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Derivatives of benzo(h)quinoline

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MANUSCRIPT THESIS
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D a r lT a tlta a o f
B a n io (h )q u in o lla a
by
w m i a * P a rry O ta ra o h la a J r .
A THBSIS
P ra a a a ta d to tb a F a c u lty o f
tb a G raduata C ollage l a th a O n i'ra ra lty o f
H abraaka l a P a r t i a l F u lf illm e n t o f
R e t i r e manta f o r tb a
Degraa o f D octor o f P h lloaopby la tba
D epartm ent o f C ham latry
L in c o ln , H abraaka
Slay 8 0 , 1940
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UMI N um ber: DP13991
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Tha a u th o r w ishes to thank
Dr* 0* S . H am ilton f o r h i s s u p e r­
v is io n o f t h i s work, and P ark a,
D avis and Company f o r a r a s e a r c h
g ran t*
3*73017
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TABLE OP CONTENTS
I*
IN TROOTOTION
1
II.
BXPKRIMENTAL
3
A. S ta p le b « n so (h )q u in o lln * B
B. Hydpoxp-
3
end etalo ro -
b*nB o(ta)quinolln»a
7
0 . C ondensation p ro d u c ts from
c h lo ro -b e n bo(h )q u in o lin e® end
s ta p le eatn o ooapeund®
11
D. A llp h a tio a m ln o -n ltrlle ® end
d le a tn e s
16
B . D la lk y la m ln o a lk jla in in o benB o(h)quinoline®
83
P . A n a ly tic a l nethod®
87
O. G rap h lo al «t*noBary
88
III.
DISCUSSION
50
IV.
SOMKAfflf
39
V.
BIBLIOGRAPHY
41
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I.
INTRODUCTIOir
Sine* th e t i n t o f th a work w hich e s ta b li s h e d th e
com plete cont t i t u t Ion o f th o n a tu r a lly - o c c u r r in g a n t l p y r e tic d ru g , q u in in e , as ho la g a q u in o lin e r i n g
s u b s t i t u t e d by o complex t e r t i a r y amino s id e c h a in * ,
many a tte m p ts have boon made to s y n th e s is e compounds
which would bo e q u a lly e f f e c t i v e a g a in s t m a la r ia . I t
haa boon hoped t h a t d ra g s would bo found com bining a
p r a c t i c a l o f f tc io n a y a g a in s t th o Plasmodium p a r a s 1te a
w ith a t o x i c i t y to th o h o s t l e s s o r th an t h a t m a n ife ste d
by q u in in e*
Sctauleman, S ch o en h e efer, and W lngler*
d isc o v e re d t h a t th e b o a t o f a la rg o number o f s y n th e tic
a n t lm a la r la l drugs mads and t e s t e d by them was
6-m* th o x y -8 - (°<-m e th y l- S -d ie thylam inebu ty la m ln o ) q u in o lin e .
T his compound, commonly c a lle d "P lasm oquine",
i s now w id e ly u se d in chem otherapy, as i s a ls o an
a c r ld in e d e r i v a t i v e , 11A te b rin " , c o n ta in in g th e same s i d e chain in th e 9 - p o s ltlo n * .
Plasm oquine has a s p e c i f i c
and po w erfu l a c tio n oh th e gamete form s o f th e p a r a s i t e s ,
and when u se d alo n e i s b e t t e r as a p r o p h y la c tic th in as
a th e r a p e u tic a g e n t,
{ptlnine and Plasm oquine u se d to g e th e r
give b e t t e r r e s u l t s th an to e s e i t h e r by i t s e l f .
A teb rln
has th o most s p e c i f i c a c tio n oft th e a c h is o n t forms o f a l l
a n t lm a la r la l d ru g s , b u t has no a c tio n on th e g av e to cy b e e*
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-8 Alone I t la th a b a s t s in g le d rag f o r h o ary In fo o tIo n a o f
s u b te r t ia n (m a lig n a n t) m o la rla j and a P lasm o q u in e-A teb rln
com bination la a a id to bo an id o a l ono f o r tho tre a tm e n t
o f tho same in f e c tio n * .
Tho o h a r a e t a r l a t l o f o a ta ro a o f tho a y n th a tla a n t i m a la r ia l druga a re a d la lk y la m ln e a lk y la m ln o S id e c h a in and
a q u in o lin e o r a o r ld ln a n u c lo a a .
I t ap p ears t h a t in o ro aao
In m o le cu lar co m p lex ity , aa In th o rep lacem en t o f q u in o lin e
by a c r id in e when p a a a in g from Plaamoquino to A te b rin , o r In
le n g th e n in g th e Plasm oquine s id e e h a ln , cause a a change
from a e t l r l t y a g a in s t s e x u a l to a c t i v i t y a g a in s t a se x u a l
forma*
Thus, t h e o r e t i c a l l y a t l e a s t , i t sh o u ld be p o ss­
ib l e to s y n th e s is e compounds w ith h ig h a e t l r l t y b o th a g a ln a t
th e s e x u a l and a se x u a l form s o f m a la ria p a r a s ite s *
In view o f t h i s th e o ry , i t seemed l o g i c a l to i n v e s t i ­
gate th e s y n th e s is o f compounds c o n ta in in g a d la lk y la m ln o alkylam lno a id e c h a in and a b o n n e (h )q u in o lin e n u c le u s , th e
r in g sy stem o f th e l a t t e r b e in g l s o a s r l e .w l t h t h a t o f
s e
a c rid in e * P re v io u s w orkers
h a re claim ed t h a t c e r t a in
2 - and ^ s u b s t i t u t e d q u in o lin e and b e n s o q u in o lin e s h are
a n t i- m a la r i a l p r o p e r tie s *
The p r e s e n t r e s e a r c h problem
was an a tte m p t to e x te n d t h a t e a r l i e r work to th e sy n ­
t h e s i s o f s u b s t i t u t e d b e n s o (h )q u in o lin e s h a r in g a r in g
system and s id e c h a in s s im ila r to th o se o f compounds
a lre a d y r e p o r te d as b e in g e f f e c t i v e In th e tre a tm e n t o f
m a la r ia l In fe c tio n s *
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-5 -
IX .
EXPERIMSHTAL
A ll m e ltin g and b o ili n g p o in t* reo o rd ed h are a re
c o r r e c te d v a lu e s .
A.
P re p a ra tio n o f sim ple b e n * o { h )q u in o lin e s .
1 . i* g lS g » rl-n a P h .tb g la a la c
v '
Method o f Saunders .
T his wan p re p a re d by th a
1-nap h th y lam in e was a o a ty la ta d by
a e e t l e anhy d rid e In g l a c i a l a c e t i c a c id s o l u t i o n . N i t r i c
a c id ( e . g . 1 .4 ) was th an slo w ly added to tb a a c e t i c a c id
s o l u t i o n , g iv in g a p r e o l p l t a t e o f mixed 4 - and 8 - n i t r o l-a c e ty la m ln o -n a p h th a le n e s •
I b i s m ix tu re was f i l t e r e d
o f f , washed w ith 50 % a c e t i c a e id , and d is s o lv e d In h o t
m ethyl a lc o h o l.
Through th e b o ili n g a lc o h o llo s o lu tio n
hydrogen c h lo rid e gas from an e x t e r n a l g e n e ra to r was
p a s se d u n t i l p r e c i p i t a t i o n was com plete ( ab o u t 3 .5 h o u r s ) .
The p r e c i p i t a t e , w hich was th e h y d ro c h lo rid e o f 4 - n i t r o 1 -n ap h th y la m in e, was f i l t e r e d o u t , s t i r r e d up in w a te r,
and t r e a t e d w ith enough sodium hydroxide to produce a
perm an en tly a l k a li n e r e a c t i o n .
The p r e c i p i t a t e d base
was r e c r y s t a l l i s e d by r e p e a te d e x t r a c tio n w ith b o ili n g
m ethyl 1*1 c o h o l.
The y ie ld and m e ltin g p o in t were about
th e same as th o se r e p o r te d by S au n d ers.
2 . f«,
-
by th e method o f Hodgson and Crook9 .
« * ••• » »
p re p a re d
P h th a lo - l- n a p h th y l-
amide was p re p a re d by th e p o rtlo n w ls e a d d itio n o f
1-naphthylam ine to a b o ili n g s o lu tio n o f p h th a lle anhy­
d rid e In te tra h y d ro n a p h th a le n e .
T his was n i t r a t e d w ith
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add
« s p e c ia l n lfe rl adm ixture ( o n e - h a lf o f s . g . 1 .4 , o n e - h a lf
o f s .g . 1 .5 ) .
The n i t r e compounds o b ta in e d by p o u rin g
the n i t r a t i o n m ix tu re I n to an e x c e ss o f co ld w a te r were
h y d ro ly sed by h e a tin g f o r one h o ar a t 180*130
w ith
c o n c e n tra te d ammonium hydroxide in on a u to c la v e .
The
t a r r y p ro d u e t was p a r t i a l l y p u r i f i e d by s o lu tio n in
n itro b e n z e n e and p r e c i p i t a t i o n w ith d ry hydrogen c h lo rid e
gee*
Prom tb la h y d ro c h lo rid e p r e c i p i t a t e th e f r e e b ases
were l i b e r a t e d by th e a c tio n o f anasonlua h y d ro x id e .
The
s e p a r a tio n o f th e mixed 4 - , 5 - , end 8 -n itr o - 1 - n a p h th y lamines was then c a r r ie d o u t as d ir e c te d by Hodgson and
Crook, b u t th e f i n a l p ro d u c ts I s o la t e d were n o t as pure
as th e ones o b ta in e d by th e s e men.
Prom 143 g . o f
1 -n a p h th y l am ine, 18 g . o f 8-n 1 tro -l-n a p h th y la m in e m elt*
a
in g a t 86*90 , and 13 g . o f 8 -n Itro « l* n a p h th y la m in e
s
m e ltin g a t 113 were f i n a l l y o b ta in e d .
3* to g g a a rj^ g .ftp h th y l|ffllflf >-
K-ace ty l-l-n a p h th y la m in e
was suspended In carbon d i s u l f i d e , and t r e a te d w ith
bromine a c c o rd in g to th e pro o ed u re o f R o th er* .
The
a o e ty la te d p ro d u c t was h y d ro ly sed t o th e f r e e b ase by
r e f lu x in g f o r s e v e r a l hours w ith 50 jtf p o ta ssiu m
it
•
hydroxide s o l u t i o n .
The p ro d u c t m elted a t 97*99 .
This h y d ro ly s is i s d i f f i c u l t to e f f e c t , and steam
d i s t i l l a t i o n , a lth o u g h a slow m ethod, seemed to be
th e b e s t way to i s o l a t e th e p ro d u c t.
