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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 National Taiwan University, Taipei, 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 Pharmaceutical Chemistry of the Faculty of Pharmaceutical Sciences We accept t h i s thesis 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 Cycl o a l k y l analogues of Antergan with the basic struc-ture of N.N-dimethyl-N'-cycloalkylmethyl-N'-phenylethylenedi-amlne have been synthesized In good y i e l d s . The a l k y l group was a butyl-, pentyl-, hexyl-, or heptyl-ring structure. The compounds with the benzyl group of Antergan substituted by a hydrogen or a methyl group were also synthesized i n good y i e l d s . The general reaction sequence followed was to s t a r t with the appropriate cycloalkanecarboxyllc acid and b u i l d up to a secondary amine v i a an acid chloride and an amide. Leung's methods (1) were followed and checked up to t h i s step. Further reaction sequences were developed during t h i s study. The de-si r e d amine was reacted with chloroacetyl chloride, dimethyl-amine and then reduced to the t e r t i a r y diamine analogues. The preliminary a n t i h i s t a m i n e a c t i v i t y of these ana-logues was studied and compared with that of Diphenhydramine Hydrochloride Standard Solution. The r e l a t i v e a c t i v i t y of each analogue was also determined. Signature of Examiners 11 ACKNOWLEDGEMENT My sincere gratitude i s extended to my major pro-fessor, Dr. T. H. Brown, f o r professional guidance, under-standing and encouragement during the course of t h i s study. I wish to express my thanks to Dr. J . E. Halliday f o r his guidance i n pharmacological tests, and my sincere thanks to Dr. F. S. Abbott f o r advice and counseling. F i n a n c i a l support by the National Research Council 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 to fellow graduate students f o r t h e i r friendship and h e l p f u l advice. i i i TABLE OF CONTENTS Part Page Abstract . 1 Acknowledgement i l L i s t of Tables v i L i s t of Figures v i i I. INTRODUCTION 1 A. Histamine 1 B. Analogs of Histamine 7 C. Antihistamines and Relationship between Structure and Pharmacological A c t i v i t y 9 I I . STATEMENT OF PROBLEM 13 I I I . ANALYTICAL METHODS 14 IV. EXPERIMENTAL 15 A. Synthesis of N,N-Dimethyl-N'-Phenylethylene-d i amine 15 1. c*-Chloroacetanllide 15 2. o<-Dimethylaminoacetanilide 16 3. N,N-Dlmethyl-N*-Phenylethylenedlamlne 17 B. Synthesis of 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 thylene-diamine... 21 C. Synthesis of N.N-Dimethyl-N'-Cyclobutylmethyl-N' -Phenylethylenedlamlne 22 1. Cyclobutanecarbonyl Chloride... 22 2. Cyclobutanecarboxanilide 23 i v Part Page 3 . N-Cyclobutylmethyl-N-Phenylamine 23 4. o<-Chloro-N-Cyclobutylmethyl-N-Phenyl-acetamide 25 5 . crt-Dimethylamino-N-Cyclobutylmethyl-N-Phenylacetamide 26 6. N,N-Dimethyl-N•-Cyclobutylmethyl-N*-Phenylethylenediamine 27 D. Synthesis of N,N-Dimethyl-N'-Cyclopentylmethyl- 1 N*-Phenylethylenediamine 29 1. Cyclopentanecarbonyl Chloride 29 2 . Cyclopentanecarboxanilide......... 29 3 . N-Cyclopentylmethyl-N-Phenylamine. 30 *K o<-Chloro-N-Cyclopentylmethyl-N-Phenylacetamide 31 5 . oC-Dimethylamino-N-Cyclopentylmethyl-N-Phenylacetamide 32 6 . N,N-Dlmethyl-N*-Cyclopentylmethyl-N'-Phenylethylenediamlne 33 E. Synthesis of N,N-Dimethyl-N'-Cyclohexylnethyl-N'-Phenylethylenediamine 3^ -1. Cyclohexanecarbonyl Chloride 3^ 2 . Cyclohexanecarboxanilide 35 3 . N-Cyclohexylmethyl-N-Phenylamine 35 4 „ crf-Chloro-N-Cyclohexylme thyl-N-Phenylacetamide 36 5 . crf-Dimethylamino-N-Cyclohexylmethyl-N-Phenylacetamide 37 6. N,N-Dimethyl-N•-Cyclohexylmethyl-N•-Phenylethylenediamine 39 F. Synthesis of N,N-Dimethyl-N*-Cycloheptylmethyl-N' -Phenylethylenediamine 4-0 1. Cycloheptanecarboxylic Acid 4-0 V Part Page 2. Cycloheptanecarbonyl Chloride 42 3 . Cycloheptanecarboxanilide 42 4. N-Cycloheptylmethyl-N-Phenylamine 43 5. <X-Chloro-N-Cycloheptylmethyl-N-Phenylacetamide 44 6. o<-Dimethylamino-N-Cycloheptylmethyl-N-Phenylacetaraide 45 7. N.N-Dimethyl-N 1-Cycloheptylmethyl-N'-Phenylethylenedlamlne 46 V. DISCUSSION OF CHEMISTRY 48 VI. PRELIMINARY ANTIHISTAMINE ACTIVITY STUDIES 63 VII. SUMMARY 68 VIII. INFRARED SPECTRA 70 IX. LIST OF REFERENCES 8 9 Biographical Information .- 9 1 v i LIST OP TABLES Table Page 1. Histamine Content of Tissues Compared with Heparin Content and the Relative Mast-cell 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 0 N-Cycloalkylmethyl-N-Phenylamines 52 7. Cyclo a l k y l Analogues of Antergan 52 8. o<-Chloro-N-(R)-Acetanilides 59 9. o<-Dime thy lamino-N-(R)-N-Pheny lace tamlde 60 10. N.N-Dimethyl-N'-UJ-N' -Phenylethylenedlamlne 61 11. E f f e c t s of Cyclo a l k y l Analogues of Antergan (Mono-HC1 Salts) and Diphenhydramine HCl on Response of Isolated Guinea-pig Ileum .v 64 v i i LIST OP FIGURES F i g u r e Page 1. Major Routes of Histamine C a t a b o l i s m i n V i v o 7 2. pA 2 Value f o r Mono-HCl S a l t s of C y c l o a l l c y l Analogues of Antergan v s . Diphenhydramine HCl 66 I n f r a r e d Spectrum o f i 3. o t - C h l o r o a c e t a n i l i d e 71 4. ot-Dirnethylaminoacetanilide 72 5. N,N-Dimethyl-N' -Phenylethylenedlamlne 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 10. <*-Dimethylamino-N-Cyclobutylmethyl-N-Phenylacetamide 78 11. N,N-Dlmethyl-N•-Cyclobutylmethyl-N* -Phenylethylenedlamlne 79 12. oC-Chloro-N-Cyclopentylmethyl-N-Phenylacetamide 80 13. erf-Dime thylamlno-N-Cyclopentylme t h y l - N -Phenylacetamide 81 14. N,N-Dimethyl-N'-Cyclopentylmethyl-N•-Phenylethylenedlamlne 82 15. o<-Chloro-N-Cyclohexylmethyl-N-Phenylacetamide 83 16. o<-Dimethylamino-N-Cyclohexylmethyl-N-Phenylacetamlde 84 17. N,N-Dlmethyl-N'-Cyclohexylmethyl-N•-Phenylethylenedlamlne 85 « 18. o<-Chloro-N-Cycloheptylmethyl-N-Phenylacetamide 86 19. o<-Dimethylamino-N-Cycloheptylmethyl-N-Phenylacetamide. 87 20. N,N-Dimethyl-N'-Cycloheptylmethyl-N * -Phenylethylenedlamlne 88 PART I INTRODUCTION Leung (1) f i r s t reported "Cycloalkyl Analogues of Antergan" i n 1964. The benzyl group of Antergan was replaced by a cyclopropylmethyl, a cyclobutylmethyl, a cyclopentylmethyl, a cyclohexylmethyl or a cycloheptylmethyl group, but the y i e l d of each of these analogues was very poor. The purpose of t h i s study was to increase the y i e l d s of four analogues (cyclobutyl-methyl to cycloheptylmethyl) by new synthetic methods and make them available f o r pharmacological investigations into the na-ture of antihlstaminlc receptors. Two other compounds with the benzyl group of Antergan replaced by a hydrogen or a methyl group were also synthesized i n order to complete the a n t l h i s t -amlnlc a c t i v i t y studies f o r a series of these compounds. Antergan, N-benzyl -N-phenyl-N*,N'-dimethylethylene-diamine, 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 antihlstaminlc drug produced i n 19^2. Although i t caused a number of unpleasant side e f f e c t s such as potentiating the reponses to epinephrine and the stimulation of adrenergic nerves ( 2 ) , the basic Antergan structure has served as a model f o r a number of the antihistamine drugs i n use today. I t was hoped i n the present study that by replacing one phenyl group i n the parent compound with a l l c y c l i c structures, a gradual a l t e r a t i o n i n potency and or s e l e c t i v i t y would be found i n a series of these compounds. A. HISTAMINE Histamine i s k(or 5 ) - ( 2 '-aminoethyl)imidazole, C ^ H Q N - , and i s represented s t r u c t u r a l l y by e i t h e r formula I or I I : H • HC CH HC CH W ll \ II N C-CH2-CH2-NH2 N — C-CHg-CHg-NHg I II The imlno hydrogen of the Imidazole r i n g i s mobile and can s h i f t from one nitrogen atom to the other with a con-comitant s h i f t of the double bond. Thus, the two forms, I and II , of histamine coexist. I t has l i t t l e therapeutic value. Histamine i s widely d i s t r i b u t e d i n mammalian tissues, but the concentration i n a given organ has species v a r i a t i o n . Much of the tissue histamine i s formed i n mast c e l l s from L-his-tidine by enzymatic decarboxylation and i t i s held i n the mast c e l l granule (3)« The histamine content per mast c e l l i s rea-sonably constant i n normal tissue (4). The mast c e l l s are l o -cated mainly i n connective tissue i n r e l a t i o n to blood vessels. Inspection of Table 1 indicates that 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 heparin and mast c e l l s i n these tissues (3)« TABLE 1 HISTAMINE CONTENT (jug/g) OF TISSUES COMPARED WITH HEPARIN CONTENT (mg STANDARD HEPARIN/Kg) AND THE RELATIVE MAST-CELL CONTENT i TISSUE HISTAMINE HEPARIN MAST CELLS Rat l i v e r 0.3 0 0 Pig aorta 0.7 0 0 Ox-liver parenchyma 4.5 56-75 + (to be continued) 3 . TISSUE HISTAMINE HEPARIN MAST CELL Ox aorta 10.0 5-65 + Rat subcutaneous tissue 16.0 63 ++ Ox I n f e r i o r vena cava 20 .0 100-120 ++ Ox-liver capsule ko.o 5^0-830 +++ However, the mast c e l l s are not the only c e l l s con-ta i n i n g histamine. Histamine has been found i n p l a t e l e t s and 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 region 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 ignificance of histamine i n mast c e l l s i s at present unknown. The release of histamine from mast c e l l s i s connected with the morphological change of the mast c e l l . Most of the substances known to release histamine, cause damage to the mast c e l l s . In anaphylaxis, although each species has i t s own p e c u l i a r i t i e s , there i s l i t t l e room f o r doubt that most - although c e r t a i n l y not a l l - of the histamine released by a n t i -gen, comes from the mast c e l l s . Mota (5) investigated antigen-induced mast c e l l damage and histamine release l n the i n t a c t guinea-pig. The re s u l t s of the experiment showed that anaphy-l a x i s produced a s i g n i f i c a n t reduction i n the number of mast c e l l s and i n the histamine content of the lung (see Table 2 and 3) (5)» 4. TABLE 2 MAST CELL NUMBER (*) IN GUINEA-PIG INFERIOR PULMONARY LOBES BEFORE AND AFTER ANAPHYLAXIS* G.P. 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 (*) The c e l l s were counted under a magnification of 250X. Each figure was mean of 100 f i e l d s . Difference between the means of the two lobes highly 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 Difference between the means of the two lobes highly s i g n i f i c a n t (P< 0.01). BEFORE AFTER BEFORE AFTER 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 I t i s well known that the anaphylactic phenomenon can be considered as a sequence of reactions s t a r t i n g by the union of antigen with antibody and having as one of i t s many consequences the release of histamine. Notwithstanding a great volume of research i n the f i e l d there i s not yet a com-prehensive explanation f o r the mechanism of histamine release by antigen i n anaphylaxis. In the in v e s t i g a t i o n of the mech-anism of histamine release i t was thought that the study of i n h i b i t i o n of histamine release by chemical compounds of known properties could possibly contribute to c l e a r up t h i s issue. For instance, the experiments with phenol (5) showed that the release of histamine from the mast c e l l by antigen was not a d i r e c t consequence of the antigen-antibody reaction but the union of antigen with antibody only triggered o f f a complex series of events leading to mast c e l l damage and histamine re-lease. The i n h i b i t i o n of the anaphylactic release of histamine from the mast c e l l s by various metabolic i n h i b i t o r s (iodoace-tate, chloromercuribenzoate and cyanide etc.) and i t s depen-dence on pH and temperature strongly.suggested the existence of an enzymatic mechanism i n t h i s phenomenon (5). The f a c t that chymotrypsin i n h i b i t o r s and substrates i n h i b i t e d the ana-phylactic release of histamine strongly implied the involve-ment of an enzymatic a c t i v i t y s i m i l a r to that of alpha-chymo-tr y p s i n . Furthermore, the discovery of a h e a t - l a b i l e f a c t o r i n the tissues, probably a pro-enzyme that required calcium f o r i t s a c t i v a t i o n and was necessary f o r the anaphylactic re-lease of histamine, 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 spite of observations i n favor of the p a r t i c i p a t i o n of complement i n anaphylaxis there i s not yet evidence that complement i s necessary f o r the ana-phylactic release of histamine from the mast c e l l . Another fac t o r necessary f o r the anaphylactic release of histamine i s c e l l u l a r i n t e g r i t y ( 5 ) » Histamine release from I n t r a c e l l u l a r p a r t i c l e s could be demonstrated only when antigen was applied to i n t a c t c e l l s , but not when i t was added to Isolated i n t r a -c e l l u l a r p a r t i c l e s . Since histamine i s located i n the mast c e l l granules, the union of antigen with antibody on the mast c e l l membrane must t r i g g e r o f f an enzymatic mechanism able to release histamine from I n t r a c e l l u l a r mast c e l l granules. Therefore, probably both membrane and i n t r a c e l l u l a r enzymes were involved i n the anaphylactic release of histamine from the mast c e l l s ( 5 ) » Some of the established pharmacological actions of