Antihistaminics: Basic Derivatives of Ethyl Diphenylacetate

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P U R D U E U N IV E R SIT Y

THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION

BY

-J ack- Payne Come r

e n title d

ANTIHLSTAMINICS*

BASIC DERIVATIVES OF____________

___________ ETHYL DIPHKNYLACETATE_______________________________

COMPLIES WITH THE UNIVERSITY REGULATIONS ON GRADUATION THESES

AND IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS

FOR THE DEGREE OF

-----------------Doctor - o f P h il os ophy-------------------------------------------------

P r o f e s s o r in Ch a r o e o f Th e s is

H e a d o f S chool, o r D e p a r t m e n t

-A pril 7__

ig 50-

TO THE LIBRARIAN:---IS 'fYO THIS THESIS IP nüO T TO BE REGARDED AS CONFIDENTIAL.

A & y

PRO FESS
F e in b e rg (3 8 ), and B e rn s te in (39)* r e p o r te d by H u ttr e r e t a l . (4 0 ).

The s y n th e s is was

A second m e d ic in a lly u s e f u l compound

o f th e d ia m in e -h e te ro c y c lic ty p e i s H eteram ine ( XI ) .

The p h a m a co lo g —

i c a l p r o p e r tie s f o r H eteram ine were r e p o r te d by N e te r ( 4 l) i n 1947*

I HCH2 C H ^ I ( C t t j ) 2

ngh2c h ^ ( c h 3 )2

/A y X II F u r th e r stu d y on t h e diam ine ty p e o f compounds re v e a le d t h a t th e b e n z y l r a d i c a l could be r e p la c e d by t h e t h e n y l r a d i c a l w ith o u t s e rio u s lo s s o f a c tiv ity .

T his le d t o th e d is c o v e ry o f th e t h e r a p e u t i c a l l y

u s e f u l compound X II♦

Compound X I I , c a l le d H is ta d y l o r T henylene, was

re p o r te d by Clapp e t a l . (42) and by Weston (43)* C e rta in s t u d i e s re v e a le d t h a t th e t e r t i a r y aminogroup o f th e diam ine ty p e of compound c o u ld b e re p la c e d by th e im id a z o lin y l r a d i c a l t o g iv e a c t iv e compounds.

T his le d t o t h e i n tr o d u c tio n o f th e m e d ic in a lly

u s e f u l compound A n tis t i n (X III ) r e p o r te d by M eir and Bucher (44)*

8

/ \

Y

?H2

H

A -

i X III

A new ty p e o f compound p o ss e s sin g a n tih is ta m in ic a c t i v i t y was found when one o f th e amino groups o f th e diam ine n u c le u s was r e ­ p la c e d by a m ethylene group* t h i s type*

Brown (45) has re p o r te d compounds o f

T rim eton (XIV) i s an example o f a t h e r a p e u t i c a l l y u s e f u l

compound o f th e d ia lk y la m in o a lk a n e type*

The c o n d e n sa tio n o f th e

P -d im eth y lam in o eth y l s id e c h a in i n t o a h e te r o c y c lic s t r u c t u r e g iv e s T hephorin (XV).

Lehman e t al* (46) have d is c u s s e d th e pharm acology

CH2CH2N(CH3 ) 2 " V XIV

v * XV

o f T h ep h orin. As soon a s th e v a lu e s o f th e b a s ic n u c le i f o r a n tih is ta m in ic a c t i v i t y were f a i r l y w e ll e s t a b l is h e d , a number o f compounds were p re p a re d i n w hich m inor changes were in tro d u c e d i n t o th e p a re n t com-

9 pounds.

I n some c a se s t h i s l e d t o compounds o f enhanced a c t i v i t y *

Such compounds a re N eoantergan (XVI), N eoheteram ine (XVII ) 9 Chloro* th e n (X V III), and C h lo ro trim e to n (XIX)# O-CHc

0-CH3

V CHo N-CH2CH2N( CH-j ) 2

1 n -c h 2ch2h ( c h 3 ) 2 NvH

XVII Cl

c iy f\ I

V CH A Z \ CH2CH^ï(CH3 ) 2 I V \

XVIII

/

XIX

The e th e r ty p e o f compound was a ls o m o d ifie d s u c c e s s fu lly # H l f o r d e t a l . ( 4 7 ) r e p o r te d on a group o f compounds w hich in c lu d e d th e t h e r a p e u t i c a l l y u s e f u l Decapryn (XX)•

10

0-CH2CHÿî(CH3)2

The r e s e a r c h on th e u s u a l e th e r and d iam ine ty p e o f a n tih is ta m in ic compounds has become v e ry d i v e r s i f i e d d u rin g th e l a s t two y e a r s .

To

i l l u s t r a t e t h i s p o i n t , a few o f th e a c t i v e compounds t h a t have been p re p a re d and t e s t e d r e c e n t l y a re t a b u l a t e d i n Table 1 . Table 1 A L i s t o f A Few o f t h e R e c e n tly P re p a re d Compounds P o s se ss in g A n tih is ta m in ic A c tiv ity H1 ^ n c h 2ch2-y

Rl p-M ethoxybenzyl 2 -F u rfu ry l 2 -F u rfu ry l 2-T henvl

R2 2 -P y r id y l 2 -P y rid y l P henyl P henvl

X

R e feren c e s

1 - P y r r o lid y l Dim ethylamino Dim ethylam ino Dim ethylam ino

(4 8 ) (49) (50) (51)

R -0CH2CH2- I R 2-B en zy lp h en y l B enzohydryl l- ( p ~ C h lo r o p h e n y l) -l( 2- p y r i d y l ) e th y l l-(p -T o ly l)( 2- o y r i d y l ) e t h y l

Y

R e fe re n c e s

Dimethylamino 1 - P y r r o lid y l

(5 2 ,5 3 ) (54)

Dim ethylam ino

(55)

Dimethylamino

(47)

11 The p r e s e n t t r e n d o f r e s e a r c h i n t h e f i e l d o f a n ti h i s t a m i n ic s i s th e e x p lo r a tio n f o r new b a s ic n u c le i#

T his may b e i l l u s t r a t e d by th e

work o f T urner e t a l . (56) who have i n i t i a t e d s t u d i e s on s u b s t i t u t e d im id a z o le compounds o f th e g e n e r a l s t r u c t u r e XXI i n w hich R^* and R2 a r e h y d ro gen, p h e n y l, o r b e n z y l. N

-CH2NR3R2

Sheehan and R obinson (5 7 ) have made t — ~ t ’-CH2GH2NH2

J

H XXI

XXII

th e T ria z o le an alo g (XXII ) o f h ista m in e i n th e hope t h a t t h i s compound would be a m e ta b o lic a n ta g o n is t to h is ta m in e .

B eitsem a and H unter (5 8 ,

59) have s t a r t e d a s tu d y o f some 3 - and 4 -a m in o p ip e rid in e s (X X III) i n which B"*" i s e th y l o r m e th y l, R2 i s p y r id y l and R^ i s b e n z y l.

Hamlin

e t a l . ( 60, 6l ) have r e p o r te d s e v e r a l 1 , 4- d i s u b s t i t u t e d p ip e r a z in e s o f th e g e n e ra l fo rm u la XXIV i n which R i s e th y l o r m eth y l and R2 i s one o f v a rio u s s u b s t i t u t e d b e n zo h y d ry l r a d i c a l s . R

Â

y Rl

XXIII

XXIV

S e v e ra l re v ie w a r t i c l e s on th e a n ti h i s t a m i n ic d ru g s have been p u b lis h e d ( 62 , 63, 64, 65, 66, 67, 68) , th e more com prehensive o f which a re th o s e o f H aley ( 69 ) , H u ttr e r ( 7 0 ) , and Loew ( l ) «

12 RELATIONSHIP OF CHEMICAL STRUCTURE TO PHYSIOLOGICAL ACTIVITY The u ltim a te e v a lu a tio n o f t h e v a rio u s a n tih is ta m in ic d ru g s can be accom plished o n ly b y c a r e f u l l y c o n tr o lle d c l i n i c a l experim ents# There i s a p a u c ity of c l i n i c a l r e p o r t s d e sig n e d to compare system ­ a t i c a l l y th e e f f e c t s o f ch em ic al s t r u c t u r e t o a n tih is ta m in ic a c t i v i t y ; so i t i s n e c e s s a ry t o u se v a rio u s r e p o r t s co n cern ed w ith th e r e s u l t s o f an im al t e s t s i n such a s tu d y .

S in ce v a rio u s te c h n iq u e s have been

employed f o r th e q u a n t i t a t i v e com parison o f th e d i f f e r e n t s e r i e s o f compounds, i t i s d i f f i c u l t t o compare p ro p e rly th e r e s u lts o f d i f f e r e n t in v e s tig a to rs .

The r e l a t i o n s h i p s d is c u s s e d h e r e in have been ta k e n

from th e c o n c lu sio n d e riv e d by th e v a rio u s i n v e s t i g a t o r s . I n o rd e r to p r e s e n t th e s e r e l a t i o n s h i p s i n a s y s te m a tic m anner, i t a p p ea rs a p p ro p ria te to d iv id e th e d is c u s s io n i n to t h r e e g e n e r a l to p ic s which a re b a se d on th e ch em ical c l a s s i f i c a t i o n o f th e compounds used t h e r a p e u t i c a l l y a s a n tih is ta m in ic a g e n ts ; nam ely, th e e th e r d e r i v a t i v e s , th e diam ine d e r i v a t i v e s , and th e a lk a n e d e r i v a t i v e s . E th e r D e riv a tiv e s R-O-C^CHgN ^ XXV The R S u b s t it u e n t .

For compounds i n which R i s p henyl i n th e

g e n e r a l fo rm u la XXV, S taub (2 9 ,7 1 ) found t h a t th e in tr o d u c ti o n o f c e r t a i n s u b s ti t u e n t s i n t o th e phenyl r i n g caused th e fo llo w in g change in a c tiv ity : a* The a c t i v i t y in c r e a s e s p r o g r e s s iv e ly w ith m e th y l, d im e th y l, and 2- p ro p y l g ro u p s, r e s p e c tiv e ly #

13 b e Methoxy and a l l y l s u b s ti t u e n t s g iv e i n a c ti v e compounds * c . P henyl s u b s t i t u e n t s g iv e s a c t iv e compounds# The rep la ce m e n t o f th e ph en y l r a d i c a l i n XXV by th e b e n z o h y d ry l r a d i c a l enhanced th e a c t i v i t y ( 3 3 )* T ilf o r d e t al» (47) i n v e s ti g a t e d compounds o f th e g e n e r a l fo rm u la XXV i n w hich R i s th e r a d i c a l XXVIe

These i n v e s t i g a t o r s drew th e

XXVI fo llo w in g c o n c lu sio n s: a# The m ost a c tiv e compounds a r e th o s e i n which R^- i s phenyl and R^ i s hydrogen o r m ethyl* b* The a c t i v i t y i s n o t in c re a s e d by th e s u b s t i t u t i o n o f an alk o x y o r h alo g e n group i n th e p h en y l r i n g , R • c# Compounds i n v h ich R^ i s m eth y l and i s n a p h th y l, p y r i d y l , t h i e n y l , o r c y c lo h e x y l a re l e s s a c t iv e th a n th o s e i n which R2 i s phenyl# d e The g r e a t e r t h e deg ree o f h y d ro g e n a tio n o f th e c y c lic s t r u c t u r e , th e low er th e a c t i v i t y # From th e a v a ila b le in fo rm a tio n on th e R p o r tio n o f g e n e ra l fozm ula XXV, one may summarize t h a t t h e m ost a c t iv e s u b s t i t u e n t s a re th o s e i n v h ich R i s a d i s u b s t i t u t e d m ethylene g ro u p , th e p re ­ f e r r e d s u b s ti t u e n t s b e in g two phenyls o r a phen y l and a h e te r o c y c lic r a d i c a l such a s p y rid y l*

14 The Aminoftliorl S u b s t it u e n t s »

S tau b found i n h e r work (2 9 ,7 1 )

t h a t th e amino g ro u p i n XXV sh o u ld be t e r t i a r y f o r maximum a c t i v i t y and t h a t t h e rep la ce m e n t o f th e d ie th y la m in o g ro u p w ith th e p i p e r i d y l group d im in ish e s th e a c t i v i t y .

Loew e t a l . (72) i n t h e i r stu d y o f th e e t h e r

ty p e (R i n XXV i s b en zo h y d ry l) l i s t e d th e o r d e r o f th e d e c re a s in g a c t i v i t y o f v a rio u s am in o alk y l c h a in s a s f o llo w s :

p -d im e th y la m in o -

e t h y l , 3- p i p e r i d i n o e t h y l , p -m o rp h o lin o e th y l, ^ -m e th y la m in o e th y l, p -is o p ro p y la m in o e th y l, y -d ie th y la m in o p r o p y l, / -m o rp h o lin o p ro p y l, P—a m in o e th y l, p -(P -m o rp h o lin o e th y la m in o ) e t h y l , 6-m o rp h o lin o h e x y l, p -n -b u ty la m in o e th y l, P-^nethyl-Pnaaorpho l i n o p ro p y l > P -( p - d ie t hylam inoe th o x y ) e th y l, P -d ic y c lo h e x y la m in o e th y l, and P -d i-n - b u ty la m in o e th y l. G raver e t a l . (73) have found t h a t re p la ce m e n t o f th e am in o alk y l group by th e im id a z o lin y lm e th y l group g iv e s a c t i v e compounds • I n g e n e ra l i t may be s t a t e d t h a t t h e optimum le n g th o f t h e amino­ a lk y l group i s two carb o n ato m s, and i n m ost c a s e s th e dim ethylam ino group g iv e s t h e m ost a c t iv e compounds* Diamine D e r iv a tiv e s b3

/R l N'-CHoCHo-N „ R *' ^ R^ XXVII

The H - S u b s titu e n ts .

S taub (2 9 ,7 1 ) h a s found t h a t t h e N

s u b s ti t u e n t s should p r e f e r a b ly be i d e n t i c a l a lk y l g ro u p s. f e r r e d group f o r R^* and

i s m ethyl#

The p re ­

C e rta in s t u d i e s (44) have

r e v e a le d t h a t t h e t e r t i a r y amino group may b e re p la c e d by th e im id a z o -

15 l i n y l r a d i c a l t o g iv e a c t i v e compounds*

H alpern (30) has found t h a t

th e optimum le n g th o f th e a lk y l amino s u b s t i t u e n t s R^“ and R^ i s one carb o n atom* The N»- S u b s t i t u e n t s , t h a t R^ and

r4

I t was p o in te d o u t e a r l y b y S taub (2 9 ,7 1 )

sh o u ld be c y c l ic g ro u p s, p r e f e r a b ly a ro m a tic i n n a tu r e ,

f o r maximum a c t i v i t y .

T his e a r ly o b s e rv a tio n has b een v e r i f i e d by

su bsequent i n v e s t i g a t i o n s .

However, th e c y c lic g roups have b een

ex ten d ed to in c lu d e s e v e r a l h e te r o c y c lic r a d ic a ls * Viaud (74) h as made a s y s te m a tic s tu d y o f a la r g e number o f diam ine d e r i v a ti v e s .

He has made t h e fo llo w in g o b s e rv a tio n s co n cern ­

in g th e a c t i v i t y o f th e s e d e r i v a ti v e s a s compared to th e a c t i v i t y o f a compound i n which R^ and R^ a re m e th y l,

i s b e n z y l and R^ i s

phenyl i n th e g e n e ra l fo rm u la XXVII : a . S u b s t it u t io n o f t h e b e n z y l g roup w ith a lk y l and o th e r a r y l — a lk y l groups r e s u l t s i n a d e c is iv e l o s s o f a c t i v i t y . b* S u b s t it u t io n o f th e b e n z y l group w ith c e r t a i n alk o x y groups g iv e s compounds w hich a re s t i l l a c tiv e * c . S u b s titu tio n o f th e p h en y l group w ith p -m eth y lp h en y l m ain­ ta in e d th e o r i g i n a l a c t i v i t y w h ile p-am inophenyl, b e n z y l, o r c y clo h ex y l c a u se s com plete l o s s o f a c t i v i t y . d* Of th e v a rio u s s u b s ti t u e n t s t h a t were i n v e s ti g a t e d on th e phenyl r a d i c a l , t h e p-m ethoxy g roup g iv e s th e b e s t r e s u l t s * e* S u b s t it u t io n o f t h e phenyl group w ith h e te r o c y c lic groups g iv e s v e ry a c tiv e compounds* f* The 2 - p y r id y l r a d i c a l g iv e s an a c t i v e compound, b u t th e 3— and 4- p y r i d y l r a d i c a l s r e s u l t i n i n a c ti v e compounds* In compounds o f th e g e n e ra l fo rm ula XXVII i n which R^ and R^ a re m eth y l and R^ i s 2- p y r i d y l , th e R^ group may a ls o b e a second h e te ro — c y d ô a l k y l group in s te a d o f th e b e n z y l group*

The 2 - f u r f u r y l (49)

16 and t h e 2—th e n y l (51) d e r i v a ti v e s have b een found to b e a c t i v e com­ pounds. A few g e n e r a liz a tio n s may b e made a b o u t th e diam ine ty p e .