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-5 -
*•
* h i* ty -se v e n grams o f
crude 4 -b ro n e -l-n a p h th y la m ln e ( l a t e r found to be con­
ta m in a ted w ith a c o n s id e ra b le Q u a n tity o f th e a c e ty l
d e r i v a t i v e ) , 50 g . o f sy ru p y a r s e n ic a c id , and 90 g*
o f g ly c e ro l were p la c e d in a 600 m l. 3-neoked f l a s k
u n d e r r e f l u x , and mixed w e ll w ith a me chan1e a l s t i r r e r *
F ifty -s e v e n g . o f come* s u l f u r i c a c id was th en added
drepw lse th ro u g h a s e p a r a to r y fu n n el*
The m ix tu re was
h e a te d in an o i l b a th f o r one h o u r a t a te m p eratu re
•
g r a d u a lly in c r e a s in g from 96 to 135 , and then a t 165
f o r s i x h o u rs .
*
The h e a tin g had to be c a r e f u l l y c o n tr o lle d
d u rin g th e e a r l y p a r t o f th e r e a c t i o n , as c o n s id e ra b le
foam ing r e s u l t e d from to o sudden a r i s e In te m p e ra tu re .
M echanical s t i r r i n g was c o n tin u e d d u rin g tb s e n t i r e course
o f th e r e a c tio n *
The m ix tu re was poured
in to e x c e ss c o ld w a te r, and
allow ed to s ta n d s e v e r a l d a y s .
A d ark s o l i d
p re c ip ita te
was f i l t e r e d o f f , and th e f i l t r a t e was c h i l l e d and made
a lk a lin e w ith co ld sodium hyd ro x id e s o l u t i o n » A y ello w
p r e c i p i t a t e was o b ta in e d , w hich when d ry weighed 9 g*
H e e r y s t a lli s a ti o n from l l g r o l n ( b .p . 76-100 ) gave a
h ard y ello w s o l i d , w ith sup* 110-118 •
A n aly sis showed
t h i s m a te r ia l to be Im pure, and so i t was tw ice r e c r y s t ­
a l l i s e d from 76 m l. o f alo o h o l*
This gave 6 g* o f a
pure p ro d u c t, w h ite f l u f f y n e e d le s , sup* 1 1 5 .6 -1 1 6 * .
Anal)
C a lc , f o r C*,H,HBri
Pound I
% Br
% Br 50 .9 7
30 .8 6 , 50.98
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5*
6 * n ltr o * b a n s o (h )q u in o lin e .*
Four d i f f e r e n t modi*
f lo a ti o n s o f tho Skraup r e a c tio n were t r i e d , u s in g
10 g . o f 4*n 1 tro * l* n ap h th y lam ln e as th e s t a r t i n g no to r*
i a l i n o so h caa®.
Ths f i r s t was th a method d e v ise d by
Kneuppel to p ro p aro 6 - n ltr o - q u in c lin e from p - n i t r a n i l i n e ,
u
In which n ltro b a n s a n a I s th s o x id is in g agont . Tho Cohn
thot hod,
u s in g fo rro u s s u l f a to , b o r lo s o ld , and a rs o n lo
.
ta
s o ld (and no n ltro b o n s o n o ), was n o x t employed • T his was
is
fo llo w ed by a d a p ta tio n s o f th s a c e t i c a c id m o d ific a tio n
and o f th o method u sed by M o se ttlg and K rueger f o r tho
p r e p a r a tio n o f a n a p h th o q u in o lin o from 5-am lno~phanan­
sa
th ro n e • In a l l th e se t r i a l s th e r e a c t a n t s , p ro p o rtio n s
o f r e a c t a n t s , and methods o f tre a tm e n t were th e same as
in tho v a rio u s r e s p e c tiv e p ro ced u res b e in g fo llo w e d .
From no no o f them was more than a v e ry sm a ll amount o f
a c ld - s o lu b le m a te r ia l o b ta in e d } th s l a r g e s t volume o f
such m a te r ia l r e s u l t e d from th e a o e t l e s o ld m o d if ic a tio n .
The combined a c id - s o lu b le m a te r ia l from a l l f o u r ru n s
was r e c r y s t a l l i s e d tw ice from 98 % e th y l a lc o h o l, then
once from a m ethyl a lc o h o l- w s te r m ix tu re , w ith th e a id
o f c h a r c o a l.
T his gave a f l u f f y , volum inous, l i g h t *
yello w p r e c i p i t a t e , In th e form o f f in e n e e d le s .
A fte r
f i l t r a t i o n , w ashing w ith w a te r, and d ry in g , 0 .8 g . o f
su b sta n c e m e ltin g s h a rp ly a t 149
A nali
C a lc , f o r
Founds
was o b ta in e d .
% Q 6 9 .6
% C 6 9 .5 , 6 9 .4 )
% H 3 .5 7
% H 8 .6 5 , 3 .5 8
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-7
6 * 7 -n ltro > b s n « o i l x i m I n o lln o .*
To a m ix tu re o f 1 .5 g .
o f f e r r o u s s u l f a t o and 7 .0 g . o f 5 - n Itro -l-n a p h th y la m in e
was added 1 3 .5 g* o f g ly o o ro l in whloh 4 .6 g . o f b o r ic
a c id had boon p r e v io u s ly d is s o lv e d .
Next 10 g . o f sy ru p y
(85 %) a re o n lo a c id and f i n a l l y 7 .5 a d . o f oone. s u l f u r i c
ao ld wore add ed , tho l a t t e r slo w ly and w ith s t i r r i n g .
m ix tu re was h o ato d u n d e r r e f l u x in an o i l h a th a t 140
Tho
•
fo r
tw elve h o u rs , th e n poured In to 300 m l. o f w a te r and allow ed
to s ta n d o v e r n i g h t .
The su sp e n sio n was h e a te d to b o ili n g
and f i l t e r e d w h ile h o t.
gave no p r o d u c t.
Tho f i l t r a t e upon b a s l c i f i c a t i o n
Tho re s id u e was b o ile d w ith th r e e sue*
c e s s lv e 50 a d . p o r tio n s o f a lc o h o l, u s in g c h a rc o a l.
A fte r
f i l t r a t i o n and c o o lin g , a f lo c c u le n t s o l i d ap p eared In th e
filtra te .
A nother a lc o h o l r e c r y s t a l l i s a t i o n , ag a in u s in g
c h a rc o a l, gave a w hite f e a th e r y p ro d u c t, a . p . 174.5*175 ,
y ie ld 0 .3 g .
A nal:
G ale, f o r C*s H*0*Na :
Foundi
5.
$ 0
% C 6 9 .6
5 9 .6 , 6 9 .5 ;
% H 3 .5 7
% H 3 .5 5 , 3 .6 1
P re p a ra tio n o f hydroxy* and c h lo ro *
b en so (h ) q u in o lin e s •
7*
th rl* 4 * b v d ro x y * b en g o tM g a lB o lln e.*
Molar quant*
i t l e e o f l« n a p h th y la a la e and a e e to a e e tle e s t e r were con*
densod to g e th e r in th e p resen ce o f s e v e r a l drops o f 6 H
h y d ro c h lo ric a c id to g iv e e th y lp -1 -naphthylam ino *c r o t *
o n a te .
Ths two s u b sta n c e s were h e a te d to g e th e r in a f l a s k
in a b o ili n g w a te r b a th
f o r f iv e h o u rs , and th e m ix tu re
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Allowed to s ta n d o v er n i g h t .
The crude, co n d en satio n
p ro d u ct was a re d o i l , and was n o t f u r t h e r p u r i f i e d .
This c ro to n a te e s t e r was then o y c lls e d In h o t
xe
p a r a f f in ac c o rd in g to th e method o f Llrapach
to give
2 -m e th y l-4 -h y d ro x y « b e n z o (h )q u in o lin e »
The m a te r ia l
was c y c lls e d In 15 g , l o t s , u s in g o n e -e ig h th pound o f
p a r a f f in wax f o r ea ch run* F i l t r a t i o n w hile h o t
e
(150-175 ) removed much o f the p a r a f f in ) most o f th e
r e s t was tak en o u t by e x tr a c tio n w ith te o h n le a l grade
e th e r*
The p u r i f i e d hydroxy compound was a v e ry In*
s o lu b le , f l u f f y , lig h t-b ro w n s o l i d ( y ie ld , 50-55 %)•
®* 2*msthvl-4-ohloro- and 4*methyl-2-ohioro-bepEO>**
These were o b ta in e d from 2 -m e th y l-
4-h y d ro x y - and 4-m©th y l- 2 - h y d r oxy- (Union C arbide and
Carbon Co* p ro d u c t) b e n s o (h )q u ln o lin e s by u se o f th e
xe
g e n e ra l method developed by G ibson, e t a l • T y p ical
runs were as fo llo w s :
o f phosphorus
25 g . o f hydroxy compound, 25 g*
p e n ta c h lo r id e , and 50 ml* o f t e t r a e h l o r -
eth an e were re flu x e d to g e th e r two hours*
Because o f the
i n i t i a l v io le n c e o f th e r e a o t lo n , h e a t was a p p lie d
c a u tio u s ly a t f i r s t *
The m ix tu re was co o le d , ab o u t 200
ml* o f w a te r added to decompose th e rem ain in g phos­
phorus
h a l i d e s , and th e te tr a o h lo r e th a n e was removed
by steam d i s t i l l a t i o n *
In th e case o f th e 4 -o h lo ro compound, th e s o lu tio n
rem ain in g in the f l a s k was th en f i l t e r e d from any t a r
p r e s e n t, and th e crude p ro d u c t was o b ta in e d by making
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
th e f i l t r a t e b a s ic w ith sodium o r ammonium hydroxide*
R e c r y s ta llie a tio n from a lc o h o l, u sin g ch a rco a l, gave
a l i g h t c o lo re d p ro d u c t, m.p* 90*92 .
The y ie ld from
th e c h lo r in a tio n r e a c tio n was about 14 g * , o r SO %*
The o v e r a l l y ie ld o f 2 -n » th y l-4 ~ c h lo ro -b e n zo { h )q u in o ~
l i n e f r o a th e 1-nap h th y lam ln e u se d as th e s t a r t i n g
p ro d u ct was about 26 %»
The 4 -m etliy l-2 » eh lo r0 -b 9 n zo (h ) q u in o lin e , due to
I t s l e s s b a s ic c h a r a c te r , s e p a r a te d as a g am y s o l i d
in the f l a s k th ro u g h w hich steam wse b e in g passed*
I t was f i l t e r e d o f f and th e f i l t r a t e d isc ard ed *
The
crude m a te r ia l was r e c r y s t a l l i s e d from e t h y l a lc o h o l,
a
and had a m.p* o f 136*13? * I t i s l e s s s o lu b le in
a lc o h o l th an i t s 4~ ohloro iso m er, and la hence th e
h a rd e r one to r e c r y s t a l l i z e .
A b e t t e r method o f
p r e p a r a tio n was to remove th e e x c e ss phosphorus
h a lid e s by reduced p re s s u re d i s t i l l a t i o n r a t h e r th an
by steam d i s t i l l a t i o n , to t r i t u r a t e th e r e s id u e w ith
1 N sodium hydroxide s o l u t i o n , and then to r e c r y s t a l l *
Iso from alco h o l*
9* B jth v l/3 * i4 * b ro ao » l» n aB h th y lftad n o i-o ro tQ n ate*-
s ix *
teen and o n e - h a lf g* o f 4 -b ro m o -l-n a p h th y la » ln e was
m elted in a ro u nd-bottom f l a s k , 10 g* o f a e e to a e e tie
e s t e r and 2 drops o f 8 H h y d ro c h lo ric a c id added and
s t i r r e d in w ith th e am ine, and th e f l a s k was p la c e d
in a b a th o f b o ili n g w ate r f o r an h o u r.