histamine include increase of c a p i l l a r y permeability, bron-c h i o l a r and other smooth muscle c o n s t r i c t i o n , and stimulation of the glands of exocrine secretion (4). Histamine i s degraded eith e r by oxidation or by methylation such that the p r i n c i p l e excretion products are imidazoleacetic acid riboside or 1,4-methylimidazole a c e t i c acid ( 6 ) , respectively (see Figure 1 ) . FIGURE 1 MAJOR ROUTES OF HISTAMINE CATABOLISM IN VIVO: Diamine oxidase I ^CH2-CHQ H N ^ N Imidazoleacetaldehyde / =^GH 2-CH 2-NH 2 HN ^N Histamine t Aldehyde dehydrogenase ^r^CHg-COOH H N ^ N Imidazoleacetlc acid Enzymatic synthesis ^z^CHg-COOH N- . N / ^ ribose Methylation Monoamine oxidase 1,4-Methylhlstamlne ^=^CH 2-CHO H 3 C - N N ^ N 1,4-Methylimidazole acetaldehyde Aldehyde dehydrogenase ¥ / r-CHr-C00H / \ H 3 C - N \ ^ N 1,4-Methylimidazole a c e t i c acid Imidazoleacetlc acid riboside B. ANALOGS OF HISTAMINE Most of the compounds that have histamine-like ac-t i v i t i e s contain i n t h e i r structures the fragments • C - C - C - N : or =N -N* .C-C-C-N. 8. The d e f i n i t i o n of histaraine-like a c t i v i t y i s that a compound causes contraction of smooth muscle and lowering of blood pressure, this a c t i v i t y i s histamine-like only i f i t i s in h i b i t e d by one of the t y p i c a l antihistamine drugs. I t i s to be noted here, however, that, although many of the histamine analogs possess a c t i v i t i e s resembling those of histamine, none has yet been discovered that antagonizes any of the a c t i v i t i e s of histamine. The antihistamine drugs are not analogs of h i s t amine i n a chemical sense. vatives of imidazole, but i n 19^1 Walter, Hunt and Fosbinder (12) observed that 2 - ( 2-aminoethyl)-pyridine exhibited t y p i c a l histamine a c t i v i t y on smooth muscle. Since then many compounds not containing the imidazole r i n g have been found to have phy-s i o l o g i c a l a c t i v i t i e s resembling histamine. The analogs were divided into seven groups according to t h e i r chemical struc-tures ( 7 ) J I. Imidazole compounds; I I . Pyrazole compounds; I I I . 1 , 2 , 3-Trlazole compounds; IV. 1 , 2 , 4-Triazoles; V. Thiazole compounds; VI. Pyridine compounds; and VII. Miscellaneous com-pounds. At f i r s t the synthetic analogs were confined to d e r i -N N —R N NH I II III Imidazole cpds. Pyrazole cpds. 1 , 2 , 3-Trlazole cpds. 9. f >R HN — N IV 1,2,4-Triazoles. Thiazole cpds. Pyridine cpds, R = Derivatives of 2-aminoethyl group. A number of the compounds mimic histamine In a l l of i t s e f f e c t s while others may possess only one of histamine's a c t i v i t i e s . Generally a l l of the analogs are less active than the parent histamine, but there are two exceptions. N-Methyl-histamine and N BN-dlmethylhistamine are more active than h i s t -amine as stimulants of ga s t r i c secretion 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 increas-i n g l y d i f f i c u l t to formulate any general rule r e l a t i n g struc-ture to histamine-like a c t i v i t y . About a l l that can be said i s that compounds possessing appreciable histamine-like a c t i -v i t y consist of small nitrogen-heterocyclic aromatic rings to which are attached 2-aminoethyl side chains. C. ANTIHISTAMINES AND RELATIONSHIP BETWEEN STRUCTURE AND PHARMACOLOGICAL ACTIVITY Antihistamines are drugs with the a b i l i t y to anta-gonize i n varying degree most, but not a l l , of the pharmaco-l o g i c actions of histamine (8). They f a l l into that large group of pharmacological antagonists that appear to act by occupying the "receptor s i t e " on the e f f e c t o r c e l l s to the ex-10. elusion of the agonist. Apparently they bind with the histamine receptor without i n i t i a t i n g a response. Most antihistamines act as competitive antagonists to histamine. Antihistamines have found wide therapeutic a p p l i c a -tio n , c h i e f l y f o r the symptomatic control of a l l e r g i c diseases, due to t h e i r high degree of effectiveness a f t e r o r a l adminis-t r a t i o n . I t i s evident from t h e i r mechanism of action and the etiology of a l l e r g i c diseases that the antihistamine drugs i n no sense achieve a cure of the patient's a l l e r g y (9)» A f t e r the administration of a therapeutic dose, temporary block of the e f f e c t s of histamine i s obtained f o r periods varying from 2 to 12 hours, a f t e r which time readmlnistratlon of the drug i s necessary. Antihistamines were able to i n h i b i t the anaphylactic mast c e l l damage and histamine release induced by antigen. Mota (5) showed that previous contact of sensitized guinea-pig or r a t tissues with antihistamines prevents histamine release and mast c e l l damage induced by l a t e r contact with antigen. The actual mechanism of the i n h i b i t o r y e f f e c t of antihistamines on the anaphylactic mast c e l l damage and histamine release i s no yet known. Probably the i n h i b i t i o n was due to the release by the antihistamine of a large proportion of the available tissue histamine, and therefore the residue l e f t f o r release by antigen was considerably diminished. I t i s also possible that antihistamine molecules i n a c r i t i c a l concentration near to that required f o r histamine release become attached to the mast c e l l membrane and i n t e r f e r e with the antigen-antibody re-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. required i n the anaphylactic reaction. The i n h i b i t i o n of h i s t -amine release i n anaphylaxis by antihistamines may help to ex-p l a i n the protective e f f e c t of these drugs i n anaphylaxis. In some cases, at l e a s t , the protection may be due more to i n h i b i -t i o n of c e l l u l a r damage than to competition at receptor s i t e . As most medicinals, agents used as antihistamines po-ssess a d d i t i o n a l pharmacological a c t i v i t i e s (sedative-hypnotic, a n t i c h o l i n e r g i c , antiserotonin, antitussive, l o c a l anesthetic, and anti-emetic) (9)» The parasympatholytic action accounts f o r the dryness of the mouth experienced by some patients. Certain antihistamines can potentiate the cardiovascular action of norepinephrine. This has been att r i b u t e d to i n h i b i t i o n of uptake of norepinephrine by various tissues, r e s u l t i n g i n an increased amount of unbound drug i n the plasma reacting with the active receptor s i t e s (8). Thus, there may be a hazard when antihistamines are administered to patients taking mono-amine oxidase i n h i b i t i n g drugs. From a chemical standpoint, a l l of the compounds ex-h i b i t i n g a high degree of antihlstaminlc a c t i v i t y , with only a few exceptions, are derived from a common s t r u c t u r a l formula: R2 R5 R^  and R^  are commonly a r y l , aryl-methyl (as benzyl), hetero-c y c l i c , or heterocyclic-methyl; X i s =N- (diamine d e r i v a t i v e ) , =C-0- (aminoalkyl ether), or =CH- (alkylamine); R^ i s most f r e -quently a -CH2-CH2- group but, i n several cases, t h i s group i s part of a c y c l i c r i n g ; R^ and R,- are usually methyl groups, but, 12. considered with nitrogen, can be part of a heterocyclic r i n g . I t i s once apparent that the core of t h i s structure i s a sub-st i t u t e d ethylamine, -CH2-CH2-N=, also present i n histamine} and i t may be presumed that i t i s t h i s portion of the mole-cule that competes with histamine f o r c e l l receptors. 13. PART II STATEMENT OF PROBLEM The y i e l d s of each of "Cycloalkyl Analogues of An-tergan" reported by Leung (1) were very poor. Attempts were to be made to increase the y i e l d s of these compounds by new syn-theti c methods. The presence of an unsaturated ri n g attached to the nitrogen conforms to the required structure f o r a n t i -histaminic a c t i v i t y . Two related compounds with the benzyl group of An-tergan substituted by a hydrogen or- a methyl group were also to be synthesized. 14. FART III ANALYTICAL METHODS Melting points were determined using 640.6-H Thomas-Hoover Melting Point Apparatus (Arthur H. Thomas Co., P h i l a -delphia, PA., U.S.A.). A l l melting points and b o i l i n g points were reported uncorrected. A Beckman IR 10 Infrared 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, nitrogen, chlorine and iodine de-terminations were performed by A l f r e d Bernhardt Mlkroanaly-tisches Laboratorium, Im Max - Planck I n s t i t u t f u r Kohlen-forschung, 433 Mulheim (Ruhr), West Germany. PART IV EXPERIMENTAL A. Synthesis of N,N-Dimethyl-N*-Phenylethylenediamine:  1. rX-Chloroacetanlllde : To a 0 . 5 - l i t e r three-necked f l a s k equipped with a re f l u x condenser (carrying a drying tube), a side arm f o r setting a thermometer (range from -100 to 50°C.) and a drop-ping funnel (125 ml.), and a mechanical s t i r r e r was added a solution of a n i l i n e (93 S»» 1 mole, A.C.S. reagent) i n sodium-dried ether (250 ml.) (Note: hereafter referred as dry ether). The solution was s t i r r e d over an i c e - s a l t bath f o r 30 minutes to reach - 5 to - 1 0 ° C . Chloroacetyl chloride (56.5 S»» °»5 mole, A l d r i c h Chemical Co.) was added dropwise to the vigorous-l y s t i r r e d solution from the dropping funnel at such a rate as to keep the temperature of the reaction not higher than 0 ° C . A f t e r the addition was complete, s t i r r i n g was continued at 0°C. f o r another hour and the mixture was then refluxed on a heating mantle f o r one hour. The mixture was poured into a beaker^and washed with 100 ml. of HC1 solution and 100 ml. of d i s t i l l e d water. The white product which p r e c i p i t a t e d was suction f i l -tered and the layers were separated. The ethereal layer was dried over anhydrous sodium sulfate and reduced i n volume to recover 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 g. ( 0 . 5 mole, 100#). The a n i l i d e was r e c r y s t a l l i z e d from 60% ethanol and melted at 134.5-135.5°C.. Infrared spectrum of the s o l i d amide l n KBr showed a strong C-0 stretching band at 1675 cm.""^ , and the C-H v i b r a -1 6 . t i o n a l stretching f o r an a l i p h a t i c hydrocarbon at 2970 cm.~^ and 2920 cm.~^; also the absence of N-H stretching f o r a n i l i n e at 3370 cm.~^ and 3440 cm. ^ and the presence of C-Cl stretch-- 1 ing at 770 cm. proved the a n i l i d e structure (Figure 3 ) . Anal. Calcd. f o r CgHgONCl: C, 56.64; H, 4 . 7 6 ; N, 8 . 2 6 1 ' C l , 2 0 . 9 0 . Found: C, 5 6 . 5 3 ? H, 4 . 8 5 $ N, 8 . 2 8 ; C l , 2 1 . 1 0 . 2 . c<-Dlmethylaminoacetanilide: Dimethylamine (32 ml., approx. 0.48 mole) was trapped from a dimethylamine cylinder by an acetone-dry ice bath into a 0 . 5 - l i t e r three-necked f l a s k equipped with a mechanical s t i r -rer, and two side arms f o r s e t t i n g a dropping funnel (500 ml.), a thermometer (range from - 1 0 0 to 50°C.) and an acetone-dry ice condenser (carrying a drying tube). <X-Chloroacetanilide (40 g., 0 . 2 3 6 mole) was dissolved by the aid of heat i n 400 ml. of ab-solute methanol. (10) and the solution was placed i n the dropping funnel. The a n i l i d e solution was then added dropwise to the vigorously s t i r r e d l i q u i d dimethylamine at such a rate as to keep the temperature of the reaction not higher than - 2 ° C . A f t e r the addition was complete, the acetone-dry ice bath was replaced by an i c e - s a l t bath and the reaction mixture was s t i r -red continuously at -2 to - 10°C. f o r at le a s t 3 hours and then overnight at room temperature. After t h i s time, the white a-mine HCl s a l t was f i l t e r e d off and the solvent methanol was re-duced i n volume by f l a s h evaporation. In order to get r i d of the dimethylamine HCl s a l t which had dissolved i n methanol, the concentrated residue was dispersed i n 200 ml. of d i s t i l l e d wa-te r and then extracted with two 200 ml. portions of solvent 17. ether. The combined ethereal extract was dried over anhydrous sodium sulfate and then reduced i n volume. The residue was fractionated under reduced pressure to y i e l d 39.5 g» (0.222 mole, 9k%) o4-dimethylaminoacetanlllde b.p. 124°C. (1 .4 mm.). Infrared spectrum indicated the presence of dimethyl-amino group at 2840 cm.""1, 2800 cm."1, and 2750 cm. - 1 (C-H stretching f o r R-N(CH-j)2), and the absence of C-Cl stretching band at 770 cm."1 (Figure 4 ) . Preparation of Methyl Iodide Derivative: The t e r t i a r y amine ( 0 . 5 g.) was mixed with methyl iodide (2 ml.); i f no immediate reaction occurred, i t was heated on a steam-bath f o r 15 minutes or u n t i l the excess rea-gent had evaporated. The o<-dimethylaminoacetanillde methyl iodide s a l t was r e c r y s t a l l i z e d from absolute methanol; m.p. 212. 5 - 2 1 3 . 5°C . Anal. Calcd. f o r C^H^ONgli C, 41 . 2 6 ; H, 5 .36; N, 8 . 7 5 ; I. 3 9 . 6 3 . Found: C, 41 . 4 4 ; H, 5 . 4 5 ; N, 8 . 9 5 ; I. 3 9 . 7 5 . 3. N.N-Dlmethyl-N'-Phenylethylenedlamlne: 400 ml. of dry ether was placed i n a 0 . 