Hie

optimum c h a in le n g th betw een t h e two n itr o g e n s i s two c arb o n atom s. One o f th e amino groups sh o u ld have two a lk y l s u b s t i t u e n t s , p r e f e r a b ly m e th y l, o r an analogous c y c lic s u b s t i t u e n t , p r e f e r a b ly im id a z o lin y l. The o th e r amino group sh o u ld be s u b s t i t u t e d w ith a t l e a s t one c y c l ic g ro u p , p r e f e r a b ly a ro m a tic o r h e t e r o c y c li c .

Optimum a c t i v i t y i s

o b ta in e d when th e o th e r r a d i c a l i s a c arb o cy clo m eth y l o r a h e te r o cy clo m ethyl g ro u p , b o th c y c lic groups b e in g a ro m a tic i n n a tu r e . Alkane D e riv a tiv e s R *-CHCH2CH2N( CH3 >2 R2 XXVTII An e x te n s iv e stu d y o f compounds o f th e g e n e r a l fo rm u la XXVIII co u ld n o t be found i n th e l i t e r a t u r e .

Brown (45) has r e p o r te d t h a t

th e compound i n which R^ i s p henyl and R2 i s 2 - p y r id y l i s h ig h ly a c tiv e .

Jackmann e t a l . ( 75 ) s t a t e d t h a t o f th e group o f compounds

s tu d ie d i n t h e i r work th e compound i n w hich c y e lo p e n ty lid in e i s th e m ost a c t i v e .

i s phenyl and R2 i s

As i n th e e th e r and. diam ine

d e r i v a t i v e s , i t a p p e a rs t h a t th e a r y l group p ro b ab ly may be o f s i g ­ n i f ic a n c e . Thus, sum m arizing th e in fo rm a tio n a v a i la b l e and a p p ly in g i t to th e g e n e r a l fo rm u la XXXIX i n which R i s any v a r ia b le and i n which X i s n itr o g e n , oxygen, o r c a rb o n , th e fo llo w in g g e n e r a liz a tio n s have

17 a

&

z

R-.X-CH2CH2N^ XXIX been made ( 6 7 ): a . W ith t h e e x c e p tio n o f th e 2-m e th y lim id a z o lin e s id e c h a in , th e an in o group m ust b e a t e r t i a r y a l i p h a t i c am ine, b . G e n e ra lly , th e d im eth y la m in o e th y l d e r i v a ti v e s g iv e th e m ost a c tiv e compounds. L ess a c t iv e compounds a r e o b ta in e d w ith h ig h e r a lk y l s u b s t i t u e n t s on th e amino g ro u p . The p ip e r id in o and m orpholino s id e c h a in s produce l e s s a c t iv e compounds. c . An in c r e a s e i n th e le n g th o f th e s id e c h a in from e th y le n e to trim e th y le n e produces a s h a rp d ro p i n a c t i v i t y i n a l l o f th e s e r i e s i n v e s t i g a t e d . d . A m eth y l group a tta c h e d t o th e a lp h a c a rb o n atom may in c r e a s e th e p o ten cy and p ro lo n g th e d u r a tio n o f a c t io n w h ile a m eth y l group on th e b e ta c arb o n atom s h a rp ly re d u c e s th e a c t i v i t y . A se a rc h o f th e l i t e r a t u r e has r e v e a le d no s y s te m a tic s tu d y o f th e r e l a t i o n s h i p o f ch em ical s t r u c t u r e t o p h y s io lo g ic a l a c t i v i t y o f compounds o f th e g e n e ra l form ula XXIX i n which R i s k e p t c o n s ta n t and X i s v a rie d .

18 NATURE OF THE PROBLEM Three o f t h e s e v e r a l d ru g s p o s s e s s in g a n tih is ta m in ic a c t i v i t y have c e r t a i n s t r u c t u r a l f e a t u r e s i n common»

These d ru g s a r e B en ad ry l

( I X) , C h lo ro c y c liz in e (XXX), and T rim eton (XIV)*

H-C-O-CH2CH2N( CH3 ) 2

, / ch2ch2< IÎ-CH3 HC-N X

V

HC-CH2CH2N ( CH3 ) 2

CH2 Gii2

IX

XIV

These may b e re g a rd e d a s d ia ry lm e th y le n e o r b e n z o h y d ry lid in e d e r i v a t i v e s , (XXXI) , e x ce p t i n th e case o f T rim eton (XIV) i n w hich one o f th e c y c lic rin g s i s h e te r o c y c lic i n n a t u r e ♦

O ther compounds w hich a r e b e in g used i n p r e s e n t day th e ra p y t h a t c o n ta in th e b e n z o h y d ry lid in e group (XXXI) a re T ra s e n tin e (XXXII) and M ethadon (XXXIII)*

Thus, th e b e n z o h y d ry lid in e r a d i c a l a p p e a rs t o be

19 o f some th e r a p e u tic s ig n ific a n c e *

v

HÇ-CO2CH2CH2N(C2H5)2 CH^CH2-C-C-CH2GH-N(GH^)2 CH3

A v XXXIII

XXXII

Most o f th e a n tih is ta m in ic s a r e d e r i v a t i v e s o f one o f t h e th r e e fo llo w in g groups :

(a ) dim ethylam inoethoxy (XXXIV) , (b ) dim ethylam ino-

ethylam ino (XXXV), and (c ) dim ethylam inopropyl (XXXVI) . CH ^ N -C H 2 C H ^ ch3

CH ^ N-CH2CH2~0-. CH3

XXXIV

XXXV

CH '^N-CH2CH2CH2 ch3 XXXVI

T h eir re o c c u rre n c e i n compounds p o s s e s s in g a n tih is ta m in ic a c t i v i t y seems to i n d i c a t e t h a t th e s e s t r u c t u r e s a re o f t h e r a p e u tic s ig n if ic a n c e f o r a n tih is ta m in ic a c t i v i t y . Com bination o f group XXXI w ith XXXIV, XXXV, o r XXXVI g iv e s r i s e t o s t r u c t u r e XXXVII i n which

V

,

c

z '

.

yvX

X -C H 2 CH2 H ( CH^ ) 2

I

V X i s -N -, - 0 - , o r -GH2-*

xxxvn

I t appeared o f i n t e r e s t to in tro d u c e a

2b c a rb e th o x y group (XXXVIII) i n t o s t r u c t u r e XXXVII t o s a t i s f y th e v a le n c e . Compounds o f th e g e n e r a l form ula XXXIX would be th e r e s u l t o f su ch —COgCgH^

a c o m b in atio n .

XXXVIII

A

i

V\ /

GOzCzH5

X-CH2CH2N(GH3 ) 2

XXXIX The c arb e th o x y group was s e le c te d s in c e i t a p p e a rs t h a t i t may have c e r t a i n f a v o ra b le p h y s io lo g ic a l p r o p e r t i e s o f i t s own.

For

exam ple, th e p re lim in a ry r e p o r t s (?6 ) i n d i c a t e t h a t th e in tr o d u c tio n o f a carb eth o x y g ro u p i n t o b a s ic e s t e r s o f d i a l k y l a c e t i c a c id d e r iv ­ a t i v e s enhances th e sp a sm o ly tic p r o p e r tie s o f th e s e compounds. A rev iew of th e l i t e r a t u r e r e v e a le d t h a t o n ly a few r e p o r ts have been made on compounds o f t h i s ty p e (XXXIX).

A Sw iss p a te n t (77)

r e c e n t l y in c lu d e d th e compound XL.

A

I C02C2H5 C

0-CH2CH2N(C2H5)2

t

V

XL

The method o f p r e p a r a tio n o f XL was g iv e n b u t th e y i e l d s and a n a ly s e s

21 were n o t r e p o r te d , u s e fu l*

I t was s t a t e d t h a t compound XL was t h e r a p e u t i c a l l y

A nother compound o f t h i s ty p e (XLI) i s m entioned by M o rriso n

and K o n ig ste in ( 7 8 ) , b u t th e m ethod f o r t h e p r e p a r a tio n o f X U i s n o t d e s c rib e d . GO2C2H5 ^ / C /

\

0-CH2CH2N(GH3 ) 2

XU S in ce t h e r e i s i n d ic a t i o n t h a t th e d ie th y la m in o e th o x y compound XL may b e u s e f u l t h e r a p e u t i c a l l y , th e e s t e r s e r i e s (XXXIX) u n d e r c o n s id e r­ a tio n i n t h i s s tu d y was exten d ed t o t h e d ie th y la m in o compounds# The f i n a l s e r i e s of compounds which were chosen f o r p r e p a r a tio n a re l i s t e d i n T able 2* T able 2 T a b u la tio n o f Compounds To Be P re p are d 1 C X-CHgCHgNRg

XUI Compound N o.

1 2

3 4 5 6

X

- » —0 — NH — — NH — CH2 — — CH2 —

R

c 2h 5

22

I f a s e r i e s o f compounds a s l i s t e d i n T able 2 were a v a i l a b l e , a p h a rm a co lo g ica l s tu d y o f t h i s s e r i e s would be o f i n t e r e s t f o r th e fo llo w in g reasons*

F i r s t , i t would show i f any o f th e s e compounds

p o sse sse d th e d e s ir e d a n tih is ta m in ic a c tio n a n d , i f s o , t h i s p re lim in a r y stu d y co uld be e x te n d e d .

Second, i t would show th e e f f e c t produced b y

th e in tr o d u c tio n o f th e c arb eth o x y group i n t o compounds o f th e Bena­ d r y l (DC) ty p e .

T h ird , i t would d e m o n stra te t h e p h a rm a c o lo g ic a l

e f f e c t s produced by th e s u c c e s s iv e in tr o d u c tio n o f - 0 —, - NH - , and - GHg — r a d i c a l s i n t o th e X p o r tio n o f t h e compounds re p r e s e n te d by g e n e ra l fo m m la XLII*

F o u rth , i t would g iv e a co m p arativ e a c t i v i t y

o f th e d ieth y lam in o to th e dim ethylam ino d e r i v a t i v e s . Thus, th e compounds l i s t e d i n Table 2 were p re p a re d i n hope t h a t th e s e compounds when t e s t e d m ight p o sse ss b e t t e r a n tih is ta m in ic pro p ­ e r t i e s th a n th e e f f e c t i v e a n tih is ta m in ic compounds now i n u s e , and a l s o , t h a t th e compounds s e le c te d f o r p r e p a r a tio n would p e rm it a s tu d y o f th e r e l a t i o n s h i p o f c e r t a i n ch em ical s t r u c t u r e s to p h y s io lo g ic a l a c t i v i t y a s in d ic a te d above.

23 METHODS OF SYNTHESES

Three m ethods were f i n a l l y adopted f o r t h e p r e p a r a tio n o f com­ pounds o f th e g e n e ra l fo rm u la I i n which X i s n i tr o g e n , oxygen, o r

CO2C2H5 C X-CH2CH2-Y

I a m ethylene r a d i c a l and f o r each o f th e s e compounds Y i s e i t h e r th e dim ethylam ino o r th e d ie th y la m in o g ro u p .

These t h r e e m ethods may b e

c l a s s i f i e d a s f o llo w s : A. P r e p a r a tio n o f d ialk y lam in o a lk o x y d e r i v a ti v e s B. P re p a ra tio n o f d ialk y lam in o a lk y la m in o d e r i v a ti v e s C. P r e p a r a tio n o f d ia lk y la m in o a lk y l d e r i v a ti v e s A b r i e f d is c u s s io n o f each o f th e s e m ethods i s p re s e n te d . A.

P r e p a r a tio n o f th e D ialk y lam in o alk o x y D e r iv a tiv e s

Compounds o f t h i s ty p e a re r e p r e s e n te d by th e g e n e r a l fo rm u la I i n which X i s oxygen and Y i s th e dim ethylam ino o r d ie th y la m in o group* Such compounds were p re p a re d by r e a c tin g e th y l b e n z i la t e (X L III) w ith m e t a l l ic sodium i n anhydrous e t h e r , and th e r e s u l t a n t p ro d u ct was allow ed t o r e a c t w ith d iaH cy lam in o eth y l c h lo r id e t o g iv e e th y l a -(3 -d ia lk y la m in o e th o x y )d ip h e n y la c e ta te (XLIV).

The two p ro d u c ts

24 1 . Na 2 . (R)2NCH2CH2C1 >

c Z NZ

A

i N ^/

/ C02C2Ii5

a»

0-CH2C H ^ (R )2

X L III

XZ

XLIV

p re p a re d by t h i s method were e t h y l a -(p -d im e th y la m in o e th o x y ) d ip h e n y l— a c e ta te (R i n XLIV i s m eth y l) and e t h y l a - (£ -d ie th y la m in o e th o x y ) d i p h e n y la c e ta te (R i n XLIV i s e t h y l ) . p rep a red f o r c h a r a c t e r i z a t io n .

The o x a la te s a l t o f each b a s e was

The h y d ro c h lo rid e s a l t s o f th e b a s e s

were o i l y . B.

P r e p a r a tio n o f th e D ialkylam inoalkylam ino D e riv a tiv e s

Compounds o f t h i s ty p e a re r e p r e s e n te d by th e g e n e r a l form ula I i n which X i s n itr o g e n and Y i s th e dim ethylam ino o r th e d ieth y la m in o g ro u p .

These compounds were p re p a re d a s fo llo w s .

E th y l a - c h lo r o -

d ip h e n y la c e ta te (XLV) was allow ed to r e a c t w ith N,N - d ia lk y le th y le n e diam ine to g iv e e t h y l et-(^ -d ia lk y la m in o e th y la m in o )d ip h e n y la c et a t e (XLVI).

C02g2h5

c

(R)^CH2CH2NH2

CO^C^H^

c

\

\

Cl

w- ch2 ch^

H XLV

XLVI

(

r )2

25 The two p ro d u c ts p re p a re d by t h i s m ethod a re e th y l cx—(@—dim ethylanu.no— e th y la m in o ) d ip h e n y la c e ta te (R i n XLVI i s m e th y l) and e t h y l Cl—(p—d i ­ eth y lam in o ethylam ino )d ip h e n y la c e ta te (R i n XLVI i s e t h y l ) .

These two

b a se s f a i l e d t o g iv e s o l i d d e r i v a ti v e s f o r c h a r a c t e r i z a t i o n . C.

P r e p a r a tio n o f D ia lk y la m in o a lk y l D e r iv a tiv e s

Compounds o f t h i s ty p e a re re p re s e n te d by th e g e n e ra l f o r a u l a I i n which X i s -CH2- and Y i s th e dim ethylam ino o r th e d ie th y la m in o g ro u p .

D ip h e n y la c e to n itr ile (XLVIl) was a llo w e d t o r e a c t w ith y - d i -

alk y lam in o p ro p y l c h lo r id e u s in g sodium amide a s t h e condensing a g e n t t o g iv e 5 -d ia lk y la m in o -2 , 2 -d ip h e n y lp e n ta n e n i t r i l e (X L V III). H y d ro ly sis o f th e n i t r i l e (XLVIII ) w ith s u l f u r i c a c id and w a te r y ie ld e d th e co rre sp o n d in g p e n ta n o ic a c id (XLIX). to th e a c id c h lo r id e .

The a c id XLIX was c o n v erted

The crude a c id c h lo r id e was r e a c te d w ith a lc o ­

h o l t o g iv e e th y l 5 -d ia lk y la m in o -2 ,2 -d ip h e n y lp e n ta n o a te (L ). E th y l 5-d im eth y lam in o -2 92 -d ip h e n y lp e n ta n o a te (R i n L i s m eth y l) and e th y l 5 -d ie th y la m in o -2 ,2 -d ip h e n y lp e n ta n o a te (R i n L i s e th y l) were p re p a re d by t h i s m ethod.

