United S ta tes P a tent [ 1 9 1

C o nti
[ 5 4 ] S TEREOIS OMERS 0F
1 - ( 1 B EN Z Y L - Z P Y RRY L ) - 2 - D I- S EC .
B UTY L AMIN OETHAN OL AN D
P HARMAC EUTIC AL C OMP OS ITION S
C OMP RIS IN G S AME
[ 7 5 ] Inv ento r : Fr a nc o C o nti, Mil a n, Ita l y
[ 7 3 ] As s ig nee:
[ 2 1 ] Ap p l . N o . : 8 5 2 , 6 8 5
[ 2 2 ] Fil ed: N o v . 1 8 , 1 9 7 7
[ 3 0] Fo r eig n Ap p l ic a tio n P r io r ity D a ta
N o v . 1 3 , 1 9 7 6 [ B E] B el g ium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 5 5 4 6 6
[ 5 1 ] Int. 01 . 1 . . . . . . . . . . . . . . . . . . . . . A6 1 K 3 1 /4 0; c 07 1 ) 2 01 /4 4
[ 5 2 ] U5 . ( : 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2 4 /2 7 4 ; 2 6 0/3 2 6 . 5 L
[ 5 8 ] Fiel d Of S ea r c h . . . . . . . . . . . . . . . . . . 2 6 0/3 2 6 5 L ; 4 2 4 /2 7 4
[ 5 6 ] Ref er enc es C ited
U. S . P ATEN T D OC UMEN TS
3 , 5 5 8 , 6 5 2 l / 1 9 7 1 Teo tino et a 1 . . . . . . . . . . . . . . . . 2 6 0/3 2 6 5 L
3 , 6 2 9 , 4 3 5 1 2 /1 9 7 1 Teo tino et a ] . . . . . . . . . . 4 2 4 /2 7 4
3 , 8 5 7 , 8 5 7 1 2 /1 9 7 4 B el l a et a ] . . . . . . . . . . . . . . . . . . . . . 2 6 0/3 2 6 5 L
FOREIGN P ATEN T D OC UMEN TS
1 1 5 4 7 4 4 6 /1 9 6 9 United King do m.
Eta b l is s ement V ir idis , L iec htens tein
[ 1 1 ] 4 , 1 4 8 , 9 07
[ 4 5 ] Ap r . 1 0, 1 9 7 9
P r ima r y Ex a miner J o s e To v a r
Atto r ney , Ag ent, o r Fir m- J o s ep h W. Mo l a s k y
[ 5 7 ] AB S TRAC T
N o v el s ter eo is o mer s o f l - ( l ' - b enz y 1 - 2 ' p y r r y l ) - 2 - di- s c c .
b uty l a mino etha no l o f the f o r mul a :
2 2 1 1 ( C H ) c H ( I)
3 2 5
U . A /
N C HOH- C l - l r - N
I \
C H2 C H( C H3 ) C 2 H5
'
R
wher ein R is ?uo r O o r tr i?uo r o methy l a nd the no n
to x ic ther a p eutic a l l y a c c ep ta b l e s a l ts ther eo f ; inc l uding
p ha r ma c eutic a l c o mp o s itio ns c o mp r is ing s a me. The
s a id p r o duc ts a nd c o mp o s itio ns ha v e util ity a s a na l g e
s 1 c s .
4 C l a ims , N o D r a wing s
4 , 1 4 8 , 9 07
1
S TEREOIS OMERS OF I
l - ( 1 ' B EN Z Y L - 2 ' P Y RRY L ) - 2 - D I- S EC .
B UTY L AMIN OETHAN OL AN D
P HARMAC EUTIC AL C OMP OS ITION S
C OMP RIS IN G S AME
This inv entio n r el a tes to no v el s ter eo is o mer s o f a
l - ( l - b enz y l - 2 - p y r r y l ) - 2 - di- s ec . - b uty l a mino etha no l o f
the f o r mul a :
Uc no H- c m- N /
\
wher ein R is ?uo r o o r tr i?uo r o methy l ; to the no n- to x ic
s a l ts ther eo f a nd to p ha r ma c eutic a l c o mp o s itio ns c o m
p r is ing s a me a s the a c tiv e ing r edient. The s a id' p r o duc ts
a nd c o mp o s itio ns ex hib it a na l g es ic a c tiv ity .