5 - l i t e r three-necked f l a s k equipped with a dropping funnel (125 ml.), a re-fl u x condenser (drying tube), and a mechanical s t i r r e r . L i -thium aluminum hydride (10.7 g.» 0.28 mole) was added to the ether, and was gently refluxed with s t i r r i n g f o r 4 hours. A solution of <x*-dimethylaminoacetanilide (25 g., 0.14 mole) i n dry ether (50 ml.) was placed i n the dropping funnel, and added to the LiAlH^ solution at such a rate as to maintain gentle 18. reflux. -After the addition was complete, the mixture was s t i r -red and refluxed f o r 4 days. A f t e r t h i s time, the heating mantle was replaced by an ice bath and 45 ml. of water was slowly added to the vigo-rously 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 continued f o r 30 minutes a f t e r the water addition was complete. S u f f i c i e n t 40$ NaOH solution was added to cause a c l e a r separation of the ethereal layer. The mixture was centrifuged and the ether layer was dried over anhydrous sodium s u l f a t e . The solvent was removed by f l a s h evaporation to y i e l d 21 g. (0.128 mole, 91.3/0 N,N-dimethyl-N 1-phenyl-ethylenediamine b.p. 81°C. (0.75 mm.). Infrared spectrum indicated complete reduction by the absence of the carbonyl absorption band at I69O cm. \ and by the s h i f t of the N-H stretching v i b r a t i o n to 3400 cm."1 (Figure 5 ) . Methyl Iodide Derivative 1 The t e r t i a r y amine (0.5 g«) was mixed with methyl iodide (2 ml.) and worked up as described f o r the o<-dimethyl-aminoacetanllide methyl iodide d e r i v a t i v e . N,N-Dimethyl-N'-Phenylethylenediamine methyl iodide s a l t was r e c r y s t a l l i z e d from absolute ethanol and melted at 179.7-180.5°C.. Anal. Calcd. f o r C ^ H ^ N g l * C, 4 3 . l 4 j H, 6.27; N, , 9.15f I, 41.44. Foundt C, 43.07; H, 6.38; N, 9.22; I, 41.58. B. Synthesis of N,N-Dlmethyl-N*-Methyl-N*-Phenylethylene- diamine : ' ' ~~~ 1. c<-Chloro-N-MethyIacetanllide1 19. To a 0 . 5 - l i t e r three-necked f l a s k equipped with a re f l u x condenser (drying tube), a side arm f o r set t i n g a ther-mometer (range from -100 to 50°C.) and a dropping funnel (125 ml.), and a mechanical s t i r r e r was placed a solution of N-methylaniline (70 g., O.65 mole, Eastman Organic Chemicals) i n dry ether (300 ml.). The solution was s t i r r e d over an i c e -s a l t bath f o r 30 minutes to reach - 5 to -10°C. Chloroacetyl chloride (37.3 g«> 0.33 mole) was added dropwise into the v i -gorously s t i r r e d solution from the dropping funnel at such a rate as to keep the temperature of the reaction not higher than 0 ° C . A f t e r the addition was complete, s t i r r i n g was con-tinued at 0°C. f o r 2 hours and the mixture was then refluxed on a heating mantle f o r one hour. Afte r t h i s time, 50 ml. of 3% HCl solution was added and re f l u x l n g was continued with 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 layers were.separated. The ethereal layer was f u r -ther washed with 50 ml. of 5% HCl solution and two 50 ml. por-tions of water and then dried over anhydrous sodium s u l f a t e . The solvent was removed by f l a s h evaporation to obtain 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-methyl-acetanilide m.p. 67.8-68.8°C.. Infrared spectrum showed the absence of N-H stretch-ing v i b r a t i o n band at 3^40 cm. \ and the presence of a strong carbonyl absorption at 1700 cm. 1 and C-Cl stretching band at 800 cm.""1 (Figure 6 ) . Anal. Calcd. f o r C QH 1 n0NCl» C, 58.86; H, 5.50; N, 20. 7 . 6 3 ; C l , 1 9 . 3 0 . Found* C, 5 9 . 0 5 ; H, 5 . 6 4 ; N, 7 . 7 6 ; C l , 19 . 5 5 . 2. o<--Dlmethylamlno-N~Methyl-N-Phenylacetamide t' Dimethylamine ( 3 0 ml., approx. 0 . 4 5 mole) was trapped from a dimethylamine cylinder by an acetone-dry ice bath into a 0 . 5 - l i t e r three-necked f l a s k equipped with a mechanical s t i r -rer, and two side arms f o r s e t t i n g a dropping funnel ( 5 0 0 ml.), a thermometer (range from -100 to 5 0 ° C ) , and an acetone-dry ice condenser with drying tubes. A solu t i o n of c<-chloro -N-methylacetanllide ( 4 0 . 4 g., 0.22 mole) i n 4 0 0 ml. of absolute methanol (10) was placed into the dropping funnel and was added dropwise to the vigorously s t i r r e d l i q u i d dimethylamine at such a rate as to keep the temperature of the reaction not higher than -2°C. A f t e r the addition was complete, the ace-tone-dry ice bath was replaced by an i c e - s a l t bath and the re-action mixture was s t i r r e d continuously f o r at l e a s t 3 hours at -2 to -10°C. and then overnight at room temperature. A f t e r t h i s time, the white amine HCl s a l t was f i l t e r e d o f f and the solvent methanol was reduced i n volume by f l a s h evaporation. In order to get r i d of the dimethylamine HCl s a l t which had dissolved i n methanol, the concentrated residue was dispersed i n 200 ml. of d i s t i l l e d water and then extracted with two 200 ml. portions of solvent ether. The combined ethereal extract was dried over anhydrous sodium s u l f a t e . The solvent was re-moved by f l a s h evaporation to y i e l d 38.1 g. (O.I98 mole, 90 .5 %) otr-dimethylamino-N-methyl-N-phenylacetamide b.p« 106°C. ( 0 . 3 mm.). The i n f r a r e d spectrum indicated the presence of a 2 1 . dimethylamino group at 2880 cm. \ 2840 cm. 1 and 2?80 cm. (C-H s t r e t c h i n g v i b r a t i o n f o r R - N ( C H 3 ) 2 ) , and the absence of C-Cl s t r e t c h i n g band a t 800 cm. 1 ( F i g u r e 7 ) . Methyl Iodide D e r i v a t i v e t The t e r t i a r y amine (0 . 5 g«) was mixed wi t h methyl Iodide (2 ml.) and worked up as d e s c r i b e d f o r the c*-dimethyl-a m l 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 <x-dimethylamino N-methyl-N-phenylacetamide 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 e t h a n o l and then e t h y l a c e t a t e ; m.p. 148.8-1 5 0 . 0 ° C . A n a l . C a l c d . f o r C 1 2 H 1 Q 0 N 2 I : C, 43.12; H . 5.74; N, 8.38; I, 37.97. Found* C, 43.21; H, 5.80; N, 8.21; I, 38.20. 3. N.N-Dlmethyl-N'-Methyl-N 8-Phenylethylenediaminei In a 0 . 5 - l i t e r three-necked f l a s k equipped w i t h a dropping f u n n e l (125 ml.), a r e f l u x condenser ( d r y i n g tube), and a mechanical s t i r r e r was p l a c e d 320 ml. of d r y e t h e r . L i -thium aluminum hydride ( 7 . 9 g«» 0.2 mole) was added to 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 cV-dimethylamino-N-methyl-N-phenylacetamlde ( 20 g., 0.1 mole) i n d r y e t h e r (50 ml.) was p l a c e d i n t o the drop-p i n g f u n n e l , and was 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 r e f l u x . A f t e r the a d d i t i o n was complete, the mixture was s t i r r e d 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 30 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 h y d r i d e . S t i r r i n g was c o n t i n u e d f o r 30 minutes a f t e r the water 22. addition was complete. S u f f i c i e n t 40$ NaOH solution was added to allow a clear separation of the ethereal layer. The mixture was centrifuged and the ether layer was dried over anhydrous sodium s u l f a t e . The solvent was removed by f l a s h evaporation to y i e l d 14.3 g. (0.08 mole, 77.3$) N,N-dlmethyl-N'-methyl-N'-phenylethylenediamine b.p. 97-98°C. (1.9 mm.). A t e r t i a r y amine was indicated by the absence of C=0 absorption band at 1680 cm. 1 due to complete reduction of the t e r t i a r y amide carbonyl group (Figure 8). Methyl Iodide Derivative: The t e r t i a r y amine (0.5 g«) was mixed with methyl iodide (2 ml.) and worked up as described f o r the o<-dimethyl-aminoacetanilide methyl iodide d e r i v a t i v e . The N,N-dimethyl-N'-methyl-N'-phenylethylenediamine methyl iodide s a l t was-re-- O c r y s t a l l i z e d from absolute ethanol and melted at 195-196 C.. Anal. Calcd. f o r C 1 2H" 2 1N 2I: C, 45.00} H, 6.62; N, 8.75; I, 39.63. Found: C, 44.93; H, 7.065 N, 8.66; I, 39.68. C. Synthesis of N.N-Dlmethyl-N'-Cyclobutylmethyl-N'-Phenyl- ethylenediamine : 1. Cyclobutanecarbonyl Chloride: Cyclobutanecarboxylic acid (100 g., 1 mole, A l d r l c h Chemical Co.) was placed i n a 0 . 5-liter three-necked f l a s k f i t t e d with a mechanical s t i r r e r , a r e f l u x condenser (drying tube) and a dropping funnel (250 ml.). To the s t i r r e d acid was added thionyl chloride (200 g., 1.68 mole, reagent grade-The B r i t i s h Drug Houses Ltd.) and the mixture was refluxed on a heating mantle f o r 2 hours. The product was d i s t i l l e d to 2 3 . give a forerun and cyclobutanecarbonyl chloride b.p. 130-136 C. (1 atm.). Y i e l d : 80.8 g. (0.68 mole, 68.1$). ( L i t . (1) b.p. 130-142°C, 63^5 (11) b.p. 130-140°C, 70%). 2. Cyclobutanecarboxanllide: A mixture of a n i l i n e (93 S«» 1 mole), pyridine (79 g., 1 mole) and dry benzene (180 ml.) was placed i n 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 (drying tube) and a dropping funnel (250 ml.). Cy-clobutane carbonyl chloride (80.8 g., 0.68 mole) was added drop-wise from the dropping funnel into the s t i r r e d mixture. A f t e r the addition was complete, the reaction was s t i r r e d f o r 1 hour at room temperature, and was poured into a beaker cooled i n an ice-bath. The white amide which pr e c i p i t a t e d was suction f i l -tered and washed with water (300 ml.). The benzene layer was separated and dried with anhydrous sodium s u l f a t e . The s o l -vent was reduced i n volume to c o l l e c t more of the crude a n i -l i d e with t o t a l y i e l d of 115.4 g. .(0.66 mole, 9 6 .6$). Cyclo-butane carboxanilide was r e c r y s t a l l i z e d from a benzene-petro-leum ether mixture; m.p. 111-112°C. ( L i t . (13) m.p. 109.0-110.6°C . s (14) m.p. 111-112°C.). Infrared spectrum of cyclobutanecarboxanilide showed the N-H stretching v i b r a t i o n of a secondary amide at 3250 cm. and 3300 cm. \ and C-H stretching v i b r a t i o n of aromatic ben-zene r i n g at 3050 cm. 1 and 3080 cm. ^; also the C=0 absorp-t i o n was s h i f t e d from 1800 cm. - 1 (carbonyl chloride) to the secondary amide carbonyl absorption at 1660 cm.'1 (1). 3. N-Cyclobutylmethyl-N-Phenylamlne: 24. A 1 - l i t e r three-necked f l a s k was equipped with a dropping funnel (250 ml.), a mechanical s t i r r e r and a Soxhlet apparatus protected with a calcium chloride drying tube. L i -thium aluminum hydride (30.4 g.e. 0.8 mole) i n dry ether (600 ml.) xvas placed into the f l a s k , and refluxed gently with s t i r -r ing f o r 4 hours. Then cyclobutanecarboxanllide (60 g., 0.34 mole) was packed into the Soxhlet extractor whose bottom was l i n e d with glass wool and a f i l t e r paper to prevent the bloc-kage of the siphon arm. Three glass rods were inserted into the powder as channels f o r the extracting solvent. Refluxing was continued u n t i l a l l the a n i l i d e had been car r i e d Into the f l a s k . The reaction was then refluxed f o r 4 days. At the end of t h i s time, 100 ml. of water was added slowly to decompose the excess hydride. The f l a s k was cooled i n an ice-bath and s t i r r i n g was continued u n t i l the mixture became white i n color (30 minutes approx.); then s u f f i c i e n t 40$ NaOH solution was added to allow c l e a r separation of the ethereal layer. The ether insoluble residue was separated by centrifugation; the ethereal layer was dried over anhydrous sodium sulfate over-night. The solvent was removed by f l a s h evaporation and the residue 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$) of the amine with b.p. range of 88-96°C. (0.8 mm.). ( L i t . (1) b.p. 15O - l60°C. (20 mm.), 98%). Infrared spectrum f o r the reduction product showed the absence of the carbonyl band at 1660 cm. \ Due to the absence of the oxygen-hydrogen i n t e r a c t i o n , the N-H stretching s h i f t e d to 3420 cm."1 from 3250 cm."1 and 3300 cm."1 (anilide) (1) . 25. 4. o<-Chloro-N-Cyclobutylmethyl-N-Phenylacetamlde: In a 0 . 5 - l i t e r three-necked f l a s k equipped with a ref l u x condenser (drying tube), a side arm f o r s e t t i n g a ther-mometer (range from -100 to 50°C.) and a dropping funnel (125 ml.), and a mechanical s t i r r e r was placed a solution of N-cyclobutylmethyl-N-phenylamine (47 g., 0 .29 mole) i n dry ether (250 ml.). The solution was s t i r r e d over an i c e - s a l t bath f o r 30 minutes to reach - 5 to -10°C. Chloroacetyl chloride (17 g., 0 .15 mole) was added from the dropping funnel to the vigorously s t i r r e d s o l u t i o n at such a rate as to keep the temperature of the reaction not higher than 0 ° C . A f t e r the addition was complete, the reaction was continued s t i r r i n g at 0°C. f o r 3 hours and then refluxed on a heating mantle f o r one hour. A f t e r t h i s time, 50 ml. of 5% HCl solution was added and re-f l u x i n g was continued with s t i r r i n g f o r 30 minutes. The white amine KC1 s a l t was f i l t e r e d o f f and the ethereal l a y e r was separated. The organic layer was further washed with 50 ml. of 5$ HCl and two 50 ml. portions of d i s t i l l e d water and then dried with anhydrous sodium s u l f a t e . The solvent ether was re-moved by f l a s h evaporation and the residue d i s t i l l e d under vacuum to y i e l d g. (0.145 mole, 100$) cx-chloro-N-cyclo-butylmethyl-N-phenylacetamide b.p. 149-150°C. (1 mm.) which c r y s t a l l i z e d out a f t e r standing overnight. The compound was o r e c r y s t a l l i z e d from n-pentane (b.p. 35-37 C., latm.); m.p. 45.2-46.2°C.. The t e r t i a r y amide was indicated by the absence of N-H stretching band at 3420 cm.- 1 , and by the presence of 26. carbonyl stretching at 1675 cm. 1 and C-Cl stretching band at 790 cm."1 (Figure 9). Anal. Calcd. f o r C 1 3H l 6ONCli C, 65.67; H, 6.80; N, 5.89; CI, 14.91. Found: C, 65.62; H, 7.11; N, 5.87; CI, 15.08. 