The dim ethylam ino d e r i v a ti v e was i s o ­

l a t e d a s t h e hydro c h lo r id e s a l t , and th e d ie th y la m in o d e r i v a ti v e was i s o l a t e d a s th e f r e e b a se and c h a r a c te r iz e d a s th e o x a la te s a l t* The new in te r m e d ia te n i t r i l e (R i n XLVIII i s e th y l ) was c h a r a c te r ­ iz e d a s th e hydrogen o x a la te s a l t , and th e new amino a c id s (R i n XT,«XX i s m ethyl o r e th y l ) were i d e n t i f i e d by s u i t a b l e n itr o g e n a s s a y .

26

1 , NaNH2

2. (E)2NCH2CH2CH2C1 * ch 2ch 2 ch 2n ( r ) 2

x L ra h2so 4 h 20

1. soci2 x 7 y .

¥V\

co2 c2h 5

2 . C2H5OH

C Z \

COgH X

/ x

/X / ch2ch2ch2n ( r ) 2

c \

/y \

CH2CH2CH^I(R)2

V

XLIX

In c o n ju n c tio n w ith th e developm ent o f th e above m eth o d s, a number o f p re lim in a ry r e a c tio n s were i n v e s ti g a t e d which a r e w orthy o f m en tio n in g .

In o rd e r to become a c q u a in te d w ith th e r e a c tio n s o f

a lc o h o ls and p rim a ry and seco n d ary am ines w ith C fr-chlorodiphenylacetic a c id and e th y l a - c h lo r o d ip h e n y la c e ta te , th e fo llo w in g a re some o f th e r e a c tio n s which were in v e s tig a te d * E th y l O fr-chlorodiphenylacetate was allo w ed t o r e a c t w ith a n il i n e to g iv e a n in e te e n p e rc e n t y i e l d o f e th y l a - a n ilin o d ip h e n y la c e ta te (U )*

R e a c tio n o f a - c h lo r o d ip h e n y la c e tic a c id w ith a n i l i n e gave a

e ig h ty - f iv e p e rc e n t y i e l d o f a - a n ilin o d ip h e n y la c e tic a c id (L II)*

The

d if f e r e n c e i n th e y i e l d i s p ro b a b ly due t o th e g r e a t e r s t e r i c e f f e c t o f

27 « A

V\ c / A

^

NH

V fA V LX 1

Ai V\ c/

C02H

/ A

NH

/

V L II

c arb eth o x y g ro u p , to th e low ered r e a c t i v i t y o f th e a —c h lo r in e atom o f th e e s t e r , and, i n th e c a se o f th e a c i d , to th e e a se o f p u r i f i ­ c a tio n o f th e p ro d u c ts from th e r e a c tio n m ix tu re , a -G h lo ro d ip h e n y la c e tic a c id was r e a c te d w ith b e n z y l amine to g iv e a s i x t y - th r e e p e rc e n t y i e l d o f a -b e n z y la m in o d ip h e n y la c e tic a c id ( L I I I ) , A s im ila r r e a c t i o n w ith N ,N -d im eth y leth y len ed iam in e gave a poor y i e l d o f a -O -d im e th y la m in o e th y la m in o )d ip h e n y la c e tic a c id (U V )*

A V \ C / C02H 1

/

\

I

i

/

p

a

rA V \ c / C02H A1 NCH2CH2N(CH3 ) 2 V LIV

ch2

v A v

\

L III

However, when an N -su b stitu fced a n i l i n e , H ,N -dim ethyl-N —phenyl— e th y le n e d ia m in e , was a llo w e d to r e a c t w ith a -c h lo r o d ip h e n y la c e tic a c i d , none o f th e d e s ir e d p ro d u c t was o b ta in e d .

28 250 m l. o f w a te r , 250*0 Gnu (2 .3 m oles) o f f r e s h l y d i s t i l l e d b e n za ld e h y d e, and 25*0 Gm* o f sodium cyanide (98$) a c c o rd in g to t h e p ro ce d u re d e s c rib e d by Adams and M arvel (8 0 ).

A v ig o ro u s r e a c tio n o c c u rre d i n n e a r ly ev ery ex p erim en t a f t e r

b o ilin g th e m ix tu re f o r a few m inutes* The cru d e b e n zo in was c o n v e rte d i n t o b e n z i l i c a c id w ith 2 5 0 .0 Gm. (6*3 m oles) o f sodium hydro x id e and 6 2 .0 Gm. (0 .3 7 m ole) o f potassiu m brornate by th e m ethod d e s c rib e d by B a lla r d and Dehn (81 ) .

The y i e l d

was 230.0 Gm. (84$) o f p ro d u c t, m .p. 149-150°; r e p o r te d (81) m.p# 14 9 150°. P r e p a ra tio n o f a -C h lo ro d ip h e n y la c e tic A cid. - In a 500 m l. f l a s k th e r e was p la c e d 68.5 Gm. (0 .3 m ole) o f b e n z i l i c a c i d , 37 m l. ( 0 .4 m ole) o f phosphorous o x y c h lo rid e , and 150 m l. o f d ry b en zen e.

The m ix tu re

was h e a te d i n a w ater b a th t o 70-75° i n a b o u t f o r t y - f i v e m in u te s.

The

te m p e ra tu re o f th e r e a c t i o n m ix tu re was m a in ta in e d a t 70- 75° f o r t h i r t y m in u te s.

The h o t s o l u t io n was f i l t e r e d , and f i l t r a t e c o n c e n tra te d

n e a r ly t o d ry n e s s a t red u c ed p r e s s u re .

The r e s id u e was s t i r r e d w ith

150 m l. o f l i g r o i n u n t i l c r y s t a l l i z a t i o n o c c u rre d .

The s o l i d was

f i l t e r e d , washed w ith l i g r o i n , and th e n d r ie d i n a vacuum d e s i c c a t o r . The y i e l d was 53 Gm# (70$) o f p ro d u c t, m .p. 115-117°> re p o r te d (82) m .p. 1 1 8 -U 9 0 .

P r e p a r a tio n o f a -C h lo ro d ip h e n v Ia c e ty l C h lo rid e . - In a 500 ml# th re e -n e c k e d f l a s k eq u ip p ed w ith a r e f l u x co n d en ser h o ld in g a d ry in g tu b e f i l l e d w ith calciu m c h lo r id e , a th erm o m eter, and a ground g l a s s s to p p e r , t h e r e was p la c e d 1 5 0 .0 Cfcn* (0 .? 2 m ole) o f phosphorous p e n ta c h lo r id e .

M ixing was accom plished w ith a s t i r r i n g ro d w h ile 8 2 .0 Gm.

(0 .3 6 m ole) o f b e n z i li c a c id was added i n sm a ll p o r t i o n s .

A fte r th e

r e a c t i o n had been i n i t i a t e d by b r i e f l y warming on a steam b a th , th e b e n z i li c a c id was added a t su ch a r a t e a s to m a in ta in th e e v o lu tio n o f hydrogen c h lo r id e .

A f te r t h e a d d itio n o f th e b e n z i l i c a c id was com­

p l e t e d , th e m ix tu re was allo w ed t o sta n d u n t i l th e e v o lu tio n o f hydrogen c h lo r id e had c ea se d .

The m ix tu re was th e n h e a te d a t 100° f o r t h i r t y

m in u tes and f i n a l l y a t 115-120° f o r f i f t e e n m in u te s.

The m ix tu re was

cooled to room te m p e ra tu re and poured slo w ly w h ile s t i r r i n g i n t o 500 Gm. o f cru sh ed i c e . o f c ru sh ed i c e .

The te m p e ra tu re was k e p t a t 0 -5 ° by th e a d d itio n

The s o l i d which form ed was f i l t e r e d , p re s s e d n e a r ly

d ry , and th e n d is s o lv e d i n 600 m l. o f p etro leu m e th e r (3 0 -6 0 ° ).

The

e th e r l a y e r was d r ie d o v e r D r i e r i t e , f i l t e r e d and th e s o lv e n t removed by d i s t i l l a t i o n .

The r e s id u e was f r a c t io n a te d to y i e l d 66#0 Gm. ( 68$ )

o f a -c h lo r o d ip h e n y la c e ty l c h lo r id e , b . p . 145-149° a t 2 ram. p r e s s u r e , m#p. 50-51°; re p o rte d ( 83) m .p. 50-51°* P r e p a ra tio n o f E th y l B e n z ila te . - A m ix tu re o f 1 0 0 .0 Gm# (0 .4 3 m ole) o f b e n z i l i c a c id , 100 m l. o f a b s o lu te a lc o h o l, and 300 m l. o f d r y benzene was re f lu x e d f o r two days i n a S o x h le t e x t r a c t o r w ith

D r i e r i t e i n th e th im b le to remove w ater from th e s o l v e n t .

The s o lu ­

t i o n was c o n c e n tra te d t o about 250 m l. and th e n e x tr a c te d s e v e r a l tim e s w ith c o ld sodium c a rb o n a te s o lu tio n (5 $ ).

The o rg a n ic la y e r was d r ie d

31 o v er anl^rdrous sodium s u l f a t e , t h e s o lv e n t removed u n d e r red u c ed p r e s ­ s u r e , and th e re s id u e f r a c t i o n a t e d t o g iv e 9 6 .5 Gm. (83$) o f p ro d u c t, b * p . 150-153° a t 3 nun. p r e s s u r e ; re p o r te d (84) b . p . 188- 190° a t 15 mm. p r e s s u r e . P r e p a r a tio n o f E th y l a -G h lo ro d ip h e n v la c e ta te . - T his p ro d u c t was p rep a red by s e v e r a l m ethods. a . A s o lu tio n o f 3 0 .0 Gm. (0 .1 2 m ole) o f e t h y l b e n z i la t e and 30 m l. o f phosphorous o x y c h lo rid e i n 100 m l. o f d ry benzene was m a in ta in e d a t 70-80° f o r fo u r h o u rs .

The m ix tu re was c o o le d , poured i n t o 200 Gba.

o f cru sh ed i c e , and th e m ix tu re s t i r r e d u n t i l n e a r ly a l l th e phosphorous o x y c h lo rid e was h y d ro ly z e d .

The o rg a n ic la y e r s were s e p a r a te d .

aqueous l a y e r was e x tr a c te d s e v e r a l tim e s w ith b e n ze n e.

The

The benzene

l a y e r s were com bined, e x tr a c te d w ith i c e w a te r , d r ie d over D r i e r i t e , and f i l t e r e d .

The f i l t r a t e was d i s t i l l e d to y i e l d 2 9 .3 Gm. (95$) o f

e s t e r , b .p . 150-154° a t 3 mm. p r e s s u r e .

The d i s t i l l a t e c r y s t a l l i z e d

i n t o a s o l i d , m .p . 43- 44° ; r e p o r te d ( 85) b .p . 185° a t 14 mm. p re s s u r e and m .p. 43- 44° • b . A s o lu tio n o f 1 9 .7 Gba. (0 .2 5 m oles) o f anhydrous p y rid in e ( d r ie d o v e r barium oxide and d i s t i l l e d ) i n 20 m l. o f d ry benzene was added d u rin g 45 m in u tes t o a s t i r r e d s o l u t io n o f 6 5 .7 Gbn. ( 0 .2 5 m ole) o f a * -c h lo ro d ip h e n y la c e ty l c h lo rid e in 100 m l. o f d ry benzene W iile m a in ta in in g th e te m p e ra tu re a t 20-25°.

The m ix tu re was s t i r r e d f o r

an a d d i t i o n a l f i f t e e n m in u te s , and th e n a s o lu tio n o f 1 1 .5 Cbn. ( 0 .2 5 m ole) o f a b s o lu te a lc o h o l i n 50 m l. o f d ry benzene was added d ro p w ise . The s o l u t io n was s t i r r e d and m a in ta in e d a t 20-25° f o r f i v e h o u rs and th e n poured i n to 300 m l. o f crushed i c e .

The m ix tu re was e x tr a c te d

32 w ith 150 m l. o f p etro leu m e th e r (30- 60° ) .

The o rg a n ic la y e r s were

s e p a r a te d , d r ie d o v e r D r i e r i t e , and f i l t e r e d .

The f i l t r a t e was con­

c e n t r a t e d , and th e re s id u e was poured i n t h i n l a y e r s i n t o a c r y s t a l ­ l i z i n g d is h which was c o o le d i n a d ry i c e —a c e to n e b a th .

The s o l i d

l a y e r s which f o ra e d were c o ll e c t e d t o y i e l d 61*0 Gm. (90$) o f p ro d u c t, m.p* 38—4 2 ° .

R e c r y s t a l l i z a t i o n o f th e s o l i d from p e tro leu m e t h e r w ith

a 20$ l o s s gave a pure p ro d u c t, m .p . 43- 44°♦ P r e p a ra tio n o f E th y l a -A n ilin o d ip h e n v la c e t a t e * - A m ix tu re o f 1 1 .0 Gm. (0 .0 4 m ole) e th y l a -c h lo r o d ip h e n y la c e ta te and 7*9 Gm. (0 .0 8 5 m ole) o f a n i l i n e was h e a te d o v e rn ig h t on a steam b a th and th e n a t 130-140° f o r two h o u rs .

The co o led m ix tu re was d is s o lv e d i n benzene

and f i l t e r e d .

The benzene and e x ce ss a n i l i n e were removed by vacuum

d is tilla tio n .

The gummy r e s id u e was d is s o lv e d i n a lc o h o l, and th e

s o lu tio n c l a r i f i e d w ith a c t iv a t e d carbon and f i l t e r e d . to th e warn f i l t r a t e u n t i l i t was c lo u d y . c o o lin g was r e c r y s t a l l i z e d from a lc o h o l.

W ater was added

The s o l i d which s e p a r a te d on The y i e l d was 2 .5 Gm. (19$)

o f p ro d u c t, m .p. 114—115°; re p o rte d ( 86) m .p. 114-115°♦ P re p a ra tio n o f a -A n ilin o d ip h e n v la c e tic A cid. - A m ix tu re o f 2 4 .7 Gm. ( 0 .1 m ole) o f a -c h lo r o d ip h e n y la c e tic a c id and 2 7 .9 Gm. (0 .3 m ole) o f a n il i n e i n 100 m l. o f d ry to lu e n e was r e f lu x e d f o r tw e lv e h o u rs. The warm r e a c t i o n m ix tu re was s t i r r e d w ith 50 m l. o f sodium hydroxide s o lu tio n (30$) u n t i l a l l o f th e s o l i d had d is s o lv e d . s e p a r a te d .

The la y e r s were

The to lu e n e l a y e r was e x tr a c te d w ith th r e e 50 m l. p o r­

tio n s o f w a te r.

The low er la y e r s were com bined, e x tr a c te d w ith 150 m l.

o f e t h e r , and th e n a c i d i f i e d w ith h y d ro c h lo ric a c id (1 0 $ ). c i p i t a t e d s o lid was f i l t e r e d and washed w ith w a te r.

The p re ­

The s o l i d was

33 t r i t u r a t e d w ith b o ilin g a lc o h o l, and th e su sp e n sio n co o le d and f i l t e r e d * The y i e l d was 2 6 .1 Gm. (85$) o f p ro d u c t, m .p. 165-167°; r e p o r te d (86) m .p . 1 6 8 °. P r e p a r a tio n o f a -B e n z y la m in o d jp h e n v la c e tic A cid. - A m ix tu re o f 4 9 .4 Chi. ( 0 .2 m ole) o f a -c h lo r o d ip h e n y la c e tic a c i d , 4 2 .8 Gm. ( 0 .4 m ole) o f b en zy lam ine, and 200 m l. o f d ry to lu e n e was r e f lu x e d f o r two h o u rs . The s o l i d which form ed was f i l t e r e d and washed w ith d i l u t e h y d ro c h lo ric a c id and th e n w ith w a te r.

The s o l i d was t r i t u r a t e d i n b o i li n g a lc o h o l,

and t h e su sp e n sio n was cooled and f i l t e r e d .

The y i e l d was 4 0 .0 Gm.

(63$) o f p ro d u c t, m .p. 210-212°; re p o rte d (8 7 ) m .p. 212°. P r e p a ra tio n o f a - ( p ^ im e th v la m in o e th o x y )d ip h e n y la c e tic Acid Hydro­ c h lo r id e . - To a re flu x ! n g s o lu tio n o f 3 2 .0 Chi. (0*36 m ole) o f 8 - d i m eth y lam in o eth an o l, th e r e was added dropw ise a s o l u t io n o f 4 4 .0 Gm. (0 .1 8 m ole) o f a—c h lo ro d ip h e n y la c e tic a c id i n 300 m l. o f d ry to lu e n e . The m ix tu re was r e f lu x e d f o r s ix te e n h o u rs , c o o le d , and th e n s t i r r e d w ith a s o lu tio n o f 20 Gm. o f sodium hydroxide i n 50 m l. o f w a te r u n t i l a l l o f th e s o l i d had d is s o lv e d .