A fte r c o o lin g
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-10
and s ta n d in g o v er n i g h t , th a m a te r ia l in th a f l a s k had
become a h a rd , la v e n d e r - c o lo r e d s o lid *
The a s t e r a f t e r
two r e c r y s t a l l i s a t i o n s f r o a a 50 % a lc o h o l-w a te r m ix tu re
was a volum inous s o l i d , l i g h t la v e n d e r in c o lo r , m .p.
113-114
Anal»
a f t e r b e in g d r ie d in an oven ( y i e l d , 51 % ).
Calc* f o r G*>«H*#0*HBri
% N 4*99, 4*24
Foundt
10 •
% H 4 .1 9
th v l- 4 - h v d r oxr-d-brom o-benao (h ) q u in o lin e . - Ten
g* o f e th y l /3 - (4 - b ro m o -l-n a p h th y la a in o )-o ro to n a te was
powdered and added to o n e - f o u rth pound o f p a r a f f in wax
t •
p r e v io u s ly h e a te d to 260 * The te m p eratu re was m ainta in e d above 050
f o r f iv e m inutes*
th e c y e lis a tio n r e a c tio n took p la ee*
A s o l i d formed as
T his was f i l t e r e d
o f f w h ile th e m ix tu re was s t i l l h o t, washed w ith l l g r o l n
and w ith e t h e r , and d rie d *
The m a te r ia l was a la v e n d e r*
o
c o lo re d , amorphous s o l i d , and d id n o t m e lt below 270 •
The y ie ld was a l i t t l e more th an 5 g .(6 0 %)*
A p o r tio n o f th e crude p ro d u c t was p u r i f i e d by
r e f lu x in g w ith c h a rc o a l in m ethanol s o lu t io n , f i l t e r i n g ,
and ad d in g w a te r to th e f i l t r a t e u n t i l no f u r t h e r p r e ­
c i p i t a t i o n o ccu rred *
and volum inous*
A nali
The p u re hydroxy compound was w hite
I t was f i l t e r e d o f f and d r ie d in th e oven*
C a lc , f o r C**Hi*GNBri
Found!
% IT 4 .8 5
% 9 4 .8 5 , 4*95
n *
p<wr
■
g . o f 2 -x aethyl-4-hydroxy-6-brom o-benso(h ) q u in o lin e , 4 g*
o f phosphorus
p e n ta c h lo r id e , and 15 ml* o f phosphorus
o x y c h lo rld e were h e a te d to g e th e r in an open f l a s k in an
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-11
o i l b o th a t 110-116
t
f o r f o r t y m in u te s, fo llo w in g tho
method o f F ia c h e r e t a l.* *
The s o l i d m a te r ia l g r a d u a lly
d is s o lv e d , and tho l i q u i d slo w ly b o ile d o u t o f th e f l a s k
d u rin g t h i s t i n s .
,
The m ix tu re was th en poured i n t o co ld
!
. w ater and th e whole was s t i r r e d in o r d e r to docompose th e
C.‘
u n re a c te d phosphorus
|
h a lid e s * A d ark s o l i d form ed a t th e
bottom o f th e c o n ta in e r .
A fte r th e s o lu tio n had been made
b a s ic , th e s o l i d m a te r ia l was f i l t e r e d o f f and d rie d *
It
was r e c r y s t a l l i s e d from a lc o h o l w ith th e a id o f ch arco al*
The f i n a l p ro d u c t ap p eared as f in e w h ite c r y s t a l s , m.p*
146*5-147*, y ie ld 85 £ •
Anal:
% H 4 .5 7
Calc* f o r Gi*H*XBrGlt
Founds
0*
% N 4*40, 4*42
C ondensation p ro d u c ts from c h lo ro -b e n so ( h )q u ln o lin e s and sim p le amino compounds.
12.
g - » t h T l ~ t - ( / 3 - b T d r e x y th r lM iln a ) - m d 4 - w t f a r t-
B -(/3 -hyjSro»T «thT l»«laei-b»ii«)ib)<m li> ollB «. -
On. p a r t
by w eig h t o f th e 8 - e h lo r o - o r 4 -c h lo ro -b e n s o (h )q u in o lin e
compound and 4 p a r t s o f e th a n o la a ln e were g e n tly re flu x e d
to g e th e r f o r e i g h t h o u rs , and th e m ix tu re was th en poured
I n to an e x c e ss o f c o ld w ater*
A gum form ed a t f i r s t ,
which changed to a h a rd s o l i d upon s ta n d in g In th e r e f r i g ­
e r a t o r o v er n ig h t*
The m a te r ia l In t h i s form was s u f f i c ­
i e n t l y p ure f o r f u r t h e r s y n t h e t i c a l work*
i
To a t t a i n f u r t h e r
p u r i t y , I t was r e c r y s t a l l i s e d from m ethyl o r e t h y l alco h o l*
From th e form er s o lv e n t I t s e p a r a te d o u t a s s m a ll, h a rd ,
diam ond-shaped c r y s t a l s , w ith a s l i g h t brow nish c o lo r ,
372017
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*12-
m .p. 181 -1 8 1 .5
§
( y ie ld b e fo re r e c r y s t a l l i s a t i o n , about
90 % ). (2 -m e th y l-4 - (/3 -h y d ro x y eth y lam ln o ) -b en so (h ) q u ln o lin e )
Anal:
G ale, f o r 0**11*,OH, *
Pounds
%I
11.10
% V 1 0 .8 5 , 10.87
The crude 4 - m e th y l- 2 - ( ^ -h y d ro x y sth y lam ln o ) -b en so (h )q u in o lin e was r e c r y s t a l l i s e d tw ice f r o a a 60 %
a lc o h o l-w a te r m ix tu re , w ith th e a id o f ch arco al*
The
•
pure compound forma snow -w hite n e e d le s , m .p. 108 ,
y ie ld 50 f .
A nalt
C a lc , f o r C*eH*,0H,i
Founds
$ H
% N 11.10
1 0 .9 7 , 1 0 .9 9
In b o th o f th e s e s y n th e s e s , ab o u t 10 g . o f pure
hydro xye thylam lno compound may be o b ta in e d from 15 g .
o f th e co rresp o n d in g o h lo ro compound.
Three grans o f 2-me t h y l - 4 - (,<3 -hydroxys th y la m ln o ) -ben *o(h )q u in o lin e and 15 m l. o f phosphorus
o x y ch lo rld e were
s t i r r e d to g e th e r , and a f t e r th e i n i t i a l r e a c tio n
su b sid e d th e m ix tu re was g e n tly r e f lu x e d f o r
o n e -h a lf h o u r s .
had
two and
Most o f th e e x c e ss s o lv e n t was d i s t i l l e d
o f f , and th e re s id u e was poured In to co ld w a te r; th e
rem ain in g phosphorus
a cream -co lo red s o l i d .
o x y c h lo rld e soon r e a c te d , le a v in g
R e c r y s ta ll1s a tI o n , u s in g c h a rc o a l,
from m ethyl a lc o h o l gave a w h ite p r e c i p i t a t e o f f in e
c r y s t a l s . T his p ro d u e t d id n o t m e lt a t te m p e ra tu re s u n d er
a
850 , and was e v id e n tly a h y d ro c h lo rid e s a l t . I t s e x a c t
com position was n o t d e te rm in e d .
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-1 5 -
The above h y d ro c h lo rid e was d la a o lv e d in warm w a te r,
and sodium hyd ro x id e s o lu tio n was added.
A heavy f l o e -
c u le n t p r e c i p i t a t e form ed, w hich was r e e r y s t a l l i s e d
from m ethyl a lc o h o l.
The p ro d u ct was alm ost w h ite , and
In th e form o f lo n g n e e d le s .
I t m e lte d a t 85-84 , and
decomposed w ith e v o lu tio n o f v ap o r a t 88 •
These f a c t s ,
and th e fo llo w in g a n a ly s is , in d ic a te d t h a t th e su b sta n c e
c o n ta in e d m ethyl a lc o h o l o f c r y s t a l l i s a t i o n .
Anal:
G ale, f o r (Ci«£isfts<&)eGg»0B*
Found!
i Cl 1 8 .3 8
i 01 1 S .S 8 , I S . 35
Some o f th e crude p ro d u c t from th e phosphorus
oxy­
c h lo rld e tre a tm e n t was r e c r y s t a l l i s e d from an e th y l
a lc o h o l-w a te r s o l u t i o n .
The w h ite p ro d u c t, f r e e from
a lc o h o l o f c r y s t a l l i s a t i o n , m elted a t 153 .
14.
4 - a s th T l-8 -v ln y la w la o -b e n s o C h i a u i n c l i n e Four and
o n e - h a lf g . o f 4 - m e th y l-8 - (^ -h y d ro x y sth y lam ln o ) -benso*
(h )q u in o lin e was t r e a t e d w ith about 8 m l. o f th lo n y l
c h lo r id e .
A v io le n t r e a c tio n en su ed , and a y ello w c o lo r
a p p e a re d . E th e r and more th lo n y l c h lo rid e were added,
the m ix tu re was re f lu x e d f o r a s h o r t tim e , th e e t h e r was
d i s t i l l e d o f f , and th e r e s id u e was poured I n to w a te r.
N e u tr a lis a tio n w ith ammonium hydroxide gave a gummy
yello w p r e c i p i t a t e , w hich a f t e r warming w ith d i l u t e so d ­
ium hydroxide s o lu tio n was f r e e f r o a h a lo g e n . T his
m a te r ia l was r e o r y a t a l l l s e d f r o a a lc o h o l- w a te r, and then
d is s o lv e d in d i l u t e h y d ro c h lo ric a e ld .
The s o lu tio n was
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
u
filte re d
f r o a a a l i g h t amount o f a d ark im p u rity .
A d d itio n o f an e x c e ss o f d i l u t e sodium hydroxide
s o lu tio n to th e f i l t r a t e produced a b r ig h t y ello w
s o li d p r e c i p i t a t e , w hich was shown to be co m p letely
h a lo g e n - f r e e .
A fte r b e in g d r ie d in an oven, t h i s mat­
e r i a l had a m.p* o f 184*6-186.6 d ( y ie ld , 60 JO*
The
a c id s o lu tio n s o f t h i s compound were c o lo r le s s *
Clem,
in h is work on 1-m eth y l- 6 - (/3 -hydroxys th y la m ln o ) -b en so
( f ) q u ln o lin e , o b ta in e d a compound o f s im ila r p r o p e r tie s
A nal:
O slo , f o r Cl a H**If«t
Founds
15•
%H
«
%»
11*86* 1 1 .8 7
4-ma t h v l - 8 - I - p 1p o rld ln o -b e n a o (h ) q u in o lin e . - Ten
g . o f 4 - n s th y l- 8 -e h lo r e - b e n s o ( h )q u in o lin e and 10 g .
o f p ip e r id in e were r e f lu x e d to g e th e r f o r two h o u rs .