5. c4-Dlmethylamino-N-Cyclobutylmethyl-N-Phenylacetamlde: Dimethylamine (17.5 ml., approx. 0.26. mole) was trapped from a dimethylamine cylinder by an acetone-dry ice bath i n t o a 0 . 5 - l i t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , and two side arms f o r se t t i n g a dropping funnel (500 ml.), a thermometer (range from -100 to 5 0 ° C ) , and an acetone-dry ice condenser (drying tube). A solution of c*-chloro-N-cyclobutylmethyl-N-phenylacetamide (30 g., 0.126 mole) i n dry ether (300 ml.) was added dropwise to the vigorous-l y s t i r r e d l i q u i d dimethylamine i n the flask at such a rate as to keep the temperature of the reaction not higher than -2°C.. A f t e r the addition was complete, the acetone-dry ice bath was replaced by an i c e - s a l t bath and the reaction mixture was con-o j tinued s t i r r i n g at -2 to -10 C. f o r at l e a s t 3 hours and then overnight at room temperature. After t h i s time, the white amine HC1 s a l t was f i l t e r e d ' o f f and the solvent ether was re-duced i n volume by f l a s h evaporation. The residue was f r a c -tionated under vacuum to y i e l d 25.1 g. (80.7$) c<-dimethylamino-N-cyclobutylmethyl-N-phenylacetamide b.p. 134-135°C. (0.9 mm.). The infrared spectrum showed the presence of a d i -methylamino group at 2850 cm. \ 2800 cm. "*"and 2760 cm. 1 (C-H stretching v i b r a t i o n f o r R-^CH^Jg). and the absence of the C-Cl stretching band at 790 cm."1 (Figure 10). Methyl Iodide Derivative: 2?. The t e r t i a r y amine (0.5 g.) was mixed with methyl iodide (2 ml.) and worked up as described f o r the cx-dimethyl-aminoacetanilide methyl iodide d e r i v a t i v e . The «*-dimethylamlno-N-cyclobutylmethyl-N-phenylacetamide methyl Iodide s a l t was re-c r y s t a l l i z e d from absolute ethanol and acetone; m.p. 147°C. Anal. Calcd. f o r C l 6 H 2 5 O N 2 I « C, 49.48; H, 6 .50; N, 7.22; I, 32.68. Founds C, 49.23? H, 6 .75 ; N, 7.04; I, 32.68. 6. N,N-Dimethyl-N'-Cyclobutylmethyl-N 8-Phenylethylene- dlamlne » 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 funnel (125 ml.) and a re f l u x condenser (drying tube) was placed 300 ml. of dry ether. L i -thium aluminum hydride (6.2 g., 0.16 mole) was added to the ether, and was gently refluxed with s t i r r i n g f o r 4 hours. A solution of ctf-dlmethylamino-N-cyclobutylmethyl-N-phenylacet-amide (20 g., 0.08 mole) i n dry ether (50 ml.) was placed i n the dropping funnel, and was added to the Lithium aluminum hydride solution at such a rate as to maintain gentle re f l u x . A f t e r the a d d i t t l o n was complete, the mixture was s t i r r e d and refluxed f o r 4 days. At the end of th i s time, the heating mantle was re-placed by an ice-bath. 20 ml. of water was slowly added to the f l a s k to decompose the excess hydride. S t i r r i n g was con-tinued f o r 30 minutes; then enough 40$ NaOH solution was added to cause a c l e a r separation of the ethereal layer. The mix-ture was centrifuged and the ether layer was dried over anhy-drous sodium s u l f a t e . The solvent was removed by f l a s h eva-poration to y i e l d 17.4 g. (0.075 mole, 92.1$) N,N-dimethyl-28. o N'-cyclobutylmethyl-N'-phenylethylenediamine b.p. 120-125 C. (0 .8 mm.). ( L i t . (1) b.p. l 6 8-l ? 9°C (20 mm.), 10$). A t e r t i a r y amine was indicated by the absence of -1 C=0 absorption band at 1675 cm. ^ due to complete reduction of the t e r t i a r y amide carbonyl group (1) (Figure 11). Methyl Iodide Derivative i The t e r t i a r y amine (0 . 5 g.) was mixed with methyl iodide (2 ml.) and worked up as described f o r the o<-dimethyl-aminoacetanilide methyl iodide d e r i v a t i v e . The N,N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenediamine methyl iodide s a l t was r e c r y s t a l l i z e d from reagent acetone-.- Observed m.p. 135-136°C.. Anal. Calcd. f o r C l 6 H 2 y N 2 I i C, 51.33s H, 7.28; N, 7.48s I, 33-90. Found: C, 51.41; H , 7.64; N, 7.42; I, 34.09. Preparation of Hydrochloride Derivative: Dry hydrogen chloride was passed from a cylinder into a solution of the t e r t i a r y amine (1 g.) i n dry ether (50 ml.). When p r e c i p i t a t i o n was complete, the s o l i d was suction f i l t e r e d under a stream of dry nitrogen gas to prevent i t from contacting a i r moisture and was washed with a small amount of dry ether. The white HC1 s a l t was r e c r y s t a l l i z e d from abso-lute ethanol (10) and dry ether. The N,N-dimethyl-N'-cyclo-butylmethyl-N'-phenylethylenediamine HC1 s a l t melted at 180 . 5 -181. 5°C Anal. Calcd. f o r C^Hg^NgCli C, 67.00; H, 9 .39 ; N, 10.42; CI, 13.19. Found: C, 67 .01 ; H, 9 .25 ; N, 10 .33; CI, 13.11. 29. D. Synthesis of N.N-Dimethyl-N0-Cyclo-pentylme thyl-N'-Phenyl- ethylenedlamlne t 1. 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 reflux condenser (drying tube) and a dropping funnel (250 ml.) was placed cyclopentanecarboxyllc acid (75.4 g., 0.66 mole, A l d r i c h Chemical Co.). To the s t i r -red acid was added t h i o n y l chloride (125 ml., approx. 1.72 mole) from the dropping funnel. The mixture was then refluxed f o r 2 hours with s t i r r i n g and the excess thion y l chloride re-moved by c o - d i s t i l l a t i o n with 110 ml. of dry benzene. The re-sidue was d i s t i l l e d under reduced pressure; the f r a c t i o n b.p. 157-l60°C. (760 mm.) was c o l l e c t e d i n 53.5 g. (0.4 mole, 61$) y i e l d . ( L i t . (1) b.p. l 6 0 - l 6 3 ° C , 76$; (14) b.p. l 6 0 - l 6 2 ° C , 86$). 2. Cyclopentanecarboxanlllde? Anil i n e (37.2 g.„ 0 .4 mole) and pyridine (31.6 g., 0.4 mole) i n dry benzene (100 ml.) were placed i n a 0 . 5 - l l t e r three-necked f l a s k equipped with a mechanical s t i r r e r , a re-f l u x condenser (drying tube) and a dropping funnel (125 ml.). Cyclopentanecarbonyl chloride (53 g.« 0.4 mole) was added drop-wise to the s t i r r e d and cooled mixture. A f t e r the addition was complete, the reaction was s t i r r e d f o r 30 minutes at room temperature. The mixture was poured into a beaker and washed with 200 ml. of water. The white product which p r e c i p i t a t e d was suction f i l t e r e d and the benzene lay e r was reduced i n vo-lume to recover more of the a n i l i d e i n a t o t a l y i e l d of 74 g. (0.39 mole, 97 .9$) . The amide was r e c r y s t a l l i z e d from carbon 30. tetrachloride; m.p. 159 - l6 l°C.. ( L i t . (15) m.p. l 6 0 . 1 - l 6 l . 2°C.) . 1 Infrared spectrum showed the N-H stretching v i b r a -t i o n of a secondary amide at 3300 cm. 1 and 3260 cm. \ C-H stretching v i b r a t i o n of aromatic benzene r i n g at 3040 cm. 1 and 3060 cm. 1 , and the C=0 absorption was s h i f t e d from 1790 cm. - 1 (carbonyl chloride) to the secondary amide carbonyl absorption at 1660 cm. 1 (1) . 3. N-Cyclopentylmethyl-N-Phenylamlne1 To 850 ml. of dry ether i n a 1 - l l t e r three-necked f l a s k equipped with a mechanical s t i r r e r , a dropping funnel (250 ml.) and a Soxhlet extractor protected from moisture by a calcium chloride tube was added lithium aluminum hydride ( 30.4 g., 0.8 mole). The mixture was s t i r r e d with gentle re-fl u x i n g f o r 4 hours. A f t e r t h i s time, cyclopentanecarboxanl-l i d e (73 g«» O.386 mole) was packed into the Soxhlet extractor as described f o r cyclobutanecarboxanillde under section PART IV C . 3 . Refluxing was continued u n t i l a l l the a n i l i d e had been dissolved. The reaction then allowed to re f l u x f o r 4 days, and was then worked up with water (100 ml.) and 40$ NaOH solu-t i o n . The s o l i d was separated by centrifugation and the ethe-r e a l layer was dried over anhydrous sodium s u l f a t e . The s o l -vent was removed and the residue b.p. 124°C. (2.8 mm.) was co l l e c t e d i n 57.3 g. (0.327 mole, 84.8$) y i e l d . ( L i t . (1) b.p. 154°C. (20 mm.), 97$). Infrared spectrum showed the absence of the C=0 band at 1660 cm. 1 i n d i c a t i n g complete reduction had occurred. The strong N-H v i b r a t i o n a l band of a secondary amine was observed 31. at 3440 cm. \ shifted 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 with a r e f l u x condenser (drying tube), a side arm f o r setting a ther-o mometer (range from -100 to 50 C.) and a dropping funnel (125 ml.), and a mechanical s t i r r e r was placed a solution of N-cyclopentylmethyl-N-phenylamine (50.8 g., 0.29 mole) i n dry ether (300 ml.). The solution was s t i r r e d over an i c e - s a l t bath f o r 30 minutes to reach -5 to -10°C. Chloroacetyl chlo-ride (17 g., 0.15 mole) was added to the vigorously s t i r r e d s olution from the dropping funnel at such a rate as to keep the temperature of the reaction not higher than 0 ° C . After the addition was complete (approx. 1 hour), the reaction was s t i r r e d continuously at 0°C. f o r 3 hours and then refluxed on a heating'mantle f o r one hour. A f t e r t h i s time, 50 ml. of 5$ HC1 solution was added and r e f l u x i n g with s t i r r i n g was c o n t i -nued f o r 30 minutes. The white amine HC1 s a l t was f i l t e r e d o f f and the layers were separated. The ethereal layer was further washed with 50 ml. of 5$ HC1 solution and two 50 ml. portions of water and then dried over anhydrous sodium s u l f a t e . The solvent ether was removed by f l a s h evaporation and the residue c r y s t a l l i z e d when mixed with a small amount of petroleum ether (b.p. range from 30 to 6o°C.) and cooled over dry ice and scratched. The crude product was r e c r y s t a l l i z e d from n-pentane (b.p. 35-37°C, 1 atm.) to y i e l d 36.5 g. (0.145 mole, 100$) oC-chloro-N-cyclopentylmethy 1-N-phenylacetamide j m.p. 55-56°C. 3 2 . -Infrared spectrum of c<-chloro-N-cyclopentylmethyl-N-phenylacetamide was indicated by the absence of N-H s t r e --1 tching band at 3^40 cm. and by the presence of a strong -1 -1 carbonyl band at 1 6 7 0 cm. and C-Cl stretching at 8 0 0 cm. (Figure 1 2 ) . Anal. Calcd. f o r C 1^H l g0NCli C, 6 6 . 7 8 5 H, 7 . 2 2 ? N, 5 . 5 6 ; C l , 1 4 . 0 8 . Found: C, 6 6 . 7 2 ; H, 7 . 2 3 s N, 5 - 6 1 ; C l , 1 3 - 9 2 . 5. ol-Dimethylamlno-N-Cyclopentylmethyl-N-Phenylacetamlde: Dimethylamine ( 1 3 * 3 ml., approx. 0 . 2 mole) was trap-ped from a dimethylamine cylinder by an acetone-dry ice bath into 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 , and two side arms f o r se t t i n g a dropping funnel ( 5 0 0 ml.), a thermometer (range from - 1 0 0 to 50°C.) and an acetone-dry ice condenser (drying tube). A solution of o<-chloro-N-cyclopentylmethyl-N-phenylacetamlde ( 2 5 . 2 g., 0 . 1 mole) i n 2 5 0 ml. of dry ether was added dropwise to the vigorously s t i r r e d l i q u i d dimethylamine i n the f l a s k at such a rate as to keep the temperature of the reaction not higher than - 2 ° C . After the addition was complete, the acetone-dry ice bath was re-placed by an i c e - s a l t bath and the reaction mixture was s t i r -red continuously at - 2 to - 1 0°C. f o r at le a s t 3 hours and then overnight at room temperature. A f t e r t h i s time, the white amine HCl s a l t was f i l t e r e d o f f and the solvent ether was reduced i n volume by f l a s h evaporation. The residue c r y s t a l l i z e d when mixed with a small amount of petroleum ether (b.p. range from 3 0 to 60°C.) and cooled over dry ice and scratched. The crude product ( 2 3 » 4 g.» 0 . 0 9 mole, 9 0 $ yield) was r e c r y s t a l l i z e d from 33. n-pentane (b.p. 3 5 - 3 7°C, 1 atm.); m.p. 4 5 - 4 6 ° C Infrared spectrum of c<-dimethylamino-N-cyclopentyl-methyl-N-?henylacetamide showed the presence of the dimethyl-amino group at 2830 cm. - 1, 2780 cm. 1 and 2750 cm. - 1 (C-H s t r e -tching v i b r a t i o n f o r R-NtCH^^K and the absence of C-Cl s t r e -tching band at 800 cm."1 (Figure 1 3 ) . 6. N,N-Dlmethyl-N'-Cyclopentylmethyl-N'-Phenylethylene- dlamlne i To a 0 . 5 - l i t e r three-necked f l a s k equipped with a dropping funnel (250 ml.), a r e f l u x condenser (drying tube) and a mechanical s t i r r e d was added 250 ml. of dry ether. L i -thium aluminum hydride (6.1 g., 0.16 mole) was added to the ether, and was gently refluxed with s t i r r i n g f o r 4 hours. A solution of c*-dimethylamino-N-cyclopentylmethyl TN-phenylacet-amide (20.8 g., 0 .08 mole) i n dry ether (100 ml.) was placed into the dropping funnel, and was added at such a rate as to maintain gentle reflux. A f t e r the addition was complete, the mixture was s t i r r e d and refluxed f o r 4 days. The reaction was then worked up with d i s t i l l e d water (20 ml,) and s u f f i c i e n t 40$ NaOH solution to give separation. The separated ethereal layer was dried over anhydrous sodium sulfate and reduced i n volume to y i e l d 17.8 g. (0 .072 mole, 90.J%) N,N-dimethyl-N'-cyclopentylmethyl-N'-phenylethylene-dlamlne b.p. 136-138°C. (1mm.). ( L i t . (1) b.p. 1 8 5 - 1 8 9°C (21 mm.), 10.2$). The t e r t i a r y amine was shown by the absence of the C=0 absorption band at 1670 cm."1'due to complete reduction of the t e r t i a r y amide carbonyl group (1) (Figure 14). 3^. Methyl Iodide Derivative: The t e r t i a r y amine ( 0 . 5 g.) was mixed with methyl iodide (2 ml.) and worked up as described f o r the o<-dimethyl-amino-acetanilide methyl iodide d e r i v a t i v e . The N,N-dimethyl-N'-cyclopentylmethyl-N'-phenylethylenediamine methyl iodide s a l t was r e c r y s t a l l i z e d from reagent acetone; m.p. 163-164°C. Anal. Calcd. f o r C-^Hg^Ngl: C, 52.57s H, 7 .54; N, 7 .21 ; I, 3 2 . 