The l a y e r s were s e p a r a te d , and th e

to lu e n e l a y e r was e x tr a c t e d w ith e ig h t 50 m l. p o rtio n s o f w a te r.

The

aqueous p o rtio n s were combined and a c i d i f i e d w ith h y d ro c h lo ric a c id (37$)*

The c o o le d m ix tu re was e x tr a c te d w ith e th e r u n t i l th e aqueous

p o r tio n was c l e a r , and th e n th e aqueous s o lu tio n was e v a p o ra te d to d ry n ess u n d e r red u ced p re s s u re w hile h e a tin g i n a w a te r b a th a t 4 0 °. The r e s id u e was d is s o lv e d i n 300 m l. o f a lc o h o l (95$)> f i l t e r e d , and th e s o lu tio n e v a p o ra te d n e a r ly t o d ry n e ss u n d er red u c ed p re s s u r e . E th e r was added u n t i l p r e c i p i t a t i o n was co m p lete. f i l t e r e d o f f and d r ie d i n an oven a t 1 0 5 °.

The s o l i d was

The y i e l d was 3 6 .0 Gm*

34 ( 56$ ) o f p r o d u c t, m .p. 195-198° w ith d e c o m p o sitio n .

A d d itio n a l c r y s t a l ­

l i z a t i o n s from a lc o h o l- e t h y l a c e t a t e gave a p ro d u c t m e ltin g a t 197— 198° w ith d eco m p o sitio n . A nal. C a lc d . f o r G^^ggNO^Cl:

N, 4*18.

Found:

N, 4*05*

P r e p a r a tio n o f D im e th y l« m in o a c e to n itrile . - T his compound was p re p a re d by th e p ro ced u re d e s c rib e d by T urner ( 8 8 ).

I n to a th re e -n e c k e d

f l a s k th e r e was in tro d u c e d 660.0 Gm. (3 .7 m oles) o f aqueous d im e th y lamine s o lu tio n (2 5 $ ).

To th e s t i r r e d s o l u t i o n , c o o le d i n a w a ter b a th ,

th e r e was added 3 3 0 .0 Gbn. (4 .0 m o les) o f aqueous fo m a ld e h y d e s o l u t i o n (37$) a t such a r a t e t h a t t h e te m p e ra tu re d id n o t r a i s e beyond 25°* While m a in ta in in g th e same te m p e ra tu re , 1 9 6 .0 Gm. ( 4 .0 m oles) o f sodium cyanide (96$) was added, fo llo w e d a f t e r one hour by 305 Gbn. ( 3 .6 m oles) o f h y d ro c h lo ric a c id (3 7 $ ).

A fte r a llo w in g th e m ix tu re to s ta n d o v e r­

n i g h t , i t was e x tr a c t e d b y c o n tin u o u s e x tr a c t i o n w ith th io p h e n e f r e e benzene f o r f i v e d a y s.

The benzene l a y e r was d r i e d o v e r sodium s u l f a t e

and th e n d i s t i l l e d i n th e p resen c e o f W-6 Raney n i c k e l c a t a l y s t (89) th ro u g h a 25 cm. V igreaux column.

The y i e l d was 1 4 2 .0 Gm. (46$) o f

p ro d u c t, b . p . 133-135° a t 747 mm. p r e s s u r e ; re p o r te d (88) b .p . 134-137°* P r e p a r a tio n o f N .N -D im ethv^ethvlenedn amine. - A m ix tu re o f 6 2 .0 Gm. (0 .7 5 m ole) d im e th y la m in o a c e to n itrile and 21 Gm. W-6 Raney n ic k e l c a t a l y s t was h e a te d t o 7 5-80° and k e p t a t t h i s te m p e ra tu re u n d er 1000 pounds p r e s s u re o f hydrogen f o r t h r e e h o u rs .

The m ix tu re was f i l t e r e d ,

and th e f i l t r a t e d i s t i l l e d th ro u g h a 25 cm. V igreaux colum n.

The

y i e l d was 2 6 .0 Gm. (40$) o f p ro d u ct d i s t i l l i n g a t 100-110° a t 750 mm. p re ssu re .

T urner (88) i n a p ro ced u re s i m i l a r t o th e above one re p o rte d

a b o ilin g p o in t o f 105 -1 0 8 °.

35 P r e p a ra tio n o f a - ( B -D im ethvlam inoethyl am ino)d i p h e n y la c e tic Acid D ih v d ro c h lo rid e . - A s o l u t io n o f 12*4 Gm. (0 .0 5 m ole) o f N ,N -d im eth y leth y len e d iam in e i n 50 m l. o f d ry benzene was allo w ed t o sta n d a t room te m p e ra tu re f o r two h o u rs and th e n re flu x e d f o r s i x t e e n h o u rs.

The

benzene and u n re a c te d amine were removed u n d er red u ced p r e s s u r e .

The

re s id u e was s t i r r e d w ith 20 m l. o f sodium h y d ro x id e s o lu tio n (2 0 $ ). The m ix tu re was e x tr a c t e d w ith 30 m l. o f e th e r and th e e t h e r l a y e r washed w ith 15 m l. o f w a te r.

The combined aqueous l a y e r s were a c i d i f i e d

w ith 30 m l. o f h y d ro c h lo ric a c id (2 0 $ ). t a t e was c o o le d u n t i l i t s o l i d i f i e d .

The r e s u l t i n g gummy p r e c i p i ­

The s o l i d was p r e c i p i t a t e d s e v e r a l

tim es from a lc o h o l s o lu tio n w ith e th y l a c e t a t e and f i n a l l y r e c r y s t a l — l i z e d from 95$ a lc o h o l.

The y i e l d was 2 .1 Gm. (13$) o f p ro d u c t, m .p .

1 62-163°. A nal. C alcd. f o r CigH24M2°2c^2$

7 .5 4 .

Found:

N, 7.59*

The R e a c tio n o f a -C h lo ro d ip h e n v la c e tic Acid W ith N .N -D im ethvlN -p h e n v le th v le n ed ia m in e . - To 1 2 .3 Gm. (0 .0 7 5 m ole) o f N ,N -d im eth y lN*-p h e n y le th y le n e d ia m in e (40) d is s o lv e d i n 75 m l. o f benzene th e r e was added 9 .2 Gm. (0 .0 3 7 m ole) o f a - c h lo r o d ip h e n y la c e tic a c id d is s o lv e d i n 75 m l. o f b e n ze n e.

The m ix tu re was r e f lu x e d f o r tw e n ty -fo u r h o u rs .

The benzene was e v a p o ra te d , and th e r e s id u e m ixed w ith 50 m l. o f sodium hydroxide s o l u t io n (2 0 $ ).

The m ix tu re was e x tr a c t e d w ith b e n z e n e , th e

benzene l a y e r was washed w ith w a te r, and th e aqueous la y e r s were com­ b in e d and a c i d i f i e d w ith h y d ro c h lo ric a c id (1 0 $ ).

The a c id s o l u t io n

was c o n c e n tra te d to d ry n e ss under reduced p r e s s u r e , and th e s o l i d re s id u e d is s o lv e d i n a lc o h o l (9 5 $ ). and e v a p o ra te d .

The a lc o h o l s o lu tio n was f i l t e r e d

The s o l i d r e s id u e ( 4 .4 Gnu ) was r e c r y s t a l l i z e d s i x

36 tim e s from a b so lu te a lc o h o l.

175° •

The h y d ro sco p ic c r y s t a l s m elted a t 1 7 3 -

The r e p o r te d m e ltin g p o in t f o r N ,N -d im eth yl—N—p h e n y le th y le n e —

diam ine d ih y d r o c h lo r id e i s 1 7 6 -1 7 7 ° ( 4 0 ) .

A n al. C alcd. f o r C1 oH18N2C:l2 $

n > H * 01*

Found: N, 11.42*

P r e p a r a tio n o f B-Diet h v lam in o eth v l q-B enzy^amlpodi p h e n y la c e ta te . To one e q u iv a le n t of sodium hyd ro x id e i n a lc o h o l (95$) t h e r e was added in sm all p o r tio n s 31*8 Gm. (0*1 m ole) o f a -b e n zy la m in o d ip h en y lac et i c a c id .

The s o l u t io n was shaken a f t e r each a d d it i o n t o d is s o lv e th e

s o lid .

The s o lu tio n was f i l t e r e d and th e s o lv e n t was removed u n d e r

reduced p r e s s u r e .

The r e s id u e was mixed w ith 200 m l. o f to lu e n e , and

th e to lu e n e d i s t i l l e d u n t i l th e d i s t i l l a t e was c l e a r .

To th e r e f lu x in g

m ix tu re th e r e was added dropw ise 1 7 .0 Gbn. (0 .1 2 m ole) o f p - d i e t h y l am inoethyl c h lo rid e (90) d u rin g two h o u rs . f o r f o u r h o u rs .

R e flu x in g was c o n tin u e d

The c o o le d m ix tu re was made a lk a li n e w ith sodium

carb o n ate s o lu tio n (5 $ ), and th e o i l which s e p a ra te d was e x tr a c te d w ith e t h e r .

The e th e r e x t r a c t was d r ie d o v e r anhydrous sodium s u l f a t e

and f i l t e r e d .

Removal o f th e s o lv e n t gave a v is c o u s o i l d i s t i l l i n g

a t 208-225° a t 2 mm. p r e s s u r e .

Re d i s t i l l â t io n o f th e d i s t i l l a t e

y ie ld e d 2 1 .1 Gm. (50$) o f p ro d u c t d i s t i l l i n g a t 220-225° a t 2 mm. p re ssu re .

An a n a l y t i c a l sam ple was c o lle c te d a t 224-225° a t 2 mm.

p ressu re . A nal. C alcd. f o r

6 .7 2 .

Found:

N, 6 .6 8 .

P r e p a r a tio n o f B -D ieth v lam in o eth v l nr- ( ft-D im ethvlam inoethoxv ) d ip h e n y la c e ta te . - A su sp e n sio n o f 3 3 .6 Gm. ( 0 .1 m ole) o f a - O - d i me th y lam inoethoxy )d ip h en y lac e t i c a c id hydro c h lo r id e i n 100 m l. o f a lc o h o l (95$) was a d ju s te d t o pH 9-10 w ith an a lc o h o lic s o l u t io n o f

37 sodium h y d ro x id e (1 0 $ ). s e v e r a l tim e s w ith e t h e r .

The f la k y p r e c i p i t a t e was f i l t e r e d and washed The s o l i d was suspended i n 200 m l. o f d ry

to lu e n e , and th e so lv e n t was d i s t i l l e d u n t i l th e d i s t i l l a t e was c l e a r . To th e r e f l u x i n g , s t i r r e d su sp e n sio n th e r e was added dropw ise d u rin g two h o u rs 2 0 .4 Gtau (0 .1 5 m ole) o f P -d ie th y la m in o e th y l c h lo r id e (90) d is s o lv e d i n 75 m l. o f d ry to lu e n e .

The su sp e n sio n was re flu x e d f o r

an a d d it i o n a l fo u r hours and th e n c o o le d .

The r e a c t i o n m ix tu re was

made a l k a li n e w ith d i l u t e sodium b ic a r b o n a te s o l u t i o n , and th e n e x tr a c te d w ith e th e r .

The o rg a n ic l a y e r was d r ie d o v er sodium s u l f a t e , f i l t e r e d ,

and d i s t i l l e d .

The y i e l d o f p ro d u c t, d i s t i l l e d f o r th e t h i r d tim e a t

181-185° a t 2 mm. p r e s s u r e , was 19*0 Gm. (4 7 $ ); re p o r te d (91) b . p . 168-170° a t 0 .3 mm. p r e s s u r e . P re p a ra tio n of E th y l a - ( B-Dimet hvlam inoet hoxv ) d ip h en y lac e t a t e . - To a s t i r r e d su sp e n sio n o f 2 .3 Gbn. (0 .1 m ole) o f powdered sodium i n 200 m l. o f anhydrous e t h e r , th e r e was added dropw ise 2 5 .6 Gm. (0 .1 m ole) o f e th y l b e n z i l a t e . r e a c te d .

The m ix tu re was re f lu x e d u n t i l th e sodium had

To th e s o lu tio n th e r e was added dropw ise 1 3 .0 Gm. (0 .1 2 m ole)

o f P -d im eth y lam in o eth y l c h lo r id e i n 150 m l. o f d ry to lu e n e .

The m ix tu re

was re flu x e d f o r f o u r h o u rs, th e e th e r was d i s t i l l e d o f f , and th e s o lu ­ t i o n was h e a te d o v e rn ig h t on a steam b a th .

The cooled r e a c t i o n m ix tu re

was e x tr a c te d th r e e tim e s w ith 50 m l. o f h y d ro c h lo ric a c id (1 0 $ ).

The

combined aqueous e x t r a c t s were made a lk a lin e w ith sodium c a rb o n a te (1 0 $ ), and th e m ix tu re e x tr a c t e d w ith b e n ze n e.

The benzene s o lu tio n

was d r ie d w ith D r i e r i t e , th e s o lv e n t removed by d i s t i l l a t i o n un d er reduced p r e s s u r e , and th e re s id u e f r a c t i o n a t e d to g iv e 1 0 .1 Gm. (33$) o f p ro d u c t, b . p . 157-160° a t 0 .1 3 mm* p r e s s u r e . A nal. C alcd. f o r O ^H ^N O ^:

N, 4 .2 8 .

Found:

N, 4*24*

38 The b a se gave a s o l i d a c id o x a la te s a l t which was r e c r y s t a l l i z e d from m eth yl e th y l k e to n e to g iv e c r y s t a l l i n e e t h y l CX—( {3—dim e t hylam ino— e th o x y )d ip h e n y la c e t a te hydrogen o x a l a t e , m .p. 1 4 5 -1 4 6 °. A nal. C alcd. f o r C^H^yNOy:

N, 3 .3 5 .

Found:

N, 3 .5 0 .

P r e p a r a tio n of E th y l a - CB -D iethylam inoethoxv) d ip h e n y la c e ta te . - T his compound was p re p a re d e s s e n t i a l l y b y th e method r e p o r te d i n a Sw iss p a te n t (7 7 ).

To a r e f lu x in g s t i r r e d su sp e n sio n o f 2 .3 Gm. ( 0 .1 m ole)

o f powdered sodium in 200 m l. o f d ry e th e r th e r e was added 2 5 .6 Gm. ( 0 .1 m ole) o f e th y l b e n z i la t e d u rin g two h o u rs.

R e flu x in g was c o n tin u e d

u n t i l n e a r ly a l l o f th e sodium had r e a c t e d , and th e n 1 5 .0 Gm. (0 .1 1 m ole) o f p -d ie th y la m in o e th y l c h lo r id e was added d u rin g t h i r t y m in u te s.

The

m ix tu re was r e f lu x e d f o r fo u r h o u rs and th e n d i lu t e d w ith 100 m l. o f d ry to lu e n e .

The e th e r was removed by d i s t i l l a t i o n .

The rem ain in g

s o lu tio n was warmed on a steam b a th f o r fo u r h o u rs , c o o le d and th e n e x tr a c te d w ith 100 m l. o f h y d ro c h lo ric a c id (1 0 $ ).

The a c id s o lu tio n

was made a l k a li n e w ith sodium hydroxide s o l u t io n ( 5 $ ).

The o i l which

s e p a ra te d was e x tr a c te d w ith e th e r .

The e t h e r s o lu tio n was d r i e d o v e r

D r i e r i t e , f i l t e r e d and c o n c e n tr a te d .

The r e s id u e was f r a c t i o n a t e d t o

y i e l d 1 5 .0 Gm. (41$) o f p ro d u c t, b .p . 145-148° a t 0 .0 5 mm. p r e s s u r e ; re p o rte d (77) b .p . 148-151° a t 0 .0 8 nan. p r e s s u r e . A nal. C alcd . f o r C22^29^^31

3*94.

Found:

N, 4*11*

The hydrogen o x a la te s a l t was p re p a re d by th e a d d itio n o f an e th e r e a l s o lu tio n o f th e amine to an e x c e ss o f an e t h e r e a l s o l u t io n o f anhydrous o x a lic a c id .

