1  ping  mole) i n d r y e t h e r  f u n n e l , and  r a t e as  to maintain  complete,  i c e bath  rously  and  stirred  hydride.  added gentle  t h e m i x t u r e was After  an  was  this 30  time,  ml.  mixture  S t i r r i n g was  (50  ml.)  t o the  ether. L i -  added t o  the  f o r 4 hours.  placed  into  (  the  A 20  drop-  L i A l H ^ s o l u t i o n at such  reflux. stirred  was  a  (drying tube),  s o l u t i o n of cV-dimethylamino-N-methyl-N-phenylacetamlde g.,  N,  N.N-Dlmethyl-N'-Methyl-N -Phenylethylenediaminei In a 0 . 5 - l i t e r three-necked  and  43.12; H . 5 . 7 4 ;  0 N I : C,  1 Q  A f t e r the and  addition  refluxed for 4  t h e h e a t i n g m a n t l e was  a  was  days.  replaced  by  o f w a t e r was  s l o w l y a d d e d t o the, v i g o -  i n the  t o decompose t h e  flask  continued  f o r 30  minutes a f t e r  excess the  water  22. a d d i t i o n was complete.  S u f f i c i e n t 40$ NaOH s o l u t i o n was added  to a l l o w a c l e a r s e p a r a t i o n of the e t h e r e a l l a y e r .  The mixture  was c e n t r i f u g e d and the e t h e r l a y e r was d r i e d over sodium  sulfate.  to y i e l d  anhydrous  The s o l v e n t was removed by f l a s h e v a p o r a t i o n  14.3 g. (0.08 mole, 77.3$) N,N-dlmethyl-N'-methyl-N'(1.9  phenylethylenediamine b.p. 97-98°C.  mm.).  A t e r t i a r y amine was i n d i c a t e d by the absence of C=0 a b s o r p t i o n band a t 1680 cm.  1  t e r t i a r y amide c a r b o n y l group  due to complete r e d u c t i o n of the 8).  (Figure  Methyl Iodide D e r i v a t i v e : The t e r t i a r y amine (0.5 iodide  g«) was mixed w i t h methyl  (2 ml.) and worked up as d e s c r i b e d f o r the o<-dimethyl-  a m i n o a c e t a n i l i d e methyl i o d i d e d e r i v a t i v e . N'-methyl-N'-phenylethylenediamine  The N,N-dimethyl-  methyl i o d i d e s a l t  was-re-O  c r y s t a l l i z e d from a b s o l u t e e t h a n o l and melted a t 195-196 C.. Anal.  8.75; C.  I,  39.63.  C a l c d . f o r C H " N I : C, 12  Found: C,  21  44.93;  2  45.00}  H, 7.065 N,  H,  8.66;  6.62; I,  N,  39.68.  S y n t h e s i s of N.N-Dlmethyl-N'-Cyclobutylmethyl-N'-Phenylethylenediamine : 1.  Cyclobutanecarbonyl Chloride: Cyclobutanecarboxylic acid  (100 g., 1 mole, A l d r l c h  Chemical Co.) was p l a c e d i n a 0 . 5 - l i t e r three-necked f l a s k f i t t e d w i t h a mechanical s t i r r e r , a r e f l u x condenser tube) and a d r o p p i n g f u n n e l (250 was added  thionyl chloride  ml.).  (drying  To the s t i r r e d  acid  (200 g., 1.68 mole, reagent grade-  The B r i t i s h Drug Houses L t d . ) and the mixture was r e f l u x e d on a h e a t i n g mantle f o r 2 hours.  The p r o d u c t was d i s t i l l e d to  23.  give a f o r e r u n and c y c l o b u t a n e c a r b o n y l c h l o r i d e b.p. 130-136 C. (1 atm.).  Yield:  130-142°C,  80.8  g. (0.68 mole, 68.1$).  63^5 (11) b.p. 1 3 0 - 1 4 0 ° C ,  ( L i t . (1) b.p.  70%).  2. C y c l o b u t a n e c a r b o x a n l l i d e : (93 S«»  A mixture of a n i l i n e  1 mole), p y r i d i n e  g., 1 mole) and d r y benzene (180 ml.) was  (79  placed i n a 0 . 5 - l i t e r  three-necked f l a s k equipped w i t h a mechanical s t i r r e r , a r e f l u x condenser  ( d r y i n g tube) and a dropping f u n n e l (250 m l . ) .  clobutane c a r b o n y l c h l o r i d e  (80.8 g., 0.68  mole) was  Cy-  added drop-  wise from the d r o p p i n g f u n n e l i n t o the s t i r r e d m i x t u r e . the a d d i t i o n was  complete,  the r e a c t i o n was  a t room temperature, and was ice-bath.  poured i n t o a beaker c o o l e d i n an  (300 m l . ) .  separated and d r i e d w i t h anhydrous vent was  s t i r r e d f o r 1 hour  The white amide which p r e c i p i t a t e d was  t e r e d and washed w i t h water  After  suction  The benzene l a y e r  sodium  sulfate.  The  filwas  sol-  reduced i n volume to c o l l e c t more of the crude a n i -  l i d e w i t h t o t a l y i e l d of 115.4 butane c a r b o x a n i l i d e was leum e t h e r mixture; m.p. 110.6°C.s  (14) m.p.  g. .(0.66 mole, 9 6 . 6 $ ) .  Cyclo-  r e c r y s t a l l i z e d from a benzene-petro111-112°C.  ( L i t . (13) m.p.  109.0-  111-112°C.).  I n f r a r e d spectrum o f c y c l o b u t a n e c a r b o x a n i l i d e showed s t r e t c h i n g v i b r a t i o n of a secondary amide a t 3250  the N-H  and 3300 cm.  \  and C-H  zene r i n g a t 3050 cm. t i o n was  1  s t r e t c h i n g v i b r a t i o n of aromatic benand 3080 cm.  s h i f t e d from 1800  cm.  -1  ^; a l s o the C=0  absorp-  ( c a r b o n y l c h l o r i d e ) to the  secondary amide c a r b o n y l a b s o r p t i o n a t 1660 cm.' 3.  cm.  N-Cyclobutylmethyl-N-Phenylamlne:  1  (1).  24. A 1 - l i t e r three-necked dropping f u n n e l (250 apparatus  ml.), a mechanical  equipped  with a  s t i r r e r and a Soxhlet  p r o t e c t e d with a c a l c i u m c h l o r i d e d r y i n g tube. (30.4  thium aluminum hydride ml.)  f l a s k was  g. . 0.8  (600  mole) i n d r y e t h e r  e  xvas p l a c e d i n t o the f l a s k , and r e f l u x e d g e n t l y with  r i n g f o r 4 hours. mole) was  Then c y c l o b u t a n e c a r b o x a n l l i d e (60  Li-  stir0.34  g.,  packed i n t o the S o x h l e t e x t r a c t o r whose bottom  was  l i n e d w i t h g l a s s wool and a f i l t e r paper to prevent the b l o c kage of the siphon arm.  Three g l a s s rods were i n s e r t e d  the powder as channels f o r the e x t r a c t i n g s o l v e n t . was  The  r e a c t i o n was  then r e f l u x e d f o r 4 days.  t h i s time, 100 ml. of water was  the excess h y d r i d e . s t i r r i n g was (30  Refluxing  continued u n t i l a l l the a n i l i d e had been c a r r i e d Into the  flask. of  into  The  f l a s k was  At the  added s l o w l y to decompose c o o l e d i n an i c e - b a t h and  continued u n t i l the mixture became white i n c o l o r  minutes approx.);  then s u f f i c i e n t 40$ NaOH s o l u t i o n  was  added to a l l o w c l e a r s e p a r a t i o n of the e t h e r e a l l a y e r . e t h e r i n s o l u b l e r e s i d u e was e t h e r e a l l a y e r was night.  The  end  separated by c e n t r i f u g a t i o n ;  d r i e d over anhydrous sodium s u l f a t e  s o l v e n t was  The the  over-  removed by f l a s h e v a p o r a t i o n and  the  r e s i d u e d i s t i l l e d under vacuum to y i e l d 47„5 g. (0.295 mole, 86.5$) of the amine with b.p.  (Lit.  (1)  range of 88-96°C. (0.8  b.p. 15O-l60°C. (20 mm.), I n f r a r e d spectrum  98%).  f o r the r e d u c t i o n product showed  the absence of the c a r b o n y l band a t 1660  cm.  \  Due  absence of the oxygen-hydrogen i n t e r a c t i o n , the N-H s h i f t e d to 3420 cm."  (1).  1  mm.).  from 3250 cm."  1  and 3300 cm."  to the stretching  1  (anilide)  25. 4.  o<-Chloro-N-Cyclobutylmethyl-N-Phenylacetamlde: In a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a  r e f l u x condenser  ( d r y i n g tube), a side arm f o r s e t t i n g a t h e r -  mometer (range from -100  to 50°C.) and a dropping f u n n e l  (125  ml.), and a mechanical s t i r r e r was p l a c e d a s o l u t i o n of Ncyclobutylmethyl-N-phenylamine (47 (250  ml.).  The s o l u t i o n was  30 minutes to reach - 5 0.15  mole) was added  g., 0.29  mole) i n dry e t h e r  s t i r r e d over an i c e - s a l t bath f o r  to - 1 0 ° C .  C h l o r o a c e t y l c h l o r i d e (17 g.,  from the d r o p p i n g f u n n e l to the v i g o r o u s l y  s t i r r e d s o l u t i o n a t such a r a t e as to keep the temperature of the r e a c t i o n not h i g h e r than 0 ° C . complete, the r e a c t i o n was  A f t e r the a d d i t i o n  was  continued s t i r r i n g at 0°C. f o r 3  hours and then r e f l u x e d on a h e a t i n g mantle f o r one  hour.  A f t e r t h i s time, 50 ml. of 5% HCl s o l u t i o n was added and r e f l u x i n g was  continued w i t h s t i r r i n g f o r 30 minutes.  amine KC1 s a l t was separated.  The white  f i l t e r e d o f f and the e t h e r e a l l a y e r  The o r g a n i c l a y e r was  was  f u r t h e r washed w i t h 50 ml.  of 5$ HCl and two 50 ml. p o r t i o n s of d i s t i l l e d water and then d r i e d with anhydrous  sodium s u l f a t e .  The s o l v e n t e t h e r was r e -  moved by f l a s h e v a p o r a t i o n and the r e s i d u e d i s t i l l e d vacuum to y i e l d  under  g. (0.145 mole, 100$) cx-chloro-N-cyclo-  butylmethyl-N-phenylacetamide b.p. 149-150°C. (1 mm.) c r y s t a l l i z e d out a f t e r s t a n d i n g o v e r n i g h t . o r e c r y s t a l l i z e d from n-pentane  which  The compound  (b.p. 35-37 C.,  latm.);  was  m.p.  45.2-46.2°C.. The t e r t i a r y amide was N-H  i n d i c a t e d by the absence of  s t r e t c h i n g band a t 3420 cm.- , and by the presence of 1  26. c a r b o n y l s t r e t c h i n g a t 1675 790 cm."  1  5.  1  and C-Cl s t r e t c h i n g band a t  (Figure 9 ) . Anal.  5.89;  cm.  Calcd.  CI, 14.91.  f o r C H O N C l i C, 65.67; H, 6.80; 1 3  N,  l 6  Found: C, 65.62; H, 7.11;  N, 5.87;  CI, 15.08.  c4-Dlmethylamino-N-Cyclobutylmethyl-N-Phenylacetamlde: Dimethylamine  (17.5 ml., approx. 0.26. mole) was  trapped from a dimethylamine  c y l i n d e r by an acetone-dry i c e  bath i n t o a 0 . 5 - l i t e r three-necked f l a s k equipped with a  me-  c h a n i c a l s t i r r e r , and two s i d e arms f o r s e t t i n g a d r o p p i n g f u n n e l (500 m l . ) , a thermometer (range from -100  to 5 0 ° C ) ,  and an acetone-dry i c e condenser  A solution  (drying tube).  of c*-chloro-N-cyclobutylmethyl-N-phenylacetamide (30 g., mole) i n d r y e t h e r (300 ml.) was added dropwise ly stirred  l i q u i d dimethylamine  to the v i g o r o u s -  i n the f l a s k a t such a r a t e as  to keep the temperature of the r e a c t i o n not h i g h e r than A f t e r the a d d i t i o n was  0.126  complete,  -2°C..  the acetone-dry i c e bath  r e p l a c e d by an i c e - s a l t b a t h and the r e a c t i o n mixture was o  o v e r n i g h t a t room temperature. s a l t was  l e a s t 3 hours and then  A f t e r t h i s time, the white  f i l t e r e d ' o f f and the s o l v e n t e t h e r was r e -  duced i n volume by f l a s h e v a p o r a t i o n . t i o n a t e d under vacuum to y i e l d 25.1  The r e s i d u e was  infrared  spectrum  methylamino group a t 2850 cm.  2800 cm.  "*"and 2760 cm.  s t r e t c h i n g v i b r a t i o n f o r R - ^ C H ^ J g ) . and the absence  Methyl Iodide D e r i v a t i v e :  (0.9  mm.).  showed the presence o f a d i -  \  C - C l s t r e t c h i n g band a t 790 cm."  frac-  g. (80.7$) c<-dimethylamino-  N-cyclobutylmethyl-N-phenylacetamide b.p. 134-135°C. The  con-  j  t i n u e d s t i r r i n g a t -2 to -10 C. f o r a t  amine HC1  was  1  ( F i g u r e 10).  