At
th e end o f t h i s t l a e th e m ix tu re In th e f l a s k was n e a r ly
a ll s o lid .
T his m a te r ia l was t r e a t e d w ith d i l u t e sodium
h y d ro x id e , and tak en up in e t h e r .
Redueed p r e s s u r e d i s ­
t i l l a t i o n o f th e re s id u e from th e e t h e r s o lu tio n gave a
v isc o u s y ello w l i q u i d w hich changed to a cream -co lo red
s o l i d upon s ta n d in g f o r two days*
Three r e c r y s t a l l i s a t i o n s
from a le o h o l f a i l e d to g iv e a pure compound, and a t e s t
f o r halogen I n d ic a te d t h a t some o f th e o r i g i n a l ch lo ro
compound was e v id e n tly s t i l l p r e s e n t.
T reatm ent w ith
h o t 6 % h y d ro c h lo ric a d d d is s o lv e d th e p lp e r ld ln o com­
pound, le a v in g u n d lsa o lv e d th e l e s s b a s ic c h lo ro compound.
B a s d e ific a tio n o f th e f i l t r a t e gave a p ro d u c t w hich a f t e r
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•1 5 -
re c r y s t a l l i z a t i o n f r o a m ethanol ap p eared as w h ite c ry •
.
a t a l a , m .p. 79*80 , y ie ld 50 $ • The a lc o h o l s o lu tio n
d is p la y e d a a l i g h t la v e n d e r f lu o re s c e n c e .
A nalt
Calc* f o r C*eH,*N«}
Found}
%W
% H 10*15
9*95, 10*00
16* /3 -h y d roxrw 3 - (g -me t h r l-4 - b c n ao (h le a I b o I t I amine 1«
and
\*
d ie th y l aaln ea* *
F ir e g . o f th e 2* o r 4 -c h lo ro -b e n s o -
( h )q u ln o lln e and 10 g . o f f i -h y d ro x y sth y le th y le n e diam ine
were h e a te d In an o i l b a th a t 190
f o r e ig h t hours*
The
m ix tu re waa poured I n to w a te r, g iv in g a gum w hich la r g e l y
s o l i d i f i e d upon s ta n d in g in th e r e f r i g e r a t o r *
R epeated
r e c r y s t a l l i s a t i o n o f t h i s au b atan ee f r o a e th y l a lc o h o l,
e th y l a lc o h o l- w a te r, o r dloxane (w a te r added to f i l t r a t e s
In a l l c a se s to Induce p r e c i p i t a t i o n ) f a i l e d to g iv e a
p ro d u c t o f th a d e s ir e d p u r ity *
Work was c a r r ie d o u t
u n t i l f u r t h e r r e c r y s t a l l i s a t i o n gave no h ig h e r a m e ltin g
p o in t ( 4-m ethyl isom er 115*118*, 2-m ethyl isom er 4 7 -5 0 * }.
A lcohol s o lu tio n s o f b o th s u b sta n c e s e x h ib ite d a s l i g h t
flu o re s c e n c e *
A nal:
Calc* f o r Ci«H*iOX# !
Found}
17•
% N 14*24
4-m eth y l Isom er
% X 13*55, 13*75
2-m eth y l isom er
% W 1 3 .5 8 , 15*68
3 * N -a o rP b o lln o -4 -» sth y l- and 4 -H -a o rp h o lln o -2 -m e th y l-
b c n s o (h ) q u in o lin e s **
Fiwe g* o f th e 2* o r 4 - c h lo ro -
b e n s o (h )q u in o lin e and 10 g* o f m orphollne were r e f lu x e d
f o r e i g h t hours*
A fte r c o o lin g , th e m ix tu re was poured
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-1 8 -
In to c o ld w a te r to d is s o lv e th e ex cess m o rp h o lln e, and
th e whole wee allow ed to s ta n d o v e r n ig h t*
The r e s u l t i n g
s o l i d m a te r ia l was tw ice r e c r y s t a l l i s e d f r o a e th a n o l,
u s in g c h a r c o a l•
Both compounds were o b ta in e d as f in e w h ite
n e e d le s , th s 2*V -m orphoiino*4*m ethyl-benso(h)< |alnollne
m e ltin g a t 101*8 , and th e 4 » H -aorphollno»2-iaethyl le o a e r
a t 187*8*.
Ana l l
They i e l d s were ab o u t 45*50
% V 10.07
G alo. f o r C lH lO N .:
Pounds
D*
%*
2-H -m orphollno I s o n er
%V
9*85, 9*85
4-N -m orphollno
%8
9*98, 9 .9 8
ls o a e r
P re p a ra tio n o f a l l p h a t l e a a l n o - n l t r i l e s
and d ia a ln e s *
18*
S th y le n e oyanohydrln was
p re p a re d f r o a e th y le n e e h lo ro h y d rla by th e method o f
O rganic S y ntbaeos**.
This was co n v e rted I n to /3 - c h lo r o -
p r o p i o n l t r l l e by th e r e a c tio n o f th lo n y l c h lo rid e w ith
at
i t in ch lo ro fo rm s o lu tio n •
I 0*
•»* /? - y - q o r p h o l l n e - p r o p l o n l t r l i e s *-
In to 50 g« o f d le th y la a ln e o r a o rp h o lln e p la c e d in a
b e a k e r was poured 20 g . o f /3 - c h l o r o p r o p l o n ltr lle in
sm a ll p o rtio n s *
A fte r a s h o r t p e r io d o f I n a c t i v i t y , a
v ig o ro u s r e a c tio n to o k p la c e , g iv in g a w h ite c r y s t a l l i n e
p r e c i p i t a t e o f d le th y la a ln e * o r a o rp h o lla e -h y d ro c h lo rld e *
Much h e a t was e v o lv e d , and th e r e a c tio n m ix tu re was cooled
w ith c o ld w ater*
The h y d ro c h lo rid e p r e c i p i t a t e was f i l t e r e d
o f f , then washed th o ro u g h ly w ith e t h e r and ag ain f i l t e r e d *
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-17*
The combined f i l t r a t e and w ashings v e r t f r a c tio n a te d
u n d er red u ce d p r e s s u re in a 200 m l. C la lse n f l a s k .
Two
f r a c tio n a tio n s gave th e a m in o - n itr lle in a p ure fo rm . The
y ie ld s wore as f o llo w s t
th e d ie th y la m in o - p r o p io n itr ile
56 %, th e K * w o rp h o lin o * p ro p lo n ltrile 77 %•
/3 * d lc th y la m ln o - p r o p lo n ltr lia .*
B .p . 8 8 .5 * 8 4 .5 / l 5 mm.
n*J
Mol. r e f r a c t .
3 0 .2 ?
An a l l
C a le .i
1.4543
Found
0.8761
57*54
% V 22.88
C a lc , f o r
% X 2 1 .9 8 * 8 1 .9 8
Founds
£
S .g .* *
S3WBBtflWtf>MMft *
B .p . 155*184 /1 4 am.
Mol. r e f r a c t .
A nalt
«**
C a le .t
37 .8 5
C a lc , f o r G*H**0H*s
%I
Founds
1.4700
S .g .* J
Founds
%V
1 .0375
57.71
20.00
1 9 .7 3 , 1 9 .9 5
80 • %-aifthjiM ln.- u t &-»-rerph«ll»o->»otYr«iltrll»i & -o h lo ro b u ty ro n 11 r i l e was p re p a re d by th e awthod o f
as
.
O rganic S y n th eses . A y ie ld o f 85 % was o b ta in e d , an
improvement o v er p r e v io u s ly r e p o r te d y i e l d s . F i f t y g .
o f th e n i t r i l e and 90 g . o f d ie tb y ls a la e were r e f lu x e d
to g e th e r e ig h te e n h ours on a steam b a t h .
The p r e c i p i ­
t a t e d d le th y la m ln e -h y d ro o h lo rid e was f i l t e r e d o f f and
washed w ith e t h e r .
The f i l t r a t e and w ashings were
f r a c t i o n a t e d in a C la lse n f l a s k , u s in g reduced p r e s s u r e .
The y ie ld o f
^ * d ie th y la m ln o * b u ty ro n ltrlle was 4 6 .5 g .
(69
Tw enty*five g« o f
^ - e h l o r o b u t y r o n i t r l l e and 60 g .
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*18*
o f m orphollne were r e f lu x e d to g e th e r o v er n ig h t*
Upon
c o o lin g , a c r y s t a l l i n e p r e c i p i t a t e o f m orphollne hydro*
c h lo rid e had form ed, w hich wee f i l t e r e d o f f and washed
w ith e t h e r .
F r a c tio n a tio n o f th e f i l t r a t e and w ashings
gave 2 0 .5 g .( 8 6 %) o f th e d e e lr e d p ro d u c t.
B .p . 91 / l i
B O B .,
Mol. r e f r a c t .
Anal*
100#/1 9 mm.
G a le • t
48.87
Gale* f o r 09nk§S Bt
Found*
n** 1.4563 S .g .* J
Found;
% C 68 .5 7
$ 0 8 8 .4 3 , 68*38
Anal*
48*43
Calc* f o r <goS|,4Oir*t
Found*
81.
O tic .;
%9
48.58
% H 11*43
% H 11*51, 11.36
y -n -M ?rp h aX H i» « tm ty ro altrl.l« ^
B.p* 148 A® an*
n ^ 1*4848
Mol. r e f r a c t .
0.8001
49
S .g* « 1.0031
Found:
48 .4 7
18.18
$ 9 18*33, 18.30
< f* d leth v laaln o * and &»S*»orphollneH>butvl aminos .*
These wore p re p a re d by re d u o tlo n o f th e co rresp o n d in g
n l t r l l e e , u s in g sodium In an a lc o h o l-to lu e n e s o l u t i o n ,
ac c o rd in g to th e method d ev elo p ed by Magldaon and Grig*
'
a*
orowaky f o r p r e p a r a tio n o f a s i m i l a r compound •
^
To 18 g . o f f l n e l y * s l l c e d sodium u n d e r to lu e n e a
s o lu tio n o f 85 g . o f
- d le th y la m ln o - b u ty r o n ltr lle in
100 m l. o f a b s o lu te a lc o h o l was added In sm a ll p o r tio n s ,
w ith v ig o ro u s s t i r r i n g .
Toward th e end o f th e r e a c t i o n ,
w hich was p re v e n te d from becoming to o v i o l e n t by o ccas*
to n a l c o o lin g in c o ld w a te r, sodium e th o x ld e s e p a r a te d
o u t and by c o a tin g o v e r the rem ain in g sodium h in d e re d
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
“19»
com pletion o f th e r e a c t i o n .
H eatin g th e Mixture tin d er
r e f l u x f o r a s h o r t t i n e r e s u l t e d In th e d isa p p e a ra n c e
o f th e u n re a c te d sodium .
A d d itio n o f ab o u t 50 n il. o f
co ld w a te r caused a s e p a r a tio n in to two l a y e r s .
The
low er aqueous la y e r was s e p a ra te d o f f and d is c a r d e d .
To
th e a l co h o i - to lu e n e la y e r enough 6 If h y d ro c h lo ric a c id was
added to produce a m ix tu re d e f i n i t e l y a c id to Congo Red
p a p e r.