6 7 . Pound: C, 5 2 . 3 9 ; H, 7 .96; N, 7 . 2 3 ; I. 32 .71 . Hydrochloride Derivative: The white HCl s a l t was prepared as described f o r the N,N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenediamine HCl o d e r i v a t i v e . Observed m.p. 180-181 C . Anal. Calcd. f o r C l 6 H 2 7 N 2 C l i C, 67.92? H, 9.64; N, 9 . 9 0 ; CI, 1 2 . 5 3 . Pound: C, 6 7 . 8 3 ; H, 9 .^6; N, 10.11; CI, 1 2 . 3 9 . S. Synthesis of N,N-Dlmethyl-N°-Cyclohexylmethyl-N'-Phenyl- ethylenediamine : 1. Cyclohexanecarbonyl Chloride: To a 1 - l i t e r three-necked f l a s k f i t t e d with a re f l u x condenser (drying tube), a dropping funnel (250 ml.) and a me-chanical s t i r r e r was placed cyclohexanecarboxylic acid (128 g., 1 mole, p r a c t i c a l grade - Eastman Kodak). To the s t i r r e d acid was added th i o n y l chloride (238 g., 2 moles) from the dropping funnel. The f l a s k was placed on a heating mantle and heated at reflux f o r 1.5-2 hours. A f t e r that time, the mixture was d i s t i l l e d , c o l l e c t i n g the crude product from 1 6 0 - 1 8 5°C. This f r a c t i o n was r e d i s t i l l e d under reduced pressure 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 at 82-85°C. (14-15 mm.) to y i e l d 118 g. (0.8 3 5 . mole, 8 0 . 5 $ ) . ( L i t . (16) b.p. 6 7 - 6 7 . 5 ° C (l4mm.), 81$; (17) b.p. 76°C. (17 mm.)). 2. Cyclohexanecarboxanillde; A mixture of a n i l i n e (93 g., 1 mole), pyridine (79 g., 1 mole), and dry benzene (100 ml.) was placed i n a 1 - l i t e r three-necked f l a s k f i t t e d with a mechanical s t i r r e r , a r e f l u x condenser (drying tube) and a dropping funnel (250 ml.). To the s t i r r e d mixture i n the f l a s k (cooled i n an ice-bath) was added cyclohexanecarbonyl chloride ( 1 0 5 . 5 g.1 0.72 mole) drop-wise. A f t e r the addition was complete, the reaction was re-fluxed with s t i r r i n g f o r 1 hour, cooled and washed with water (200 ml.). The s o l i d which pr e c i p i t a t e d was suction f i l t e r e d and the layers were separated. The aqueous phase was extracted with two 100 ml. portions of ether. The ether extracts were combined with the benzene layer, and dried with anhydrous so-dium s u l f a t e . The solvents were removed by f l a s h evaporation to recover 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 g. ( 0 . 6 2 mole, 8 6 . 3 $ ) . The amide was r e c r y s t a l l i z e d from isopro-pyl alcohol; m.p. 145-l46°C. ( L i t . (18) m.p. l43-l45°C. 5 (19) m.p. li+ 5-l46 0C. 1 (20) m.p. 1 4 6 ° C ) . 3. N-Cyclohexylmethyl-N-Phenylamlne t In a 2 - l i t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , a Soxhlet extractor (drying tube) and a dropping funnel (250 ml.) was placed lithium aluminum hydride (38 g., 1 mole) i n dry ether (1600 ml.). The mixture was s t i r -red with gentle re f l u x on a heating mantle f o r 4 hours. A f t e r t h i s time, cyclohexanecarboxanillde (101.5 g. , 0 . 5 mole) was 3 6 . packed into the Soxhlet extractor as described f o r cyclobutane-carboxanllide under section PART IV C . 3 . Refluxlng with s t i r -r i n g was continued u n t i l a l l the a n i l i d e had been dissolved. The r e f l u x i n g was continued with s t i r r i n g f o r 72 hours. The reaction was then worked up with water (100 ml.) and s u f f i c i e n t 40$ NaOH solution f o r complete separation. To separate the free amine from any unreduced amide, the ether solution was extracted with 5$ HCl solution. The aqueous phase was separa-ted and treated with 40$ NaOH solution to reform the free amine which was then extracted with ether solvent. The combined ether extracts were dried over anhydrous sodium s u l f a t e . The ether solvent was removed by f l a s h evaporation to y i e l d 8 0 . 6 g. (0 . 4 2 6 mole, 8 5 . 3 $ ) N-cyclohexylmethyl-N-phenylamlne b.p. 1 12-l l 4 ° C . (1 mm.); the HCl s a l t of the amine melted at 2 2 0 - 2 2 2 ° C . ( L i t . (1) b.p. 170-174°C. (12 mm.), 5 9 $ ; (21) b.p. l 6 8 - 1 7 0°C. (11 mm.), HCl s a l t m.p. 2 3 2 ° C ) . Infrared spectrum f o r the amine showed the absence of the C=0 band at 1670 cm.""1 i n d i c a t i n g complete reduction of the amide. N-H stretching v i b r a t i o n with one sharp peak at 3435 cm. 1 was c h a r a c t e r i s t i c of a secondary amine ( 1 ) . 4 . o<-Chloro-N-Cyclohexylmethyl-N-Phenylacetamlde i In a 0 . 5 - l i t e r three-necked f l a s k equipped with a reflu x condenser (drying tube), a side arm f o r s e t t i n g a ther-mometer (range from - 1 0 0 to 50°C.) and a dropping funnel (125 ml.), and a mechanical s t i r r e r was placed a soluti o n of N-cyclohexylmethyl-N-phenylamine (79«5 g.. 0.42 mole) i n dry ether (250 ml.). The solution 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 reach - 5 to - 1 0 ° C . Chloroacetyl chloride (24 .9 g., 0.22 mole) was added from the dropping funnel to the vigo-rously s t i r r e d solution at such a rate as to keep the tem-perature of the reaction not higher than 0 ° C . A f t e r the addi-tion was complete (approx. 1 hour), the reaction was continued s t i r r i n g at 0°C. f o r 3 hours and then refluxed on a heating mantle f o r one hour. At the end of t h i s time, 80 ml. of 5% HCl solu t i o n was added and re f l u x i n g was continued with 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 layers were separated. The ethereal layer was further washed with 50 ml. of 5% HCl solution and two 50 ml. portions of d i s t i l l e d water and then dried over anhydrous so-dium s u l f a t e . The solvent ether was removed by f l a s h evapora-ti o n to y i e l d 55.8 g. (0.21 mole, 100$) crt-chloro-N-cyclohexyl-methyl-N-phenylacetamide b.p. 170-182°C. ( 2 . 4 - 2 . 6 mm.) which c r y s t a l l i z e d a f t e r standing overnight. The compound was re-c r y s t a l l i z e d from n-pehtane (b.p. 3 5 - 3 7°C, 1 atm.) and melted at 5 2 - 5 3°C. Infrared spectrum of the amide was indicated by the absence of the N-H stretching v i b r a t i o n band at 3435 cm. \ and by the presence of a strong carbonyl absorption at 1680 cm.~^ ( c h a r a c t e r i s t i c of t e r t i a r y amide) and C-Cl stretching at 800 cm.*"1 (Figure 15) . Anal. Calcd. f o r C 1 5H 2 00NC1: C, 67.78; H, 7.59? N, 5.27; C l , 13.34. Found: C, 67.94; H, 7.40; N, 5 .13; C l , 13.44. 5. o<-Dlmethylamlno-N-Cyclohexylmethyl-N-Phenylacetamlde: Dimethylamine (25.2 ml.,, approx. O.38 mole) was 38. trapped from a dimethylamine cylinder by an acetone-dry ice bath into a 0 . 5 - l i t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , and two side arms f o r s e t t i n g a dropping funnel (500 ml.), a thermometer (range from -100 to 5 0 ° C ) , and an acetone-dry ice condenser (drying tube). A solution of ot-chloro-N-cyclohexylmethyl-N-phenylacetamide (50.5 g.» 0 .19 mole) i n dry ether (300 ml.) was added dropwise to the vigo-rously s t i r r e d l i q u i d dimethylamine i n the fl a s k at such a rate as to keep the temperature of the reaction not higher than - 2 ° C . A f t e r the addition was complete, the acetone-dry ice bath was replaced by an i c e - s a l t bath and the reaction mix-ture was s t i r r e d continuously at -2 to -10°C. f o r at le a s t 3 hours and then overnight at room temperature. The white amine KC1 s a l t was f i l t e r e d off and the solvent was removed. The residue c r y s t a l l i z e d a f t e r standing overnight at room tempera-ture to y i e l d 43.3 g. (0.158 mole, 83 .1$) . The crude product was 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 - 5 4 . 5°C The bands at 2820 cm.""1, 2780 cm.""1 and 2740 cm."1 (C-H stretching f o r R-N(CH 3) 2) and the absence of C-Cl s t r e t c h -ing at 800 cm."1 indicated that the dimethylamino group had replaced the chlorine group of o<-chloro-N-cyclohexylmethyl-N-phenylacetamide (Figure 16). Anal. Calcd. f o r C 1 7H 2 60N 2: C, 74.41; H, 9 .55 ; N, 10.21. Found: C, 74.30; H, 9 .62 ; N, 10.13. Hydrochloride Derivative: The white HCl s a l t was prepared as described f o r the 39 o N,N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenediamine HCl de r i v a t i v e . Observed m.p. 183«5-185.0°C.. Anal. Calcd. f o r C-^H^ONgCl: C, 65.68; H, 8.76; N, 9.01; CI, 11.40. Found: C, 65.54; H, 8.72; N, 8.96; CI, 11.57. 6. N,N-Dlmethyl-N'-Cyclohexylmethyl-N'-Phenylethylene- diamine : To a 0 . 5 - l i t e r three-necked f l a s k f i t t e d with a drop-ping funnel (250 ml.), a re f l u x condenser (drying tube) and a mechanical s t i r r e r was placed 300 ml. of dry ether. Lithium aluminum hydride (8.4 g., 0.22 mole) was added to the ether, and the mixture was gently refluxed with s t i r r i n g f o r 4 hours. A solution of o<-dimethylamino-N-cyclohexylmethyl-N-phenylacet-amide (30.2 g., 0.11 mole) i n dry ether (100 ml.) was placed into the dropping funnel, and was added at such a rate as to maintain gentle reflux* A f t e r the addition was complete, the mixture was s t i r r e d and refluxed f o r 4 days. The reaction 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 solution to give separation. The separated ethereal layer was dried over anhydrous sodium sulfate and reduced i n volume to y i e l d 26.7 g. (0.1 mole, 93.3$) N,N-dimethyl-N'-cyclohexylmethyl-N'-phenylethylenediamine b.p. 158-159°C (2.2mm.). ( L i t . (1) b.p. 194-195°C (15mm.), 21.8$). A t e r t i a r y amine was shown by the absence of C=0 absorption band at 1675 cm. 1 due to complete reduction of the t e r t i a r y amide carbonyl group (1) (Figure 17). Mono-Plcrate Derivative: A sample of the t e r t i a r y amine (0.5 g.) was added to 40. 95$ ethanol (10 ml.). This solution was then added to 10 ml. of a saturated solution of p i c r i c acid i n 95$ ethanol, and was heated to b o i l i n g . The solution was allowed to cool slowly, and the.bright yellow c r y s t a l s of the plcrate were i s o l a t e d by 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 from 95$ ethanols m.p. 1 3 5 . 5 - 1 3 6 . 5°C. Anal. Calcd. f o r C ^ H ^ O ^ : C, 56.43; H, 6 .38; N, 14 .31 . Founds C, 56.41; H, 6 .38 ; N, 14 .37 . Hydrochloride Derivatives The white HCl s a l t was prepared as described for the N.N-dimethyl-N'-cyclobutylmethyl-N'-phenylethylenedlamlne HCl d e r i v a t i v e . Observed m.p, 199-200°C.. Anal. Calcd. f o r C^H^NgCl: C, 68.77; H, 9 .85; N, 9.44; C l , 11.94. Founds C, 68.69; H, 9 .78 ; N, 9 - 3 1 ; C, 12.12. F. Synthesis of N.N-Dlmethyl-N'-Cycloheptylmethyl-N'-Phenyl- ethylenedlamlne s 1. Cycloheotanecarboxyllc Acids In a 2 - l i t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , a r e f l u x condenser (drying tube) and a drop-ping funnel (500 ml.) was placed. 28 g. (1.15 mole) of magnesium turnings which had previously been washed with sodium-dried ether, dried at 1 0 0°C, and allowed to cool i n desiccator. A small amount of cycloheptyl bromide (Aldrich Chemical Co.) and 240 ml. of dry ether was added to i n i t i a t e the reaction. A solution of cycloheptyl bromide (200 g., 1.13 mole) i n dry ether (600 ml.) was then added over a period of 1 hour. The reaction started r e a d i l y and moderate cooling was necessary. Following 41. complete addition of the bromide, the mixture was s t i r r e d over-night with gentle reflux. At the end of thi s time, about £ of the o r i g i n a l magnesium turnings remained unreacted. In a 3 - l i t e r three-necked f l a s k equipped with a s t i r -rer, a r e f l u x condenser (drying tube) and a dropping funnel (500 ml.) was placed a s l u r r y of dry ether (1200 ml.) and pow-dered dry ice (2000 g.) (the dry ice was f i r s t funneled Into the f l a s k and then the dry ether was added dropwise with s t i r -r i n g ) . The Grignard solution was quickly decanted into the dropping funnel and added to the s t i r r e d dry ice s l u r r y over a period of 15-25 minutes (22). A f t e r complete addition of the Grignard solution, another 2000 g. of dry ice was added and s t i r r i n g was continued f o r 4 hours during which time the dry ice had evaporated. The Grignard complex then hydrolyzed by the dropwise addition of 450 ml. of 6N hydrochloric acid (cold) to the vigorously s t i r r e d mixture. The ether layer was separa-ted and the aqueous layer was twice extracted with 400 ml. por-tions of ether. The combined ether solution was washed with water, dried over anhydrous sodium su l f a t e , and the solvent removed. The residue was fractionated under reduced pressure o and the f r a c t i o n b o i l i n g at 91-93 C. (1 mm.) was co l l e c t e d to y i e l d 69.3 g. (0.48 mole, 43 .2$) . ( L i t . (1) b.p. 138-140°C. (15 mm.), 46 .7$ ; (23) b.p. 133-135°C (9 mm.),' 53$ and 43$; (24) b.p. 130-131°C (8 mm.)). The i n f r a r e d spectrum showed a strong C=0 absorption band at 1710 cm. 1 and a broad 0-H band at around 3000 cm."1 both c h a r a c t e r i s t i c of carboxylic acids (1) . 42. 2 . Cycloheptanecarbonyl Chloride t Cycloheptanecarboxylic acid (60 g., 0.42 mole) was placed i n a 0 . 