1  (C-H  of the  2?. The t e r t i a r y amine (0.5  g.) was mixed w i t h methyl  i o d i d e (2 ml.) and worked up as d e s c r i b e d f o r the cx-dimethyla m i n o a c e t a n i l i d e methyl i o d i d e d e r i v a t i v e . N-cyclobutylmethyl-N-phenylacetamide crystallized  methyl Iodide s a l t was r e -  from a b s o l u t e e t h a n o l and acetone; m.p.  Anal.  7 . 2 2 ; I, 32.68. 6.  The «*-dimethylamlno-  Calcd.  for C  l 6  H  2 5  147°C.  O N I « C, 49.48; H, 6.50;  N,  2  Founds C, 49.23? H, 6 . 7 5 ; N, 7.04; I, 32.68.  N,N-Dimethyl-N'-Cyclobutylmethyl-N -Phenylethylenedlamlne » 8  In a 0 . 5 - l i t e r three-necked f l a s k equipped with a mechanical s t i r r e r , a dropping f u n n e l (125 condenser  ml.) and a r e f l u x  ( d r y i n g tube) was p l a c e d 300 ml. of d r y e t h e r . L i -  thium aluminum h y d r i d e (6.2 e t h e r , and was  g., 0.16  mole) was added to the  g e n t l y r e f l u x e d w i t h s t i r r i n g f o r 4 hours.  A  s o l u t i o n of ctf-dlmethylamino-N-cyclobutylmethyl-N-phenylacetamide (20  g., 0.08  mole) i n d r y e t h e r (50  ml.) was  placed i n  the d r o p p i n g f u n n e l , and was added t o the L i t h i u m aluminum h y d r i d e s o l u t i o n a t such a r a t e as to m a i n t a i n g e n t l e r e f l u x . A f t e r the a d d i t t l o n was  complete,  the mixture was  stirred  and  r e f l u x e d f o r 4 days. At the end of t h i s time, the h e a t i n g mantle was r e p l a c e d by an i c e - b a t h .  20 ml. of water was  the f l a s k to decompose the excess h y d r i d e .  s l o w l y added to S t i r r i n g was  t i n u e d f o r 30 minutes; then enough 40$ NaOH s o l u t i o n was to cause a c l e a r s e p a r a t i o n of the e t h e r e a l l a y e r . ture was  c e n t r i f u g e d and the e t h e r l a y e r was  drous sodium  sulfate.  The s o l v e n t was  conadded  The mix-  d r i e d over anhy-  removed by f l a s h eva-  p o r a t i o n to y i e l d 17.4 g. (0.075 mole, 92.1$)  N,N-dimethyl-  28. N'-cyclobutylmethyl-N'-phenylethylenediamine  o b.p. 120-125 C.  ( L i t . (1) b.p. l 6 8 - l ? 9 ° C (20 mm.),  (0.8 mm.).  A t e r t i a r y amine was  10$).  i n d i c a t e d by the absence  of  -1 C=0  a b s o r p t i o n band a t 1675  cm.  ^ due to complete r e d u c t i o n  of the t e r t i a r y amide c a r b o n y l group  (1) (Figure 11).  Methyl Iodide D e r i v a t i v e i The  t e r t i a r y amine ( 0 . 5 g.) was  i o d i d e (2 ml.)  mixed w i t h methyl  and worked up as d e s c r i b e d f o r the o<-dimethyl-  a m i n o a c e t a n i l i d e methyl i o d i d e d e r i v a t i v e . N'-cyclobutylmethyl-N'-phenylethylenediamine s a l t was  The  N,N-dimethyl-  methyl  r e c r y s t a l l i z e d from reagent acetone-.-  iodide  Observed  m.p.  135-136°C.. Anal.  7.48s I, 33-90.  Calcd. f o r C  l 6  H  2 y  N Ii 2  C, 51.33s  H, 7.28;  Found: C, 51.41; H , 7.64; N, 7.42;  N,  I, 34.09.  P r e p a r a t i o n of H y d r o c h l o r i d e D e r i v a t i v e : Dry hydrogen  c h l o r i d e was passed from a c y l i n d e r  i n t o a s o l u t i o n of the t e r t i a r y amine (1 g.) i n d r y e t h e r ml.).  When p r e c i p i t a t i o n was  complete,  the s o l i d was  (50  suction  f i l t e r e d under a stream of d r y n i t r o g e n gas to prevent i t from c o n t a c t i n g a i r moisture and was dry ether.  The white HC1  l u t e e t h a n o l (10)  washed w i t h a s m a l l amount of  s a l t was  and d r y e t h e r .  r e c r y s t a l l i z e d from The  butylmethyl-N'-phenylethylenediamine  abso-  N,N-dimethyl-N'-cycloHC1  s a l t melted a t 1 8 0 . 5 -  181.5°C Anal.  10.42; CI, 13.19.  Calcd.  f o r C ^ H g ^ N g C l i C, 67.00; H, 9 . 3 9 ;  N,  Found: C, 6 7 . 0 1 ; H, 9 . 2 5 ; N, 1 0 . 3 3 ; CI, 13.11.  29. D.  S y n t h e s i s of N.N-Dimethyl-N -Cyclo-pentylme ethylenedlamlne t 0  1.  thyl-N'-Phenyl-  Cyclopentanecarbonyl Chloride; In  a 0 . 5 - l i t e r three-necked f l a s k equipped with a  mechanical s t i r r e r , a r e f l u x condenser ( d r y i n g tube) and a dropping f u n n e l (250 (75.4  acid red  g., 0.66  a c i d was  ml.) was p l a c e d  mole, A l d r i c h Chemical Co.).  added  thionyl chloride  mole) from the d r o p p i n g f u n n e l . for  cyclopentanecarboxyllc  (125  To the  ml., approx.  The mixture was  stir-  1.72  then r e f l u x e d  2 hours with s t i r r i n g and the excess t h i o n y l c h l o r i d e r e -  moved by c o - d i s t i l l a t i o n w i t h 110 ml. of d r y benzene. sidue was  d i s t i l l e d under reduced p r e s s u r e ; the f r a c t i o n  1 5 7 - l 6 0 ° C . (760  yield.  The r e -  mm.)  ( L i t . (1)  was  c o l l e c t e d i n 53.5  b.p. l 6 0 - l 6 3 ° C ,  76$;  g. (0.4  (14) b.p.  b.p. 61$)  mole,  l60-l62°C,  86$). 2.  Cyclopentanecarboxanlllde? Aniline  0.4  (37.2  g.„ 0.4  mole) i n d r y benzene (100  mole) and p y r i d i n e  (31.6  g.,  ml.) were p l a c e d i n a 0 . 5 - l l t e r  three-necked f l a s k equipped w i t h a mechanical s t i r r e r , a r e f l u x condenser ( d r y i n g tube) and a d r o p p i n g f u n n e l (125 Cyclopentanecarbonyl c h l o r i d e  (53  g.« 0.4  wise to the s t i r r e d and c o o l e d mixture. was  complete, the r e a c t i o n was  temperature.  added  drop-  A f t e r the a d d i t i o n  s t i r r e d f o r 30 minutes a t room  The mixture was poured i n t o a beaker and washed  w i t h 200 ml. of water. was  mole) was  ml.).  The white product which  s u c t i o n f i l t e r e d and the benzene l a y e r was  precipitated reduced i n vo-  lume to r e c o v e r more of the a n i l i d e i n a t o t a l y i e l d of 74 g.  (0.39 mole, 9 7 . 9 $ ) .  The amide was  r e c r y s t a l l i z e d from carbon  30. t e t r a c h l o r i d e ; m.p. 1 5 9 - l 6 l ° C . . I n f r a r e d spectrum  ( L i t . (15) m.p. l 6 0 . 1 - l 6 l . 2 ° C . ) . 1  showed the N-H s t r e t c h i n g  t i o n o f a secondary amide a t 3300 cm.  1  vibra-  and 3260 cm. \  C-H  s t r e t c h i n g v i b r a t i o n o f aromatic benzene r i n g a t 3040 cm.  1  and 3060 cm. , and the C=0 a b s o r p t i o n was s h i f t e d from 1790 1  cm.  -1  ( c a r b o n y l c h l o r i d e ) t o the secondary amide c a r b o n y l  a b s o r p t i o n a t 1660 cm. 3.  1  (1).  N-Cyclopentylmethyl-N-Phenylamlne1 To 850 ml. o f d r y e t h e r i n a 1 - l l t e r three-necked  f l a s k equipped w i t h a mechanical s t i r r e r , a d r o p p i n g f u n n e l (250 ml.) and a S o x h l e t e x t r a c t o r p r o t e c t e d from moisture by a c a l c i u m c h l o r i d e tube was added l i t h i u m aluminum h y d r i d e ( 30.4  g., 0 . 8 mole).  The mixture was s t i r r e d w i t h g e n t l e r e -  f l u x i n g f o r 4 hours. lide  A f t e r t h i s time, c y c l o p e n t a n e c a r b o x a n l -  (73 g«» O.386 mole) was packed  i n t o the Soxhlet e x t r a c t o r  as d e s c r i b e d f o r c y c l o b u t a n e c a r b o x a n i l l d e under s e c t i o n PART IV C . 3 .  R e f l u x i n g was c o n t i n u e d u n t i l a l l the a n i l i d e had been The r e a c t i o n then a l l o w e d to r e f l u x f o r 4 days,  dissolved.  and was then worked up w i t h water tion.  (100 ml.) and 40$ NaOH s o l u -  The s o l i d was s e p a r a t e d by c e n t r i f u g a t i o n and the ethe-  r e a l l a y e r was d r i e d over anhydrous  sodium  sulfate.  vent was removed and the r e s i d u e b.p. 124°C. c o l l e c t e d i n 5 7 . 3 g. (0.327 mole, 84.8$)  The s o l -  (2.8 mm.)  yield.  was  ( L i t . (1) b.p.  154°C. (20 mm.), 97$). I n f r a r e d spectrum showed the absence at  1660 cm.  1  i n d i c a t i n g complete  of the C=0 band  r e d u c t i o n had o c c u r r e d .  The  s t r o n g N-H v i b r a t i o n a l band of a secondary amine was observed  31. a t 3440 cm.  \  s h i f t e d i n frequency from the same N-H  f o r the  a n i l i d e compound ( 1 ) . 4.  cy-Chloro-N-Cyclopentylmethyl-N-Phenylacetamide; In a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a  r e f l u x condenser  ( d r y i n g tube), a s i d e arm f o r s e t t i n g a t h e r o to 50 C.)  mometer (range from -100  ml.), and a mechanical s t i r r e r was cyclopentylmethyl-N-phenylamine e t h e r (300  ml.).  The  placed a s o l u t i o n of N-  (50.8  s o l u t i o n was  g., 0.29  (17 g., 0.15  mole) was  mole) i n dry  s t i r r e d over an  b a t h f o r 30 minutes to reach -5 to - 1 0 ° C . ride  (125  and a d r o p p i n g f u n n e l  ice-salt  Chloroacetyl chlo-  added to the v i g o r o u s l y  stirred  s o l u t i o n from the d r o p p i n g f u n n e l a t such a r a t e as to keep the temperature  of the r e a c t i o n not h i g h e r than 0 ° C .  the a d d i t i o n was  complete  After  (approx. 1 hour), the r e a c t i o n  was  s t i r r e d c o n t i n u o u s l y a t 0°C. f o r 3 hours and then r e f l u x e d on a heating'mantle f o r one hour. HC1  s o l u t i o n was  A f t e r t h i s time, 50 ml. of 5$  added and r e f l u x i n g w i t h s t i r r i n g was  nued f o r 30 minutes.  The white amine HC1  and the l a y e r s were s e p a r a t e d . washed w i t h 50 ml. of 5$ HC1  filtered off  The e t h e r e a l l a y e r was  s o l u t i o n and two  of water and then d r i e d over anhydrous s o l v e n t e t h e r was  s a l t was  sodium  conti-  further  50 ml. p o r t i o n s sulfate.  The  removed by f l a s h e v a p o r a t i o n and the r e s i d u e  c r y s t a l l i z e d when mixed w i t h a s m a l l amount o f petroleum e t h e r (b.p. range from 30 to 6o°C.) and c o o l e d over d r y i c e and scratched.  The crude product was  (b.p. 3 5 - 3 7 ° C ,  1 atm.)  r e c r y s t a l l i z e d from n-pentane  to y i e l d 36.5  g. (0.145 mole,  oC-chloro-N-cyclopentylmethy 1-N-phenylacetamidej  m.p.  100$) 55-56°C.  32.  -  I n f r a r e d spectrum of c<-chloro-N-cyclopentylmethylN-phenylacetamide  was  i n d i c a t e d by the absence of N-H  t c h i n g band a t 3^40 cm. c a r b o n y l band a t 1 6 7 0  stre-  -1  and by the presence of a s t r o n g -1  cm.  -1  and C - C l s t r e t c h i n g a t 8 0 0 cm.  (Figure 1 2 ) . Anal. Cl, 14.08.  5.56;  5.  Calcd.  l g  C, 6 6 . 7 8 5  H, 7 . 2 3 s  N,  H, 7 . 2 2 ?  N,  5-61; Cl, 13-92.  ol-Dimethylamlno-N-Cyclopentylmethyl-N-Phenylacetamlde:  ped from a dimethylamine into a 0 . 5 - l i t e r stirrer,  dry  1  Found: C, 6 6 . 7 2 ;  Dimethylamine  ml.),  for C ^H 0NCli  (13*3  ml., approx. 0 . 2 mole) was  trap-  c y l i n d e r by an acetone-dry i c e bath  three-necked f l a s k equipped w i t h a mechanical  and two s i d e arms f o r s e t t i n g a d r o p p i n g f u n n e l ( 5 0 0  a thermometer (range from - 1 0 0 i c e condenser  (drying tube).  to 5 0 ° C . ) and an acetone-  A s o l u t i o n of o<-chloro-N-  cyclopentylmethyl-N-phenylacetamlde ( 2 5 . 2 g., 0 . 1 mole) i n 2 5 0 ml. of dry e t h e r was  added dropwise to the v i g o r o u s l y  stirred  l i q u i d dimethylamine i n the f l a s k a t such a r a t e as to keep the  temperature of the r e a c t i o n not h i g h e r than - 2 ° C . A f t e r  the  a d d i t i o n was  complete, the acetone-dry i c e bath was r e -  p l a c e d by an i c e - s a l t b a t h and the r e a c t i o n mixture was red  stir-  c o n t i n u o u s l y a t - 2 to - 1 0 ° C . f o r at l e a s t 3 hours and then  o v e r n i g h t a t room temperature. HCl s a l t was  filtered  A f t e r t h i s time, the white amine  o f f and the s o l v e n t e t h e r was  volume by f l a s h e v a p o r a t i o n .  