The s o l i d w hich form ed was f i l t e r e d and r e ­

c r y s t a l l i z e d from m eth y l e th y l k e to n e t o g iv e c r y s t a l l i n e e th y l a - ( p -d ie th y la m in o e th o x y )d ip h e n y la c e ta te hydrogen o x a l a t e , m .p. 1241 2 5 °.

39 A nal. C alcd. f o r C^H^^NOy:

N, 3*15*

Found:

N, 2.96*

P r e p a r a tio n o f E th y l a - ( B -D im ethylam inoethylam ino) d ip h e n y l­ a c e t a t e . - A m ix tu re o f 12.3 Gm. (0 .0 1 4 m ole) o f N ,N -dim ethylam ino— e th y le n e d i amine and 1 8 .2 Gm. (0 .0 7 m ole) o f e th y l a -c h lo ro d ip h e n y l­ a c e ta te was h e a te d a t 120-130° f o r tw enty—two h o u rs .

The u n re a c te d

amine was d i s t i l l e d from th e h o t s o lu tio n u n d e r red u ced p r e s s u r e .

The

re s id u e was c o o le d , t r i t u r a t e d w ith 100 m l. o f h y d ro c h lo ric a c id (1 0 $ ), and th e n e x tr a c te d w ith 200 m l. o f b e n ze n e.

The c o ld a c id l a y e r was

made a lk a li n e w ith sodium hydroxide s o l u t io n (5$)« formed was e x tr a c te d w ith 100 m l. o f b e n ze n e.

The o i l y l a y e r t h a t

The benzene e x t r a c t was

d r ie d o v er D r i e r i t e , and th e f i l t e r e d s o lu tio n d i s t i l l e d .

The y i e l d

was 6 .9 Gm. (30$) o f p ro d u c t, b .p . 172-174° a t 3 mm. p r e s s u r e . A nal. C alcd. f o r 0 2 q ^ 26 ^ 2 ^ 2 :

N, 8 .5 6 .

Found:

N, 8 .4 0 .

P r e p a ra tio n o f D ie t h y la m in o a c e to n i t r i l e . - T his compound was p re ­ p ared a cco rd in g t o th e pro ced u re o f A lle n and Van A llan (9 2 ).

From

7 8 .0 Chn. (6 .7 5 m ole) o f sodium b i s u l f i t e , 57 m l. o f 37-40$ form alde­ hyde s o l u t io n , 55*0 Gfrn. (0 .7 5 m ole) o f d ie th y la m in e , and 37*0 Gm* (0*75 m ole) o f sodium cy an id e th e r e was o b ta in e d 69*0 Gm. (82$) o f p ro d u c t, b . p . 64-66° a t 17 mm. p r e s s u r e ; r e p o rte d ( 92) b .p . 61-63° a t 14 ram. p r e s s u r e . P re p a ra tio n o f N .N -D ieth v leth y l enediam in e . - T his compound was p re p a re d by sodium r e d u c tio n o f th e n i t r i l e a s d e s c rib e d by H a ll and T urner (93)*

From 5 6 .0 Gm. (0 .5 m ole) o f d i e t h y l a m in o a c e t o n it r i le ,

115 Gm. (5*0 m o les) o f sodium , and 1050 m l. o f a b s o lu te a lc o h o l th e r e was o b ta in e d 1 8 .9 Gba. (33$) o f p r o d u c t, b .p . 148-149° a t 750 ram. p re s s u re ; r e p o r te d (93) b .p . 149° a t 764 ram. p r e s s u r e .

40

P r e p a r a tio n o f E th y l tt-fB -D ieth y lam in o eth y lam ln o ) d ip h e n y la c e ta te * - A m ix tu re o f 1 8 .7 Gm. (0 .1 6 m ole) o f N ,N -d ie th y le th y le n e d ia m in e and 2 5 .6 &a. ( 0 .1 m ole) o f e th y l a -c h lo r o d ip h e n y la c e ta te was h e a te d a t 120-130° f o r tw enty-tw o h o u rs .

The e x c e ss amine was d i s t i l l e d from th e h o t

s o l u t io n u n d er red u ced p r e s s u r e .

The re s id u e was c o o le d , t r i t u r a t e d

w ith 100 m l. o f h y d ro c h lo ric a c id (1 0 $ ), and th e n e x tr a c te d w ith 200 m l. o f b e n ze n e.

The c o ld a c id la y e r was made a lk a li n e w ith sodium h y d ro x id e

s o lu tio n ( 5 $ ). o f b en zen e.

The o i l y la y e r t h a t formed was e x tr a c te d w ith 200 m l.

The benzene e x t r a c t was d r ie d over D r i e r i t e , and th e f i l ­

t e r e d s o lu tio n was c o n c e n tra te d .

The r e s id u e was d i s t i l l e d t o y i e l d

4*2 Gm. o f p ro d u c t, b .p . 173-178° a t 0 .4 mm. p r e s s u r e .

An a n a l y t i c a l

sample was c o ll e c t e d a t 178° a t 0*4 mm* p r e s s u r e . A nal. C alcd. f o r CppHyfeOp:

N, 7*90.

Found:

N, 8 .0 6 .

P r e p a ra tio n o f 1—G hloro—3 -io d o o ro o a n e . — T his compound was p re p a re d a c c o rd in g to th e pro ced u re o f Hass and Huffman ( 9 4 ).

A m ix tu re o f

1 0 0 .0 Gm. (0 .8 9 m ole) o f trim e th y le n e c h lo r i d e , 139*0 Gm. (0 .8 9 m ole) o f sodium io d id e , and 500 m l. o f d ry a c e to n e was r e f lu x e d o v e rn ig h t (15 h o u r s ).

The c o o le d m ix tu re was f i l t e r e d , and t h e f i l t r a t e f r a c ­

tio n a te d th ro u g h a 30 cm. m o d ified Widmer column t o g iv e 86 Gams. (47$) o f 1 -c h lo ro —3 -io d o p ro p a n e ; b .p . 51-52° a t 9 mm. p r e s s u r e ; r e p o r te d (94) b . p . 6 0 .8 ° a t 15 mm. p r e s s u r e . P r e p a ra tio n o f y -D im ethylam inopropyl C h lo rid e . - D im ethylam ine, 53*0 m l. ( 0 .8 m o le ), was added to 200 m l. o f d ry benzene p re v io u s ly co o led t o 0 - 5 ° , and th e s o lu tio n th e n added d u rin g t h i r t y m in u tes t o a s t i r r e d s o lu tio n o f 82*0 Gm. ( 0 .4 m ole) o f l - c h lo r o - 3 - io d o propane i n

100 m l. o f d ry benzene w h ile m a in ta in in g th e te m p e ra tu re a t 0—10°* The s o l u t io n was s e a le d i n a p re s s u r e v e s s e l and k e p t i n an i c e b a th f o r two h o u rs and th e n a t room te m p e ra tu re f o r two d a y s .

The r e a c t i o n mix­

t u r e was t r e a t e d w ith s u f f i c i e n t hydrogen c h lo r id e t o p r e c i p i t a t e th e b a s ic m a t e r i a ls from s o l u t io n .

The benzene s o lv e n t was d e c a n te d from

th e p r e c i p i t a t e , and th e o i l y mass washed by t r i t u r a t i o n w ith s e v e r a l 50 ml* p o r tio n s o f e th e r .

E th e r , 200 m l . , was added t o th e r e s i d u e ,

and th e m ix tu re th e n t r i t u r a t e d w ith 50*0 Gm. o f f la k e sodium h y d ro x id e. The e th e r l a y e r was d e c a n te d , th e r e s id u e e x tr a c t e d s e v e r a l tim e s w ith e t h e r , and th e combined e t h e r e a l s o lu tio n s were d r i e d w ith anhydrous sodium s u l f a t e .

The f i l t e r e d e th e r e a l s o lu tio n was c o n c e n tra te d under

reduced p r e s s u r e , and th e r e s id u e f r a c t i o n a t e d to g iv e 2 7 .2 Gm. (56$) o f p ro d u c t, b .p * 32-35° a t 17 mm. p re s s u r e ; r e p o r te d (95) b .p * 29-32° a t 17 mm. p r e s s u r e . P r e p a ra tio n o f D ip h e n y la c e to n itr ile . — D ip h e n y la c e to n itr ile was p re p a re d by th e method o f G insberg and B a iz e r (9 6 ).

B enzyl c y a n id e ,

8 8 .2 Gm. (0 .7 4 m o le ), was h e a te d t o 105-110°, and th e n 39*0 m l. (0 .7 6 m ole) o f brom ine added d u rin g s i x t y m in u tes w h ile s t i r r i n g th e r e a c t i o n m ix tu re and m a in ta in in g th e te m p e ra tu re a t 105-110°•

A f te r th e a d d i­

t i o n was com pleted, 400 m l. o f d ry benzene was ad d ed , and th e m ix tu re re f lu x e d f o r one h o u r.

The r e a c t i o n m ix tu re was c o o le d to 20, and

101*4 Gm. (0*76 m ole) o f anhydrous aluminum c h lo r id e added i n sm a ll p o rtio n s d u rin g one hour w h ile m a in ta in in g th e te m p e ra tu re a t 20-25°* The tem p e ra tu re was th e n r a i s e d slo w ly t o 3 5 -4 0 °, a t which te m p e ra tu re a v ig o ro u s e v o lu tio n o f hydrogen bromide o c c u rre d .

A fte r th e r e a c t i o n

42 had s u b s id e d , th e r e a c t i o n m ix tu re was h e a te d a t r e f l u x f o r s i x t y min­ u t e s , c o o le d to room te m p e ra tu re , and th e n poured slo w ly i n t o a m ix tu re o f 350 Gm. o f ic e and 150 ml* o f h y d ro c h lo ric a c id .

The benzene l a y e r

was s e p a r a te d , t h e aqueous l a y e r e x tr a c te d s e v e r a l tim e s w ith 150 m l. p o rtio n s o f b en zen e, and t h e benzene s o lu tio n s were combined and d r ie d w ith anhydrous sodium s u l f a t e .

The s o l u t io n was c o n c e n tra te d by d i s ­

t i l l a t i o n , and th e r e s id u e f r a c t i o n a t e d .

The f r a c t i o n b o i li n g a t 150-

170° a t 5 mm. p re s s u re was c o l l e c t e d , and th e n r e c r y s t a l l i z e d from m eth y l a lc o h o l t o g iv e 91*0 Gm. (64$) o f d i p h e n y l a c e t o n i tr i l e m e ltin g a t 72- 74° ; r e p o r te d ( 96 ) m .p . 73-74°» P r e p a ra tio n o f 5-Dimethvl amjno -2 .2 - d ip h e n v lp e n ta n e n itr ile . - T his compound was p re p a re d e s s e n t i a l l y by th e m ethod o f E a s to n , G ard n er, E v an ick , and S te v en s (97)* To a w e ll s t i r r e d su sp en sio n o f 9*0 Gm. (0 .2 3 m ole) o f sodium amide i n 50 m l. o f d ry benzene h e a te d to 4 5 -5 0 °, th e r e was added d u rin g a f i f t e e n m inute p e rio d 39*0 Gm. (0 .1 3 m ole) o f d i p h e n y l a c e t o n i tr i l e d is s o lv e d i n 75 m l. o f d ry b e n z e n e , and th e r e a c t i o n m ix tu re was m ain­ ta in e d a t t h i s te m p e ra tu re f o r n in e ty m in u te s .

The m ix tu re was co o led

to 2 0 -2 5 °, and a s o lu tio n o f y -d im e t hylam ino p ro p y l c h lo r id e i n 50 m l. o f x y len e was added d u rin g t h i r t y m in u te s.

The m ix tu re was re flu x e d f o r

f iv e h o u rs and a f t e r s ta n d in g o v e rn ig h t was poured i n t o w a te r.

The

benzene l a y e r was e x tr a c te d w ith f o u r 50 m l. p o r tio n s o f h y d ro c h lo ric a c id (2 0 $ ).

The a c id s o l u t io n was made a l k a l i n e w ith sodium hydroxid e

s o lu tio n (1 0 $ ), and th e l i b e r a t e d o i l e x tr a c t e d w ith e t h e r .

The e t h e r e a l

e x tr a c t was d r ie d w ith D r i e r i t e , f i l t e r e d , and e v a p o ra te d t o d r y n e s s . The re s id u e was r e c r y s t a l l i z e d from p e tro le u m e th e r (3 0 -6 0 °) to g iv e

43 3 0 .1 Ota. (54/^) o f p ro d u c t, n u p . 64- ^ 6° ; re p o rte d (9 7 )

6 4-65°•

P r e p a ra tio n o f 5—Dim ethylam ino—2 .2 —d ip h e n v lp e n ta n o ic Acid B i s u l f a t e , - A m ix tu re o f 13*9 Gnu (0 .0 5 m ole) o f 5~ diinethylam ino-2, 2 d ip h e n y lp e n ta n e n itr ile , 16 m l. o f s u l f u r i c a c id ( 94$ ) , and 12 m l. o f w ater was h e a te d i n an o i l b a th a t 145-155° f o r f i v e h o u rs .

The co o le d

r e a c tio n m ix tu re was poured i n to 175 m l. o f w a te r, and th e m ix tu re made a lk a lin e w ith sodium hyd ro x id e (1 0 $ ).

The aqueous m ix tu re was e x tr a c te d

s e v e r a l tim e s w ith e t h e r , and th e aqueous l a y e r a d ju s te d t o pH 5-6 w ith a c e tic a c id .

The p r e c i p i t a t e d s o l i d was f i l t e r e d , and th e p ro d u ct

d r ie d u n d er 14 mm. vacuo a t 8 0 °.

The s o l i d was suspended i n 15 m l. o f

a b s o lu te a lc o h o l, and th e m ix tu re made a c i d ic w ith a s o l u t io n o f 5 m l. o f s u l f u r i c a c id (94$) and 25 m l. o f a b s o lu te a lc o h o l.

The s o lu tio n

was warmed, anhydrous e th e r added u n t i l th e s o l u t io n became c lo u d y , and th e m ix tu re was cooled i n an ic e - b a t h .

R e c r y s t a l l i z a t i o n o f th e

s o l i d once from a lc o h o l- e th e r gave 8 .0 Gms. o f p ro d u c t m e ltin g a t 175-178°•

S e v e ra l r e c r y s t a l l i z a t i o n s from a lc o h o l- e th e r gave a

p ro d u ct m e ltin g a t 178—179° • A nal. C alcd. f o r C19H25NSO6:

N, 3#54.

Foundi

N, 3*42$

P r e p a ra tio n o f E th y l 5-D im ethvlam ino—2 . 2 -d ip h e n v lp e n ta n o a te H y d ro c h lo rid e . - 5 -D im eth y la m in o -2 ,2 -d ip h en y lp e n ta n o ic a c id b i s u l f a t e , 6 .0 Gm. (0.015 m o le ), was added t o 100 m l. o f b e n ze n e.

The m ix tu re was

d i s t i l l e d u n t i l th e d i s t i l l a t e was c l e a r i n d ic a t i n g th e rem oval o f t r a c e s o f m o is tu re .

To th e c o ld m ix tu re th e r e was added 1 2 .0 Gkn.

(0 .1 m ole) o f th io n y l c h lo r id e i n 25 m l. o f d ry b e n ze n e.

The r e a c tio n

m ix tu re was h e a te d t o 55° and m a in ta in e d a t 50- 55° f o r fo u r h o u rs . The s o lv e n t and e x ce ss t h io n y l c h lo rid e were removed u n d er red u ced

44 p r e s s u r e , 30 m l. o f a b s o lu te a lc o h o l was ad d ed , and th e r e a c t i o n m ix tu re was h e a te d a t 50-55° f o r t h i r t y m in u te s and th e n r e f lu x e d f o r two h o u rs . The e x c e ss a lc o h o l was removed u n d e r red u ced p r e s s u r e , 25 ml# o f w a te r was a d d ed , and th e r e a c t i o n m ix tu re was made a lk a li n e w ith s u f f i c i e n t sodium h y dro xide s o lu tio n ( 5 $ ).

The o i l y l a y e r was e x tr a c t e d w ith

e t h e r , th e e t h e r e a l e x t r a c t was d r ie d w ith D r ie r i t e and th e s o l u t io n filte re d .

An e t h e r e a l s o l u t io n o f hydrogen c h lo r id e was added t o th e

f i l t e r e d e t h e r e a l s o lu tio n u n t i l th e p r e c i p i t a t i o n o f th e o i l y hydro­ c h lo r id e was c o m p lete . re s u lte d .