5 - l i t e r three-necked f l a s k equipped with a reflux condenser (drying tube), a dropping funnel and a mechanical s t i r r e r . Thionyl chloride (150 g., 1 .26 mole) was added drop-wise to the s t i r r e d a c i d . A f t e r addition was complete*, the mixture was s t i r r e d f o r 3 hours at room temperature; then the excess thion y l chloride was removed under reduced pressure by c o d l s t i l l a t i o n with two 90 ml. portions of dry benzene. Slight warming with a water bath was employed to aid d i s t i l l a t i o n of the l a s t traces of thio n y l chloride. The red l i q u i d residue i n the f l a s k was then fractionated under reduced pressure. After a small forerun, 5 4 . 3 g. ( 0 . 3 3 8 mole, 80$) y i e l d of cycloheptanecarbonyl chloride b.p. 89-98°C. (14 mm.) was ob-tained. 3 . Cycloheptanecarboxanilldes A 0 . 5 - H t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , a r e f l u x condenser (drying tube) and a drop-ping funnel (125 ml.) was placed a mixture of a n i l i n e ( 2 9 . 8 g., 0 . 3 2 mole), pyridine ( 2 5 . 3 g.. 0 . 3 2 mole) and dry benzene (125 ml.). To the cooled and s t i r r e d mixture was added cyclohep-tanecarbonyl chloride (50 g., 0 . 3 1 mole) dropwise from the dropping funnel. Aft e r addition was complete, the reaction was s t i r r e d f o r 1 hour at room temperature; then poured into a beaker. The s o l i d p r e c i p i t a t e was suction f i l t e r e d and washed with 125 ml. of water. The benzene layer was "separa-ted, dried with anhydrous sodium sulfate and reduced i n volume 43. to c o l l e c t a further crop of a n i l i d e with 48 .7 g. (0.224 mole, 72$) t o t a l y i e l d . Cycloheptanecarboxanllide was r e c r y s t a l l i z e d from a benzene-petroleum ether mixture ( l s l ) { m.p. 137.5-139°C.• ( L i t . (1) m.p. 135-136°C, 74.6$) . The i n f r a r e d spectrum showed s i m i l a r absorption bands to other a n i l i d e analogues of t h i s series with C=0 stretching at 1660 cm."1 and N-H band at 3300 cm."1 (1) . 4. N-Cycloheptylmethyl-N-Phenylamine; In a 1 - l i t e r three-necked f l a s k equipped with a me-chanical s t i r r e r , a Soxhlet extractor (drying tube) and a drop-ping funnel (250 ml.) was placed l i t h i u m aluminum hydride (17.1 g., 0.45 mole) i n dry ether (750 ml.). The mixture was s t i r r e d with gentle r e f l u x i n g on a heating mantle f o r 4 hours. Afte r t h i s time cycloheptanecarboxanilide (46 g., 0.21 mole) was packed into the Soxhlet extractor as described f o r cyclobutane-carboxanilide under section PART IV C . 3 . Refluxing with s t i r -r i n g was continued u n t i l a l l the a n i l i d e had been dissolved. 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 re-action was then worked up with water (70 ml.) and s u f f i c i e n t 40$ NaOH solut i o n to give complete separation. The separated ethereal layer was dried with anhydrous sodium sulfate and re-duced i n volume to y i e l d 34.4 g. (0.169 mole, 80$) N-cyclo-heptylmethyl-N-phenylamine b.p. 106°C. (0 .1 mm.). ( L i t . (1) b.p. 154°C. (17 mm.), 78 .2$) . The i n f r a r e d spectrum indicated complete reduction by the absence of the carbonyl absorption band at 1660 cm. ~, and by the s h i f t of the N-H stretching 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 with a re-f l u x condenser (drying tube), a side arm f o r setting a thermo-meter (range from -100 to 5 0°C) and a dropping funnel (125 ml.), and a mechanical s t i r r e r was placed a solution of N-cycloheptylmethyl-N-phenylamine (31 g«» 0.15 mole) i n dry ether (150 ml.). The solution was s t i r r e d over an i c e - s a l t bath f o r 30 minutes to reach - 5 to - 1 0 ° C . Chloroacetyl chloride (9-1 g., 0 .08 mole) was added dropwise from the dropping funnel to the vigorously s t i r r e d solution at such a rate as to keep the temperature of the reaction not higher than 0 ° C . A f t e r the addition was complete (approx. 1 hour), the reaction was s t i r -red continuously at 0°C. f o r 3 hours and then refluxed on a heating mantle f o r 1 hour. At the end of t h i s time, 25 ml. of 5$ HCl solution was added and re f l u x i n g was continued with 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 layers were separated. The ethereal layer was f u r -ther washed with 25 ml. of 5% HCl and two 50 ml. portions of d i s t i l l e d water and then dried over anhydrous sodium s u l f a t e . The solvent ether was removed by f l a s h evaporation to y i e l d 21.3 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 with a small amount of petroleum ether (b.p. range 3 0 - 6 o ° C ) , cooled over dry ice and scratched; m.p. 2 7 . 5 - 2 8 . 5°C. Infrared spectrum of the amide was indicated by a strong t e r t i a r y amide C=0 absorption band at 1670 cm. \ and ^ 5 . C-Cl stretching at 7 9 0 cm.-"1", and by the absence of N-H stre t c h -ing v i b r a t i o n at 3 ^ 3 0 cm. x (Figure 18). Anal. Calcd. f o r C l 6 H 2 2 0 N C l i C, 6 8 . 6 7 ; H, 7 . 9 ^ ; N, 5 . 0 1 ; CI, 1 2 . 6 7 . Found: C, 6 8 . 9 1 ; H, 7 . 7 7 ; Nf 4 . 9 2 ; CI, 1 2 . 6 5 . 6 . o<-Dimethylamlno-N-Cycloheptylmethyl-N-rhenylacetamlde: Dimethylamine ( 1 0 ml., approx.. 0 . 1 5 mole) was trap-ped from a dimethylamine cylinder by an acetone-dry ice bath into a 2 5 0 ml. three-necked f l a s k equipped with a mechanical s t i r r e r , and two side arms f o r setting a dropping funnel ( 2 5 0 o ml,), a thermometer (range from - 1 0 0 to 5 0 C.) and an acetone-dry ice condenser (drying tube). A solution of o<.-chloro-N-cycloheptylmethyl-N-phenylacetamide ( 2 0 g., 0 . 0 7 mole) i n dry ether ( 2 0 0 ml.) was added dropwise to the vigorously s t i r r e d l i q u i d dimethylamine i n the f l a s k at such a rate as to keep the temperature of the reaction not higher than - 2 ° C . After the addition was complete, the acetone-dry ice bath was re-placed by an i c e - s a l t bath and the reaction mixture was s t i r -red continuously at - 2 to - 1 0 ° C . f o r at lea s t 3 hours and then overnight at room temperature. The white amine HCl s a l t was f i l t e r e d o f f and the solvent ether removed. The residue was fractionated under reduced pressure to y i e l d 1 6 . 6 g. ( 0 . 0 5 7 mole, 8 0 . 5 $ ) <X-dimethylamino-N-cycloheptylmethyl-N-phenylacet-o 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 stretching v i -bration f o r dimethylamino group (R-N(CH 3) 2) at 2820 cm.""1, - 1 - 1 2 7 8 0 . cm. and 2 7 3 0 cm. , and the absence of C-Cl stretching band at 800 cm."1 (Figure 1 9 ) . 46. Methyl Iodide Derivative; The t e r t i a r y amine (0.5 g.) was mixed with methyl iodide (2 ml.) and worked up as described f o r the o<-dimethyl-amino-acetanilide methyl iodide d e r i v a t i v e . The o<-dimethyl-amlno-N-cycloheptylmethyl-N-phenylacetamide methyl iodide s a l t was r e c r y s t a l l i z e d from reagent acetone; m.p. 195-195.5°C.. Anal. Calcd. f o r C^H^ONgl: C, 53.01; H, 7.2?; N, 6.51; I, 29.48. Founds c, 53.06; H, 7.35; N, 6.53; I, 29.33. 7. N»N-Dimethyl-N'-Cycloheptylmethyl-N'-Phenylethylene- dlamlne ; To a 0.5-liter three-necked flask equipped with a dropping funnel (250 ml.), a re f l u x condenser (drying tube) and a mechanical s t i r r e r was placed 200 ml. of dry ether. L i -thium aluminum hydride (4.2 g., 0.11 mole) was added to the ether, and the mixture was gently refluxed with s t i r r i n g f o r 4 hours. A solution of c*-dimethylamino-N-cycloheptylmethyl-N-phenylacetamide (15 g., 0.052 mole) i n dry ether (100 ml.) was placed into the dropping funnel, and was added at such a rate as to maintain gentle reflux. A f t e r the addition was complete, the mixture was s t i r r e d and refluxed f o r 4 days. The reaction was then worked up with water (20 ml.) and s u f f i c i e n t 40$ NaOH solution to give complete separation. The separated ethereal layer was dried over anhydrous sodium s u l f a t e . The solvent was removed by f l a s h evaporation to y i e l d 13.6 g. (0.49 mole, 95.1$) N.N-dimethyl-N*-cycloheptyl-methyl-N'-phenylethylenedlamlne b.p. 148-153°C. (1 mm.). ( L i t , (1) b.p. 204-210°C. (17 mm.), 29$). A t e r t i a r y amine was shown by the absence of C=0 absorption band at 1670 era. 1 due to complete reduction of the t e r t i a r y amide carbonyl group (1) (Figure 2 0 ) . Mono-Picrate Derivative} A sample of the t e r t i a r y amine ( 0 . 5 g.) was added to 95$ ethanol (10 ml.) and was treated with a saturated solution of p i c r i c acid as f o r the monocyclohexyl analogues m.p. 1 2 6 . 5 -1 2 7 . 5 ° C Anal. Calcd. f o r C ^ H ^ O r ^ : C, 57 .23; H, 6 .62; N, 1 3 . 9 1 . Found: C, 56.99? H, 6.82; N, 14 . 1 1 . Hydrochloride Derivative: The white HCl s a l t was prepared as described f o r the N,N-dimethyl-N 8-cyclobutylmethyl-N'-phenylethylenediamine HCl o deri v a t i v e ; m.p. I98-I99 C . Anal. Calcd. f o r C^H^NgClt C, 69 ,52 ; H, 10 .07; N, 9 . 01 ; CI, 11.40. Found: C, 6 9 . 6 5 ; H, 10 .06 ; N, 8 .90 ; CI, 11 .26 . 48. PART V DISCUSSION OF CHEMISTRY The appropriate cycloalkanecarboxylic acid was used as the s t a r t i n g compound f o r each ethylenediamine product. Cyclobutanecarboxylic acid, cyclopentanecarboxylic acid and cyclohexanecarboxylic acid were a l l commercially available ( Al d r l c h Chemicals). As cycloheptylbromide was available com-mercially (Aldrich Chemicals), t h i s compound was used to pre-pare the Grignard reagent, and then cycloheptanecarboxylic acid by the procedure of Hussey ( 2 2 ) and Royals and Neal ( 2 3 ) . ( V-Br + Ether / \ Vry Ice Mg >- L >-MgBr HoO i » C02MgBr - *- ( >-C00H + MgOHBr Af t e r obtaining the appropriate cycloalkanecarboxylic acid, the next step was to prepare the aci d chloride interme-di a t e . An ac i d chloride was prepared by substitution of -CI f o r the -OH of a carboxylic a c i d . Three reagents are commonly used f o r t h i s purpose: thionyl chloride, S0C1 2; phosphorus t r i c h l o r i d e , PCl^; and phosphorus pentachloride, PCl^. R-CO-OH + S0C1 2 — R - C 0 - C 1 + S0 2 + HCl 3R-C0-0H + PCl^ — 3 R - C 0 - C 1 + H^PO^ R-CO-OH + PCl^ —>- R-C0-C1 + HCl + POCl^ • Thionyl chloride was chosen as the reagent f o r the 4 9 . 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 easily separated from the acid chloride, but because the acid chlorides formed were found to have higher boiling points than this reagent; any excess of the low-boiling thionyl chlo-ride (b.p. 79°C., 1 atm.) was easily removed by d i s t i l l a t i o n . Two precautions were taken for running this reaction. The f i r s t was to protect the reaction and the acid chloride from moist air; 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 pyrolysis 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 1 3 0 - 1 3 6 ( 1 atm.) 6 8 . 1 6 3 ( 1 ) ; 7 0 ( 1 1 ) Cyclopentane 1 5 7 - 1 6 0 ( 1 atm.) 6 1 . 0 7 6 ( 1 ) Cyclohexane 8 2 - 8 5 (14-15 mm.) 80.5 80 . 5 ( 1 ) ; 81(16) Cycloheptane 8 9 - 9 8 (14 mm. )• 80 .0 80(1) Upon obtaining the a l i c y c l i c carbonyl chlorides, the next step in 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, aniline was used to form the amide intermediates. RC0C1 + ^ ^ ~ W H 2 P y r i d l T > . R-{j-N-^ • + Pyridine-HCl 50. Separation of the amide and amine HCl depended on a difference i n s o l u b i l i t y . The cycloalkane substituted amides were found to be water-insoluble, and on completion of the re-action, water was added to extract the amine HCl. Pyridine was added to the primary amine to neutralize the hydrogen chlo-ride formed. The a n i l i d e s f o r cyclobutane to cycloheptane rea-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 Grignard reagent and phenyl iso-cyanate: TABLE 5 CYCL0ALKANECAR30XANILIDES RING SIZE MELTING POINT °C. $YIELD vs. 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 order to obtain the c y c l o a l k y l substituted amine, the corresponding amide was reduced with lithium aluminum hy-dride. The reagent discovered'by F i n h o l t , Bond and Schlesinger (25) i n 1947 (4L1H + AICI3 *-LiAlIfy + 3L1C1) has proved to be a remarkable reducing agent f o r the carbonyl group i n amides and s i m i l a r carbonyl compounds (26). Amides are not r e a d i l y 51. reducible to pure amines by other chemical methods.. Hydrogena-tion with a cat a l y s t at high temperatures and pressures can be accomplished, but usually results i n a mixture of products. Powdered LiAlH^ i s available commercially (Ventron Corp.), and i f protected from moist a i r and carbon dioxide, i t i s stable i n d e f i n i t e l y at room temperature. The hydride can be safel y handled, even i n very humid a i r , probably because of the formation of a protective coating of aluminum hydroxide ( 25). I t i s generally used i n solution or suspension i n dry ether (25-30 g. s o l i d hydride dissolves i n 100 g. ether at 2 5°C). In the normal procedure the substance to be reduced i s added to an ethereal solution or s l u r r y of the hydride. If the subs-tance to be reduced i s a l i q u i d or s o l i d , ether soluble, the solution i s added dropwise to produce gentle r e f l u x . For mode-rate l y soluble materials, a Soxhlet extractor or a continuous-return type of extractor i s used. In the reduction of the amides, an excess (2- to 3-f o l d of the stoichiometrlcal quantities) of Li A l H ^ was used. 2R-C-N-<V /> + L i AIR" 1, S~ 2R-CH--N-A ,} + L1A10 0 Water was then added to destroy the excess hydride with the evolution of hydrogen, and the p r e c i p i t a t i o n of lithium- and aluminum-hydroxide. LiAlH^ + 4H20 ^ LiOH + A1(0H)^ + 4R"2 As the amine was ether soluble, the mixture was treated with strong hydroxide solution to dissolve the precipitated alumina. This allowed a clear-cut separation of phases on centrifugation. 