reduced i n  The r e s i d u e c r y s t a l l i z e d when  mixed with a s m a l l amount of petroleum e t h e r (b.p. range from 30  to 6 0 ° C . ) and c o o l e d over d r y i c e and s c r a t c h e d .  product  (23»4  g.» 0 . 0 9 mole, 9 0 $ y i e l d ) was  The  crude  recrystallized  from  33.  n-pentane  (b.p. 3 5 - 3 7 ° C ,  1 atm.); m.p.  45-46°C  I n f r a r e d spectrum of c<-dimethylamino-N-cyclopentylmethyl-N-?henylacetamide  showed the presence of the d i m e t h y l -  amino group a t 2830 cm. , 2780 cm. -1  1  tching vibration f o r R-NtCH^^K  and  t c h i n g band a t 800  13).  6.  cm."  1  (Figure  and 2750 cm. the absence  (C-H  -1  stre-  of C - C l s t r e -  N,N-Dlmethyl-N'-Cyclopentylmethyl-N'-Phenylethylenedlamlne i To a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a  d r o p p i n g f u n n e l (250 m l . ) , a r e f l u x condenser and a mechanical s t i r r e d was  tube)  added 250 ml. of dry e t h e r . L i -  thium aluminum h y d r i d e (6.1 g., 0.16 e t h e r , and was  (drying  mole) was  added to the  g e n t l y r e f l u x e d w i t h s t i r r i n g f o r 4 hours.  A  s o l u t i o n of c*-dimethylamino-N-cyclopentylmethyl N-phenylacetT  amide (20.8 g., 0 . 0 8 mole) i n d r y e t h e r (100 ml.) was i n t o the d r o p p i n g f u n n e l , and was maintain gentle r e f l u x . mixture was  added a t such a r a t e as to  A f t e r the a d d i t i o n was  (20 ml,) and  r e a c t i o n was  then worked up w i t h d i s t i l l e d  s u f f i c i e n t 40$ NaOH s o l u t i o n to give  separated e t h e r e a l l a y e r was  water  sodium  g. ( 0 . 0 7 2 mole,  N,N-dimethyl-N'-cyclopentylmethyl-N'-phenylethylene-  dlamlne b.p. (21 mm.),  136-138°C.  (1mm.).  ( L i t . (1) b.p.  185-189°C  10.2$). The  C=0  the  separation.  d r i e d over anhydrous  s u l f a t e and reduced i n volume to y i e l d 17.8 90.J%)  complete,  s t i r r e d and r e f l u x e d f o r 4 days.  The  The  placed  t e r t i a r y amine was  a b s o r p t i o n band a t 1670  shown by the absence  cm." 'due to complete 1  of the t e r t i a r y amide c a r b o n y l group  of the  reduction  (1) ( F i g u r e 14).  3^. Methyl Iodide D e r i v a t i v e : The  t e r t i a r y amine ( 0 . 5  g.) was mixed w i t h methyl  i o d i d e (2 ml.) and worked up as d e s c r i b e d f o r the o<-dimethyla m i n o - a c e t a n i l i d e methyl i o d i d e d e r i v a t i v e .  The  N,N-dimethyl-  N'-cyclopentylmethyl-N'-phenylethylenediamine methyl s a l t was  r e c r y s t a l l i z e d from reagent acetone; m.p. Anal.  7.21;  I, 3 2 . 6 7 .  Calcd.  iodide  163-164°C.  f o r C-^Hg^Ngl: C, 52.57s H, 7 . 5 4 ;  Pound: C, 5 2 . 3 9 ; H, 7 . 9 6 ;  N, 7 . 2 3 ;  N,  I. 3 2 . 7 1 .  Hydrochloride D e r i v a t i v e : The white HCl s a l t was  prepared as d e s c r i b e d f o r the  N,N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenediamine o derivative.  Observed m.p.  Anal. 9.90; S.  CI, 1 2 . 5 3 .  Calcd.  180-181 for C  l 6  H  2 7  HCl  C.  N Cli 2  C, 67.92? H, 9.64;  Pound: C, 6 7 . 8 3 ; H, 9 . ^ 6 ;  N,  N, 10.11; CI, 1 2 . 3 9 .  S y n t h e s i s of N,N-Dlmethyl-N°-Cyclohexylmethyl-N'-Phenylethylenediamine : 1.  Cyclohexanecarbonyl C h l o r i d e : To a 1 - l i t e r three-necked f l a s k f i t t e d w i t h a r e f l u x ( d r y i n g t u b e ) , a d r o p p i n g f u n n e l (250 ml.) and a  condenser  c h a n i c a l s t i r r e r was  placed cyclohexanecarboxylic acid  1 mole, p r a c t i c a l grade - Eastman Kodak). was  added t h i o n y l c h l o r i d e  funnel.  The f l a s k was  a t r e f l u x f o r 1.5-2 distilled,  (128 g.,  To the s t i r r e d  heated  A f t e r that time, the mixture  c o l l e c t i n g the crude product from 1 6 0 - 1 8 5 ° C .  f r a c t i o n was  acid  (238 g., 2 moles) from the dropping  p l a c e d on a h e a t i n g mantle and  hours.  me-  was This  r e d i s t i l l e d under reduced p r e s s u r e c o l l e c t i n g the  f r a c t i o n b o i l i n g a t 82-85°C. (14-15 mm.)  to y i e l d 118 g.  (0.8  35. mole, 8 0 . 5 $ ) . b.p. 2.  ( L i t . (16)  b.p.  67-67.5°C  (l4mm.), 81$;  (17)  76°C. (17 mm.)). Cyclohexanecarboxanillde; A mixture  of a n i l i n e  (93 g., 1 mole),  g., 1 mole),  and dry benzene (100 ml.)  was  three-necked  f l a s k f i t t e d with a mechanical  (79  pyridine  placed i n a 1 - l i t e r stirrer, a reflux  condenser ( d r y i n g tube) and a dropping f u n n e l (250 m l . ) . the s t i r r e d mixture  i n the f l a s k  added c y c l o h e x a n e c a r b o n y l wise.  ( c o o l e d i n an i c e - b a t h ) ( 1 0 5 . 5 g . 1 0.72  chloride  A f t e r the a d d i t i o n was  To  complete,  was  mole) drop-  the r e a c t i o n was  re-  f l u x e d w i t h s t i r r i n g f o r 1 hour, c o o l e d and washed with water (200 m l . ) .  The  s o l i d which p r e c i p i t a t e d was  and the l a y e r s were separated. w i t h two  suction f i l t e r e d  The aqueous phase was  100 ml. p o r t i o n s of e t h e r .  extracted  The e t h e r e x t r a c t s were  combined with the benzene l a y e r , and d r i e d w i t h anhydrous sodium s u l f a t e .  The  s o l v e n t s were removed by f l a s h e v a p o r a t i o n  to r e c o v e r more of the a n i l i d e i n a t o t a l y i e l d of 126.1 0.62  mole, 8 6 . 3 $ ) .  p y l a l c o h o l ; m.p.  The amide was 145-l46°C.  l i + 5 - l 4 6 C . 1 (20) m.p.  m.p.  0  3.  g. (  r e c r y s t a l l i z e d from i s o p r o -  ( L i t . (18) m.p.  l43-l45°C. 5  (19)  146°C).  N-Cyclohexylmethyl-N-Phenylamlne t In a 2 - l i t e r three-necked  f l a s k equipped  with a  c h a n i c a l s t i r r e r , a Soxhlet e x t r a c t o r ( d r y i n g tube) and dropping f u n n e l (250 ml.)  was  me-  a  p l a c e d l i t h i u m aluminum h y d r i d e  (38 g., 1 mole) i n dry e t h e r (1600  ml.).  The mixture  was  red w i t h g e n t l e r e f l u x on a h e a t i n g mantle f o r 4 hours. t h i s time, c y c l o h e x a n e c a r b o x a n i l l d e (101.5 g.,  0 . 5 mole)  stirAfter was  36. packed  i n t o the Soxhlet e x t r a c t o r as d e s c r i b e d f o r c y c l o b u t a n e -  c a r b o x a n l l i d e under s e c t i o n PART IV C . 3 .  Refluxlng with  stir-  r i n g was c o n t i n u e d u n t i l a l l the a n i l i d e had been d i s s o l v e d . The r e f l u x i n g was continued w i t h s t i r r i n g f o r 72 hours. r e a c t i o n was then worked up w i t h water 40$ NaOH s o l u t i o n f o r complete f r e e amine from any unreduced  The  ( 1 0 0 ml.) and s u f f i c i e n t  separation.  To separate the  amide, the e t h e r s o l u t i o n was  e x t r a c t e d w i t h 5$ HCl s o l u t i o n .  The aqueous phase was separa-  t e d and t r e a t e d w i t h 40$ NaOH s o l u t i o n t o reform the f r e e amine which was then e x t r a c t e d w i t h e t h e r s o l v e n t . e t h e r e x t r a c t s were d r i e d over anhydrous  The combined  sodium  sulfate.  The  e t h e r s o l v e n t was removed by f l a s h e v a p o r a t i o n t o y i e l d 8 0 . 6 g. ( 0 . 4 2 6 mole, 8 5 . 3 $ ) ll4°C. (Lit. (11  N-cyclohexylmethyl-N-phenylamlne  b.p.  112-  ( 1 mm.); the HCl s a l t of the amine melted a t 2 2 0 - 2 2 2 ° C . ( 1 ) b.p. 1 7 0 - 1 7 4 ° C . ( 1 2 mm.), 5 9 $ ; ( 2 1 ) b.p. l 6 8 - 1 7 0 ° C .  mm.), HCl s a l t m.p. 2 3 2 ° C ) . I n f r a r e d spectrum f o r the amine showed the absence  of the C=0 band a t 1670 cm."" i n d i c a t i n g complete 1  the amide. 3435 cm. 4.  1  reduction of  N-H s t r e t c h i n g v i b r a t i o n w i t h one sharp peak a t was c h a r a c t e r i s t i c o f a secondary amine ( 1 ) .  o<-Chloro-N-Cyclohexylmethyl-N-Phenylacetamlde  i  In a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a r e f l u x condenser  ( d r y i n g t u b e ) , a s i d e arm f o r s e t t i n g a t h e r -  mometer (range from - 1 0 0 t o 50°C.) and a d r o p p i n g f u n n e l ( 1 2 5 ml.), and a mechanical s t i r r e r was p l a c e d a s o l u t i o n of Ncyclohexylmethyl-N-phenylamine (250 m l . ) .  ( 7 9 « 5 g.. 0.42 mole) i n d r y e t h e r  The s o l u t i o n was s t i r r e d over an i c e - s a l t bath f o r  37. 30 minutes to r e a c h - 5 to - 1 0 ° C . C h l o r o a c e t y l c h l o r i d e g., 0.22  mole) was  (24.9  added from the d r o p p i n g f u n n e l to the v i g o -  r o u s l y s t i r r e d s o l u t i o n a t such a  r a t e as t o keep the tem-  p e r a t u r e of the r e a c t i o n not h i g h e r than 0 ° C . A f t e r the a d d i t i o n was  complete (approx. 1 hour), the r e a c t i o n was  continued  s t i r r i n g a t 0°C. f o r 3 hours and then r e f l u x e d on a h e a t i n g mantle f o r one hour. HCl s o l u t i o n was  At the end of t h i s time, 80 ml. of 5%  added and r e f l u x i n g was  r i n g f o r 30 minutes.  continued w i t h s t i r -  The white amine HCl s a l t was  o f f and the l a y e r s were s e p a r a t e d .  filtered  The e t h e r e a l l a y e r  was  f u r t h e r washed w i t h 50 ml. o f 5% HCl s o l u t i o n and two 50 ml. p o r t i o n s of d i s t i l l e d water and then d r i e d over anhydrous sodium s u l f a t e . t i o n to y i e l d  The s o l v e n t e t h e r was 55.8  g. (0.21  removed by f l a s h evapora-  mole, 100$)  crt-chloro-N-cyclohexyl-  methyl-N-phenylacetamide b.p. 170-182°C. ( 2 . 4 - 2 . 6 mm.) c r y s t a l l i z e d a f t e r standing overnight. c r y s t a l l i z e d from n-pehtane  which  The compound was r e -  (b.p. 3 5 - 3 7 ° C , 1 atm.)  and melted  at 5 2 - 5 3 ° C . I n f r a r e d spectrum o f the amide was absence of the N-H  i n d i c a t e d by the  s t r e t c h i n g v i b r a t i o n band a t 3435 cm.  and by the presence of a s t r o n g c a r b o n y l a b s o r p t i o n a t cm.~^  1680  ( c h a r a c t e r i s t i c of t e r t i a r y amide) and C - C l s t r e t c h i n g  a t 800 cm.*" ( F i g u r e 1  Anal. 5 . 2 7 ; C l , 13.34. 5.  \  15).  Calcd.  f o r C H 0 N C 1 : C, 6 7 . 7 8 ; H, 7.59? N, 15  20  Found: C, 67.94; H, 7.40; N, 5 . 1 3 ; C l , 13.44.  o<-Dlmethylamlno-N-Cyclohexylmethyl-N-Phenylacetamlde: Dimethylamine  (25.2  ml.,, approx. O.38  mole) was  38. trapped from a dimethylamine  c y l i n d e r by an acetone-dry i c e  bath i n t o a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a mec h a n i c a l s t i r r e r , and two side arms f o r s e t t i n g a d r o p p i n g f u n n e l (500 m l . ) , a thermometer (range from -100 to 5 0 ° C ) , and an acetone-dry i c e condenser  (drying tube).  chloro-N-cyclohexylmethyl-N-phenylacetamide  A s o l u t i o n of ot(50.5 g.» 0.19  mole) i n d r y e t h e r (300 ml.) was added dropwise r o u s l y s t i r r e d l i q u i d dimethylamine  to the v i g o -  i n the f l a s k a t such a  r a t e as t o keep the temperature of the r e a c t i o n n o t h i g h e r than - 2 ° C .  