Upon s ta n d in g f o r s e v e r a l days c r y s t a l l i z a t i o n

The y i e l d was 3 .0 Gm. o f p ro d u c t m e ltin g a t 165—1 6 8 °.

S e v e ra l

r e c r y s t a l l i z a t i o n s from e th a n o l- e th e r s o lu tio n gave a p ro d u c t m e ltin g a t 167 -1 6 9°. A nal. C a lcd . f o r G z ^ a R K ^ C l:

N, 3 .3 7 .

Found:

N, 3.98#

P r e p a ra tio n o f y -D ie th v la m in o p ro p v l C h lo rid e . - T his compound was p re p a re d e s s e n t i a l l y by th e m ethod o u tlin e d by W alker (9 8 ). A s o l u t io n o f 6 5 .6 Gm. (0 .5 m ole) o f / -d ie th y la m in o p ro p y l a lc o h o l (Eastman Kodak and Co. ) i n 600 ml# o f d ry benzene was t r e a t e d dropw ise d u rin g one hour w ith 119 Gm. (1 m ole) o f th io n y l c h lo r id e w h ile c o o lin g i n an i c e b a th .

A f te r t h e a d d itio n was c o m p leted , th e r e a c t i o n m ix tu re

was allo w ed t o come t o room te m p e ra tu re and th e n h e a te d a t r e f l u x f o r fo u r h o u rs.

The s o lv e n ts were removed u n d er red u ced p r e s s u r e .

The

o i l y r e s id u e was washed by d é c a n ta tio n w ith 300 ml# o f e th e r and th e n d is s o lv e d i n 200 m l. o f w a te r.

The aqueous s o l u t io n was washed w ith

100 m l. o f e t h e r , made a lk a li n e w ith sodium hydroxide s o l u t io n (2 0 $ ), and e x tr a c t e d w ith f i v e 50 m l. p o rtio n s o f e t h e r .

The e t h e r l a y e r was

45 d r ie d o v e r Dri e r i t e and th e f i l t e r e d s o lu tio n d i s t i l l e d .

The y i e l d

was 3 3 .9 Gm. (44%) o f p ro d u c t d i s t i l l i n g a t 58-59° a t 13 mm. p r e s s u r e ; r e p o r te d (95) b . p . 53-57° a t 12 mm. p r e s s u r e . P r e p a r a tio n o f 5 -D ieth v l « m in o - 2 .2 - d ip h e n y lp e n ta n e n itr ile . - T his compound was p re p a re d e s s e n t i a l l y b y th e method o f E a s to n , G ard n er, E v an ick , and S tev en s (97) f o r 5 -d im eth y lam in o -2 , 2 -d ip h e n y lp e n ta n e n itrile . To a w e ll s t i r r e d su sp e n sio n o f 9 .0 Gm. (0 .2 3 m ole) o f sodium amide i n 50 m l. o f d ry benzene h e a te d t o 4 5 -5 0 ° , th e r e was added d u rin g 15 m in u tes 3 9 .0 Gm. (0 .1 3 m ole) o f d ip h e n y l a c e t o n i tr i l e d is s o lv e d i n 100 m l. o f d ry b e n ze n e.

The r e a c t i o n was m a in ta in e d a t t h i s tem per­

a tu r e f o r n in e ty m in u te s.

The m ix tu re was co o le d t o 2 0 -2 5 °, and a

s o lu tio n o f 3 0 .0 G&a. ( 0 .2 m ole) o f ^ -d ie th y la m in o p ro p y l c h lo r id e in 50 m l. o f x y len e was added d u rin g t h i r t y m in u te s.

The m ix tu re was

re flu x e d f o r f i v e h ours and a f t e r s ta n d in g o v e rn ig h t was poured i n t o 250 m l. o f w a te r.

The benzene l a y e r was e x tr a c te d w ith fo u r 50 m l.

p o r tio n s o f h y d ro c h lo ric a c id (20%).

The a c id s o lu tio n was made a lk a ­

l i n e w ith sodium hydroxide s o lu tio n (20%), and th e l i b e r a t e d o i l was e x tr a c te d w ith e t h e r .

The e t h e r e a l e x t r a c t was d r ie d w ith D r i e r i t e ,

f i l t e r e d , and th e s o lv e n t removed by d i s t i l l a t i o n .

The r e s id u e was

f r a c t io n a te d t o g iv e 5 0 .0 Gm. (81%) o f p ro d u c t, b . p . 157-159° a t 0 .1 mm. p r e s s u r e . A p o r tio n o f t h e o i l was c o n v e rte d i n t o th e a c id o x a la te s a l t f o r c h a ra c te riz a tio n .

R e c r y s t a l l i z a t i o n o f th e s a l t from a c e to n e —e th e r

gave c r y s t a l l i n e 5 -d ie th y la m in o -2 , 2 -d ip h e n y lp e n t a n e n i t r i l e hydrogen o x a l a t e , m .p. l 6 0 - l 6 l ° . A nal. C a lcd . f o r

N, 7 .0 6 .

Found:

N, 6 .8 4 .

46 P r e p a r a tio n o f 5—DietbvT ami n o -2 .2—d jp h e n y lp e n ta n o ic A cid. — A mix­ t u r e o f 1 5 .3 Gm. (0 .0 5 m ole) o f 5 -d ie th y la m in o -2 ,2 -d ip h e n y lp e n ta n e n i t r i l e , 16 m l. o f s u l f u r i c a c id (94%) > and 12 m l. o f w a ter was h e a te d a t 150-160° f o r e ig h te e n h o u rs. i n t o 25 m l. o f w a te r. ml* o f h o t w a te r.

The r e a c t i o n m ix tu re was th e n poured

The s o l i d was f i l t e r e d and th e n d is s o lv e d i n 75

The h o t s o lu tio n was a d ju s te d t o pH 7 -8 w ith sodium

hydroxide s o lu tio n (5% ), and th e s o l u t io n cooled* t e r e d and a i r d r i e d .

The s o l i d was f i l ­

The cru d e p ro d u c t was r e c r y s t a l l i z e d tw ice from

m eth y l e th y l k e to n e to g iv e 9 .7 Gm. (60%) o f p ro d u c t, m .p. 142-143°• A nal. C alcd. f o r Cp-jH^NQ?:

N,

4 .3 3 .

Found:

N, 4 .3 3 .

P r e p a ra tio n o f E th y l 5 -D ie th y l am ino-2. 2 -d ip h e n v lp e n ta n o a te . - A m ix tu re o f 9 .2 Gm. (0 .0 3 m ole) o f 5 -d ie th y la m in o -2 , 2 -d ip h e n y lp e n ta n o ic a c i d , 2 4 .0 Gm. ( 0 .2 m ole) o f t h io n y l c h lo r i d e , and 25 ml* o f d ry ben­ zene was h e a te d a t 50-55° f o r n in e ty m in u tes and th e n r e f lu x e d f o r one h o u r.

The s o lv e n t and e x c e ss t h io n y l c h lo r id e were removed un d er

reduced p r e s s u r e , and to th e r e s id u e t h e r e was added 25 ml* o f anhydrous a lc o h o l.

The r e a c t i o n m ix tu re was re f lu x e d f o r one h o u r, th e s o lv e n t

removed, and th e r e s id u e d is s o lv e d i n w a te r.

The aqueous s o lu tio n

was made a lk a li n e w ith sodium h ydroxide (5%), th e s o l u t io n e x tr a c te d s e v e r a l tim es w ith e t h e r , and th e combined e th e r e a l e x tr a c t s d r ie d o v e r D r ie r ite #

The f i l t e r e d e t h e r e a l s o lu tio n was c o n c e n tr a te d ,

th e r e s id u e was f r a c t io n a te d

and

t o g iv e 4 .2 Cka. (39%) o f p ro d u c t,b .p *

164- 167° a t 0*4 ram. p re s su re * A nal. C alcd. f o r

N, 3 .9 6 .

Found:

N, 3*85*

The b a se gave a s o l i d a c id o x a la te s a l t w hich was r e c r y s t a l l i z e d

47 from a m ix tu re o f m eth y l e th y l k e to n e and e t h e r t o g iv e c r y s t a l l i n e e th y l 5- d ie th y la m in o - 2 , 2-d ip h e n y lp e n ta n o a te hydrogen o x a la te , m .p . 129 -1 3 0 °. A nal. C alcd . f o r C25H33NO6 :

N, 3 .1 6 .

Found:

N, 3*02#

48 SUMMARY I,

The m ethods f o r th e p r e p a r a tio n s o f th e compounds o f th e

b a s ic s t r u c t u r e r e p r e s e n te d by form ula I i n which X i s n i tr o g e n .

^02^2^5 C

I oxygen, o r a m ethylene r a d i c a l and f o r each o f th e s e compounds Y i s e i t h e r th e dim ethylam ino o r th e d ie th y la m in o group have b een developed# 2.

E th y l a -(£ -d im e th y la m in o e th o x y )d ip h e n y la c e ta te , e th y l a-({3-

d ieth y la m in o e th o x y ) d ip h e n y la c e ta te , e th y l

(p -d im e th y la m in o e th y l-

a m in o )d ip h e n y la c e ta te , e th y l a -O -d ie th y la m in o e th y la m in o )d ip h e n y l­ a c e t a t e , e th y l 5-dime th y la m in o -2 ,2 -d ip h e n y lp e n ta n o a te , and e th y l 5 -d ie th y la m in o -2 , 2 -d ip h e n y lp e n ta n o a te have b een p re p a re d f o r p h y sio ­ l o g i c a l e v a lu a tio n # 3#

The m ethods f o r t h e p r e p a r a tio n o f th e new in te r m e d ia te s

5 -d im e th y l-2 ,2 —d ip h e n y lp e n ta n o ic a c id b i s u l f a t e , 5 -d ie th y la m in o -2 ,2 d ip h e n y lp e n ta n e n itr ile , and 5 -d ie th y la m in o -2 ,2 -d ip h e n y lp e n ta n o ic a c id a re g iv e n . 4*

C e r ta in p re lim in a ry e x p erim en ts were c a r r i e d o u t i n an a tte m p t

to u t i l i z e a -c h lo r o d ip h e n y la c e tic a c id a s a s t a r t i n g p o in t in th e s y n th e s is o f compounds o f g e n e r a l form ula 1#

Such an approach was

u n s a t is f a c to r y b ecau se th e a c id d e r iv a tiv e s c o u ld n o t be e s t e r i f i e d r e a d ily *

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ANTIHISTAMINICS: BASIC DERIVATIVES ΠETHYL DIPHENYLACETATE

An A b s tra c t of A T h esis S ubm itted t o t h e F a c u lty of Purdue U n iv e rs ity by J a c k Payne Comer I n P a r t i a l F u lf illm e n t o f th e R equirem ents f o r th e Degree of D o cto r of P h ilo so p h y

J u n e , 1950

1 ANTIHISÎAMIÜICS s

BASIC DERIVATIVES OF ETHYL DIPHENYLACETATE^-

By J a c k P* Ccsner'*’, Glenn L» J e n k in s , and John B. D ata Only a few compounds o f t h e g e n e r a l fo rm u la I i n w hich X i s 0 , N, o r CH2 and R i s ( 0 ^3 ) 2 o r ( 0 2 ^ ) 2 have b een r e p o r te d i n t h e l i t e r a t u r e *

^ CQQC^Htj

[ n'X-CH2CH2N-R

I M orrison and K o n ig ste in (1 , 2 ) m ention th e u se o f e th y l a -({ 3 -d im ethylam inoethoxy )d ip h e n y la c e ta te (V II) a s an in te rm e d ia te i n th e p r e p a r a tio n o f b a s ic e s t e r s o f o - ( P -dim ethylam inoethoxy) d ip h e n y la c e ­ ta te .

These i n v e s t i g a t o r s r e p o r t t h a t th e s e b a s ic e s t e r s have a n t i -

h is ta m in ic a c t i v i t y .

E th y l a - ( f3-dieth y lam in o eth o x y ) d ip h e n y la c e ta te

(V III) has b een p re p a re d and i s r e p o r te d ( 3 ) t o be t h e r a p e u t i c a l l y u se ­ fu l.

To our knowledge a d d itio n a l p h a rm a co lo g ica l d a ta p e r ta in in g t o

compounds o f th e g e n e r a l form ula I have n o t been p u b lis h e d . I t i s i n t e r e s t i n g t o n o te t h a t e th e r ( - 0 - ) , amino ( - $ ■ ) , and m eth y len e (-CHg-O d e r i v a ti v e s o f b a s i c a l l y s u b s t i t u t e d d ia ry lm e th a n e , b o th c a rb o c y c lic and c a r b o c y c lic - h e te r o c y c lic , a re e f f e c t i v e a n t i h i s — ta m in ic a g e n ts .

Examples o f such compounds a re B en ad ry l ( I I ) , P e r a z i l

•^Received , from t h e R esearch L a b o r a to r ie s , Purdue U n iv e rs ity , S chool o f Pharm acy, L a f a y e tte , I n d ia n a . +Purdue R esearch F o u n d atio n F ello w , 1948—1950. P re s e n t a d d re s s ; B ureau o f L a b o r a to r ie s , In d ia n a S ta te B oard o f H e a lth , I n d ia n a p o lis , I n d ia n a .

2 ( I I I ) , and T rim eton (IV )•

^

A

z

v

V^— ,

V

H -C -lT

I

I

H -C -O -C H gC H gN ( C H j ) 2

> -C H 3

»

x

H -C -C H gC H gN (C H 3

y Z ^N ï

I

V

II

III

IV

Thus, o th e r d e r iv a tiv e s o f d ia ry lm e th a n e , p a r t i c u l a r l y b en zo h y d ry l (V) d e r i v a t i v e s , a p p ea r w orthy o f f u r t h e r in v e s tig a tio n *

S in c e th e p h a rm aco lo g ical p ro p e rty o f e t h e r , am ino, and m ethylene d e r i v a ti v e s o f e th y l d ip h e n y la c e ta te , c arb eth o x y d e r iv a tiv e o f benzo­ h y d r y l, a s re p r e s e n te d by g e n e r a l fo rm u la I have n o t been r e p o r te d i n d e t a i l , we were prom pted to p re p a re compounds o f t h i s ty p e f o r p h ar­ m a c o lo g ic a l t e s t i n g .

Two s e r i e s

of compounds were p re p a re d i n which R

i s (GH^)2 and R i s ( 0^ 5)2 and X i s 0 , N, and CH2 f o r each s e r ie s * These compounds were p re p a re d i n

o rd e r to a s c e r t a i n th e a n tih is ta m in ic

a c t i v i t y o f such compounds and t o observe in e ac h s e r i e s th e e f f e c t o f

3 th e v a r i a b l e 0 , N, and CHg on a n tih is ta m in ic potency* S ix b a s i c d e r i v a ti v e s o f e th y l d ip h e n y la c e ta te have b e e n prep ared * These compounds were p re p a re d by one o f t h e t h r e e m ethods r e p re s e n te d b y e q u a tio n s on page 4* The e th e r d e r i v a ti v e s were p re p a re d b y a llo w in g sodium to r e a c t w ith e th y l b e n z i la t e (VI) i n anhydrous e t h e r , and t h e r e s u l t a n t p ro d u c t was condensed w ith p -d im e th y lam in o eth y l o r P—d ie th y la m in o e th y 1 c h lo r id e to g iv e e th y l o c ^ (0 -d im e th y la m in o e th o x y )d ip h en y la ce ta te (V II, R i s CH3 ) and e th y l a -( p - d ie th y la m in o e th o x y )d ip h e n y la c e ta te ( V I I I , R i s C2H5) , r e s p e c ti v e ly . The amino d e r i v a ti v e s w ere p re p a re d b y th e c o n d e n sa tio n o f e t h y l a —c h lo ro d ip h e n y la c e ta te (IX) w ith N ,N ~dim ethylethylenediam ine o r N ,N -d ie th y le th y le n e d ia m in e t o g iv e e t h y l a - (P -dim eth y lam in o eth y lam in o ) d ip h e n y la c e ta te (X, R i s CH^) and e t h y l a —(p -d ie th y la m in o e th y la m in o ) d ip h e n y la c e ta te (X I, R i s

r e s p e c tiv e ly *

The a lk a n e d e r i v a ti v e s were p re p a re d by condensing p—d im e th y l­ amino p ro p y l o r j3 -d ieth y lam in o p ro p y l c h lo r id e w ith d i p h e n y l a c e t o n i tr i l e (X II) i n th e p re se n c e of sodamide t o g iv e 5-d im eth y lam in o -2 , 2 -d ip h e n y lp e n t a n e n i t r i l e ( X I I I , R i s CH3 ) and 5- d i e t hylam in o -2 , 2 -d ip h e n y lp e n ta n e n i t r i l e (XIV, R i s C2H5 ) , r e s p e c t i v e l y . t o th e c o rre sp o n d in g a c i d .