The to lu e n e was removed b y steam d i s t i l l a t i o n ,
and th e rem ain in g s o lu tio n was c o n c e n tra te d u n d e r reduced
p re s s u re u n t i l th e r e s id u e became q u ite sy ru p y and s o l i d
m a te r ia l had begun to s e p a r a te o u t .
F ifty a l . o f 6 8
sodium h y d ro x id e s o lu tio n and ab o u t 86 g . o f s o l i d p o ta s s *
lum hy d ro x id e were th en added, and th e brown la y e r o f
crude diam ine which s e p a r a te d o u t was ta k en up by e x tr a c t*
Ion w ith th r e e 90 m l. p o r tio n s o f b e n s e n s .
The benzene
s o lu tio n was d r ie d o v e r n ig h t w ith s o l i d p o tassiu m hydrox*
lde end anhydrous p o ta ssiu m c a rb o n a te , th e s o lv e n t d i s t i l l e d
o f f u n d er norm al p r e s s u r e , and th e re s id u e d i s t i l l e d u n d er
reduced p re s s u re from a C lalaen f l a s k .
The y ie ld o f th e
d e s ir e d d iam in e, a w a te r-w h ite l i q u i d w ith a s tr o n g o d o r,
was 18 g . (50 %)•
T his compound has been p r e v io u s ly
ee
r e p o r te d in name o n ly .
cf *H *m orpholino-butyl amine was p re p a re d In an e x a c tly
analogous fa s h io n from th e c o rre sp o n d in g n i t r i l e .
From
g o .5 g# o f n l t r i l e th e r e was o b ta in e d 18 g« o f th e diam ine
(57 %), w hich was a ls o w a te r-w h ite w ith a s tr o n g amine*
l i k e o d o r.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•so *
cT ^dt^h^aiaiB O ^tm tT l am in e.B .p . 85-86#/ l 6 sou
a j*
Mol. r e f r i o t .
46*42
A n ill
C alc.}
C a lc , f o r
s
%0
1*4420
% H 1 3 .8 9
66*67
% H 1 8 .7 0 , 1 3 .7 8
/ -N -m o rp h o lln o -b u ty l am ine. •
as
B .p . 123**128 / I S ut<
1.4720
.
Mol. r e f r a c t .
A nal:
C a lc .:
48.05
C a lc, f o r C,H*#0S»t
Foundi
%8
0.8531
Pound 4 4 .7 6
% Q 8 6 .7 5 , 66 .6 5
Pound!
S .g .* J
as
S .g . ^
Found:
%I
0.9804
43 .1 9
17.72
1 7 .4 0 , 17 .6 6
22* X -d ie th y la m ln o - and
y -» -« o rp h o lln o -p ro p y l a a ln e a .-»
Both o f the so diam ines wore p re p a re d by moans o f O a b rle l
p h th a lim id e s y n th e s e s .
^ -d le th y la m in o -p ro p y l amino was
a«
made as d ir e c te d by S h rin a r and H ickey , e x c e p t t h a t th e
h y d ro ly o ia o f th e in te rm e d ia te p h th a lim id o compound was
e f f e c t e d w ith 10 H h y d ro c h lo ric a c id in s te a d o f th e d i l u t e
h y d ro c h lo ric a c id u se d by th e above a u th o r s .
«
b o ile d a t 165-170 u n d e r norm al p re ss u re *
The diam ine
^-M -m orpholino-propyl amine was p re p a re d in a s im ila r
f a s h io n , as fo llo w s :
115 g* o f K -b ro m o p ro p y l-p h th alim ido
and 115 g . o f m orphollne were r e f lu x e d to g e th e r ele v e n
hours o v er a h o t p l a t e .
While th e m ix tu re was s t i l l h o t,
th e p r e c i p i t a t e o f m orphollne hydrobrom ide was f i l t e r e d
o ff.
The f i l t r a t e was d i s t i l l e d u n d e r red u ced p re s s u re
to e lim in a te m ost o f th e e x c e ss m o rp h o lln e . The v is c o u s
l i q u i d re s id u e was h y d ro ly sed by re f lu x in g f o r f iv e h ours
w ith 130 m l. o f 10 H h y d ro c h lo ric a c id .
A fte r th e
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•2 1 -
p r * c ip it « te d p h th a llc a c id had been f i l t e r e d o f f , th e
f i l t r a t e was c o n c e n tra te d la vacuo u n t i l I t became th ic k
and sy ru p y .
To t h i e r e s id u a a s o lu tio n o f 100 g* o f
p o ta sslu m hyd ro x id e la 100 m l. o f w a te r was added, f o l ­
lowed by mere s o l i d h ydroxide u n t i l a s a tu r a te d a l k a l i
s o lu tio n was o b ta in e d *
was s e p a r a te d o ff*
A brown o i l y la y e r form ed, and
T his was d i s t i l l e d u n d er red u ced
p r e s s u r e , and th e f r a c t i o n coming o v e r a t 70-120*/ l 5 mm.
Twenty g* (26 %) o f a c l e a r
was ag ain r e f r a c tio n a te d *
w hite l i q u i d w ith a s tr o n g amine
o d o r was o b ta in ed *
The m orphollne-hydrobrom ide b y -p ro d u c t, n o t p re v io u s ly
d e s c rib e d in th e l i t e r a t u r e , was r e c r y s t a l l i s e d tw ice from
a lc o h o l, u s in g ch a rc o al*
The p ure su b sta n c e ap p eared as
b e a u tif u l w h ite n e e d le s , m .p. 214-216 •
m M iB .p . 1 0 3 -lG 6 * /l5 am*
Mol* r e f r a c t *
A nalt
n j*
C a lo .t
41*46
C a lc , f o r C,H190V«t
Found!
%6
1*4788
8*g.** 0.9991
Found 40*68
% V 19.44
19*19, 19 .2 6
Merphollns-hvdrobromldo *•
A nalt
Calc* f o r G+HiaOBBrt
Founds
23•
%I
8 .6 8
% N 8*37, 8*86
1 -d le th v la a ln o -n o n ta n o n e - 4 .- /? .d ie th y la m ln o e th y l
c h lo rid e was p re p a re d by th e a c tio n o f th lo n y l c h lo rid e
as
on (3 -d ie th y la m ln o e th a n o l In b ensens s o lu tio n .
About 30 g . o f sodium was d is s o lv e d in 800 m l. o f
a b s o lu te alo o h o l*
T his s o lu tio n and 130 g . o f a c e to a e e tlo
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•82*
e a t e r war® p la c e d 1b a t w o - l i t # r 3 -necked f l a s k eq uipped
w ith r e f l u x co n d e n ser, m echanical s t i r r e r , and d ro p p in g
fu n n el*
The m ix tu re was h e a te d to b o i l i n g , and ISO g . o f
/3 * d le th y la m ln o e th y l c h lo rid e was run i n , d ro p w ise, o v er
a p e r io d o f two h o u rs .
The whole was r e f lu x e d and s t i r r e d
c o n tin u o u sly d u rin g t h i s tim e , and d u rin g a f if t e e n - h o u r
p e r io d a f t e r th e a d d itio n o f th e a lk y l c h lo r id e .
The p r e c i p i t a t e d sodium o h lo rid e was f i l t e r e d o f f , and
th e a lc o h o l was e v a p o ra te d by h e a tin g o v e r a steam bath*
The re s id u e was s t i r r e d o v e r n ig h t w ith 1000 ml* o f 5 %
sodium hyd ro x id e s o l u t i o n , and th e s l i g h t l y y ellow o i l y
la y e r on to p was s e p a ra te d o f f .
The aqueous la y e r was
warmed, and s u l f u r i c a o id was added In s u f f i c i e n t q u a n tity
to g iv e a d e c id e d ly a o ld r e a c tio n *
d e a l o f foaming*
T his produced a good
A fte r th e e v o lu tio n o f gas had c e a s e d ,
th e m ix tu re was d i s t i l l e d *
As soon as I t was e v id e n t t h a t
n o th in g o f v alu e was In th e d i s t i l l a t e , th e re s id u e was
made a lk a lin e and ag a in d i s t i l l e d .
The d i s t i l l a t e from
th e a lk a lin e s o lu tio n was y ello w and a lk a lin e in r e a c t i o n ,
w ith an u n p le a s a n t o d o r.
T his l a t t e r d i s t i l l a t e , upon
e x t r a c tio n w ith e t h e r , y ie ld e d a y e llo w is h b a s ic l i q u i d
which was f r a c t i o n a t e d u n d e r red u ced p re ss u re *
Two
d i s t i l l a t i o n s gave a w a te r-w h ite , c l e a r l i q u i d w ith a
s te a d y b o ili n g p o in t and an a m in e -lik e o d o r.
o n ly 16 g .(1 0 %) was o b ta in ed *
A y ie ld o f
A sample o f t h i s m a te r ia l
was d is s o lv e d in d ry e t h e r , and i t s h y d ro c h lo rid e was
form ed a s a f lo e c u le n t w h ite p r e c i p i t a t e upon th e passage
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-2 3 -
o f d ry hydrogen c h lo rid e gas th ro u g h th a a t h a r s o l u t i o n .
The p r e c i p i t a t e was washed w ith e t h e r and d r ie d In a
vacuum d e s ic c a to r .
§
I t w e lte d a t 89-86 .
l-d leth y lam lP O -P O n ta n o n o -4 .B .p . 6 4 » 6 8 * /l6
Mol.
n * ‘ 1.4172
bob.
re fra c t.
C alc.*
H e u tr a l. E q u lv .
S .g .
47.7 7
C a le .s 167
0.8112
Pound 48.77
Pounds
152, 164
1 - d le th y lam ln e-p o a t a a o n e -4 -b y d ro c h lo rl d e . C a lc , f o r C«Hflie0801i
Pound!
S.
%I
% IT 7 .2 5
7 .3 6 , 7 .3 8
P re p a r a tio n o f d la lk y la m in o a lk y lam in o b e n to ( h ) q u in o lin e s •
%**
2 -( £ • d le th y la n lB o h u ty la a ln o ) - . and
4 - a » th r l- 2 - (
m prphollnobu ty lam ln o )-b c n s o (h ) q u in o lln o s . -
Two p a r ts by
w eig h t o f 8 -e h l0 re -4 * m e th y l« b e n so (h )q u in o lin e (1 mol)
and th r e e p a r ts by w eig h t o f th e diam ine (su ch as ^ - d i e t h y l <
a » ln o -p ro p y l am ine) ( 9 .0 - 2 .1 mol) were aimed to g e th e r In a
Pyrex t e s t tu b e eq u ip p ed w ith an a i r co n d en ser, and th e
whole was h e a te d a t 180-200* f o r e i g h t hours in an o i l
b a th .
The r e a c tio n m ix tu re was co o led and tak en I n to
s o lu tio n In 10 % h y d ro c h lo ric a c i d .
A fte r f i l t r a t i o n
from any I n s o lu b le m a t e r i a l , th e f i l t r a t e was made s tr o n g ly
a lk a lin e w ith sodium o r ammonium h y d ro x id e .