A f t e r the a d d i t i o n was complete,  the acetone-dry  i c e bath was r e p l a c e d by an i c e - s a l t bath and the r e a c t i o n mixture was s t i r r e d c o n t i n u o u s l y a t -2 to -10°C. f o r a t l e a s t 3 hours and then o v e r n i g h t a t room temperature. KC1  The white amine  s a l t was f i l t e r e d o f f and the s o l v e n t was removed.  r e s i d u e c r y s t a l l i z e d a f t e r s t a n d i n g o v e r n i g h t a t room ture t o y i e l d 43.3 g. (0.158 mole, 8 3 . 1 $ ) . was  The tempera-  The crude product  r e c r y s t a l l i z e d from n-pentane (b.p. 35-37°C., 1 atm.);  m.p.  53.5-54.5°C The bands a t 2820 cm."" , 2780 cm."" and 2740 cm." 1  1  (C-H s t r e t c h i n g f o r R-N(CH ) ) and the absence 3  i n g a t 800 cm."  1  2  1  of C-Cl s t r e t c h -  i n d i c a t e d t h a t the dimethylamino  group had  r e p l a c e d the c h l o r i n e group o f o<-chloro-N-cyclohexylmethyl-Nphenylacetamide Anal. 10.21.  (Figure 16). Calcd.  for C  1 7  H  2 6  0 N : C, 74.41; H, 9 . 5 5 ; N, 2  Found: C, 74.30; H, 9 . 6 2 ; N, 10.13. Hydrochloride  Derivative:  The white HCl s a l t was prepared as d e s c r i b e d f o r the  39  o  N,N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenediamine derivative.  Observed  Anal. N, 9.01;  m.p.  Calcd.  CI, 11.40.  HCl  183«5-185.0°C..  f o r C-^H^ONgCl: C, 65.68; H,  Found: C, 65.54; H, 8.72;  8.76;  N, 8.96;  CI,  11.57. 6.  N,N-Dlmethyl-N'-Cyclohexylmethyl-N'-Phenylethylenediamine : To a 0 . 5 - l i t e r three-necked f l a s k f i t t e d w i t h a drop-  p i n g f u n n e l (250 m l . ) , a r e f l u x condenser mechanical s t i r r e r was  p l a c e d 300 ml. of d r y e t h e r .  aluminum h y d r i d e (8.4 g., 0.22 and the mixture was A s o l u t i o n of  mole) was  Lithium  added to the ether,  g e n t l y r e f l u x e d with s t i r r i n g f o r 4 hours.  o<-dimethylamino-N-cyclohexylmethyl-N-phenylacet-  amide (30.2 g., 0.11  mole) i n d r y e t h e r (100 ml.) was p l a c e d  i n t o the d r o p p i n g f u n n e l , and was maintain gentle reflux* mixture was  ( d r y i n g tube) and a  added a t such a r a t e as to  A f t e r the a d d i t i o n was  complete,  the  s t i r r e d and r e f l u x e d f o r 4 days.  The r e a c t i o n was  then worked up with d i s t i l l e d  water  (30 ml.) and s u f f i c i e n t 40$ NaOH s o l u t i o n to g i v e s e p a r a t i o n . The  separated e t h e r e a l l a y e r was  d r i e d over anhydrous  s u l f a t e and reduced i n volume to y i e l d 26.7  sodium  g. (0.1 mole, 93.3$)  N,N-dimethyl-N'-cyclohexylmethyl-N'-phenylethylenediamine 158-159°C  (2.2mm.).  ( L i t . (1) b.p. 1 9 4 - 1 9 5 ° C  A t e r t i a r y amine was a b s o r p t i o n band a t 1675  cm.  1  Mono-Plcrate  shown by the absence  due  t e r t i a r y amide c a r b o n y l group  (15mm.),  to complete  of  b.p. 21.8$).  C=0  r e d u c t i o n of the  (1) ( F i g u r e 17).  Derivative:  A sample of the t e r t i a r y amine (0.5 g.) was  added t o  40. 95$ e t h a n o l (10  ml.).  T h i s s o l u t i o n was  then added to 10 ml.  of a s a t u r a t e d s o l u t i o n of p i c r i c a c i d i n 95$ e t h a n o l , and heated to b o i l i n g .  was  The s o l u t i o n was allowed to c o o l slowly,  and t h e . b r i g h t y e l l o w c r y s t a l s of the p l c r a t e were i s o l a t e d suction f i l t r a t i o n .  The s o l i d was  then r e c r y s t a l l i z e d  by  from  95$ ethanols m.p. 1 3 5 . 5 - 1 3 6 . 5 ° C . Anal.  14.31.  Calcd.  f o r C ^ H ^ O ^ : C, 56.43; H, 6.38;  N,  Founds C, 56.41; H, 6 . 3 8 ; N, 1 4 . 3 7 . Hydrochloride Derivatives The white HCl s a l t was  prepared as d e s c r i b e d f o r the  N.N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenedlamlne derivative.  Observed m.p,  Anal.  9 . 4 4 ; C l , 11.94. F.  Calcd.  HCl  199-200°C.. f o r C ^ H ^ N g C l : C, 68.77; H, 9 . 8 5 ;  N,  Founds C, 6 8 . 6 9 ; H, 9 . 7 8 ; N, 9 - 3 1 ; C, 12.12.  S y n t h e s i s of N.N-Dlmethyl-N'-Cycloheptylmethyl-N'-Phenylethylenedlamlne s 1.  C y c l o h e o t a n e c a r b o x y l l c Acids In a 2 - l i t e r three-necked f l a s k equipped w i t h a  c h a n i c a l s t i r r e r , a r e f l u x condenser p i n g f u n n e l (500  ml.) was  me-  ( d r y i n g tube) and a drop-  placed. 28 g. (1.15  mole) of magnesium  t u r n i n g s which had p r e v i o u s l y been washed with sodium-dried e t h e r , d r i e d a t 1 0 0 ° C , and allowed to c o o l i n d e s i c c a t o r .  A  s m a l l amount of c y c l o h e p t y l bromide ( A l d r i c h Chemical Co.)  and  240 ml. of d r y e t h e r was  added to i n i t i a t e the r e a c t i o n .  s o l u t i o n of c y c l o h e p t y l bromide (200 (600  ml.) was  g., 1.13  A  mole) i n dry e t h e r  then added over a p e r i o d of 1 hour.  s t a r t e d r e a d i l y and moderate c o o l i n g was n e c e s s a r y .  The  reaction  Following  41. complete a d d i t i o n of the bromide, night with gentle r e f l u x . the  A t the end of t h i s time, about £ of  o r i g i n a l magnesium t u r n i n g s remained unreacted. In  rer,  the mixture was s t i r r e d over-  a 3 - l i t e r three-necked f l a s k equipped with a s t i r -  a r e f l u x condenser  ( d r y i n g tube) and a d r o p p i n g f u n n e l  (500 ml.) was p l a c e d a s l u r r y of d r y e t h e r (1200 ml.) and powdered d r y i c e (2000 g.) (the d r y i c e was f i r s t the  f u n n e l e d Into  f l a s k and then the d r y e t h e r was added dropwise w i t h  ring).  stir-  The G r i g n a r d s o l u t i o n was q u i c k l y decanted i n t o the  d r o p p i n g f u n n e l and added t o the s t i r r e d d r y i c e s l u r r y over a p e r i o d of 15-25 minutes the  (22).  A f t e r complete  addition of  G r i g n a r d s o l u t i o n , another 2000 g. o f d r y i c e was added and  s t i r r i n g was c o n t i n u e d f o r 4 hours d u r i n g which time the d r y ice  had evaporated.  the  dropwise a d d i t i o n o f 450 ml. o f 6N h y d r o c h l o r i c a c i d  to ted  The G r i g n a r d complex then h y d r o l y z e d by  the v i g o r o u s l y s t i r r e d mixture.  (cold)  The e t h e r l a y e r was separa-  and the aqueous l a y e r was twice e x t r a c t e d w i t h 400 ml. por-  tions of ether.  The combined e t h e r s o l u t i o n was washed w i t h  water, d r i e d over anhydrous removed.  sodium  s u l f a t e , and the s o l v e n t  The r e s i d u e was f r a c t i o n a t e d under reduced p r e s s u r e o  and the f r a c t i o n b o i l i n g a t 91-93 C. (1 mm.)  y i e l d 6 9 . 3 g. (0.48 mole, 4 3 . 2 $ ) .  (Lit.  was c o l l e c t e d to  (1) b.p. 138-140°C.  (15 mm.), 4 6 . 7 $ ; (23) b.p. 133-135°C (9 mm.),' 53$ and 43$; (24) b.p. 130-131°C (8 mm.)). The i n f r a r e d spectrum showed a s t r o n g C=0 a b s o r p t i o n band a t 1710 cm.  1  and a broad 0-H band a t around 3000 cm."  both c h a r a c t e r i s t i c o f c a r b o x y l i c a c i d s  (1).  1  42. 2.  Cycloheptanecarbonyl Chloridet Cycloheptanecarboxylic acid  placed i n a 0 . 5 - l i t e r  (60 g., 0.42 mole) was  three-necked f l a s k equipped with a r e f l u x  condenser  ( d r y i n g t u b e ) , a dropping f u n n e l and a mechanical  stirrer.  Thionyl chloride  (150  g., 1 . 2 6  mole) was added drop-  wise t o the s t i r r e d  acid.  mixture was  f o r 3 hours a t room temperature;  stirred  A f t e r a d d i t i o n was  excess t h i o n y l c h l o r i d e was  complete*,  the  then the  removed under reduced p r e s s u r e by  c o d l s t i l l a t i o n w i t h two 90 ml. p o r t i o n s of d r y benzene. warming with a water bath was the  employed to a i d d i s t i l l a t i o n of  l a s t t r a c e s of t h i o n y l c h l o r i d e .  i n the f l a s k was  Slight  The r e d l i q u i d r e s i d u e  then f r a c t i o n a t e d under reduced p r e s s u r e .  A f t e r a small forerun, 5 4 . 3  g. ( 0 . 3 3 8 mole, 80$) y i e l d  c y c l o h e p t a n e c a r b o n y l c h l o r i d e b.p. 8 9 - 9 8 ° C .  (14 mm.)  of  was  ob-  A 0 . 5 - H t e r three-necked f l a s k equipped with a  me-  tained. 3.  Cycloheptanecarboxanilldes  c h a n i c a l s t i r r e r , a r e f l u x condenser p i n g f u n n e l (125  ml.) was  0 . 3 2 mole), p y r i d i n e ml.).  p l a c e d a mixture of a n i l i n e  dropping f u n n e l . stirred  a beaker.  (50 g., 0 . 3 1  A f t e r a d d i t i o n was  solid precipitate  washed w i t h 125 ml. of water. ted,  d r i e d w i t h anhydrous  g., (125  added c y c l o h e p -  mole) dropwise from the complete,  f o r 1 hour a t room temperature; The  (29.8  g.. 0 . 3 2 mole) and d r y benzene  To the c o o l e d and s t i r r e d mixture was  tanecarbonyl c h l o r i d e  was  (25.3  ( d r y i n g tube) and a drop-  was  the r e a c t i o n  then poured  suction f i l t e r e d  into and  The benzene l a y e r was "separa-  sodium  s u l f a t e and reduced i n volume  43. to c o l l e c t a f u r t h e r crop o f a n i l i d e with 4 8 . 7 g. (0.224 mole, 72$) t o t a l y i e l d .  C y c l o h e p t a n e c a r b o x a n l l i d e was r e c r y s t a l l i z e d  from a benzene-petroleum e t h e r mixture  ( L i t . (1) m.p. 1 3 5 - 1 3 6 ° C , The  74.6$).  i n f r a r e d spectrum  to o t h e r a n i l i d e analogues  ( l s l ) { m.p. 137.5-139°C.•  showed s i m i l a r a b s o r p t i o n bands  of t h i s s e r i e s with C=0 s t r e t c h i n g  at 1660 cm." and N-H band a t 3300 cm." ( 1 ) . 1  4.  1  N-Cycloheptylmethyl-N-Phenylamine; In a 1 - l i t e r three-necked  f l a s k equipped  w i t h a me-  c h a n i c a l s t i r r e r , a S o x h l e t e x t r a c t o r ( d r y i n g tube) and a dropp i n g f u n n e l (250 ml.) was p l a c e d l i t h i u m aluminum hydride g., 0.45 mole) i n d r y e t h e r (750 m l . ) .  (17.1  The mixture was s t i r r e d  w i t h g e n t l e r e f l u x i n g on a h e a t i n g mantle f o r 4 hours.  After  t h i s time c y c l o h e p t a n e c a r b o x a n i l i d e (46 g., 0 . 2 1 mole) was packed i n t o the Soxhlet e x t r a c t o r as d e s c r i b e d f o r c y c l o b u t a n e c a r b o x a n i l i d e under s e c t i o n PART IV C . 3 .  R e f l u x i n g with  stir-  r i n g was continued u n t i l a l l the a n i l i d e had been d i s s o l v e d . The  r e f l u x i n g was continued with s t i r r i n g f o r 4 days.  The r e -  a c t i o n was then worked up w i t h water (70 ml.) and s u f f i c i e n t 40$ NaOH s o l u t i o n to g i v e complete s e p a r a t i o n .  The separated  e t h e r e a l l a y e r was d r i e d w i t h anhydrous sodium s u l f a t e and r e duced i n volume t o y i e l d  34.4 g. (0.169 mole, 80$) N - c y c l o -  heptylmethyl-N-phenylamine b.p. 106°C. ( 0 . 1 mm.).  ( L i t . (1)  b.p. 154°C. (17 mm.), 7 8 . 2 $ ) . The  i n f r a r e d spectrum  i n d i c a t e d complete r e d u c t i o n  by the absence o f the c a r b o n y l a b s o r p t i o n band a t 1660 cm. ~, and by the s h i f t o f the N-H s t r e t c h i n g v i b r a t i o n to 3430 cm."  (1).  1  44. 5.  o<-Chloro-N-Cycloheptylmethyl-N-Phenylacetamlde s In.a 250 ml. three-necked f l a s k equipped w i t h a r e -  f l u x condenser  ( d r y i n g tube), a s i d e arm f o r s e t t i n g a thermo-  meter (range from -100  to 5 0 ° C ) and a d r o p p i n g f u n n e l  ml.), and a mechanical s t i r r e r was cycloheptylmethyl-N-phenylamine (150  ml.).  The s o l u t i o n was  30 minutes  to reach - 5  (31  (125  p l a c e d a s o l u t i o n of Ng«» 0.15  mole) i n d r y e t h e r  s t i r r e d over an i c e - s a l t bath f o r  to - 1 0 ° C .  (9-1  Chloroacetyl chloride  g., 0.08 mole) was added dropwise from the dropping f u n n e l to the v i g o r o u s l y s t i r r e d temperature  s o l u t i o n a t such a r a t e as to keep the  of the r e a c t i o n not h i g h e r than 0 ° C .  a d d i t i o n was  complete  A f t e r the  (approx. 1 hour), the r e a c t i o n was  stir-  red c o n t i n u o u s l y at 0°C. f o r 3 hours and then r e f l u x e d on a h e a t i n g mantle  f o r 1 hour.  of 5$ HCl s o l u t i o n was  At the end of t h i s time, 25  added and re f l u x i n g was  s t i r r i n g f o r 30 minutes.  continued with  The white amine HCl s a l t was  o f f and the l a y e r s were separated.  ml.  filtered  The e t h e r e a l l a y e r was  fur-  t h e r washed w i t h 25 ml. of 5% HCl and two 50 ml. p o r t i o n s of d i s t i l l e d water and then d r i e d over anhydrous The s o l v e n t e t h e r was 21.3  sodium  sulfate.  removed by f l a s h e v a p o r a t i o n to y i e l d  g. (O.076 mole, 100$) o(-chloro-N-cycloheptylmethyl-N-  phenylacetamide b.p. 170°C. ( 0 . 7  mm.).  The pure l i q u i d product  c r y s t a l l i z e d when mixed w i t h a s m a l l amount of petroleum e t h e r (b.p. range 3 0 - 6 o ° C ) ,  c o o l e d over dry i c e and s c r a t c h e d ;  m.p.  27.5-28.5°C. I n f r a r e d spectrum of the amide was  i n d i c a t e d by a  s t r o n g t e r t i a r y amide C=0 a b s o r p t i o n band a t 1670  cm.  \  and  ^ 5 .  C - C l s t r e t c h i n g a t 7 9 0 cm."", and by the absence of N-H s t r e t c h -  ing vibration at 3 ^ 3 0 Anal. 5 . 0 1 ;  6.  CI,  cm.  Calcd.  1  x  for C H 0NCli l 6  Found: C,  1 2 . 6 7 .  (Figure 18). C,  2 2  6 8 . 9 1 ;  H,  7 . 7 7 ;  6 8 . 6 7 ;  N  f  H,  4 . 9 2 ;  7 . 9 ^ ;  CI,  N,  1 2 . 6 5 .  o<-Dimethylamlno-N-Cycloheptylmethyl-N-rhenylacetamlde: Dimethylamine  ( 1 0 ml., a p p r o x . . 0 . 1 5 mole) was t r a p -  ped from a dimethylamine c y l i n d e r by an acetone-dry i c e bath i n t o a 2 5 0 ml. three-necked f l a s k equipped w i t h a mechanical s t i r r e r , and two s i d e arms f o r s e t t i n g a dropping f u n n e l ( 2 5 0 o ml,), a thermometer  (range from - 1 0 0  d r y i c e condenser ( d r y i n g t u b e ) .  to 5 0 C.) and an acetone-  A s o l u t i o n of o<.-chloro-N-  cycloheptylmethyl-N-phenylacetamide ( 2 0 g., 0 . 0 7 mole) i n d r y e t h e r ( 2 0 0 ml.) was added dropwise to the v i g o r o u s l y  stirred  l i q u i d dimethylamine i n the f l a s k a t such a r a t e as t o keep the temperature of the r e a c t i o n not h i g h e r than - 2 ° C .  After  the a d d i t i o n was complete, the acetone-dry i c e b a t h was r e p l a c e d by an i c e - s a l t bath and the r e a c t i o n mixture was s t i r r e d c o n t i n u o u s l y a t - 2 to - 1 0 ° C . f o r a t l e a s t 3 hours and then o v e r n i g h t a t room temperature.  The white amine HCl s a l t was  f i l t e r e d o f f and the s o l v e n t e t h e r removed.  The r e s i d u e was  f r a c t i o n a t e d under reduced p r e s s u r e to y i e l d  1 6 . 6  g.  (0.057  mole, 8 0 . 5 $ ) <X-dimethylamino-N-cycloheptylmethyl-N-phenylaceto amide b.p.  1 7 8 - 1 7 9  C.  ( 1 . 7  mm.).  The i n f r a r e d spectrum showed the C-H s t r e t c h i n g v i b r a t i o n f o r dimethylamino group - 1  - 1  ( R - N ( C H ) ) a t 2820 cm."" , 1  3  2  cm. and 2 7 3 0 cm. , and the absence of C - C l s t r e t c h i n g band a t 800 cm." ( F i g u r e 1 9 ) . 2780.  1  46. Methyl Iodide D e r i v a t i v e ; The t e r t i a r y amine (0.5 iodide  g.) was mixed with methyl  (2 ml.) and worked up as d e s c r i b e d f o r the o<-dimethyl-  a m i n o - a c e t a n i l i d e methyl i o d i d e d e r i v a t i v e .  The o<-dimethyl-  amlno-N-cycloheptylmethyl-N-phenylacetamide was  r e c r y s t a l l i z e d from reagent acetone; m.p. Anal.  6.51; 7.  methyl i o d i d e  I, 29.48.  salt  195-195.5°C..  C a l c d . f o r C ^ H ^ O N g l : C, 53.01; H, 7.2?;  Founds c, 53.06; H, 7.35;  N,  I, 29.33.  N, 6.53;  N»N-Dimethyl-N'-Cycloheptylmethyl-N'-Phenylethylenedlamlne ; To a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a  d r o p p i n g f u n n e l (250 m l . ) , a r e f l u x condenser and a mechanical s t i r r e r was thium aluminum hydride (4.2 e t h e r , and the mixture was 4 hours.  g., 0.11  mole) was added to the  gently refluxed with s t i r r i n g f o r  (15 g., 0.052 mole) i n dry e t h e r (100  r a t e as to m a i n t a i n g e n t l e r e f l u x . the mixture was The r e a c t i o n was and s u f f i c i e n t 40$ The  ml. of dry e t h e r . L i -  p l a c e d i n t o the d r o p p i n g f u n n e l , and was  complete,  tube)  A s o l u t i o n of c*-dimethylamino-N-cycloheptylmethyl-  N-phenylacetamide was  p l a c e d 200  (drying  added a t such a  A f t e r the a d d i t i o n  y i e l d 13.6  The  then worked up w i t h water  NaOH s o l u t i o n to give complete  s o l v e n t was  was  s t i r r e d and r e f l u x e d f o r 4 days. (20  ml.)  separation.  separated e t h e r e a l l a y e r was d r i e d over anhydrous  sulfate.  ml.)  sodium  removed by f l a s h e v a p o r a t i o n to  g. (0.49 mole, 95.1$) N.N-dimethyl-N*-cycloheptyl-  methyl-N'-phenylethylenedlamlne  (1) b.p. 204-210°C. (17 mm.), A t e r t i a r y amine was  b.p. 148-153°C. (1 mm.).  (Lit,  29$). shown by the absence  of  C=0  a b s o r p t i o n band a t 1670 era.  1  due to complete  t e r t i a r y amide c a r b o n y l group Mono-Picrate  (1)  20).  Derivative}  A sample of the t e r t i a r y 95$ e t h a n o l  (Figure  r e d u c t i o n of the  amine ( 0 . 5 g.) was added to  (10 ml.) and was t r e a t e d w i t h a s a t u r a t e d  solution  of p i c r i c a c i d as f o r the monocyclohexyl analogues m.p.  126.5-  127.5°C Anal. N, 1 3 . 9 1 .  Calcd.  f o r C ^ H ^ O r ^ : C, 5 7 . 2 3 ; H,  Found: C, 56.99? H, 6.82;  Hydrochloride  6.62;  N, 1 4 . 1 1 .  Derivative:  The white HCl s a l t was prepared as d e s c r i b e d  f o r the  N,N-dimethyl-N -cyclobutylmethyl-N'-phenylethylenediamine HCl o d e r i v a t i v e ; m.p. I 9 8 - I 9 9 C . 8  Anal. N, 9 . 0 1 ; 11.26.  Calcd.  CI, 11.40.  for C^H^NgClt  Found: C, 6 9 . 6 5 ;  C, 6 9 , 5 2 ;  H, 1 0 . 0 6 ;  H, 1 0 . 0 7 ;  N, 8 . 9 0 ; CI,  48. PART V DISCUSSION OF CHEMISTRY The a p p r o p r i a t e c y c l o a l k a n e c a r b o x y l i c a c i d was used as the s t a r t i n g compound f o r each ethylenediamine  product.  Cyclobutanecarboxylic  a c i d , c y c l o p e n t a n e c a r b o x y l i c a c i d and  cyclohexanecarboxylic  a c i d were a l l commercially  A l d r l c h Chemicals). mercially  As cycloheptylbromide  ( A l d r i c h Chemicals),  pare the G r i g n a r d reagent,  available (  was a v a i l a b l e  com-  t h i s compound was used t o p r e -  and then c y c l o h e p t a n e c a r b o x y l i c  acid  by the procedure o f Hussey ( 2 2 ) and Royals and Neal ( 2 3 ) .  (  V-Br  +  Ether  Mg  HoO  C0 MgBr  -  2  >-  *-  / L  \ >-MgBr  i  »  (  Vry Ice  >-C00H  +  MgOHBr  A f t e r o b t a i n i n g the a p p r o p r i a t e c y c l o a l k a n e c a r b o x y l i c a c i d , the next diate.  step was to prepare  An a c i d c h l o r i d e  was prepared  f o r the -OH of a c a r b o x y l i c used f o r t h i s purpose:  the a c i d c h l o r i d e  acid.  interme-  by s u b s t i t u t i o n  Three reagents  thionyl chloride,  of -CI  a r e commonly  S0C1 ; phosphorus 2  t r i c h l o r i d e , P C l ^ ; and phosphorus p e n t a c h l o r i d e , P C l ^ . R-CO-OH  +  S0C1  3R-C0-0H  +  PCl^ — 3 R - C 0 - C 1  R-CO-OH  +  P C l ^ —>-  Thionyl chloride  2  —R-C0-C1  + S0 +  2  + HCl H^PO^  R-C0-C1 + HCl + POCl^ •  was chosen as the reagent  f o r the  49.  preparation of the a l i c y l i c acid chlorides not only because the  products formed besides the acid chloride were gases and  thus e a s i l y separated from the acid chloride, but because the acid chlorides formed were found to have higher b o i l i n g points than this reagent; any excess of the low-boiling thionyl chloride (b.p. 79°C., 1 atm.)  was e a s i l y removed by d i s t i l l a t i o n .  Two precautions were taken f o r running t h i s reaction.  The  f i r s t was to protect the reaction and the acid chloride from moist a i r ; the second was to avoid high temperature by using water bath during the d i s t i l l a t i o n which may cause p y r o l y s i s of the acid chloride.  The results were shown as follows (Table  4) :  TABLE 4 CYCLOALKANECABBONYL CHLORIDES RING SIZE  BOILING POINT °C. $YIELD vs.LITERATURE VALUE  Cyclobutane  130-136  (1  atm.)  68.1  63(1);  Cyclopentane  157-160  (1  atm.)  61.0  76(1)  80.5  80.5(1);  80.0  80(1)  Cyclohexane  82-85  (14-15  Cycloheptane  89-98  (14 mm. )•  mm.)  70(11)  81(16)  Upon obtaining the a l i c y c l i c carbonyl chlorides, the next step i n the sequence was to form the amide by reacting the  chlorides with the appropriate amine.  As the f i r s t  series  of ethylenediamine derivatives contain an N-substituted phenyl group, the primary amine, a n i l i n e was used to form the amide intermediates.  RC0C1  +  ^  ^ ~  W  H  2  P y r i d l T  > . R-{j-N-^ •  + Pyridine-HCl  50. S e p a r a t i o n of the amide and amine HCl depended on a difference i n s o l u b i l i t y .  The c y c l o a l k a n e s u b s t i t u t e d amides  were found to be w a t e r - i n s o l u b l e , and on completion of the r e a c t i o n , water was was  added to e x t r a c t the amine HCl.  Pyridine  added to the primary amine to n e u t r a l i z e the hydrogen c h l o -  r i d e formed.  The a n i l i d e s f o r cyclobutane to cycloheptane r e a -  d i l y formed i n good y i e l d s (Table 5)«  Cyclohexanecarboxanllide  had been prepared by Schwartz and Johnson (20)  from  reacting  the G r i g n a r d reagent and phenyl i s o - c y a n a t e :  TABLE 5 CYCL0ALKANECAR30XANILIDES RING SIZE  MELTING POINT °C.  $YIELD v s . LITERATURE VALUE  Cyclobutane  111-112  96.6  72(1)  Cyclopentane  159-161  97.9  95(1)  Cyclohexane  145-146  86.3  98(1)  Cycloheptane  137.5-139  72.0  74.6(1)  In o r d e r to o b t a i n the c y c l o a l k y l s u b s t i t u t e d amine, the c o r r e s p o n d i n g amide was dride.  reduced w i t h l i t h i u m aluminum  hy-  The reagent d i s c o v e r e d ' b y F i n h o l t , Bond and S c h l e s i n g e r  (25) i n 1947 (4L1H + be a remarkable  AICI3  *-LiAlIfy +  3L1C1)  has proved  to  r e d u c i n g agent f o r the c a r b o n y l group i n amides  and s i m i l a r c a r b o n y l compounds (26).  