5 2 . The resulted amine products were tabulated as follows (Table 6 ) . TABLE 6 N-CYCLOALKYLMETHYL-N-PHENYLAMINES RING SIZE BOILING POINT °C. $YIELD v s LITERATURE * VALUE Cyclobutyl 8 8 - 9 6 ( 0 . 8 mm.) 8 6 . 5 9 8 . 0 ( 1 ) Cyclopentyl 124 ( 2 . 8 mm.) 8 4 . 8 9 7 . 0 ( 1 ) Cyclohexyl 112-114 (1 mm.) 8 5 . 3 5 9 . 0 ( 1 ) Cycloheptyl 1 0 6 ( 0 . 1 mm.) 8 0 . 0 7 8 . 2 ( 1 ) Upon obtaining the N-cycloalkylmethyl-N-phenylamine, the next portion of the molecule to be attached was the p-dl-methylamlnoethyl chain to completely form the f i n a l t e r t i a r y diamine N,N-dimethyl-N'-cycloalkylmethyl-N 0-phenylethylenedi-amine. Leung (1) had succeeded i n obtaining the t e r t i a r y d i -amine by condensing the secondary amine, N-^cycloalkylmethyl-N-phenylamine, with |3-dimethylaminoethylbromide HBr i n the pre-sence of sodamide but the y i e l d s were very low (Table 7 ) . x C H 3 2NaNH2 / C H 3 R - C H p-NH + H3r-Br-CH0-CH~-N J — — R - C H 0 - N - C H o - C H 0 - N J 1 2 2 VCH, i n dry * . ^ ^ N C H J xylene e^^X ^ or toluene TABLE 7 CYCL0ALKYL ANALOGUES OF ANTERGAN (1) R BOILING POINT °C. $YIELD Cyclobutyl 1 6 8 - 1 7 9 (20 mm.) 10.0 Cyclopentyl I 8 5 - I 8 9 (21 mm.) 10.2 Cyclohexyl 194-195 (15 mm.) 2 1 . 8 Cycloheptyl 204-210 (17 mm.) 29.0 . The purpose of t h i s study was mainly to develop a new synthetic method to approach the t e r t i a r y diamine with better y i e l d s . Various methods had been t r i e d to improve the yie l d s of the f i n a l products. Larizza (27) reported i n 1964 several new derivatives of Antergan, i . e . , N,N-dimethyl-N'-phenyl-N*-benzylenediamine de r i v a t i v e s . He used an c*-substi tuted c*-bromo-acetic acid (R-CHBr-CO-OH, R=methyl, ethyl, or phenyl, 1 mole) In benzene and treated with s t i r r i n g with 1 mole of Et^N and 1 mole of the aromatic amine (PhNHg or PhCHg-NHPh) i n benzene ( refluxed mixture) to obtain PhNH-CO-CHBr-R (I) or Ph-N-CO-CHBr-CH Ph R (II) i n good yieldss 2 (II) The l a t t e r compound (I or II, 1 mole) was added to 2.5 moles Ke2NH i n benzene, the mixture heated i n a closed tube at 120°C. f o r 16 hours to get the dimethylamino compound (III or IV) which upon lithium aluminum hydride reduction gave N,N-dimethyl-N'-phenyl-N*-benzylenediamine derivatives (V): 54. (b) \\ //-NH-C-CH-R x 0 Br (I) ° ,CR-•or + HN 0 Br II i N-C-CH-R 120 C. in' 'CH, a closed J tube ' ,CH. •NH-C-CH-N (i I 0 R (III) or CH-p R k X />-N-C-CH-N ^CH. CH. (II) LiAlHij, i n dry ether ,CH 3 y/-NH-CH~-CH-N W // • 2 £ VCH 3 or yCH-3 v //-N-CH9-CH-NV ^ ^ ^ CH, R XCH 3 (IV) (V) Similar reactions were run under the same conditions as Larizza's (equation (a) above) using o<-bromoacetic acid and N-cyclohexylmethyl-N-phenylamine instead of c<-subatituted c<-bromoacetic acid and a n i l i n e or N-benzyleneani'line respectively, but no reaction was found and the s t a r t i n g material, N-cyclo-hexylmethyl-N-phenylamine was recovered by vacuum d i s t i l l a t i o n . N-Cycloheptylmethyl-N-Phenylamine was also t r i e d i n the same reaction conditions and the r e s u l t was negative. Cyclohexanecarboxanilide was used i n place of the secondary 55-amine to react with oc-bromoacetic acid. Unfortunately, no desired product was obtained. Triethylamine seemed to be i n -e f f e c t i v e as a dehydrating agent. Since the carbonyl chloride i s usually more reactive than the corresponding acid, chloroacetyl chloride was used instead of cx-bromoacetic acid and the reaction was run under the same conditions as above (equation (a)). But upon reflux-ing the mixture, a t a r r y residue resulted. There were no ob-vious reasons to explain why the s i m i l a r reactions did not work. Triethylamine might not be suitable as a n e u t r a l i z i n g agent i n the reaction. For t h i s reason, several commonly used n e u t r a l i z i n g agents, such as potassium carbonate, pyridine and sodamlde, were employed f o r the reaction. However, none of them seemed to work successfully. O l i n (28) synthesized 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 1964 by the follow-ing method: A solution of 39.5 g. (0.35 mole) chloroacetyl chloride i n 50 ml. benzene was added during 33 minutes to a cold (0°C.) mixture of 46.5 g. (0.30 mole) N-t-butylcyclohexyl-amine, 42 g. (0.30 mole) KgCO^, 100 ml. H20, 400 g. i c e , 300 ml. benzene, and 100 ml. ether to give 45 g. oc-chloro-N-t-butyl-N-cyclohexylacetamide: K0CO3 i n benzene, C(CH 3)o-NH + CH2C1-C0C1 >- C(CH 3) 3-N-C0-CH 2Cl A ether and ice water f J mixture (0°C.) I I S i m i l a r studies were undertaken using N-cyclohexyl-methyl-N-phenylamine instead of N-t-butyl-cyclohexylamine to react with chloroacetyl chloride. The reaction f a i l e d again: 5 6 . CH0-NH + CH^Cl-COCl ether and ice water mixture (0°C.) I^CCUin benzene, No Product The f a i l u r e could be due to the fa c t that chloroacetyl chloride reacted r e a d i l y with both water and potassium carbonate before i t coupled with the amine. of the secondary amine, N-cyclohexylmethyl-N-phenylamine, seemed to be too i n e r t to replace i n the presence of weak bases such as potassium carbonate, triethylamine or pyridine (Notes This explanation was found to be incorrect l a t e r ) . For t h i s reason, equimolar sodamide was refluxed with the secondary amine i n dry ether so that the sodium ion of sodamide would replace the amino hydrogen with release of gaseous ammonia. A constant dry nitrogen gas stream was bubbled through the reaction mix-ture so as to prevent the sodamide from reacting with atmos-pheric carbon dioxide and to drive away the ammonia gas formed i n favor of the desired reaction. Refluxing was continued u n t i l no gaseous ammonia could be detected from the drying tube of the condenser (about 2 days). Excess chloroacetyl chloride was then added to the mixture to form the desired pro-duct (amide). However, a tarry residue .soon resulted a f t e r the addition of chloroacetyl chlorides In view of a l l the above f a i l u r e , the amino hydrogen No Product 57. The evidence ( 2 9 . 3 0 , 31) that amino hydrogen of primary and secondary amide reacts with sodamide made us use cyclohexanecarboxanilide f o r the reaction, R-C0-NH2 + NaNH2 R-CO-NHNa + NEU f i n benzene ^ Cyclohexanecarboxanilide was refluxed with.sodamide i n benzene solution i n the manner described i n the previous section. Ex-cess chloroacetyl chloride was then added to react with the sodium substituted a n i l i d e . Unfortunately, no re s u l t was ob-tained : 1) NaNH2 5>- No Product 2 ) CH2C1-C0C1 It was found that the secondary amine N-cyclohexyl-methyl-N-phenylamine was basic enough to serve as a neutra-l i z i n g agent. When chloroacetyl chloride was dropped into the amine i n benzene solution at room temperature, vigorous reac-tion occurred with release of a large amount of heat (exother-mic reaction). I t was found that the r i s e i n temperature of the reaction caused the decomposition of chloroacetyl chloride and consequently, only amine HCl s a l t and side products were formed with no desired amide formation. Although this reaction was a f a i l u r e , yet i t answered the reason why a l l the above reactions did not work properly. Low temperature control was es s e n t i a l f o r the desired reaction to occur and high tempera-ture tended to decompose chloroacetyl chloride and hence a tar r y residue of unknown side products resulted. At low tern-58. perature (-2 to -10°C.) benzene solvent s o l i d i f i e d , therefore dry ether was used as the solvent. The ethereal solution of the amine was cooled i n an i c e - s a l t bath (-2 to - 1 0 ° C ) . To the cooled solution was added chloroacetyl chloride dropwise at such a rate as to keep the temperature of the reaction not higher than 0 ° C . Double quantities of the amine were used f o r the reaction. One equivalent was used to couple with chlo-roacetyl chloride'to form the amide product while the second acted as the n e u t r a l i z i n g agent. Chloroacetyl chloride and the reaction must be protected from moist a i r . 5$ HCl solution was added at the end of the reaction i n order to react with ex-cess amine and to convert excess chloroacetyl chloride into more water-soluble a c i d . The white amine HCl s a l t was f i l t e r e d and the o r i g i n a l amine could be reformed from i t s HCl s a l t by the addition of strong NaOH solution and extracting with ether solvent. The r e s u l t i n g amides are shown i n Table 8 below, (a) Ether, + 59. TABLE 8 crt-CHLOBO-N-(R)-ACETANILIDES R MELTING POINT °C. RECRYST. SOLVENT $YIELD(*) H 134.5-135.5 60$ EtOH 100 CH^ 67.8-68 0 8 n-hexane 100 C y c l o b u t y l m e t h y l 45.2-46.2 n-pentane 100 C y c l o p e n t y l m e t h y l 55.0-56.0 n-pentane 100 C y c l o h e x y l m e t h y l 52.0-53.0 n-pentane 100 C y c l o h e p t y l m e t h y l 27.5-28.5 _ _ _ - _ 100 (*) The y i e l d s x^rere c a l c u l a t e d on the b a s i s of h a l f the q u a n t i t y o f t o t a l amine used f o r the r e a c t i o n , s i n c e the amine can be r e c o v e r e d as e x p l a i n e d i n the t e x t . The n e x t s t e p was t o i n t r o d u c e the d i m e t h y l a m i n o group a t the o c-carbon of the amides t o complete the second t e r t i a r y amine end. S i n c e the c<-carbon o f the amide had c h l o r i n e a t t a c h -ed t o i t , t h e whole m o l e c u l e c o u l d be assumed t o be an a l k y l h a l i d e and behaved a c c o r d i n g l y . An a l k y l h a l i d e undergoes nu-c l e o p h i l i c s u b s t i t u t i o n w i t h d i m e t h y l a m i n e t o form t e r t i a r y amine: ^CH-3 x C H o — +/CH-5 R - C l + 2HNv D ^ R-N N J + C l - H 2 N v D CH^ C r i ^ CH^ Dimethylamine e x i s t s i n the gaseous 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 the f l a s k as a l i q u i d by an a c e t o n e -d r y i c e b a t h f o r the r e a c t i o n . The te 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 . Because of the low te m p e r a t u r e o f r e a c t i o n , a l a r g e e x c e s s of s o l v e n t ( d r y e t h e r o r genuine a b s o l u t e methanol (10)) was used t o d i s s o l v e the amides a t room tem p e r a t u r e so 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 ) , the amides were s t i l l d i -ssolved in the solution. Double quantities of dimethylamine were used for the reaction. One equivalent was used to cou-ple with the amide to form the second tertiary amine end while the second acted as the neutralizing agent. If dry ether was the reaction solvent, the white amine HCl salt formed in the reaction was insoluble in ether and accumulated as the reaction went to completion. If absolute methanol was the reaction sol-vent, the amine HCl salt formed soon dissolved in the solvent. In order to separate the dissolved salt from the product, the reaction mixture was reduced in volume by flash evaporation. The concentrated residue dispersed in water vras extracted with solvent ether. The product was found in the ethereal layer and the amine HCl salt remained in the water. The results are shown in Table 9 « ^CHo -2 to /CH, - +/CEo T -"' = D _ T.T _ nrs nvs M J _i_ r>i TT M J R - N-C0 - C H 9C1 + 2HN R - N - C O - C H o - N ^ + C l - H - N X N C H , -10 C . X * N C H . ^ X C H , TABLE 9 o<-DIMETHYLAMINO-N-(R)-N-PHENYLACETAMIDE R BOILING POINT °C. P O I N T 1 ® ? . ^ Y I S L D H 124(1.4 mm.) - 94.0 Methyl 1 0 6 ( 0 . 3 mm.) - 90.5 Cyclobutylmethyl 1 3 4 - 1 3 5 ( 0 . 9 mm.) - 80.7 Cyclopentylmethyl - 45.0-46.0 90.0 Cyclohexylmethyl - 53.5-54.5 8 3 . 1 Cycloheptylmethyl 178-179(1.7 mm.) - 80.5 The f i n a l step of the series of reactions was to re 61. duce the carbonyl group of the amide to form the t e r t i a r y d i -amine compounds (Antergan analogues). Lithium aluminum hydride was used as the reducing agent i n the same manner as described f o r the reduction of cycloalkanecarboxanilides into the corres-ponding amines. The c y c l o a l k y l analogues of Antergan r e a d i l y formed i n good yiel d s (Table 10) . ^CHo •CH-3 2R-N-C0-CH--N D + L i A l H k = ± : 2R-N-CH0-CH0-N ^ + LiAlOo TABLE 10 N,N-DIMETHYL-N'-(R)-N'-PHENYLETHYLENEDIAMINE R BOILING P0INT°C. & $YIELD vs. LIT. VALUE(l) H 81(0 .75 mm.) f91.3 CH 3 97-98(1.9 mm.),77.3 Cyclobutylmethyl 120-125(0 .8 mm.),92.1 168-179(20 mm.),10.0 Cyclopentylmethyl 136-138(1 mm„),90.3 185-189(21 mm.),10.2 Cyclohexylmethyl 158-159(2.2 mm.),93.3 194-195(15 mm.),21.8 Cycloheptylmethyl 148 -153(1 mm.),95.1 204-210(17 mm.),29.0 The compounds synthesized i n Table 4 , 5 and 6 were repeated using Leung's method (1) while the compounds i n Table 8, 9 and 10 were synthesized by the present studies. 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 were sent f o r percentage composition analysis of carbon, hydrogen, nitrogen and halogen. No derivatives were made. For those l i q u i d compounds, methyliodlde-, hydrochloride- or p i c r a t e -derivatives were made f o r elemental microanalysis. 