The crude
p ro d u c t s e p a r a te d o u t as a gnnmy brown o i l , w hich was
e x tr a c te d from th e aqueous la y e r w ith e t h e r .
A fte r
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-2 4 -
th e e t h e r s o lu tio n had been d r ie d w ith anhydrous
p o ta ssiu m c a rb o n a te , and th e e t h e r e v a p o ra te d w ith an
a i r J e t , th a r e a l due was p la o s d In a 60
o v er n i g h t .
vacuum oven
I t was th an d i s t i l l e d u n d e r raduoad p r e s s ­
u r e , u s in g a Caneo vacuum pump*
A ll th r e e o f th e s e compounds were v e ry v isc o u s brown
o i l s , w ith a green f lu o r e s c e n c e .
S th e r and a lc o h o l s o l ­
u tio n s e x h ib ite d a y e llo w -g re e n , and d i l u t e h y d ro c h lo ric
a c id s o lu tio n s a b l u i s h f lu o r e s c e n c e .
Pone o f them
I n d ic a te d any ten d en cy to c r y s t a l l i s e upon s ta n d in g .
AimiMr&t,! *dle^hylg^,op^E^i^jgitI^».f2M ^2U^f-r
B.p* 275-280*/» ant.
A nal:
C a lc , f o r G**HaTX*:
Y ie ld
89 %
% X 1 5 .0 8
% X 1 2 .9 5 , 1 5 .1 1
Found:
4 r n c t h r l - 8 - ( <f-dlo th v la m ln o b u tY la n in o )-h c n so (h )q u in o lin e
B .p .
A nal:
240-845#/ 8
C a lc , f o r Ga*$ie>e*
Found:
B .p .
A nal:
2«*
i *
12*65
% X 1 1 .8 , 12*5, 1 5 .8
285-890*/4 mm.
C a lc , f o r OjpgBtrOX*:
Found:
Y ie ld 82 %
(Xtanas, sem i-m icro )
Y ie ld 61 $
% X 12 .0 5
% X 1 1 .8 2 , 11.92
ira M & ta lrjlrl^
•»*
Two p a r t s by w eig h t o f th e e h lo re -a e b h y l-b e a s e (h )q u in o lin e
ana th r e e p a r ts by w eig h t o f th e diam ine were h e a te d in an
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•08**
o i l b a th f o r t i g h t ho u rs s s b e f o r e .
The a o rp h o lin o -
amino aiix tu ro v a s ha a ta d a t ab o u t 190 , and th a d i e t h y l araino-amine m ix tu re a t ab o u t 170 .
C o o lin g , e x t r a c t Ion
w ith 10 % h y d ro c h lo ric a e id , f i l t r a t i o n , and b a s l e i f l c a tio n o f th e f i l t r a t e w ith d i l u t e sodium h ydroxide gave
a heavy brown o i l w hleh beeame a gummy s o l i d upon
sta n d in g #
T his v a s tak en up in e t h e r , th e s o lu tio n
d r ie d w ith anhydrous p o ta ssiu m c a rb o n a te , and th e s o lv e n t
e v a p o ra te d w ith an a i r J e t*
The r e s id u e v as k e p t u n d er
vacuum in a dee I oca t o r f o r a d ay , and vas th en r e c r y s t a l ­
l i s e d tv lo e from e t h e r {by s o lu tio n in d ry e t h e r , p a r t i a l
e v a p o ra tio n v l t h an a i r J e t , f i l t r a t i o n o f th e p r e c i p i t a t e d
s o lid m a te r ia l).
These tv o compounds were v e ry s o lu b le In
e t h e r and in a lc o h o l, in w hich s o lv e n ts th e y d is p la y e d a
y e llo w is h -g re e n f lu o r e s c e n c e .
T h e ir s o lu tio n s in d i l u t e
h y d ro c h lo ric s o ld p o sse sse d a b lu e flu o re se e n o e *
Both o f
th e 8 u b stan o es w ere s o l i d s v l t h a s l i g h t eream co lo r*
4 - a o t h y I - g - ( X -K -m orphollnopropvIam lno) -b en so <h ) ou in o lln e
(SoBens 73°)
M*p«
AnalI
C a lc , f o r CasHa#09«i
Founds
M.p»
A n a ly s is *
%I
10*88
% H 19*80, 1 0 .8 5
'8¥«SS * (srt-htns 81°)
C a lc , f o r C**Hav8a*
Founds
*«•
Y U M 57 %
%t
Y ie ld 00 %
i *
13*08
1 2 .8 8 ,1 3 .0 0
g -m e th v l-4 -( £ -d ieth T lam ln o b u t y l a a l n o ) -
and
These were p re p a re d from 8 -meth y l- 4 - c h lo r o -b e n s o (h ) q u in o lln e
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-86-
and th e p ro p s r diam ine in th e same fa s h io n a s were th e
compounds d o s c rib e d l a s e c tio n (85) above, v l t h th e
fo llo w in g e x c e p tio n .
The gummy brown s o l i d r e s u l t i n g
from e v a p o ra tio n o f th e o r i g i n a l e t h e r s o lu tio n v as
d is s o lv e d In ^ a b s o lu te a lc o h o l (ab o u t SO s i . f o r th e
erode p ro d u c t form ed from 4 g . o f 8-meth y l- 4 - o h lo r o b e n s o (h )q u in o lln e and 6 g* o f d ia m in e ), th e a le o h o l
s o lu tio n vas b o ile d v l t h c h a rc o a l f o r f i f t e e n m in u te s,
and th e c h a rc o a l f i l t e r e d o u t, u s in g a "Celifce" f i l t e r
bed*
C a re fu l a d d itio n o f v a t e r to th e co o led f i l t r a t e ,
accompanied by c o n s ta n t s t i r r i n g , gave a cream -co lo red
s o lid p re c ip ita te *
T his v a s f i l t e r e d o f f , d r i e d , and
r e c r y s t a l l i s e d from e t h e r a s b e f o r e .
These compounds,
l i k e some o f th o se e a r l i e r d e s c r ib e d , were crea m -co lo red
s o l i d s , r e a d i l y d is s o lv in g In e t h e r and a lc o h o l to g iv e
s o lu tio n s v l t h a y e llo v - g r e e n , and In d i l u t e h y d ro c h lo ric
a e id to g iv e s o lu tio n s v l t h a b lu e f lu o r e s c e n e e .
2 - a a th v l-4 » ( <f-d ieth v lam ln o b u tv lam ln o >-benso (h i c u I n o lln e . M .p.
Anal a
80TIOO *(SoHcns9Z°) y i e l d
Calc* f o r C»»K»»K*t
Founds
%8
26#
# N 18 .6 3
1 8 .6 , 18*5
(Dumas, sem i-m icro)
_2-g»thyl~4-( £ -jf-a o rp b o lln o b u tv l^ a in e )- b a n h ) q u I n o lln e . M.p* llO -X lf* ^ * * ™ / ° 3 °)
Ana l t
C a lc , f o r C.,HaT0H,3
Found*
f i e l d 88 %
# N 18.05
1 1 .8 7 , 11 .8 7
27 *
n o - ^ - b lJ i- ( 8 > m » th r l- 4 - te n * e ( h ) a u ln o lv l) -
am lno-propane*-
Four g . o f 2 -m e th y l-4 -c h lo ro -b e n s o { h )q u in o lin e
Reproduced with permission of the copyright owner. Further reproduction prohibited w ithout permission.
*87
(1 mol) and 6 g . o f X -K -a o rp h o lln o -p ro p y l amine {2.1 mol)
were condensed to g e th e r by h e a tin g f o r e i g h t to te n hours
In an o i l b a th a t 180* •
The r e a e tio n m ix tu re was d is s o lv e d
in 10 % h y d ro c h lo ric s o ld , th e s o lu tio n was f i l t e r e d , and
e x c e ss ammonium hydroxide was added to th e f i l t r a t e • A
gummy p r e c i p i t a t e was form ed w hich soon became co m p letely
s o lid .
Thorough e x t r a c tio n w ith e t h e r d is s o lv e d o n ly a
sm a ll p a r t o f t h i s s o l i d p ro d u c t.
The o th e r - in s o lu b le
m a te r ia l was r e c r y s t a l l i s e d from 50 m l. o f a lc o h o l, from
w hich I t s e p a r a te d a s a n e a r ly w h ite s o l i d .
T his r e c r y s t a l ­
l i s e d p ro d u c t was combined w ith th e s m a lle r e th e r e s o lu b le
f r a c t i o n , and th e m ix tu re was r e c r y s t a l l i s e d from 50 m l. o f
a lc o h o l, w ith th e a id o f c h a rc o a l.
T his l a s t r e c r y s t a l l i z a t i o n
d id n o t give a h ig h e r m e ltin g p o i n t , b u t I t removed th e
cream c o lo r from th e p r o d u c t, w hich was o b ta in e d a s w h ite
•
.
c r y s t a l s t m .p . 1 5 1 -1 5 8 .5 , y i e l d o f pure m a te r ia l 58 %•
Ana l l
C a lc , f o r G#*H*«GK# *
FoundI
F.
%8
%8
10.97
1 0 .8 7 , 1 0 .9 0
A n a ly tic a l m ethods.
The carbon-hydrogen a n a ly s e s were perform ed by th e
o r d in a r y com bustion method o f a n a ly s is f o r carbon and
hydrogen In th e p re se n c e o f n itr o g e n .
The n itr o g e n a n a ly s e s were perform ed by e i t h e r th e
Dumas o r th e K je ld a h l m ethod, th e l a t t e r b e in g employed
in most c a s e s .
The h alogen a n a ly se s were c a r r ie d o u t in th e u s u a l
fa sh io n by th e C a rlu s method f o r n o n -io n ic halogen compounds.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
G ra p h ica l SuHoaary
(8 0 ,)jB r
( 1 ° ,)
( I O ^ B p < *0.)
H (Bp )
A A
w
—
HH*
'f
OH
OH
OH,
0%
( 01 )
01 (0 % )
H»
H0«CH**CH**,
0%
H -I-R
(R-N-)
<08***
HO-OH«-CH,*HB-CH*-CHa-,< C«He )»-CH*-GH,-CH.-
(G»H# )- -(C H ,)4. , 0(0H*-CH«)(I8.<CH*).«., and O(0H,-CH.)aN-{CH.)*
/CH*-CH„\
nl* rn QSm
)
nd
ch, - ch, n
6
,CR**CV/
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-29-
Cl-(CH*)#~ C N ---- > R»H-(CH,)s-OK
0*0
//V V - 0*0
m
0*0
> Ri*-{CH,,)S-CH,-HH,
H-GH*«QE*-CHa-Br
-
0*0
RJh - (CH*)a-CHa-NH*
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*30**
I I I . DISCUSS10*
S e v e ra l ays terns have bean p ro p o sed f o r th a nomen­
c la tu r e o f th e b e n z o q u in o lin e s d e riv e d from 1 -n a p h th y lam lne.
B r i t i s h w r ite r * d e s c rib e th e s e compound* as
”a lp h a -n a p h th o q u in c lin e s " , In Oerman re fe re n d a * th e y are
term ed w4 -a z a -p h e n a n th ro n e s " , and American a u th o rs r e f e r
to them a* " 7 j8 -b e n a o q u ln o lln e » H o r a* ”h * n B o { h )q u in o lin es" .