Amides are not  readily  51. r e d u c i b l e to pure amines by o t h e r chemical methods.. t i o n w i t h a c a t a l y s t a t h i g h temperatures accomplished,  Hydrogena-  and p r e s s u r e s can be  but u s u a l l y r e s u l t s i n a mixture of p r o d u c t s .  Powdered L i A l H ^ i s a v a i l a b l e commercially  (Ventron  Corp.), and i f p r o t e c t e d from moist a i r and carbon d i o x i d e , i t i s s t a b l e i n d e f i n i t e l y a t room temperature.  The hydride can  be s a f e l y handled, even i n very humid a i r , probably because o f the f o r m a t i o n of a p r o t e c t i v e c o a t i n g o f aluminum hydroxide ( 25).  I t i s g e n e r a l l y used i n s o l u t i o n o r suspension i n d r y  e t h e r (25-30 g. s o l i d h y d r i d e d i s s o l v e s i n 100 g. e t h e r a t 2 5 ° C ) . In the normal procedure  the substance  t o be reduced i s added  to an e t h e r e a l s o l u t i o n o r s l u r r y of the h y d r i d e .  I f the subs-  tance t o be reduced i s a l i q u i d o r s o l i d , e t h e r s o l u b l e , the s o l u t i o n i s added dropwise  t o produce g e n t l e r e f l u x .  F o r mode-  r a t e l y s o l u b l e m a t e r i a l s , a Soxhlet e x t r a c t o r o r a c o n t i n u o u s r e t u r n type of e x t r a c t o r i s used. In the r e d u c t i o n of the amides, an excess  (2-  t o 3-  f o l d o f the s t o i c h i o m e t r l c a l q u a n t i t i e s ) o f L i A l H ^ was used. 2R-C-N-<  V  />  +  L i AIR" 1,  S~ 2R-CH--N-A  ,}  +  L1A10  0  Water was then added t o d e s t r o y the excess h y d r i d e w i t h the e v o l u t i o n of hydrogen, and the p r e c i p i t a t i o n of l i t h i u m - and aluminum-hydroxide. LiAlH^  +  4H 0 2  ^  LiOH  +  A1(0H)^  +  4R"  2  As the amine was e t h e r s o l u b l e , the mixture was t r e a t e d w i t h s t r o n g hydroxide  s o l u t i o n to d i s s o l v e the p r e c i p i t a t e d  alumina.  T h i s allowed a c l e a r - c u t s e p a r a t i o n o f phases on c e n t r i f u g a t i o n .  5 2 .  The r e s u l t e d amine products were t a b u l a t e d as f o l l o w s (Table 6 ) .  TABLE 6 N-CYCLOALKYLMETHYL-N-PHENYLAMINES BOILING POINT °C.  RING SIZE  $YIELD  v  s  *  LITERATURE VALUE  mm.)  8 6 . 5  98.0(1)  mm.)  84.8  97.0(1)  Cyclohexyl  112-114 (1 mm.)  8 5 . 3  5 9 . 0 ( 1 )  Cycloheptyl  1 0 6  mm.)  8 0 . 0  78.2(1)  Cyclobutyl  8 8 - 9 6  ( 0 . 8  Cyclopentyl  124  (2.8  ( 0 . 1  Upon o b t a i n i n g the N-cycloalkylmethyl-N-phenylamine, the next p o r t i o n of the molecule t o be a t t a c h e d was the p-dlmethylamlnoethyl  c h a i n t o completely form the f i n a l  tertiary  diamine N , N - d i m e t h y l - N ' - c y c l o a l k y l m e t h y l - N - p h e n y l e t h y l e n e d i 0  amine.  Leung (1) had succeeded  i n o b t a i n i n g the t e r t i a r y d i -  amine by condensing the secondary amine, N-^cycloalkylmethyl-Nphenylamine, w i t h |3-dimethylaminoethylbromide  HBr i n the p r e -  sence of sodamide b u t the y i e l d s were v e r y low (Table 7 ) . R - C H p - N H + H3r-Br-CH -CH~-N 0  1  2  2  V  x  C  3  H  —  J  CH,  J  2NaNH  / C H 3  2  —R-CH -N-CHo-CH -N 0  i n dry * . ^ xylene e^^X or toluene  TABLE 7 CYCL0ALKYL ANALOGUES OF ANTERGAN (1) R Cyclobutyl Cyclopentyl Cyclohexyl Cycloheptyl  BOILING POINT °C. (20 (21 194-195 (15 204-210 (17 168-179  I 8 5 - I 8 9  mm.) mm.) mm.) mm.)  $YIELD 10.0 10.2 21.8  29.0  J  0  ^  N  C  H  ^  . The purpose o f t h i s study was mainly to develop a new s y n t h e t i c method to approach the t e r t i a r y diamine with b e t t e r yields.  V a r i o u s methods had been t r i e d to improve the y i e l d s  of the f i n a l p r o d u c t s .  Larizza  (27) reported  i n 1964  several  new d e r i v a t i v e s of Antergan, i . e . , N,N-dimethyl-N'-phenyl-N*benzylenediamine d e r i v a t i v e s . acetic acid  He used an c*-substi tuted c*-bromo-  (R-CHBr-CO-OH, R=methyl, e t h y l , o r phenyl, 1 mole)  In benzene and t r e a t e d w i t h s t i r r i n g with 1 mole of Et^N and 1 mole of the aromatic amine (PhNHg o r PhCHg-NHPh) i n benzene ( r e f l u x e d mixture) to o b t a i n R ( I I ) i n good y i e l d s s  PhNH-CO-CHBr-R (I) o r Ph-N-CO-CHBrCH Ph 2  (II) The l a t t e r compound (I o r I I , 1 mole) was added t o 2.5 moles Ke NH i n benzene, the mixture heated i n a 2  closed  tube a t 120°C. f o r 16 hours to get the dimethylamino compound ( I I I o r IV) which upon l i t h i u m aluminum h y d r i d e r e d u c t i o n N,N-dimethyl-N'-phenyl-N*-benzylenediamine  gave  d e r i v a t i v e s (V):  54. (b) \\ x  •NH-C-CH-N  //-NH-C-CH-R 0 Br (I) •or  (i I  0 R  °  + HN  0 Br II  120 C. i n '  ,CR'CH,  i  p R  N-C-CH-R  CH-  (III) or  a closed tube '  J  ,CH.  kX  ^CH.  >-N-C-CH-N  /  CH.  (IV)  (II)  W  ,CH -NH-CH~-CH-N // • £ CH  3  y/  2  V  3  LiAlHij, i n or  dry ether  yCH-3 v  ^  -N-CH -CH-N ^ ^ CH, R CH  //  9  V  X  3  (V) S i m i l a r r e a c t i o n s were run under the same c o n d i t i o n s as L a r i z z a ' s (equation (a) above) u s i n g o<-bromoacetic N-cyclohexylmethyl-N-phenylamine  a c i d and  i n s t e a d of c<-subatituted c<-  bromoacetic a c i d and a n i l i n e o r N-benzyleneani'line  respectively,  but no r e a c t i o n was found and the s t a r t i n g m a t e r i a l , N - c y c l o hexylmethyl-N-phenylamine  was recovered by vacuum d i s t i l l a t i o n .  N-Cycloheptylmethyl-N-Phenylamine  was a l s o t r i e d i n  the same r e a c t i o n c o n d i t i o n s and the r e s u l t was n e g a t i v e . Cyclohexanecarboxanilide  was used i n p l a c e of the secondary  55amine to r e a c t with oc-bromoacetic d e s i r e d product was  obtained.  e f f e c t i v e as a d e h y d r a t i n g  acid.  U n f o r t u n a t e l y , no  T r i e t h y l a m i n e seemed to be i n -  agent.  Since the c a r b o n y l c h l o r i d e i s u s u a l l y more r e a c t i v e than the c o r r e s p o n d i n g a c i d , c h l o r o a c e t y l c h l o r i d e was i n s t e a d of cx-bromoacetic a c i d and the r e a c t i o n was the same c o n d i t i o n s as above (equation ( a ) ) . i n g the mixture, a t a r r y r e s i d u e r e s u l t e d . v i o u s reasons work.  to e x p l a i n why  used  run under  But upon r e f l u x -  There were no  ob-  the s i m i l a r r e a c t i o n s d i d not  T r i e t h y l a m i n e might not be s u i t a b l e as a n e u t r a l i z i n g  agent  i n the r e a c t i o n .  n e u t r a l i z i n g agents,  F o r t h i s reason,  such as potassium  s e v e r a l commonly used  carbonate, p y r i d i n e and  sodamlde, were employed f o r the r e a c t i o n .  However, none of  them seemed to work s u c c e s s f u l l y . Olin  (28) s y n t h e s i z e d a h e r b i c i d a l d e r i v a t i v e , o<-  chloro-N-t-butyl-N-cyclohexylacetamide, i n g method:  A s o l u t i o n of 39.5  c h l o r i d e i n 50 ml. benzene was cold  (0°C.) mixture  amine, 42 g.  (0.30  of 46.5  i n 1964  g. (0.35  by the f o l l o w -  mole) c h l o r o a c e t y l  added d u r i n g 33 minutes to a  g. (0.30  mole) N - t - b u t y l c y c l o h e x y l -  mole) KgCO^, 100 ml. H 0, 2  ml. benzene, and 100 ml. e t h e r to give 45  400  g. i c e ,  300  g. oc-chloro-N-t-  butyl-N-cyclohexylacetamide: K 0 C O 3 i n benzene, C ( C H ) o - N H + CH C1-C0C1 >- C(CH ) -N-C0-CH Cl A e t h e r and i c e water f J mixture (0°C.) I I 3  2  3  S i m i l a r s t u d i e s were undertaken  3  2  using N-cyclohexyl-  methyl-N-phenylamine i n s t e a d of N - t - b u t y l - c y c l o h e x y l a m i n e r e a c t with c h l o r o a c e t y l c h l o r i d e .  The r e a c t i o n f a i l e d  to  again:  56.  CH -NH 0  +  CH^Cl-COCl  I ^ C C U i n benzene, No  e t h e r and i c e water mixture (0°C.)  The f a i l u r e  c o u l d be due  to the f a c t t h a t c h l o r o a c e t y l  Product  chloride  reacted r e a d i l y w i t h both water and potassium carbonate b e f o r e it  coupled w i t h the amine. In view of a l l the above f a i l u r e ,  the amino  hydrogen  of the secondary amine, N-cyclohexylmethyl-N-phenylamine, to be too i n e r t to r e p l a c e i n the presence of weak bases as potassium carbonate, t r i e t h y l a m i n e o r p y r i d i n e e x p l a n a t i o n was  found to be i n c o r r e c t l a t e r ) .  equimolar sodamide was  seemed such  (Notes T h i s  F o r t h i s reason,  r e f l u x e d w i t h the secondary amine i n  d r y e t h e r so t h a t the sodium i o n of sodamide would r e p l a c e the amino hydrogen  w i t h r e l e a s e of gaseous ammonia.  d r y n i t r o g e n gas stream was  A constant  bubbled through the r e a c t i o n mix-  ture so as to prevent the sodamide from r e a c t i n g w i t h atmosp h e r i c carbon d i o x i d e and to d r i v e away the ammonia gas i n f a v o r of the d e s i r e d r e a c t i o n .  R e f l u x i n g was  formed  continued  u n t i l no gaseous ammonia c o u l d be d e t e c t e d from the d r y i n g tube of the condenser c h l o r i d e was duct  (amide).  (about 2 d a y s ) .  Excess  chloroacetyl  then added to the mixture to form the d e s i r e d p r o However, a t a r r y r e s i d u e .soon r e s u l t e d  the a d d i t i o n of c h l o r o a c e t y l  after  chlorides  No Product  57. The  evidence ( 2 9 . 3 0 , 3 1 ) t h a t amino hydrogen o f  primary and secondary amide r e a c t s w i t h sodamide made us use cyclohexanecarboxanilide R-C0-NH  2  +  NaNH  f o r the r e a c t i o n , R-CO-NHNa  2  +  i n benzene  NEU f ^  C y c l o h e x a n e c a r b o x a n i l i d e was r e f l u x e d with.sodamide i n benzene s o l u t i o n i n the manner d e s c r i b e d  i n the p r e v i o u s s e c t i o n .  Ex-  cess c h l o r o a c e t y l c h l o r i d e was then added to r e a c t w i t h the sodium s u b s t i t u t e d a n i l i d e .  Unfortunately,  no r e s u l t was ob-  tained : 1) NaNH 2)  2  5>CH C1-C0C1  No Product  2  I t was found t h a t the secondary amine  N-cyclohexyl-  methyl-N-phenylamine was b a s i c enough to serve as a n e u t r a l i z i n g agent.  When c h l o r o a c e t y l c h l o r i d e was dropped i n t o the  amine i n benzene s o l u t i o n a t room temperature, v i g o r o u s t i o n occurred  with release  of a l a r g e amount of heat  reac-  (exother-  mic  reaction).  I t was found that the r i s e i n temperature o f  the  r e a c t i o n caused the decomposition of c h l o r o a c e t y l  and  consequently, only amine HCl s a l t and s i d e products were  formed w i t h no d e s i r e d amide f o r m a t i o n . was  a failure,  chloride  Although t h i s  reaction  y e t i t answered the reason why a l l the above  r e a c t i o n s d i d n o t work p r o p e r l y . e s s e n t i a l f o r the d e s i r e d  Low temperature c o n t r o l was  r e a c t i o n to occur and high  tempera-  ture tended t o decompose c h l o r o a c e t y l c h l o r i d e and hence a t a r r y residue  of unknown s i d e products r e s u l t e d .  