Each n i t r i l e was h y d ro ly zed

Each a c id was c o n v e rte d to th e a c id - c h lo r id e

w ith th io n y l c h lo r id e and th e n e s t e r i f i e d w ith e t h y l a lc o h o l t o g iv e e th y l 5—din ieth y lam in o -2 ,2 -d ip h e n y lp e n ta n o a te (XV, R i s CH3 ) and e th y l 5-d ie th y la m in o - 2 , 2 -d ip h e n y lp e n ta n o a te (XVI, R i s C2H5) ,

1 . Na, e th e r COOC2H5

2 . R2n- CH2CH2C1

0000^5 I x O-GHgCHgHRg

V II, R i s CH3 V I I I , R i s C2H5

gooc2h 5

r 2n -c h 2ch2nh2

COOC2H5

Cl

N-CH2CH2NR2 H

IX

X , R i s CH3 X I, R i s C2H5 1 . NaNH2 2 . r 2nch2ch2ch2c i CH2CH2CH2NR2

, X I I I , R i s CH3 XIV, R i s c2 à$ 4 h 2S04 , H20

X II

CÛOCÿ5 X /-trr _r i T T

«t ch2ch2ch2n r2

1 , S0C12 2* C2H50H

COOH CH2CH2CH2NR2

5 EXPERIMENTAL A ll m e ltin g p o in ts a r e u n c o rr e c te d . m icro K je ld a h l method ( 4) . im p lie s 15-20 mm. v a c u o ♦

N itro g e n was o b ta in e d by a se m i-

U nless o th e rw ise in d ic a t e d red u ced p r e s s u r e The hydrogen o x a la te s a l t s w ere p re p a re d by

a d d it i o n o f an e t h e r e a l s o l u t io n o f th e b a se t o a d i l u t e e t h e r e a l s o lu ­ t i o n o f anhydrous o x a lic a c id (1 :1 * 5 m o lar r a t i o ) . P r e p a r a tio n o f E th y l B e n z ila te . - A m ix tu re o f 100*0 Gm. (0 .4 3 m ole) o f b e n z i l i c a c i d , 100 m l. o f a b s o lu te a lc o h o l, and 300 ml* o f d ry benzene was r e f lu x e d f o r two days i n a S o x h le t e x t r a c t o r w ith D r i e r i t e i n th e th im b le to remove w a ter from th e s o lv e n t.

The s o lu tio n was c o n c e n tra te d

t o ab o u t 250 m l. and th e n e x tr a c t e d s e v e r a l tim e s w ith c o ld sodium c a r ­ b o n a te s o lu tio n (5%).

The o rg a n ic la y e r was d r ie d o v e r anhydrous sodium

s u l f a t e , th e s o lv e n t removed u n d er red u ced p r e s s u r e , and t h e r e s id u e f r a c t i o n a t e d to g iv e 9 6 .5 Gm. (83$) o f p r o d u c t, b .p . 150-153° a t 3 mm* p r e s s u r e ; r e p o rte d ( 5 ) b*p* 188-190° a t 15 ram. p r e s s u r e . P r e p a ra tio n o f E th v l a - ( B-Dimet hvlam inoethoxy)d io h e n v la c e ta te . - To a s t i r r e d s u s p e n s io n o f 2*3 Gm. ( 0 .1 m ole) o f powdered sodium, i n 200 ml* o f anhydrous e t h e r , t h e r e was added dropw ise 2 5 .6 Gm. ( 0 .1 m ole) o f e th y l b e n z i l a t e .

The m ix tu re was re flu x e d u n t i l th e sodium had re a c te d *

To th e s o lu tio n t h e r e was added dropw ise 13*0 Cfcn. (0 .1 2 m ole) o f p -d im e th y la m in o e th y l c h lo r id e i n 150 m l. o f d ry to lu e n e .

The m ix tu re

was r e f lu x e d f o r fo u r h o u r s , th e e th e r was d i s t i l l e d o f f , and th e s o lu ­ t i o n was h e a te d o v e rn ig h t on a steam b a th .

The c o o le d r e a c t i o n m ix tu re

was e x tr a c te d t h r e e tim e s w ith 50 m l. o f h y d ro c h lo ric a c id (1 0 $ ).

The

combined aqueous e x t r a c t s were made a lk a li n e w ith sodium c a rb o n a te (1 0 $ ), and th e m ix tu re e x tr a c te d w ith b e n ze n e.

The benzene s o l u t io n was d r ie d

6 w ith D r i e r i t e , th e s o lv e n t removed by d i s t i l l a t i o n u n d er red u ced p r e s ­ s u r e , and th e r e s id u e f r a c t i o n a t e d t o g iv e 10*1 Gm* (33%) o f p ro d u c t, b * p , 157-160° a t 0*13 mm* p r e s s u r e . A nal. C alcd. f o r £20^25^3*

4»2d.

Found:

N, 4*24*

The b a se gave a s o l i d a c id o x a la te s a l t which was r e c r y s t a l l i z e d from m eth yl e th y l k e to n e t o g iv e c r y s t a l l i n e e th y l a - (|3-dim ethylam inoe th o x y )d ip h e n y la c e ta te hydrogen o x a la te , m .p . 145- 146°• A nal. C alcd . f o r CppHpyNOy:

N, 3*35*

Found:

N, 3*50.

P r e p a ra tio n o f E th y l a-C B -D iethv^am inoethoxy)d ip h e n y la c e ta te . - This compound was p re p a re d e s s e n t i a l l y b y t h e method d e s c rib e d f o r e t h y l a -(p -d im e th y la m in o e th o x y )d ip h e n y la c e ta te .

E th y l b e n z i l a t e , 25*6 Gm.

( 0 .1 m o le ), was a llo w e d t o r e a c t w ith 2 .3 Gm. ( 0 .1 m ole) o f sodium. The r e s u l t a n t p ro d u ct was condensed w ith 15*0 (in. ( O .U m ole) o f £— d ie th y la m in o e th y l c h lo r id e t o g iv e 15*0 Gm. o f p ro d u c t, b .p * 145-148° a t 0 .0 5 mm. p r e s s u r e ; r e p o r te d ( 3 ) b .p , 148- 151° a t 0 .0 8 mm. p r e s s u r e . A nal. C alcd. f o r

N,

3.94*

Found: N, 4*11*

The b a se gave a s o l i d a c id o x a la te s a l t which was r e c r y s t a l l i z e d from m eth yl e th y l k e to n e t o g iv e c r y s t a l l i n e e th y l a -( £ -d ie th y la m in o e th o x y )d ip h en y lac e t a t e hydrogen o x a l a t e , m .p. 124- 125° . A nal. C alcd. f o r C24H31NO7 :

N,

3*15*

Found: N, 2.96*

P r e p a ra tio n o f D im e th v la m in o a c e to n itrile . - T his compound was p re p a re d by th e method d e s c rib e d by T urner ( 6 ) .

From 660 Gm. o f

aqueous dim ethylam ine

(25%), 330 Gm. o f aqueous form aldehyde (37%) >

and 196 Gm. o f sodium

c y a n id e , t h e r e was o b ta in e d 142*0 Gm. ( 46%) o f

p ro d u c t, b .p . 133-135° a t 750 mm. p r e s s u r e ; r e p o rte d (6 ) b .p * 134-137°* P r e p a ra tio n o f N .N-Di m e th v le th v le n e d ia m in e . - D im ethylam inoaceto­ n i t r i l e , 6 2 .0 Gm. (0 .7 5 m ole) was reduced c a t a l y t i c a U y a c c o rd in g to

th e method d e s c rib e d b y T urner (6) t o g iv e 26*0 Cba, (40%) o f p ro d u c t d i s t i l l i n g a t 100-110° a t 750 mm. p r e s s u r e ; r e p o r te d (6 ) b*p* 105-100°• P r e p a r a tio n o f E th y l a -C h lo r o d ip h e n y la c e ta te . - A s o lu tio n o f 30*0 Gbn. o f e th y l b e n z i la t e and 30 m l. o f phosphorous o x y c h lo rid e i n 100 m l. o f d ry benzene was h e a te d slo w ly t o 70-80° and m a in ta in e d a t t h a t te m p e ra tu re f o r f o u r h o u rs .

The c o ld r e a c t i o n m ix tu re was poured

i n to 200 Gm. o f c ru sh ed i c e , and th e m ix tu re s t i r r e d u n t i l th e e x c e ss phosphorous o x y c h lo rid e had h y d ro ly z e d .

The benzene l a y e r was s e p a r­

a te d , th e aqueous l a y e r was e x tr a c te d s e v e r a l tim e s w ith b en zen e, and th e benzene s o lu tio n s were com bined.

The benzene s o lu tio n was shaken

w ith c o ld w a te r, s e p a r a te d , and d r ie d w ith D r i e r i t e .

The f i l t e r e d ben­

zene s o lu tio n was c o n c e n tra te d u n d e r red u ced p r e s s u r e , and th e r e s id u e f r a c t io n a te d to g iv e 29.3 Gm. (95%) o f p ro d u c t, b .p . 150-154° a t 3 mm* p re ssu re .

The d i s t i l l a t e c r y s t a l l i z e d , m .p. 4 3 -4 4 °J r e p o r te d (7)

m*p* 43—44°• P r e p a r a tio n o f E th y l q - ( g-D im ethylam inoethylam ino ) d ip h e n y l­ ac e t a t e . - A m ix tu re o f 12*3 Gm. (0 .1 4 m ole) o f N ,N -d im e th y le th y le n e diam ine and 1 8 .2 Gm. (0 .0 7 m ole) o f e th y l a -c h lo r o d ip h e n y la c e ta te was h e ated a t 120-130° f o r tw enty-tw o h o u rs .

The u n re a c te d amine was r e ­

moved by d i s t i l l a t i o n u n d e r reduced p r e s s u r e .

The re s id u e was c o o le d

and t r i t u r a t e d w ith 100 m l. o f h y d ro c h lo ric a c id (10%). was e x tr a c te d w ith 200 m l. o f b e n ze n e.

The s o lu tio n

The c o ld a c id l a y e r was made

a l k a l i n e w ith sodium hydroxide s o lu tio n (5%) and th e n e x tr a c te d w ith 100 m l. o f b en zen e.

The benzene e x t r a c t was d r ie d w ith D r i e r i t e , th e

f i l t e r e d s o lu tio n c o n c e n tra te d u n d er reduced p r e s s u r e , and th e r e s id u e f r a c t i o n a t e d to g iv e 6 .9 Gm. (30%) o f p ro d u c t; b * p . 172-175° a t 3 mm*

p re s su re * A nal. Calcd# f o r ^ 2Q ^26^2^2i

8 .5 6 ,

P r e p a r a tio n o f D ie th y la m inoace t o n i t r i l e .

Found:

N, 8#40#

T his compound was p re ­

p a re d a c c o rd in g t o th e p ro ced u re o f A lle n and Van A lle n ( 8 ) .

F ran

78#0 Gm. (0 .7 5 m ole) of sodium b i s u l f i t e , 57 m l. o f form aldehyde s o lu ­ t i o n (37-40% ), 5 5 .0 Gm. (0 .7 5 m ole) o f d ie th y la m in e , and 37*0 Gm. (0 .7 5 m ole) o f sodium c y a n id e , t h e r e was o b ta in e d 69*0 Gnu (82%) o f p r o d u c t, b .p . 64-66° a t 17 mm. p re s s u r e ; re p o rte d (8 ) b # p . 61-63° a t 14 mm. p r e s s u r e . P r e p a r a tio n o f H .N -D ieth v le th v le n ed ia m in e . - T his compound was p re p a re d b y sodium r e d u c tio n o f th e n i t r i l e a s d e s c rib e d by H a ll and T urner ( 9 ) .

From 5 6 .0 Gm. (0 .5 m ole) o f d i e th y la m in o a c e to n itr ile ,

115 Gm. (5*0 m o le s) o f sodium , and 1050 m l. o f a b s o lu te a lc o h o l, th e r e was o b ta in e d 1 8 .9 Gm. (33%) o f p ro d u c t, b .p # 148-149° a t 750 mm. p r e s ­ s u r e ; r e p o r te d (9 ) b .p . 149° a t 764 mm. p r e s s u r e . P r e p a r a tio n o f E th y l a - ( B -D ieth y lam in o eth y lairnno ^dip h e n y la c e ta te . T his compound was p re p a re d by th e same p ro ced u re a s d e s c rib e d f o r e th y l a - ( 3 - d i e t hylam inoe thylam ino ) d ip h e n y la c e ta te •

N,N -D ie th y le th y le n e -

d ia m in e , 1 8 .7 Gm. (0 .1 6 m ole) was condensed w ith 25*6 Gm. ( 0 .1 m ole) o f e th y l a -c h lo r o d ip h e n y la c e ta te to g iv e 4*2 Gm. o f p ro d u ct d i s t i l l i n g a t 173-178° a t 0 .4 nan. p r e s s u r e . A nal. C alcd . f o r C22%0^2^2!

7 .9 0 .

Found:

N, 8 .0 6 ,

P r e p a r a tio n o f D ip h e n y la c e to n itr ile . - D ip h e n y la c e to n itr ile was p re p a re d a c c o rd in g to th e p rocedure o f G insberg and B a iz e r (1 0 ). S t a r t i n g w ith 8 8 .2 Gm. o f b e n zy l cy an id e (0 .7 4 m ole) th e r e was o b ta in e d 9 1 .0 Gm. ( 64% y i e l d ) o f p ro d u c t, m .p. 72-74°3 re p o rte d (10) m.p# 73 -

9 P r e p a r a tio n o f l-G h lo ro -3 -io d o p ro p a n e . - This compound was p re p a re d a c c o rd in g t o t h e p ro ce d u re of Hass and Huffman ( l l ) *

From 100*0 Gnu

(0 .8 9 m ole) o f trim e th y le n e c h lo r id e and 139*0 Gm. (0 .8 9 m ole) o f sodium i o d id e , t h e r e was o b ta in e d 86*0 Gm. (47%) o f 1 -c h lo ro —3—io d o p ro p an e, b .p . 51-52° a t 9 mm. p r e s s u re ; r e p o r te d ( l l ) b*p* 60*8° a t 15 mm* p r e s s u r e . P r e p a r a tio n o f y -D im ethvlam inooropvl C h lo rid e * - D im ethylam ine, 53*0 m l. ( 0 .8 m o le ), was added to 200 ml* o f d ry benzene p r e v io u s ly co o le d to 0 v 5 °, and th e s o l u t io n th e n added d u rin g t h i r t y m in u tes t o a s t i r r e d s o l u t io n o f 82*0 Gm* ( 0 .4 m ole) o f l-c h lo ro -3 -io d o p ro p a n e in 100 m l. o f d ry benzene w h ile m a in ta in in g th e te m p e ra tu re a t 0-10°*

The

s o l u t io n was s e a le d i n a p re s s u re v e s s e l and k e p t i n an i c e b a th f o r two h ours and th e n a t room te m p e ra tu re f o r two d a y s.

The r e a c t i o n mix­

t u r e was t r e a t e d w ith s u f f i c i e n t hydrogen c h lo r id e to p r e c i p i t a t e th e b a s ic m a te r ia ls from s o l u t io n .

The benzene s o lv e n t was d e c a n te d from

th e p r e c i p i t a t e , and th e o i l y mass washed by t r i t u r a t i o n w ith s e v e r a l 50 m l. p o r tio n s o f e t h e r .

E th e r , 200 m l*, was added to th e r e s id u e ,

and th e m ix tu re th e n t r i t u r a t e d w ith 5 0 .0 Gm. o f f la k e sodium h y d ro x id e . The e th e r la y e r was d e c a n te d , t h e re s id u e was e x tr a c te d s e v e r a l tim e s w ith e t h e r , and th e combined e t h e r e a l s o lu tio n s were d r ie d w ith anhy­ d ro u s sodium s u l f a t e .

The f i l t e r e d e t h e r e a l s o l u t io n was c o n c e n tra te d

u n d er red u ced p r e s s u r e , and th e r e s id u e f r a c t i o n a t e d to g iv e 2 7 .2 Gm. (56%) o f p r o d u c t, b .p . 32- 35° a t 17 mm. p re s s u r e ; re p o rte d (12) b*p* 29-32 a t 12 mm. p r e s s u r e . P r e p a ra tio n o f 5-D im ethvlam ino-2. 2 - d ip h e n v lp e n ta n e n itr ile . - T his compound was p re p a re d e s s e n t i a l l y by th e same method a s d e s c rib e d f o r 5 -d ie th y la m in o -2 , 2 -d ip h e n y lp e n ta n e n it r i l e .