6 2 , To supplement the a n a l y t i c a l results of a deriva t i v e , an infrared spectrum was taken on the synthesized compound. The spectrum of a molecule i n the fundamental region 2 to 1 5 shows the presence of a number of bands which can be correlated with the functional groups present i n the molecule, xvhile other bands correspond to s k e l e t a l vibrations. Because of t h i s , i n frared spectroscopy was used both to obtain informa-t i o n of the functional groups present i n the unknown molecules and also to act as " f i n g e r p r i n t s " f o r the molecule. Using t h i s technique, i t was possible to determine the completion • of a reaction by the presence or absence of a p a r t i c u l a r band corresponding to a p a r t i c u l a r functional 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 antihistaminic agent, i t s cyclo-a l k y l analogues might be expected to have some antihistaminic a c t i v i t y . Therefore, quantitative comparisons of antihistaminic actions of these analogues with Diphenhydramine HCl (Benadryl HCl, Parke, Davis and Co., Ltd., Walkerville, Ontario, CANADA) were studied. The methods of Schild (32) and Reuse (33) were modified and adopted here. Histamine concentration was c a l -culated i n terms of histamine base (Histamine Dihydrochloride, N u t r i t i o n a l Blochemicals Corp., Cleveland, Ohio, USA) and those of other compounds tested were calculated as molar concentra-t i o n of monohydrochlorlde s a l t s i n terms of the s a l t s used. A l l drugs were f r e s h l y prepared i n Tyrode solution. Strips of guinea-pig's Ileum 2-3 cm. long were aerated i n a 30-c.c. bath containing Tyrode solution at 37i0 o 5°C. and l o n g i t u d i n a l contractions of the i n t e s t i n e recorded on a kymograph. The action of a single dose of histamine (0.5 Y °? histamine base) was f i r s t tested and a number of submaximal ef f e c t s (2 to 3 times, 0 .5 V each) obtained and the response (degree of ileum contraction i n mm.) measured at the end of 15 minutes was taken as the standard mean response. The test compounds were then injected into the bath. A f t e r 1 minute contact between tes t compounds and guinea-pig's ileum, a double dose of h i s t -amine ( i . e . , 1.0 J of histamine base) was then injected into the bath and the e f f e c t measured at the end of 15 minutes. 64. The o b j e c t was to f i n d two c o n c e n t r a t i o n s of the t e s t compounds such t h a t one would reduce the e f f e c t of a double dose of h i s t -amine to s l i g h t l y l e s s and the other to s l i g h t l y more than the e f f e c t of a s i n g l e dose. The pAg value was then obtained by i n t e r p o l a t i o n on a l o g a r i t h m i c s c a l e (pA_ was d e f i n e d as the negative l o g a r i t h m to base 10 of the molar c o n c e n t r a t i o n of an a n t a g o n i s t i c drug which vrould reduce the e f f e c t of a, m u l t i -p l e dose (x) of an a c t i v e drug to t h a t of a s i n g l e dose). A f r e s h p i e c e of gut was used f o r each c o n c e n t r a t i o n of the t e s t compounds. The whole experiment was repeated u n t i l the pA 2 value was found. The r e s u l t s of p r e l i m i n a r y a n a l y s i s were shown i n Table 11 and F i g u r e 2. TABLE 11 EFFECTS OF CYCLOALKYL ANALOGUES OF ANTERGAN (K0N0-HC1 SALTS) AND DIPHENHYDRAMINE HCl 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 Analogue; VI, Cycl o h e x y l m e t h y l Analogue; VII, C y c l o h e p t y l m e t h y l Analogue; D, Diphenhydramine. 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 C/A {%) 1. 2. AVE. 1. 2, AVE. 7.5 10,5 9.0 20.5 23.0 21.8 IV: 7.19 IV: 7.19 IV: 7.19 IV: 7.85 IV: 7.85 IV: 7.85 1.0 .2 .0 1.5 25.0 22.0 16,7 107.7 1« 2. AVE. 13.5 24.0 18.8 V: 7.54 21.5 V: 7 .5^ 19.5 V: 7.54 20.5 (To be continued) 109.0 1. A 12.5 Vs B 7-23 C 14.0 (C/A {%) 2. 23.0 Vs 7.23 -AVE. 17,8 Vs 7.23 14.0 78.7 1. 12.5 Vis 7.62 4.0 2. 12.0 Vis 7.62 4.5 AVE. 12.3 Vis 7.62 4.3 34.1 1. 25.0 Vis 8.52 21.0 2. 24,0 Vis 8.52 20.0 AVE. 24.5 VI: 8. 52 20.5 83.7 1. 5.0 VII 5 7.52 8.5 2. 8,5 VII: 7.52 13.5 AVE. 6.8 VII j 7.52 11.0 161.7 1. 11.0 VII: 7.22 3.0 2. 10.0 VII: 7.22 -AVE. 10.5 VII: 7.22 3.0 28.6 1. 12.5 Ds 7.62 6.5 2. 18.0 D: 7.62 6.5 AVE. 15.3 Ds 7.62 6.5 42.5 1. 9o5 D: 8.62 22.5 2. 17.0 D: 8.62 20.0 AVE. 13.3 D: 8.62 21.3 160.2 1. 14,0 D: 7.62 2.5 2. 11.5 D: 7.62 4.0 AVE. 12.8 D: 7.62 3-3 25.8 1. 23.5 D: 8.44 18.5 2. 23.0 D: 8.44 12.0 AVE. 23.3 D: 8.44 15.3 65.7 Mean Response ( rthe; Response"" to 1 - 2 tests ) to A Double Dose as % of A"Single Dose~without"Antagonist. -; — (X) — - 3 3 D-d~ i CD (T> H* "3> c t cf -d .ro 3 :r 3 <3 CD s»- -• i—* i—* j^ s \-> ; nr ss - 3 3 P- co -SB SB 4 ; H H jo ' O O 3 o . 0 3 t*} H- 4 ss ss 3 0 CD CD S O <3 o o ' 3 ' o - • M . o O H V{ M _ 3* O < 05 ( t H •• P 3 O H CD . 03_. X o 4=<: HO $o »-»o 3 3 -H- CO £ O 3 c t c t o [—1 h-* -M 3 O CD SS > C t H r -3 3 ' W-S» ^  «< M H H O -Oq > > -ss 3 3 CD S3 — M M - o o -i - f SS £ M CD CD - - CO -O < O o H O > O << 3 3" O c t CD (-« CD " W O 4 ctTf m << CD JB M 3 3 • f c t v< <* t-J CQ i * "99 67 . It was quite i n t e r e s t i n g to f i n d that N,N-dimethyl-N'-cyclohexylmethyl-N'-phenylethylenedlamlne ( i . e . , cyclohexyl-methyl analogue) was s l i g h t l y more potent than or as potent as Diphenhydramine. The high potency order of the Antergan analo-gues (pAg value i n parenthesis) was as follows: Cyclohexylmethyl analogue (8.82)^ Diphenhydramine (9.15 or 8.11)> Cyclobutylmethyl analogue (7.79)> Cyclopentylmethyl analogue (7.45)> Cycloheptylmethyl analogue (7.38) The other two compounds tested, i . e . , N,N-dimethyl-N'-phenyl-ethylenedlamlne and N 0N-dimethyl-N'-methyl-N'-phenylethylene-dlamlne were found to have no antihistaminic a c t i v i t y (results not shown i n the Figure). The action of cyclohexylmethyl ana-logue was the most persistent and s p e c i f i c among the series of compounds tested, therefore, i t was d i f f i c u l t to wash out and took longer duration f o r recovery (24 minutes). The cyclo-heptylmethyl analogue was the weakest i n action and comparative-l y easy to wash out. Although the pAg values i n the present studies were obtained from the mean of two separate determina-tions ( i n some compounds just one determination) and c o n t r i -buted l i t t l e 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 indicated by Sc h i l d and Reuse made us believe t h i s preliminary study gave valuable information to the f i n d i n g that cyclohexylmethyl analogue of Antergan was a potent a n t i h i s t a -minic agent. As a r e s u l t , i t was suggested that t h i s compound be submitted f o r more det a i l e d pharmacological study. 6 8 . PART VII SUMMARY The syntheses of four cycloalkyl analogues of Anter-gan and two related compounds have been reported in good yields. The benzyl group in Antergan was replaced by a cyclo-alkylmethyl group containing four to seven carbon atoms in the ring. These tertiary diamines are as follows: N,N-dimethyl-N'-cyclobutylmethyl -N 8-phenyle thylenediamine, N,N-dime t h y l - N ' -cyclopentylmethyl -N'-phenylethylenediamine, N jN-dimethyl -N 1 1 -cyclohexylmethyl-N'-phenylethylenediamine, and N,N-dimethyl-N'-cycloheptylmethyl -N'-phenylethylenediamine. The benzyl group in Antergan was also substituted by a hydrogen and or by a methyl group to become N„N-dimethyl -N 9-phenylethylene-diamine and N,N-dimethyl -N'-methyl -N'-phenylethylenediamine respectively. These ethylenediamine derivatives were isolated as the free base. The hydrochloride, methyl iodide, and picrate salts of these amines were prepared for elemental microanalyses. The general reaction sequence for the preparation of these derivatives started with the cycloalkanecarboxylic acid. The acid was reacted with thionyl chloride to form the acid chloride. Then the amide intermediate was prepared by reacting the acid chloride with aniline. Lithium aluminum hydride was used to form the desired amine. Leung's methods ( 1 ) were followed and showed good results up to this step. A nexv re-action sequence was used from this step on. The appropriate amine was reacted with chloroacetyl chloride, dimethyl amine, 69o and then reduced by lithium aluminum hydride to the ethylene-diamine derivatives. A l l the intermediates synthesized were characterized through their physical constants, boiling point, melting point and infrared spectra, and were verified by elemental microana-lyses of intermediates themselves (for solid intermediates) or their hydrochloride or methyl iodide salt derivatives (for liquid intermediates). The preliminary antihistaminic activity of a l l the six f i n a l compounds were studied by a modification of Schild's ( 3 2 ) and Reuse's ( 3 3 ) methods. It v/as quite interesting to find that N,N-dimethyl-N"-cyclohexylmethyl-N'-phenylethylene-dlamlne was slightly more potent or as potent as Diphenhydra-mine (Benadryl). The former compound was also the most potent and most specific among the series of compounds tested. The cycloheptylmethyl analogue was the least potent in action. The order of descending antihistaminic activity was as follows: Cyclohexylmethyl analogue^, Diphenhydramine > Cyclobutylmethyl analogue> Cyclopentylmethyl analogue> Cycloheptylmethyl ana-logue. The other two related compounds, N , N-dimethyl - N ' -phenylethylenedlamlne and N,N-dimethyl-N*-methyl-N'-phenyl-ethylenedlamlne , were found to have no antihistaminic activity. 70o FART VIII INFRARED SPECTRA 5.5 W A V E L E N G T H I N M I C R O N S 6.5 7 7.5 8 9 10 11 12 14 1 F i g . 3« IR spectrum of cst-chloroace WAVENUMBER CM W A V E L E N G T H IN MICRONS 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 9 10 11 12 14 1 00 3000 2500 2000 1800 1600 140.0 1200 1000 800 F i g . 4. IR s p e c t r u m o f o / , - d i m e t h y l a m i n o a c e t a n i l i d e „ l i q u i d b e t w e e n N a C l p l a t e s . WAVENUMBER CM"1 3 . 5 4 . 5 5 . 5 W A V E L E N G T H I N M I C R O N S 6.5 7 7 . 5 8 9 1 0 l i 1 2 1 4 1, ) 0 3 0 0 0 • 2 5 0 0 2 0 0 0 1 8 0 0 1 6 0 0 F i g . 5 . IR spectrum of N,N-dlmethyl-N 8-phenylethylene-dlamlne , l i q u i d between NaCl plates. 1 4 0 0 1 2 0 0 1 0 0 0 8 0 0 W A V E N U M B E R C M WAVELENGTH IN MICRONS 3 3.5 A 4.5 5 i-5 6 6.5 7 7.5 8 9 10 11 12 - 14 1< )0 3000 2500 2000 1800 1600 1400 1200 1000 800 Fig- 7« IR spectrum of tf.-dimethylamino-N-methyl-N-phenylacetaralde, liquid between-NaCl plates. WAVENUMBER CM"' • W A V E L E N G T H I N M I C R O N S 6.5 7 7.5 8 9 3 0 0 0 2 5 0 0 2 0 0 0 1 8 0 0 1 6 0 0 Fig. 8 . IR spectrum of N.N-dimethyl-N'-methyl-N'-phenyl-ethylenediamine, liquid between NaCl plates. WAVENUMBER CM WAVELENGTH IN MICRONS 3 3.5 ' 4 4.5 5 5.5 6 6.5 7 7.5 8 9 10 11 12 14 1< '0 3000 2500 2000 1800 1600 1400 1200 1000 800 F i g . 9. IR spectrum of c^-chloro-N-cyclobutylraethyl-N-phenyl-acetamlde, l i q u i d b e t w e e n NaCl plates. W A V E N U M B E R CM'' 3.5 4.5 5.5 WAVELENGTH IN MICRONS 6.5 7 7.5 & 9 )0 3000 2500 2000 1800 1600 F i g , 1 0 . IR spectrum of '•/-dlmethylamino-N-cyclobutylmethyl-N-phenylacetamlde, l i q u i d between NaCl plates. WAVE NUMBER CM WAVELENGTH IN MICRONS 6.5 7 7.5 8 9 DO 3000 2500 Fig. 11. IR spectrum o phenylethylen 1 200 2000 1800 1600 1400 f N.N-dimethyl-N'-cyclobutylmethyl-N'- , ediamine, liquid between NaCl plates. W A V E N U M B E R CM" WAVELENGTH IN MICRONS 6.5 7 7.5 3 9 )0 3000 2500 F i g . 12. IR spectrum of N-phenylacetam <A-chloro»N-cyclopenty line t h y l -ide ( KBr p e l l e t ). WAVENUMBER CM W A V E L E N G T H I N M I C R O N S 3 3.5 4 4.5 5 5-5 6 6.5 7 7.5 8 9 10 11 12 14 )0 3000 2500 2000 1800 1600 1400 1200 1000 800 F i g . 13. I K spectrum of c<-dimethylamino-N-cyclopentyl-methyl-N-phenylacetamide ( KBr p e l l e t ). ' WAVGNUMBER C M " " WAVELENGTH IN MICRONS 6.5 7 7.5 8 9 400 1200 10 3000 2500 2000 1800 1600 Fig. 14. 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 , liquid between NaCl plates. WAVENUMBER CM"' W A V E L E N G T H IN M I C R O N S 6.5 7 7.5 8 9 14 DO 3 0 0 0 2 5 0 0 2 0 0 0 1 8 0 0 - ^ " , u - T 6 0 0 Fig„ 1 5 . IR spectrum of r^-chloro-N-cyclohexylraeJfchyl-N-phenylacetamide ( KBr p e l l e t ) 4 0 0 1 2 0 0 1 0 0 0 W A V E N U M B E R C M / WAVELENGTH IN MICRONS 6.5 7 7.5 8 9 nun] ; J i-i )0 3000 2500 2000 F i g . 16. IR spectrum of K-dimethylamino-N-phenylacetamide ( KBr p e l l e t 1800. / VM£00 / 1400 N-cyclofrexylmethyl 1200 WAVENUMBER CM'1 WAVELENGTH IN MICRONS 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 3 9 10 11 12 14 1 30 3000 ' 2500 2000 1800 1600 1400 1200 1000 800 F i g . 17 o IR spectrum of N lN-dimethyl-N ,-cyclohexylmethyl-N»-phenyletnylenediamine, l i q u i d between NaCl plates. W A V E N U M B E R C M " ' WAVELENGTH !N MICRONS 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 9 10 11 12 14 1, )0 3000 2500. 2000 1800 1600 1400 1200 • 1000 800 Fig. 18. IR spectrum of e<-chlo~N~cycloheptylmethyl-N~ , phenylacetamlde, liquid between NaCl plates. - W A V G N U M B E R C M ' WAVELENGTH IN MICRONS DO 3000 2500- 2000 1800 1600 1400 1200 1000 800 Fie;„ 1 9 „ IR spectrum o f o(-dimethylamlno-N-cycloheptylmethyl- , N-pheftylacetamide^liquid between NaCl plates. ' WAVENUMBER CM' WAVELENGTH IN MICRONS 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 9 10 11 12 ' 14 00 3000 2500 2000 1800 1600 1400 1200 1000 SCO Fig, 2 0 o IR spectrum of N,N-dlmethyl-N*-cycloheptylr.iethyl-N'-phenylethylenedlamlne,, liquid between NaCl plates. W A V E N U M B E R C M ' 1 8 9 o FART IX LIST OF REFERENCES lo F r e d Leung, " S y n t h e s i s of C y c l o a l k y l Analogues of A n t e r -gan", Master T h e s i s , U n i v e r s i t y of B r i t i s h Columbia, Vancouver, Canada, 1964„ 2. A.Grollman, Pharmacology and T h e r a p e u t i c s , 5 t h ed., 412-4 3 1 , Chap, 1?, 1962. 3o J . F o R i l e y and G.B.West, Handb. Exp. 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