At low tern-  58. perature (-2  to -10°C.) benzene s o l v e n t  dry ether was  used as the  the amine was  cooled  the cooled  solvent.  The  solidified, ethereal  i n an i c e - s a l t bath (-2  s o l u t i o n was  therefore  s o l u t i o n of  to - 1 0 ° C ) .  To  added c h l o r o a c e t y l c h l o r i d e dropwise  a t such a r a t e as to keep the temperature of the r e a c t i o n  not  h i g h e r than 0 ° C .  Double q u a n t i t i e s of the amine were used  for  One  the r e a c t i o n .  equivalent  was  used to couple with c h l o -  r o a c e t y l c h l o r i d e ' t o form the amide product while the acted  as the n e u t r a l i z i n g agent.  the  r e a c t i o n must be p r o t e c t e d  was  added a t the end  cess amine and  from moist a i r .  The  white amine HCl  amine could be  (a)  r e s u l t i n g amides are Ether,  s a l t was  reformed from i t s HCl  the a d d i t i o n of strong NaOH s o l u t i o n and The  5$ HCl  and solution ex-  to convert excess c h l o r o a c e t y l c h l o r i d e i n t o  the o r i g i n a l  solvent.  chloride  of the r e a c t i o n i n o r d e r to r e a c t with  more w a t e r - s o l u b l e a c i d . and  Chloroacetyl  second  filtered salt  e x t r a c t i n g with  ether  shown i n Table 8 below, +  by  59. TABLE 8 crt-CHLOBO-N-(R)-ACETANILIDES  R  MELTING POINT °C.  H  134.5-135.5  CH^  RECRYST. SOLVENT  $YIELD(*)  EtOH  100  67.8-68 0 8  n-hexane  100  Cyclobutylmethyl  45.2-46.2  n-pentane  100  Cyclopentylmethyl  55.0-56.0  n-pentane  100  Cyclohexylmethyl  52.0-53.0  n-pentane  100  Cycloheptylmethyl  27.5-28.5  _  100  60$  _ _ - _  (*) The y i e l d s x^rere c a l c u l a t e d o n t h e b a s i s o f h a l f t h e q u a n t i t y o f t o t a l amine used f o r t h e r e a c t i o n , s i n c e t h e a m i n e c a n be r e c o v e r e d a s e x p l a i n e d i n t h e t e x t . The at  next step  was t o i n t r o d u c e  the dimethylamino  t h e oc-carbon o f t h e a m i d e s t o c o m p l e t e  a m i n e e n d . S i n c e t h e c<-carbon  tertiary  o f t h e amide had c h l o r i n e  ed t o i t , t h e w h o l e m o l e c u l e c o u l d h a l i d e and behaved a c c o r d i n g l y . cleophilic  t h e second  group  attach-  be a s s u m e d t o be a n a l k y l  An a l k y l h a l i d e undergoes nu-  s u b s t i t u t i o n with dimethylamine  t o form  tertiary  amine: ^CH-3  R-Cl  +  2HN  D v  x  ^  R-N  —  +  J N  CH^ Dimethylamine  CHo  /  Cl-H N 2  Cri^  e x i s t s i n t h e gaseous  + CH-5 D v  CH^  s t a t e a t room  temperature  and  s h o u l d be t r a p p e d i n t o t h e f l a s k a s a l i q u i d b y a n a c e t o n e -  dry  i c e bath f o r the r e a c t i o n .  The t e m p e r a t u r e was k e p t a t -2  t o -10°C. ( i c e - s a l t b a t h ) when r e a c t i o n s t a r t e d . the  low temperature of r e a c t i o n , a large  ether the  o r genuine absolute  methanol  a m i d e s a t room t e m p e r a t u r e  (10))  Because o f  excess of solvent  (dry  was u s e d t o d i s s o l v e  s o t h a t when r e a c t i o n o c c u r r e d  6 o .  at low temperature (-2 to - 1 0 ° C ) , ssolved i n the solution.  the amides were s t i l l d i -  Double quantities of dimethylamine  were used f o r the reaction.  One equivalent was used to cou-  ple with the amide to form the second t e r t i a r y amine end while the second acted as the n e u t r a l i z i n g agent.  If dry ether was  the reaction solvent, the white amine HCl s a l t formed i n the reaction was insoluble i n ether and accumulated as the reaction went to completion.  If absolute methanol was the reaction s o l -  vent, the amine HCl s a l t formed soon dissolved i n the solvent. In order to separate the dissolved s a l t from the product, the reaction mixture was reduced i n volume by f l a s h evaporation. The concentrated residue dispersed i n water vras extracted with solvent ether.  The product was found i n the ethereal layer  and the amine HCl s a l t remained i n the water.  The r e s u l t s are  shown i n Table 9 « ^CHo R-N-C0-CH C1 9  X  + 2HN T  -2 to  -"' N  C H ,  =  -10 C .  /  CH,  RD -_ NT.T- _C nrs O - C nvs H o - NM  X  *  N  -  + CEo /  ^J +_i_ Cr>il - HTT- NM  C H .  ^  X  J  C H ,  TABLE 9 o<-DIMETHYLAMINO-N-(R)-N-PHENYLACETAMIDE R  H Methyl Cyclobutylmethyl Cyclopentylmethyl Cyclohexylmethyl Cycloheptylmethyl  BOILING POINT °C. 124(1.4 mm.) 1 0 6 ( 0 . 3 mm.) 1 3 4 - 1 3 5 ( 0 . 9 mm.) 178-179(1.7 mm.)  P O I N T  1  ® ? .  ^  Y  I  S  L  D  94.0 90.5 80.7 45.0-46.0 90.0 53.5-54.5 8 3 . 1 80.5  The f i n a l step of the series of reactions was to re  61. duce the c a r b o n y l group of the amide to form the t e r t i a r y d i amine compounds  (Antergan analogues).  L i t h i u m aluminum hydride  was used as the r e d u c i n g agent i n the same manner as d e s c r i b e d f o r the r e d u c t i o n of c y c l o a l k a n e c a r b o x a n i l i d e s i n t o the c o r r e s ponding  amines.  The c y c l o a l k y l analogues  formed i n good y i e l d s (Table 2R-N-C0-CH--N  ^CHo  +  D  of Antergan  readily  10).  L i A l H = ± : 2R-N-CH -CH -N k  0  •CH-3  ^ + LiAlOo  0  TABLE 10 N,N-DIMETHYL-N'-(R)-N'-PHENYLETHYLENEDIAMINE R  BOILING P0INT°C. & $YIELD v s . LIT. VALUE(l)  81(0.75 mm.) 91.3  H  CH  f  97-98(1.9 mm.),77.3  3  Cyclobutylmethyl  120-125(0.8 mm.),92.1 168-179(20 mm.),10.0  C y c l o p e n t y l m e t h y l 136-138(1 Cyclohexylmethyl  mm„),90.3  158-159(2.2 mm.),93.3 194-195(15 mm.),21.8  C y c l o h e p t y l m e t h y l 148-153(1 mm.),95.1 The  204-210(17 mm.),29.0  compounds s y n t h e s i z e d i n Table 4 , 5 and 6 were  repeated u s i n g Leung's method (1) 8,  185-189(21 mm.),10.2  while the compounds i n Table  9 and 10 were s y n t h e s i z e d by the present s t u d i e s .  I f the  compounds were s o l i d , pure and r e c r y s t a l l i z e d substances sent f o r percentage  composition a n a l y s i s of carbon,  n i t r o g e n and halogen.  No d e r i v a t i v e s were made.  were  hydrogen,  F o r those  l i q u i d compounds, m e t h y l i o d l d e - , h y d r o c h l o r i d e - o r p i c r a t e d e r i v a t i v e s were made f o r elemental m i c r o a n a l y s i s .  62,  To supplement the a n a l y t i c a l r e s u l t s o f a d e r i v a t i v e , an i n f r a r e d spectrum The  spectrum  was taken on the s y n t h e s i z e d compound. r e g i o n 2 to 1 5  of a molecule i n the fundamental  shows the presence of a number of bands which can be c o r r e l a t e d with the f u n c t i o n a l groups p r e s e n t i n the molecule, xvhile o t h e r bands correspond t o s k e l e t a l v i b r a t i o n s . this,  Because of  i n f r a r e d s p e c t r o s c o p y was used both to o b t a i n informa-  t i o n of the f u n c t i o n a l groups p r e s e n t i n the unknown molecules and a l s o to a c t as " f i n g e r p r i n t s " f o r the molecule. t h i s technique, i t was p o s s i b l e  t o determine  Using  the completion •  of a r e a c t i o n by the presence o r absence  of a p a r t i c u l a r band  c o r r e s p o n d i n g to a p a r t i c u l a r f u n c t i o n a l  group.  63. PART VI PRELIMINARY ANTIHISTAMINE ACTIVITY STUDIES Since the parent compound Antergan was known as the f i r s t c l i n i c a l l y e f f e c t i v e a n t i h i s t a m i n i c agent, i t s c y c l o a l k y l analogues might be expected to have some a n t i h i s t a m i n i c activity.  T h e r e f o r e , q u a n t i t a t i v e comparisons  of a n t i h i s t a m i n i c  a c t i o n s of these analogues w i t h Diphenhydramine HCl (Benadryl HCl, Parke, Davis and Co., were s t u d i e d .  L t d . , W a l k e r v i l l e , O n t a r i o , CANADA)  The methods of S c h i l d  m o d i f i e d and adopted here.  (32)  and Reuse (33)  Histamine c o n c e n t r a t i o n was  were cal-  c u l a t e d i n terms of histamine base (Histamine D i h y d r o c h l o r i d e , N u t r i t i o n a l B l o c h e m i c a l s Corp., C l e v e l a n d , Ohio, USA) of  s a l t s i n terms of the s a l t s  A l l drugs were f r e s h l y prepared i n Tyrode guinea-pig's Ileum 2-3  b a t h c o n t a i n i n g Tyrode  cm.  solution.  used. Strips 30-c.c.  l o n g were a e r a t e d i n a  s o l u t i o n a t 3 7 i 0 5 ° C . and o  longitudinal  c o n t r a c t i o n s of the i n t e s t i n e recorded on a kymograph. a c t i o n of a s i n g l e dose of histamine (0.5 was  those  o t h e r compounds t e s t e d were c a l c u l a t e d as molar c o n c e n t r a -  t i o n of monohydrochlorlde  of  and  first  times, 0.5  Y °? histamine base)  t e s t e d and a number of submaximal e f f e c t s V each) obtained and the response  c o n t r a c t i o n i n mm.)  (2  then i n j e c t e d i n t o the bath.  The  to 3  (degree of ileum  measured a t the end of 15 minutes  taken as the standard mean response.  The  was  t e s t compounds were  A f t e r 1 minute c o n t a c t between  t e s t compounds and g u i n e a - p i g ' s ileum, a double dose of h i s t amine ( i . e . ,  1.0  J  of histamine base) was  then i n j e c t e d  the bath and the e f f e c t measured a t the end of 15  into  minutes.  64. The  o b j e c t was t o f i n d  such  t h a t one w o u l d  amine t o s l i g h t l y effect  interpolation negative an  reduce  less  of a single  dose  the e f f e c t  and t h e o t h e r  dose.  was t h e n  dose o f h i s t more t h a n t h e obtained  by  (pA_ was d e f i n e d as t h e  w h i c h vrould r e d u c e  ( x ) o f an a c t i v e  compounds. was  to s l i g h t l y  compounds  l o g a r i t h m t o b a s e 10 o f t h e m o l a r c o n c e n t r a t i o n o f  drug  f r e s h p i e c e o f g u t was u s e d  value  of a double  The pAg v a l u e  on a l o g a r i t h m i c s c a l e  a n t a g o n i s t i c drug  ple  two c o n c e n t r a t i o n s o f t h e t e s t  the e f f e c t  to that of a single  shown i n T a b l e  dose).  A  f o r each c o n c e n t r a t i o n o f the t e s t  The whole e x p e r i m e n t was r e p e a t e d found.  o f a, m u l t i -  The r e s u l t s  11 a n d F i g u r e  until  the p A  2  o f p r e l i m i n a r y a n a l y s i s were 2.  TABLE 11 EFFECTS OF CYCLOALKYL ANALOGUES OF ANTERGAN (K0N0-HC1 SALTS) AND DIPHENHYDRAMINE H C l ON RESPONSE OF ISOLATED GUINEA-PIG ILEUM (15 MINUTES EXPOSURE): IV, C y c l o b u t y l m e t h y l Analogue; V, C y c l o p e n t y l m e t h y l A n a l o g u e ; V I , C y c l o h e x y l m e t h y l A n a l o g u e ; V I I , C y c l o h e p t y l m e t h y l A n a l o g u e ; D, D i p h e n h y d r a m i n e . NLMC: Negative Log. Molar C o n c e n t r a t i o n . NO. OF TEST  A,RESPONSE " (mm.) TO HISTAMINE  (0.5'r)  B.NLMC OF ANTAGONIST  C.RESPONSE(mm.) TO HISTAMINE (1.0)') IN PRESENCE OF ANTAGONIST  7.5  IV:  7.19  1.0  10,5  IV:  7.19  .2.0  9.0  IV:  7.19  1.5  1.  20.5  IV:  7.85  25.0  2,  23.0  IV:  7.85  22.0  AVE.  21.8  IV:  7.85  1«  13.5  V:  7.54  21.5  2.  24.0  V:  7.5^  19.5  18.8  V:  7.54  20.5  1. 