The l a s t o f th e s e ays terns, w hich I s th e one now u se d by
Chemical A b s tra c t* , seems p r e f e r a b l e , and 1* th e one u sed
th ro u g h o u t t h i s paper*
In th l* sy stem , th a b a s ic r in g
s t r u c t u r e I s numbered as shown i
»
,e
The f i r s t p a r t o f th e work on t h i s problem was an
I n v e s tig a tio n o f th e p o s s i b i l i t i e s o f p ro d u c tio n o f n i t r o b e n z o (h )q u in o lin e s by a p p lic a tio n o f th a Skraup r e a c tio n to
v a rio u s n itr o - l- n a p h th y la m in e s .
Four iso m e ric m o n o -n itro -
b en zo (h ) q u in o lin e s have bean known s in cm th e s tu d ie s o f
as
Hald
on th e n i t r a t i o n o f b a n c o (h )q u in o lin e * Tha s t r u c t u r e s
o f th e s e have n e v e r been proven*
The two iso m ers w hich
formed th e p r in c ip a l p ro d u c ts from t h i s n i t r a t i o n had th e
n l t r o groups in th a r i n g f a r t h e s t removed from th a p y rid in e
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
r i n g , I . e . In two o f tho p o s itio n s marked w ith an V t
A s
X
X
w
T his was proven by tho f o o t t h a t b o th , whan red u ced to
am inos, and tho am ines o x id is e d , gave tho same q u in o lin o
d lc a r b o x y llle a c id , w ist
HOQG
*
One o f th e s e n l t r o d e r iv a tiv e s m elte d a t 860 , and th e
o th e r a t 176 •
Two o th e r n i t r o d e r iv a tiv e s were o b ta in e d
In much s m a lle r y i e l d , m e ltin g a t 166* and 165*, r e s p e c t*
i v e ly .
Ho sv id eao o as to t h e i r p o s itio n In th e r in g
t
s t r u c t u r e was g iv e n .
&> th e work In t h i s L a b o ra to ry , no c o n d itio n s were found
w hich gave more th an v e ry sm a ll y ie ld s o f n ltr o - b e n s o ( h ) q u in ­
o l i n e s , when th e Skraup r e a c tio n was a p p lie d to 5 - n ltr o *
and 4 - n itr o - l- n a p h th y la m in o s , and no p ro d u ct a t a l l co u ld be
found when th e same r e a c tio n was a p p lie d to 8 - n l t r o * l n ap h th y lam in e.
The 7 -n itro « b e n s o * h )q u in o lin e iso m er, o b ta in e d
from 5 -n itr o -l- n a p h th y la m in e and h ay in g th e n l t r o group in
th e r i n g f a r t h e s t renewed from th e p y rid in e r i n g , m elted a t
175 ,
and I t i s p ro b a b ly I d e n t i c a l w ith th e compound dee*
o rlb e d by Bald w hich m elted a t 176*.
The 6 - n i t r o
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-3 8 t
b en so (h ) q u in o lin e Isom er, m o ltin g a t 149 , may bo th a same
o
as tho I soma i* r e p o r te d by H ald aa m a ltin g a t 135 •
The v a ry poor y ie ld s in th e s e r e a c tio n a may ba a t t r i b ­
u te d in p a r t to th a f a c t t h a t no Skraup r e a c tio n s v l t h
1-naphthylam lne o r i t s d e r iv a tiv e s g iv e as h ig h y ie ld s as
v l t h th e co rresp o n d in g a n i lin e o r 8 -n a p h th y la a in e compounds,
and in p a r t to th e i n h i b i t i n g a c tio n o f th e n i t r o group*
T his l a s t f a c t o r was shown to be tr u e by th e b e t t e r y ie ld s
o b ta in e d in t h i s work o f 6 -b ro a o -b e n s o (h )q u in o lin e from
4 -b ro m o -l-n ap h th y lam in e, and In th e work o f Adam and
S te e le
ST
o f lO -chloro-bensso(h) q u in o lin e from 8 - c h lo r o -
1-naphtbylam ine •
Due to th e s e poor y i e l d s , f a r t h e r work
in t h i s d ir e c tio n was d isc o n tin u e d *
When p y r id in e , q u in o lin e , and b a n c o q u in o lin e s are
s u b s t itu te d in th e 8 - o r 4 - p o s itio n s ( i* e * , on th e
or ^
o{
carbons in th e p y rid in e r in g ) w ith a halogen atom ,
t h a t halogen i s q u ite r e a c t i v e , and th o se compounds w i l l
undergo co n d e n satio n s w ith 1
*
and 8
8 - s u b s t l t u t e d q u in o lin e amines*
»
amines to y ie ld
S in ee 8 - e h lo r e - 4 -m e th y l-
and 4 -c h lo ro -2 -m e th y l-h e n s o ( h ) q u in o lln e * a re r e a d i l y
a c c e s s ib le , th e y se rv e d as s t a r t i n g m a te r ia ls f o r th e
p ro d u c tio n o f a number o f am in o -b e n so (h )q u ln o lln e d e r iv ­
a t i v e s , by co n d en satio n w ith v a rio u s amines*
These
c h lo ro -b e n s o (h )q u in o lin e s were o b ta in e d by th e a c tio n o f
%•
phosphorus p e n ta c h lo rid e in te tr a e h lo r e th a n e s o lu tio n
on th e c o rre sp o n d in g hydroxy-ben so q u in o lin e s *
The 2 -
h y d ro x y -4 -m eth y l-b en so (h ) q u in o lin e was o b ta in e d from th e
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-3 3 -
Union C arbide and Carbon 0 .* b e in g p re p a re d by the a c tio n
o f d ik e te n # on l~ n ap h th y lam in e *
The 4-hydroxy-2-m e t h y l -
b e n s o fh jq u in o lln e was p re p a re d by condensing a o e to a c e tic
e a t e r v l t h 1 -n a p h th y l amine* and o y e lls in g th e in te rm e d ia te
t
o ro to n a te e a t e r by b e a tin g to 273 • Two Improvementa o v er
>>•
th e o r i g i n a l method
were made* One wae th e uae o f hydro*
ee
c h lo r ic a c id
in s te a d o f d ie th y la m ln e aa a c a t a l y s t in the
c o n d e n sa tio n )
th e o th e r was th e uae o f h o t p a r a f f in o i l
aa a d ilu e n t in th e c y c lia a tio n p ro c e s s* * .
In th e r e e r y a t*
a l i i s a t i o n o f 2 ~ ch lo ro -4 ~ m eth y l-b en so (h ) q u in o lin e , an
ex c ess o f s o lv e n t ( a lc o h o l) i s recommended, as o th e rw ise th e
m a te r ia l cornea o u t o f s o lu tio n to o r a p id ly and b lo c k s th e
n
openings In th e Buchner f u n n e l.
Two g e n e ra l ty p e s o f s y n th e se s were n eed f o r the prep*
a r a tio n o f th e diam inea d e s ir e d f o r co n d en satio n o n to the
q u in o lin e n u c le i*
The f i r s t c o n s is te d o f th a fo llo w in g
s e r i e s o f r e a c t i o n s t a o h l o r o n i t r i l e ( made e i t h e r from a
ohlorobrom ide by a c tio n o f p o ta ssiu m cyanide o r from a
eyanohydrin by a c tio n o f th lo n y l c h lo rid e ) v a s condensed
v l t h a seco n d ary amine to g iv e a te r t i a r y - a m i n o n i t r i l e *
*
•
w hich upon re d u c tio n w ith sodium and a lc o h o l gave a 1 ,5 d ia m in e .
The second In v o lv ed co n d en satio n o f a bromo-
a lk y lp h th a llm ld e w ith a se co n d ary am ine, fo llo w e d b y
h y d ro ly s is w ith 10 3 h y d ro c h lo ric a c id to g iv e p h th a llc
a c id and th e d e s ir e d d ia m in e .
The fo rm er o f th e s e two s y n t h e t i c a l methods was th e
e a s i e r , b u t i t co u ld n o t alw ays be a p p lie d becau se o f th e
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-34-
f a i l u r e to I s o l a t e any diam ine p ro d u c t from th a r e a c tio n
o f some o f th a a m ln o n ltr lle s w ith sodium and a le o h o l.
aa
Magldson
r e p o r te d a wary good y ie ld o f 6 -d ie th y la m in o h ex y l amine from £ - d l a t h y l a a l n o e a p r o n lt r ll a by u se o f
t h i s method*
In th e re d u c tio n o f Y -d le th y la m in o -
and
# -H - m o r p h o lln o - b u ty r o n itr lie a , f a i r y ie ld s ware o b ta in e d )
b u t from /3 -d ie th y la m in o -
and / 2 -H -m o rp h o lin e -p ro p io -
n l t r l l e a , and from d le th y la m ln o a e e to n ltr lle (made by th a
as
method o f Knoevenagel and M ercklin ) no diam ine a t a l l
could be o b ta in ed *
R eduction b o th b y use o f sodium and
a lc o h o l and by u se o f a h ig h -p re s s u re c a t a l y t i c hydrogena t o r was attem p ted *
In th e l a t t e r e a s e , th e p ro d u c ts
re c o v e re d were ammonia* th e o r i g i n a l a m ln o - n i tr lle , and
a v is c o u s , h ig h - b o ilin g r e s i d u e .
In th e fo rm er c a s e , no
d e f i n i t e p ro d u e t o f any s o r t was o b ta in ed *
I t would
ap p ear thm% th e lo n g e r th e a lk y l ch ain between th e amino
and th e n l t r l l e g ro u p s, th e b e t t e r a re th e y ie ld s o f
diam ine p re p a re d by so d iu m -aleo h o l re d u c tio n *
The diam ines w ith th r e e carbons In th e chain were
p re p a re d , t h e r e f o r e , by th e more la b o rio u s G a b rie l ty p e
s y n th e s is , r e a c tin g m orphollne o r d ie th y la m ln e w ith
# -b ro m o -p ro p y lp h th a lim ld e , and h y d ro ly s in g th e i n t e r ­
m ediate p ro d u c t w ith 10 If h y d ro c h lo ric acid *
Complete
h y d ro ly s is w ith d i l u t e h y d ro c h lo ric a c id , a s r e p o r te d by
S h rln e r and H ickey**, co u ld n o t be d u p lic a te d *
In t h i s t h e s i s , th e s u b s t i t u t i o n o f th e m orphollne
r in g f o r a d ia lk y la m in o group in a n t lm a la r la l d ru g s has
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-3 6 -
apparenfcly been r e p o r te d f o r tho f i r s t t i n * .