Using th e same m olar q u a n ti-

10 t i e s * t h e r e was o b ta in e d a 54 p e r c e n t y i e l d o f r e c r y s t a l l i z e d p ro d u c t which m e lte d a t 6 4-66°; r e p o r te d (13) n u p . 6 4 -6 5 °.

The cru d e p ro d u c t

was n o t d i s t i l l e d b u t p u r i f i e d by r e c r y s t a l l i z a t i o n from p e tro le u m e th e r (3 0 -6 0 ° ). P r e p a ra tio n o f 5 -D im e th y la m in o -2 .2 -d ip h e n y lp e n ta n o ic A cid B i s u l f a t e . - A m ix tu re o f 1 3 .0 Gm. (0 .0 5 m ole) o f 5 -d im e th y la m in o -2 ,2 — d i p h e n y lp e n ta n e n itr ile , 16 m l. o f s u l f u r i c a c id (94$) > and 12 ml* o f w ater was h e a te d i n an o i l b a th a t 145-155° f o r f i v e h o u rs •

The c o o le d

r e a c t i o n m ix tu re was poured i n t o 175 m l. o f w a te r , and th e m ix tu re made a lk a li n e w ith sodium h y d ro x id e (1 0 $ ).

The aqueous m ix tu re was e x tr a c t e d

s e v e r a l tim e s w ith e t h e r , and th e aqueous l a y e r was a d ju s te d to pH 5-6 w ith a c e ti c a c id .

The p r e c i p i t a t e d s o l i d was f i l t e r e d , and th e p ro d u ct

d r ie d u n d er 14 mm. p r e s s u re a t 8 0 °.

The s o l i d was suspended i n 15 m l.

o f a b s o lu te a lc o h o l, and th e m ix tu re made a c i d ic w ith a s o lu tio n o f 5 m l. o f s u l f u r i c a c id (94$) and 25 m l. o f a b s o lu te a lc o h o l.

The

s o lu tio n was warmed, anhydrous e th e r added u n t i l th e s o lu tio n became c lo u d y , and th e m ix tu re was c o o le d i n an i c e b a th .

B e e ry s ta lliz a tio n

o f t h e s o l i d once from a lc o h o l- e th e r gave 8 .0 Gms. o f p ro d u ct m e ltin g a t 175-178°•

S e v e ra l r e c r y s t a l l i z a t i o n s from a lc o h o l- e th e r gave a

p ro d u c t m e ltin g a t 178-179°• A nal. C alcd. f o r

N, 3*54.

Found:

N, 3.42*

P r e p a r a tio n o f E th y l 5-Dimeth v la m in o -2 .2 -d ip h e n y lp e n ta n o a te H y d ro c h lo rid e . - 5-D im ethylam ino-2, 2 -d ip h e n y lp e n ta n o ic a c id b i s u l ­ f a t e , 6*0 Gm. (0 .0 1 5 m o le ), was added to 100 m l. o f benzene.

The

m ix tu re was d i s t i l l e d u n t i l th e d i s t i l l a t e was c l e a r in d ic a tin g th e rem oval o f t r a c e s o f m o is tu re .

To th e c o ld m ix tu re t h e r e was added

11 12#0 Gm. (0*1 m ole) o f th io n y l c h lo r id e i n 25 m l. o f d ry b en zen e. The r e a c t i o n m ix tu re was h e a te d to 55° and m a in ta in e d a t 50-55° f o r f o u r h o u rs .

The s o lv e n t and e x c e ss th io n y l c h lo r id e was removed u n d er

red u ced p r e s s u r e , 30 m l. o f a b s o lu te a lc o h o l ad d ed , and th e r e a c tio n m ix tu re h e a te d a t 50-55° f o r t h i r t y m inutes and th e n r e f lu x e d f o r two h o u rs .

The e x c e ss a lc o h o l was removed under red u ced p r e s s u r e , 25 m l.

o f w a ter was added, and th e r e a c t i o n m ix tu re was made a lk a li n e w ith s u f f i c i e n t sodium hydroxide s o lu tio n (5%).

The o i l y l a y e r was e x tr a c te d

w ith e t h e r , th e e th e r e a l e x tr a c t was d rie d w ith D r i e r i t e , and th e s o lu ­ tio n f i l t e r e d .

An e th e r e a l s o lu tio n o f hydrogen c h lo r id e was added to

th e f i l t e r e d e t h e r e a l s o lu tio n u n t i l th e p r e c i p i t a t i o n o f th e o i l y h y d ro c h lo rid e was co m p lete. liz a tio n re s u lte d . 168°*

Upon s ta n d in g f o r s e v e r a l days c r y s t a l ­

The y i e l d was 3*0 Gm. o f p ro d u c t m e ltin g a t 165—

S e v e ra l r e c r y s t a l l i z a t i o n s from e th a n o l- e th e r s o lu tio n gave a

p ro d u c t m e ltin g a t 167-169°* A nal. C alcd. f o r Cp^H^gNO^Cl:

N, 3*87*

Founds N, 3*98*

P r e p a r a tio n o f ^ -D ie th y la m in o p ro p y l C h lo rid e . - This compound was p re p a re d e s s e n t i a l l y by th e method d e s c rib e d by W alker (1 4 ).

A

benzene s o l u t i o n o f 65*5 Ctow (0 .5 m ole) o f y - d i e thylam ino pro p y l a lc o ­ h o l (Eastm an Kodak) was allow ed to r e a c t w ith 119.0 Gm. ( l.O m ole) o f t h io n y l c h lo r id e t o g iv e 33*9 Gm. (44%) o f p ro d u c t d i s t i l l i n g a t 58-59° a t 13 mm. p re s s u re ; r e p o rte d (12) b*p* 53-57° a t 12 mm* p r e s ­ s u re . P r e p a r a tio n o f 5 -D ieth y lam in o -2 . 2 -d ip h e n y lp e n ta n e n it r i l e . - This compound was p re p a re d e s s e n t i a l l y by th e method o f E a s to n , G ard n er, E v a n ic k , and S te v e n s (13) f o r 5-dime th y la m in o -2 ,2 -d ip h e n y lp e n ta n e n itrile *

12 To a w e ll s t i r r e d su sp e n s io n o f 9 .0 Gm. ( 0 .2 3 m ole) o f sodium amide i n 50 m l. o f d ry benzene h e a te d t o 45- 50° , t h e r e was added d u rin g 15 m in u tes 3 9 .0 tin. (0 .1 3 m ole) o f d i p h e n y l a c e t o n i tr i l e d is s o lv e d i n 100 m l. o f d ry b en zen e.

The r e a c t i o n m ix tu re was m a in ta in e d a t t h i s

te m p e ra tu re f o r n in e ty m in u te s .

The m ix tu re was c o o le d to 2 0 -2 5 °, and

a s o lu tio n o f 3 0 .0 Gm. ( 0 .2 m ole) o f y -d ie th y la m in o p ro p y l c h lo r id e i n 50 m l. o f x y le n e was added d u rin g t h i r t y m in u te s .

The m ix tu re was

r e f lu x e d f o r f i v e h o u rs and a f t e r s ta n d in g o v e rn ig h t was poured i n to 250 ml* o f w a te r.

The benzene l a y e r was e x tr a c te d w ith f o u r 50 ml*

p o r tio n s o f h y d ro c h lo ric a c id (20%).

The a c id s o l u t io n was made a lk a ­

l i n e w ith sodium h y d ro x id e s o lu tio n ( 20%), and th e l i b e r a t e d o i l was e x tr a c te d w ith e t h e r .

The e t h e r e a l e x t r a c t was d r ie d w ith D r i e r i t e ,

f i l t e r e d , and t h e s o lv e n t removed by d i s t i l l a t i o n .

The re s id u e was

f r a c t io n a te d t o g iv e 50*0 Gm. (81%) o f p ro d u c t, b .p . 157-159° a t 0 .1 mm. p r e s s u r e . A p o r tio n o f t h e o i l was c o n v e rte d in to th e a c id o x a la te s a l t f o r c h a ra c te ris a tio n .

R e c r y s t a l l i z a t i o n o f th e s a l t from a c e to n e - e th e r

gave c r y s t a l l i n e 5-d ie th y la m in o - 2, 2- d ip h e n y lp e n ta n e n itr ile hydrogen o x a la te m e ltin g a t l 60- l 6l ° . A nal. C alcd . f o r C24H28N2O4 Î

N, 7*06.

Found:

N, 6.84*

P r e p a r a tio n o f 5 -D ieth v lam in o -2 . 2 -d ip h e n y lp e n ta n o ic A cid. - A m ix tu re o f 1 5 .3 Gm. (0 .0 5 m ole) o f 5 -d ie th y la m in o -2 ,2 -d ip h e n y lp e n ta n e n i t r i l e , 16 m l. o f s u l f u r i c a c id (94%), and 12 m l. o f w a te r was h e a te d a t 150- 160° f o r e ig h te e n h o u rs. in to 25 m l. o f w a te r. 75 ml* o f h o t w a te r.

The r e a c tio n m ix tu re was th e n poured

The s o l i d was f i l t e r e d and th e n d is s o lv e d in The h o t s o lu tio n was a d ju s te d to pH 7 -8 w ith

13 sodium hydroxide s o lu tio n (5%)> and th e s o lu tio n c o o le d . f i l t e r e d and a i r d r i e d .

The s o l i d was

The cru d e p ro d u ct was r e c r y s t a l l i z e d tw ic e

from m ethyl e t h y l ketone to g iv e 9*7 Gm. (60%) o f p ro d u ct m e ltin g a t 142 -1 4 3 °. A n al. C alcd. f o r ^ 2 '^ 2 rJ ^ 2 l

4*33*

Found:

N, 4.33*

P r e p a r a tio n o f E th v l 5 -d ie th v ] a m in o - 2 , 2 —d ip h e n y lp e n ta n o a te . - A m ix tu re o f 9*2 Gm. (0 .0 3 m ole) o f 5 -d ie th y la m in o -2 ,2 -d ip h e n y lp e n ta n o ic a c id , 24*0 Gm. o f (0 .2 m ole) o f th io n y l c h lo r id e , and 25 m l. o f d ry benzene was h e a te d a t 50-55° f o r n in e ty m in u tes and th e n r e f lu x e d f o r one h o u r.

The so lv e n t and ex cess t h io n y l c h lo r id e were removed under

red u ced p r e s s u r e . a lc o h o l.

To th e re s id u e t h e r e was added 25 m l. o f anhydrous

The r e a c tio n m ix tu re was re f lu x e d f o r one h o u r, th e so lv e n t

rem oved, and th e re s id u e d is s o lv e d i n w a te r.

The aqueous s o lu tio n was

made a l k a l i n e w ith sodium hydroxide (5%), th e s o lu tio n was e x tr a c te d s e v e r a l tim e s w ith e t h e r , and t h e combined e th e r e a l e x t r a c t s were d r ie d o v er D r i e r i t e .

The f i l t e r e d e th e r e a l s o l u t io n was c o n c e n tra te d , and

th e r e s id u e was f r a c t io n a te d t o g iv e 4*2 Gm. (39%) o f p ro d u ct d i s t i l l i n g a t I 64- I 670 a t 0 .4 mm. p r e s s u r e . A nal. C a lc d . f o r

N, 3*96.

Found:

N, 3*85»

The b a se gave a s o l i d a c id o x a la te s a l t which was r e c r y s t a l l i z e d from m ethyl e th y l k e to n e - e th e r to g iv e c r y s t a l l i n e e th y l 5 - d i e t h y lam ino-2, 2 -d ip h e n y lp e n ta n o a te hydrogen o x a la te , m .p. 1 29-130°. A n al. Calcd* f o r

N, 3*16.

Found:

N, 3»02*

14 SUMMARY 1*

A method f o r th e p r e p a r a tio n o f a lp h a ^ -d im e th y l and ^ - d i e t h y l -

em inoethoxy, ^ -d im e th y l and P—d ie th y la m in o e th y la m in o -, and p -d im e th y l and P -d ie th y la m in o p ro p y l d e r iv a tiv e s o f e th y l d ip h e n y la c e ta te has been d e scrib e d * 2*

Alpha p -d im e th y l and 3 -d ie th y la m in o e th o x y , ^ -d im e th y l and

p -d ie th y la m in o e th y la jn in o -, and ^ -d im e th y l and ^ -d ie th y la m in o p ro p y l d e r i v a ti v e s o f e th y l d ip h e n y la c e ta te have been p re p a re d f o r pharma­ c o lo g ic a l e v a lu a tio n . REFERENCES 1«

M o rriso n , A.

L . , and K o n ig s te in , M ., U. S . P a te n t 2 ,4 3 7 ,0 3 5 .

2.

M o rriso n , A.L . , and K o n ig s te in , M ,, B r i t i s h P a te n t 610,198 th ro u g h C. A ., 4 l , 3462 (1 9 4 9 ),

3#

Sw iss P a te n t 227,704 th ro u g h C. A ., L 3 . 3462 (1 9 4 9 ),

4.

“The Hengar Technique f o r K je ld a h l P ro ced u re” , Hengar Company, P h ila d e lp h ia , Pa*

5.

C u r tiu s , T ., J . p r a k t . Chem., 9 5 . 195 (1 9 1 7 ),

6*

T u rn e r, R* A ,, J* Am, Chem. S o c ., 68, l6 0 7 (1 9 4 6 ).

7.

K lin g e r , H ., A nn., 3 8 9 . 263 (1 9 1 2 ).

8.

A lle n , C. F . H ., and Van A lla n , J . A ., i n S h r in e r , R. L . , “O rganic S y n th e se s” , John W iley and S ons, New Y ork, 1947, V ol. 2 7 , p . 20.

9.

H a ll, D. M ., and T u rn e r, E. E . , J . Chem. S o c ., 1945. 696.

10.

G in sb e rg , D*, and B a iz e r , M. M ., J . Am. Chem. S o c ., 7 1 . 2254 (1 9 4 9 ),

11.

H ass, H. B ., and Huffman, H. C ., i b i d . , 62., 2254 (1 9 4 1 ),

12.

M arxer, A ., H elv. Chim. A c ta , 2 4 . 215E (1 9 4 1 ),

13.

E a s to n , N. R ., G ard n er, J . H ., E v an ick , M. L . , J . Am. Chem. S o c ., 2 2 , 77 (1 9 4 8 ).

14.

W alker, J . , J . Chem. S o c ., 1945. 632.

and S te v e n s , J . R .,

VITA Ja c k Payne Comer was b o rn i n 1922 i n I n d ia n a p o lis , In d ian a* H is c h ild h o o d was sp e n t i n In d ia n a p o lis and F r a n k lin , In d ian a*

He

a tte n d e d A rse n a l T ech n ical High School i n In d ia n a p o lis f o r one y e a r and th e n com pleted h is h ig h sc h o o l t r a i n i n g a t F ra n k lin High School* He was a d m itte d i n 1940 i n to th e School o f A g ric u ltu r e a t Purdue U n iv e rs ity to p u rsu e th e o p tio n o f A g r ic u ltu r a l Chem istry* I n 1943 he e n l i s t e d i n th e U nited S t a te s Army A ir F o rc e .

He was

m a rrie d a t Avon P a rk , F lo r id a i n 1943 t o M iss E le an o re D itm ars o f F r a n k lin , In d ia n a .

A f te r com pleting a combat to u r o f d u ty i n th e

European t h e a t e r o f o p e ra tio n a s a 1 s t P i l o t o f a heavy bom ber, he was a s s ig n e d to d u ty as a f l i g h t i n s t r u c t o r i n th e U n ited S t a t e s . Follow ing h is r e l e a s e from th e A ir F o rc e, he r e - e n te r e d Purdue U n iv e rs ity i n 1945*

Mr* Comer re c e iv e d th e B achelor o f S cien ce

Degree i n 1946 and was a c c e p te d i n to th e G raduate S chool d u rin g th e same y e a r .

The M a ste r o f S cien ce Degree in P h a rm a c e u tic a l C hem istry

was awarded to him i n 1948.

He th e n c o n tin u e d th e s tu d ie s f o r th e

Degree o f D octor o f P h ilo so p h y w ith a m ajor i n P h a rm ac eu tica l Chemis­ t r y w hich he e arn ed i n 1950*