2. AVE.  AVE.  (To be  continued)  C/A {%)  16,7  107.7  109.0  B  A  C  1.  12.5  Vs 7-23  2.  23.0  Vs 7.23  AVE.  17,8  Vs 7.23  14.0  1.  12.5  Vis 7.62  4.0  2.  12.0  Vis 7.62  4.5  AVE.  12.3  Vis 7.62  4.3  1.  25.0  Vis 8.52  21.0  2.  24,0  Vis 8.52  20.0  AVE.  24.5  VI: 8. 52  20.5  1.  5.0  VII  7.52  8.5  2.  8,5  V I I : 7.52  13.5  AVE.  6.8  VII j 7.52  11.0  1.  11.0  V I I : 7.22  3.0  2.  10.0  V I I : 7.22  -  AVE.  10.5  V I I : 7.22  3.0  1.  12.5  Ds 7.62  6.5  2.  18.0  D: 7.62  6.5  AVE.  15.3  Ds 7.62  6.5  1.  9o5  D: 8.62  22.5  2.  17.0  D: 8.62  20.0  AVE.  13.3  D: 8.62  21.3  1.  14,0  D: 7.62  2.5  2.  11.5  D: 7.62  4.0  AVE.  12.8  D: 7.62  3-3  1.  23.5  D: 8.44  18.5  2.  23.0  D: 8.44  12.0  AVE.  23.3  D: 8.44  15.3  5  14.0  (C/A  {%)  78.7  34.1  83.7  161.7  28.6  42.5  160.2  25.8  65.7  r  Mean Response ( 1 - 2 t e s t s ) to A Double Dose as % o f t h e ; Response"" to A " S i n g l e Dose~without"Antagonist.  -; —  -3 3  (X)  —  D-d~  CD  H*  (T> "3> ct cf-d.ro 3 : r 3 <3 s»- • i—* i—* j^s \-> ; nr ss - 3 3 P- co SB SB 4 jo 'O O 3 o . 0 3 t*} 4 ss ss 3 o '3' O <3 o o i  CD  ;HH H-  0 CD CD S -  •  M. o  O  V{ M H ••  H  _ 3* O < (t  05 P  H CD . 03_. X o 4=<: HO 3 O  $o » - » o  3 3  -  H- CO 3  £  O  ct ct  — [ h-* -  o  1  M 3  O  >  H  CD Ct  SS  -3 3' W-  r  S» ^ «<  M O  HH  -Oq > ss 3  >3  CD S3  --  —  o  MM  i - f SS  M  o £  CD CD CO  -  O < O o O > O << 3 3" O c t  H  CD (-« CD "  W  O  4  ctTf m  << CD JB M 3 f  ct v<  3 • <*  CQ  t-J i *  "99  67 . I t was  q u i t e i n t e r e s t i n g to f i n d t h a t N,N-dimethyl-  N'-cyclohexylmethyl-N'-phenylethylenedlamlne methyl analogue) was Diphenhydramine.  (i.e., cyclohexyl-  s l i g h t l y more potent than o r as potent  The high potency o r d e r of the Antergan  gues (pAg value i n p a r e n t h e s i s ) was  as  analo-  as f o l l o w s :  Cyclohexylmethyl analogue (8.82)^ Diphenhydramine (9.15  or  8.11)> C y c l o b u t y l m e t h y l analogue (7.79)> C y c l o p e n t y l m e t h y l analogue (7.45)> C y c l o h e p t y l m e t h y l analogue (7.38) The o t h e r two compounds t e s t e d , i . e . , N,N-dimethyl-N'-phenylethylenedlamlne  and N N-dimethyl-N'-methyl-N'-phenylethylene-  dlamlne were found  0  to have no a n t i h i s t a m i n i c a c t i v i t y  not shown i n the F i g u r e ) . logue was  The a c t i o n of c y c l o h e x y l m e t h y l ana-  the most p e r s i s t e n t and s p e c i f i c among the s e r i e s of  compounds t e s t e d , t h e r e f o r e , i t was  d i f f i c u l t to wash out  took l o n g e r d u r a t i o n f o r r e c o v e r y (24 minutes). heptylmethyl analogue was l y easy to wash out.  The  the weakest i n a c t i o n and  Although  the pAg  cyclocomparative-  separate  determina-  ( i n some compounds j u s t one d e t e r m i n a t i o n ) and  buted l i t t l e  and  values i n the p r e s e n t  s t u d i e s were o b t a i n e d from the mean of two tions  (results  contri-  s t a t i s t i c a l s i g n i f i c a n c e , yet the v a l i d i t y of the  method as i n d i c a t e d by S c h i l d and Reuse made us b e l i e v e t h i s p r e l i m i n a r y study gave v a l u a b l e i n f o r m a t i o n to the f i n d i n g t h a t c y c l o h e x y l m e t h y l analogue of Antergan m i n i c agent.  As a r e s u l t , i t was  was  a potent  suggested  antihista-  t h a t t h i s compound  be submitted f o r more d e t a i l e d p h a r m a c o l o g i c a l  study.  68.  PART VII SUMMARY The syntheses of four c y c l o a l k y l analogues of Antergan and two related compounds have been reported i n good yields.  The benzyl group i n Antergan was  replaced by a cyclo-  alkylmethyl group containing four to seven carbon atoms i n the ring.  These t e r t i a r y diamines are as follows: N,N-dimethyl-  N'-cyclobutylmethyl-N -phenyle thylenediamine, N,N-dime t h y l - N ' 8  cyclopentylmethyl-N'-phenylethylenediamine, N j N - d i m e t h y l - N  -  11  and N,N-dimethyl-  cyclohexylmethyl-N'-phenylethylenediamine,  N'-cycloheptylmethyl-N'-phenylethylenediamine.  The benzyl  group i n Antergan was also substituted by a hydrogen and or by a methyl group to become N„N-dimethyl-N -phenylethylene9  N,N-dimethyl-N'-methyl-N'-phenylethylenediamine  diamine and respectively.  These ethylenediamine derivatives were i s o l a t e d as the free base.  The hydrochloride, methyl iodide, and picrate  s a l t s of these amines were prepared f o r elemental microanalyses. The general reaction sequence f o r the preparation of these derivatives started with the cycloalkanecarboxylic a c i d . The acid was chloride.  reacted with t h i o n y l chloride to form the acid  Then the amide intermediate was prepared by reacting  the acid chloride with a n i l i n e .  Lithium aluminum hydride  used to form the desired amine.  Leung's methods ( 1 ) were  followed and showed good r e s u l t s up to t h i s step. action sequence was used from t h i s step on. amine was  was  A nexv re-  The appropriate  reacted with chloroacetyl chloride, dimethyl amine,  69o  and then reduced by lithium aluminum hydride to the ethylenediamine d e r i v a t i v e s . A l l the intermediates synthesized were characterized through t h e i r physical constants, b o i l i n g point, melting point and i n f r a r e d spectra, and were v e r i f i e d by elemental microanalyses of intermediates themselves (for s o l i d intermediates) or t h e i r hydrochloride or methyl iodide s a l t derivatives ( f o r l i q u i d intermediates). The preliminary antihistaminic a c t i v i t y of a l l the s i x f i n a l compounds were studied by a modification of Schild's ( 3 2 ) and Reuse's ( 3 3 ) methods.  I t v/as quite i n t e r e s t i n g to  find that N,N-dimethyl-N"-cyclohexylmethyl-N'-phenylethylenedlamlne was s l i g h t l y more potent or as potent as Diphenhydramine (Benadryl).  The former compound was also the most potent  and most s p e c i f i c among the series of compounds tested.  The  cycloheptylmethyl analogue was the least potent i n action. The order of descending antihistaminic a c t i v i t y was as follows: Cyclohexylmethyl analogue^, Diphenhydramine > Cyclobutylmethyl analogue> Cyclopentylmethyl analogue> Cycloheptylmethyl analogue.  The other two related compounds, N , N - d i m e t h y l - N ' -  phenylethylenedlamlne  and N,N-dimethyl-N*-methyl-N'-phenyl-  ethylenedlamlne , were found to have no antihistaminic a c t i v i t y .  70o FART V I I I INFRARED SPECTRA  WAVELENGTH  5.5  F i g . 3«  IR spectrum of cst-chloroace  6.5  7  7.5  IN  MICRONS  8  WAVENUMBER  9  CM  10  11  12  14  1  3  3.5  00  3000  Fig.  4.  4  2500  IR s p e c t r u m o f l i q u i d between  4.5  5  2000  5.5  6  1800  o/,-dimethylaminoacetanilide„ NaCl p l a t e s .  6.5  1600  W A V E L E N G T H IN MICRONS 7 7.5 8  140.0  1200  9  10  1000  WAVENUMBER CM"  1  11  12  800  14  1  WAVELENGTH 3.5  )0  3000  Fig. 5 .  •  2500  6.5  5.5  4.5  2000  1800  1600  IR spectrum of N,N-dlmethyl-N -phenylethylenedlamlne , l i q u i d between NaCl p l a t e s .  7  7.5  1400  IN  MICRONS 8  9  1200  8  WAVENUMBER C M  10  1000  li  12  800  14  1,  3  )0  3.5  3000  F i g - 7«  A  2500  4.5  5  2000  i-5  1800  6  6.5  1600  IR spectrum of tf.-dimethylamino-N-methyl-Nphenylacetaralde, l i q u i d between-NaCl plates.  WAVELENGTH IN MICRONS 7 7.5 8  1400  1200  WAVENUMBER  CM"'  9  10  1000  11  12  800  -  14  1<  6.5  3000  Fig. 8.  2500  2000  1800  • W A V E L E N G T H IN M I C R O N S 7 7.5 8  1600  IR spectrum of N.N-dimethyl-N'-methyl-N'-phenylethylenediamine, l i q u i d between NaCl p l a t e s .  WAVENUMBER CM  9  3  '0  3.5 '  3000  F i g . 9.  4  2500  4.5  5  2000  5.5  1800  6  6.5  WAVELENGTH IN MICRONS 7 7.5 8  1600  IR spectrum of c^-chloro-N-cyclobutylraethyl-N-phenylacetamlde, l i q u i d b e t w e e n NaCl p l a t e s .  1400  1200  W A V E N U M B E R CM''  9  10  1000  11  12  800  14  1<  WAVELENGTH IN MICRONS  )0  3000  Fig, 1 0 .  5.5  4.5  3.5  2500  2000  1800  6.5  7  7.5  &  9  1600  IR spectrum of '•/-dlmethylamino-N-cyclobutylmethylN-phenylacetamlde, l i q u i d between NaCl p l a t e s .  WAVE NUMBER  CM  6.5  DO  3000  F i g . 11.  2500  2000  1800  WAVELENGTH IN MICRONS 7 7.5 8 9  1600  IR spectrum o f N.N-dimethyl-N'-cyclobutylmethyl-N'phenylethylen ediamine, l i q u i d between NaCl plates.  1400  1 200  , WAVENUMBER  CM"  6.5  )0  3000  Fig.  12.  WAVELENGTH IN MICRONS 7 7.5 3  2500  IR spectrum of <A-chloro»N-cyclopenty line t h y l N-phenylacetam ide ( KBr p e l l e t ).  WAVENUMBER CM  9  WAVELENGTH  3  3.5  )0  3000  Fig.  13.  4  2500  4.5  5  2000  5-5  1800  6  6.5  1600  I K spectrum of c<-dimethylamino-N-cyclopentylm e t h y l - N - p h e n y l a c e t a m i d e ( KBr p e l l e t ). '  7  7.5  1400  IN  MICRONS  8  9  1200  WAVGNUMBER  CM"  10  1000  11  12  800  14  " WAVELENGTH IN MICRONS 6.5  10  3000  F i g . 14.  2500  2000  1800  1600  7  7.5  400  8  9  1200  IR spectrum of N,N-dimethyl-N'-cyclopentylraethyl-N°p h e n y l e t h y l e n e d i a m i n e , l i q u i d between NaCl plates.  WAVENUMBER CM"'  6.5  DO  3000  Fig„ 1 5 .  2500  2000  1800  -  ^ "  , u  -T600  IR s p e c t r u m o f r ^ - c h l o r o - N - c y c l o h e x y l r a e J f c h y l N-phenylacetamide ( KBr p e l l e t ) /  W A V E L E N G T H IN 7 7.5  MICRONS 8  400  WAVENUMBER  14  9  1200  CM  1000  WAVELENGTH IN MICRONS 7 7.5 8 9  6.5  nun] ; J i-i  )0  3000  F i g . 16.  2500  2000  1800.  / V  M£00  IR spectrum of K - d i m e t h y l a m i n o - N - c y c l o f r e x y l m e t h y l N-phenylacetamide ( KBr p e l l e t  / 1400  1200  WAVENUMBER CM'  1  3  3.5  30  3000 '  Fig.  17 o  4  4.5  2500  5  5.5  2000  1800  6  6.5  WAVELENGTH IN MICRONS 7 7.5 3  1600  I R s p e c t r u m o f N N-dimethyl-N -cyclohexylmethyl-N»phenyletnylenediamine, l i q u i d b e t w e e n NaCl p l a t e s .  1400  1200  ,  l  W A V E N U M B E R CM"'  9  10  1000  11  12  800  14  1  3  )0  3.5  3000  4  2500.  4.5  5  2000  5.5  1800  6  6.5  WAVELENGTH !N MICRONS 7 7.5 8 9  1600  F i g . 18. IR spectrum of e<-chlo~N~cycloheptylmethyl-N~ phenylacetamlde, l i q u i d between NaCl plates.  1400 -  1200 •  ,  WAVGNUMBER C M '  10  1000  11  12  800  14  1,  WAVELENGTH IN MICRONS  DO  3000  Fie;„ 1 9 „  2500-  2000  1800  1600  IR spectrum o f o(-dimethylamlno-N-cycloheptylmethylN-pheftylacetamide^liquid between NaCl p l a t e s . '  1400  1200  1000  , WAVENUMBER  CM'  800  3  00  3.5  3000  4  2500  4.5  5  2000  5.5  1800  6  6.5  1600  WAVELENGTH IN MICRONS 7 7.5 8  1400  F i g , 2 0 o IR spectrum of N,N-dlmethyl-N*-cycloheptylr.iethyl-N'phenylethylenedlamlne,, liquid between NaCl plates.  1200  WAVENUMBER CM'  9  10  1000 1  11  12 '  SCO  14  89o  FART L I S T OF  IX  REFERENCES  lo  F r e d Leung, " S y n t h e s i s o f C y c l o a l k y l A n a l o g u e s o f A n t e r gan", M a s t e r T h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , V a n c o u v e r , C a n a d a , 1964„  2.  A.Grollman, Pharmacology 4 3 1 , Chap, 1?, 1962.  3o  J . 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