I t Is n o t
to bo e x p e c te d th a t tho m orphollne r in g as so oh sh o u ld
havo any p a r t i c u l a r o f f s e t , b u t i t I s p o s s ib le t h a t tho
o th e r lin k a g e in tho r in g m ight serv o to in c re a s e th e
s o l u b i l i t y o f th e m orphollne d e r iv a tiv e in l i p o i d s and
so change th e a n t i - m a l a r i a l a c t i v i t y *
l-d le th y la m in o -p e n ta n o n e -4
v as p re p a re d from th e
r e a c tio n o f th e sodium s a l t o f a e e to a c e tle e s t e r and
d le th y la m in o e th y l c h lo r id e , fo llo w in g a s k e le to n o u tli n e
found in Chemical A b s tra c ts
39
, in w hich no methods o r
p h y s ic a l p r o p e r tie s were given*
I f enough m a te r ia l co u ld
have been p re p a re d , i t was p lan n ed to t r y to c o n v e rt i t
to th e oxim e, and th en o e to l-d leth y lam ln o « 4 * am in o -p en tan e
by so d iu m -alo o h o l r e d u c tio n .
This
diam ine would f u r n is h
th e same s id e c h a in as t h a t in A teb rin and F lasm oqulne.
However, because o f th e expense o f th e p ro ced u re and th e
poor y i e l d (10 %) o b ta in e d , i t was d e c id e d to d is c o n tin u e
t h a t phase o f th e problem*
Most o f th e c o n d e n sa tio n s attem p ted between th e c h lo ro b e n z o (h )q u in o lin e s and amino compounds were s u c c e s s f u l, and
jB ono-quinolylam ines were th e p r i n c i p a l p ro d u c ts found in a l l
oases b u t one —
th e r e a c tio n between 2 -® e th y l-4 ~ c h lo ro -
benzo(h) q u in o lin e and ^ -S -m o rp b o lin o -p ro p y l am ine, which
gave a d i-q u in o ly la m in e , c < -I-M o rp h o lin o -'^ -b Is-(2 -m eth y l4 -b e n z o (h )q u in o ly l)-a m in o p ro p an e, in s te a d o f th e monoqu in o ly lam in e ty p e o f p ro d u c t o b ta in e d in th e o th e r seven
s im ila r co n d e n satio n s e f f e c te d *
Magldaon and Hubtsov*
have r e p o r te d an e x a c tly s im ila r case in th e r e a c tio n between
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-5 6 -
£ -d ie th y la m in o b u ty l amine and 2 -o h lo ro « 6 -a» th o x y
q u in o lin e .
In th e co n d en aetlo n a between ch lo ro -b en i:o (h ) q u in o lin e s
and /3 -h y d ro x y s th y le th y le n e d iam in e, pure
n ev e r o b ta in ed *
p ro d u c ts were
Thie was p ro b a b ly due to th e p re se n c e o f
some o f th e d i-q u in o ly la m ln o compound, from w hich the
d e s ire d m ono-qulnolylam ino p ro d u c t could n o t be p u r if ie d *
When th e Iso m eric m e th y l-e h lo ro -b e n s o (h )q u in o lin e s
were condensed w ith p i p e r i d i n e , th e r e a c tio n s a p p a re n tly
f a i l e d to go to co m p letio n , even a lth o u g h an e x c e ss o f
p ip e r id in e was employed*
Zt was found p o s s ib le In th e case
o f 4 -m e th y l-a -H -p lp e rld ln o -b e n se < h ) q u in o lin e to s e p a r a te
th e d e s ir e d p ro d u c t from I t s m ix tu re w ith th e s t a r t i n g
m a te r ia l by s o lu tio n in d i l u t e h y d ro c h lo ric a c id , in which
4 -m e th y l-2 -o h lo ro -b e n s o (h )q u in o lin e i s n o t a p p re c ia b ly
so lu b le *
T his tre a tm e n t co u ld n o t be a p p lie d to th e m ix tu re
o f 2 -m e th y l-4 -e h lo ro -
and 2 -m e tb y l-4 -X -p lp e rld in o * o e n so -
( h ) q u in o lin e s , how ever, as th o se two su b sta n c e s a p p a re n tly
have e q u a l s o l u b i l i t i e s in a c id s o lu tio n s as w e ll as in
o rg a n ic s o lv e n ts *
S e v e ra l amino compounds co u ld n o t be condensed w ith
th e c h lo ro -b e n s o (h )q u in o lin e s to g iv e d e f i n i t e ls o l a b le
p ro d u cts*
These in c lu d e d a r s a n l l l o a c id , 2 -m eth y l-2 -am ln o -
p ro p a n o l-1 , and p -p h en y len e d ia m in e •
The S -m eth y l-S -am lno-
p ro p a n o l-1 u se d c o n ta in e d some w a te r , and i t was th o u g h t
t h a t a rep lacem en t o f th e c h lo rin e atom by th e h y d roxyl
group r a t h e r th an by th e propanolam lno group was th e c h ie f
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-8 7 -
r e a c tle n ta k in g p la c e .
The m a te r ia l o b ta in e d from tb a
r e a c tio n m ix tu re began to m elt a t about th e m e ltin g p o in t
o f th e s t a r t i n g o h lo ro compound, b u t was s t i l l l a r g e l y
s o l i d when h e a te d w e ll above 200*, and eo u ld n o t be s a t i s *
f a c t o r i l y r e c r y s t a l l i s e d from a lc o h o l*
The f a i l u r e o f th e
e h lo ro b e n so (h ) q u in o lln e to condense w ith areas1 1 1 c a e id
may be a t t r i b u t e d to laele o f a s u f f i c i e n t l y a c tiv e halogen
S*
atom . S l a t e r found
t h a t w h ile 2 -m * th y l-4 -c h lo ro -6 m efchoxy-quinollne would n o t condense w ith a r s a n l l l c a c id ,
i t s more re a c tiv e .4 -b re m e analogue would do so*
Conden­
s a tio n s w ith p -p h en y len e d iam in e, fo llo w in g th e p ro ced u re
aa
o f S l a t e r , seemed to ta k e p la c e , b u t no p u re r e s u l t i n g
p ro d u c t co u ld be is o la te d *
A m ix tu re o f s e v e r a l d i f f e r e n t
compounds was a p p a re n tly o b ta in ed *
An i n t e r e s t i n g d if f e r e n c e was n o tic e d in th e r e a c tio n s
o f c h l o r in a tin g ag e n ts w ith 2-B O tbyX -4-/3-hydroxys th y la w in e and 4 -m eth y l-2-/3 -h y d re x y e th y la m la o -b e n s o (h )q u in o lin e * •
T reatm ent o f th e fo rm er compound w ith phosphorus
oxy-
o h lo rid e r e s u l t e d In th e rep la cem en t o f th e h y d ro x y l group
by c h lo r in e , as ex p ected *
T reatm ent o f th e l a t t e r compound
w ith th io n y l c h lo r id e , how ever, r e s u lt e d In d e h y d ra tio n to
give an u n s a tu r a te d s ld e e h a ln c o n ta in in g no h alogen •
B a rrin g
rearran g em en t in th e s ld e e h a ln , th e p ro d u c t sh o u ld have been
4 -m e th y l-2 -v in y la m ln o -b e n * o (h )q n in o lln e •
But th e f a c t t h a t
th e p ro d u c t p o sse sse d a b r i g h t y ello w c o lo r s u g g e s ts t h a t
rearran g em en t may have tak en p la c e to y ie ld 4 -m s th y l-2 e th y lld ln e a m ln o -b e n a o < h )q u In o lln e , a compound p o s s e s s in g
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
* system o f c o n ju g a te d double bonds*
diem
u
, w orking
on l» n » tb y l-3 -'rin y lftm ln o -b e n s o < f)q u in o lin e , was l e d to
a s im ila r h y p o th e s is .
fb e a u th o r w ishes to acknowledge tb s as s i s ta n oe
given by Mr* C l i f f x» H ollenbeck In p erfo rm in g th e
K je ld a h l a n a ly s e s r e p o r te d in t h i s p a p e r, and by
Map* S* J . Cragoe Jfr. la
p re p a rin g /3 - c h lo ro p ro p io -
n l t r l l e and /3 - d ie f c h y la a in o - p r o p io n itr ile •
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
IV .
SUMMARX
d -b ro n o -b e n so (h ) q u in o lin e was p re p a re d in f a i r y ie ld
from 4 -b ro m o -l-n ep h th y lam in e, and 6- n l t r o -
and 7 - n i t r e *
b a n s o { h )q u in o lin e s were p re p a re d in p o o r y ie ld from
4 -n itro -
and 5 - n ltr o -l* n s p h th y la m ln e s , r e s p e c t i v e l y , by
means o f th e Skraup r e a c t i o n .
4-b ro m o -l-n ap h th y lam in e was eondensed w ith aca t o a c e t i c
e a t e r to y ie ld e t h y l /3 -{ 4 ~ b ro m 0 ~ l* n sp h th y lam ln o } -o ro to n ate.
P ro a t h i s , 8-m e th y l-4 -h y d ro x y -6 -b ro » o -
and 2-m sthy1 -4 -
c h lo ro -6 -b ro m Q -b en so (h )q u in o lin es were s y n th e s is e d toy
s ta n d a r d p ro e e d a re s .
2-ch io r© - 4 -m e th y l-
and 4 -eb lo ro * 2 * iae th y l-b en so -
( h ) q u in o lin e s , p re p a re d by th e a c tio n o f phosphorous
p e n ta c h lo rid e on th e c o rre sp o n d in g hydroxy compounds,
were condensed w ith e th a n o l am ine, /3 -h y d ro xye t h y l e th y le n e d ia m in e , p i p e r i d i n e , and a o r p h o lln e .
From th e
co n d en satio n p ro d u c ts w ith e th a n o la m in e , 2 -w e tb y l-4 -o h lo ro e tta y la m in o -b e n to (h )q u in o lin e end 4 - s » th y l- 2 v in y la m in o -b e n z o (h )q u in o lin e wars p re p a re d .
X -N -m orpholtno-
and X - d i e th y la m iE io -b u ty ro n itri l e a ,
and /3 -H -m orphollno-
and /3 - d ie th y la m in o * p r o p io n itr ile s
were p re p a re d by c o n d e n sa tio n s o f m orphollne and d ie th y l*
amine w ith th e p ro p e r c h l o r o n l t r l l e .
<f -d ie th y la m in o -b u ty l amine and <f-N -m orpholinob u ty l amine were o b ta in e d by r e d a c tio n o f th e c o r r e s ­
ponding n i t r i l e s w ith sodium and a lc o h o l,
am ino-propyl amine and
^ -d ie th y l-
^-H -m orphol in o -p ro p y l amine
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
-4 0 -
were made th ro u g h th e G ab riel s y n th e s is , X -fcromop ro p y l p h th a lim ld e b e in g aa I n te r m e d ia te .
C ondensations o f S -a je th y l-d -e h lo ro -
and 4 -m o th y l-
2 -c h lo ro -b e n s o (h ) q u in o lin e s w ith ^ - d ie th y la m in o Y -K -m o rp h o lln o -p ro p y l amines and w ith
and
<f -d te tb y la m in o -
and £ -H -m o rp h o lln o -b u ty l amines y lo ld e d two s e r i e s o f
now d ialk y lam in o alk y lam in o -b en so (ta) q u in o lin e s , c lo s e ly
analogous in s t r u c t u r e to p r e v io u s ly r e p o r te d compounds
claim ed to p o ss e s s a n t i - m a l a r i a l p r o p e r t i e s .
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
•41'
?.
BIBLIOGRAPHY
1*
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8.
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4087 (1904)
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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