B AC KGROUN D
It is k no wn f r o m US . P a t. N o . 3 , 6 2 9 , 4 3 5 tha t the
f o l l o wing c o mp o unds p o s s es s a na l g es ic a c tiv ity :
R1
/
N C HOH- C H- N
l \
( 1 1 )
l
R
wher ein R is b enz y l o r s ub s tituted b enz y l . In this p a tent
R is b r o a dl y de?ned b ut it a p p ea r s tha t o nl y a f ew s ub
s tituted b enz y l der iv a tiv es wer e a c tua l l y p r ep a r ed, s p e
c i?c a l l y , o nl y the o r tho - c hl o r o b enz y l der iv a tiv es
a mo ng whic h l - [ l ' ( o - c hl o r o b enz y l ) - 2 - p y r r y l ] - 2 - di- s ec .
b uty l a mino etha no l is na med: '
'
C H( C H3 ) C 2 1 1 5
N C HOH C H2 _ N \
l
C H2 ' C H( C H3 ) C 2 1 1 5
( III)
This c o mp o und is s a id to b e the mo s t a c tiv e c o mp o und
within the dis c l o s ed c l a s s o f a mino etha no l s a nd it ha s
b een ma r k eted a s a v a l ua b l e a na l g es ic under the na me
V IMIN OL O ( W. H. O. C hr o nic l e, 1 9 7 0, N 3 , l is t 2 5 ) .
Ac c o r ding to US . P a t. N o . 3 , 6 2 9 , 4 3 5 , the c o mp o unds
II a nd III a r e p r ep a r ed a s a mix tur e o f s ter eo is o mer s b y
r educ ing the c o r r es p o nding k eto p r ec ur s o r s . D es p ite
ma ny a ttemp ts to r es o l v e the s a id s ter eo is o mer ic mix
tur e, whic h c a n b e mo r e o r - l es s c o mp l ex b ec a us e o f the
numb er o f a s s y metr ic c enter s p r es ent in the mo l ec ul e, it
ha s b een imp o s s ib l e up to no w to do s o .
The U. S . P a t. N o . 3 , 8 5 7 , 8 5 7 des c r ib es a metho d f o r
dir ec tl y s y nthetiz ing ea c h o p tic a l is o mer o f l - [ l ( o
c hl o r o b enz y l ) - 2 - p y r r y l ] - 2 - di- s ec . - b uty l a mino etha no l
( III) a nd us ing this metho d f o ur is o mer s o f o p tic a l p u
2
r ity wer e p r ep a r ed a nd their a na l g es ic a c tiv ity deter
5
1 0
2 0
2 5
3 0
3 5
4 0
4 5
5 0
5 5
6 0
6 5
mined.
Fr o m this deter mina tio n it wa s f o und tha t o ne o f the
f o ur is o mer s , identif ied in s a id P a tent a s C o mp o und
R2 , is muc h mo r e a c tiv e tha n the o ther is o mer s a nd
a l s o , mo r e a c tiv e tha n the c o r r es p o nding r a c emic c o m
p o und V IMIN OL O.
THE IN V EN TION
It is a n o b j ec t o f this inv entio n to p r ep a r e two s ter eo
is o mer s o f o p tic a l p ur ity nev er b ef o r e p r ep a r ed, no t
ev en a s a r a c emic mix tur e.
Thes e s ter eo is o mer s ha v e the f o r mul a :
.
wher ein R is ?uo r o o r tr i?uo r o methy l . Thes e new c o m
p o unds ha v e q uite s ur p r is ing l y s ho wn a n a na l g es ic ef
f ec t o f a muc h hig her o r der tha n tha t ex hib ited b y
V IMIN OL O a nd, a l s o , hig her tha n tha t o f the R2
C o mp o und c o mmo nl y c o ns ider ed a s the b es t o f the
c l a s s .
Mo r eo v er , this inc r ea s e in a c tiv ity is no t a c c o mp a
nied, a s is us ua l l y the c a s e, b y hig her to x ic ity b ut, o n the
c o ntr a r y , the new c o mp o unds ha v e a r educ ed to x ic ity
when c o mp a r ed a g a ins t V IMIN OL O a nd the R2
C o mp o und.
The new c o mp o unds o f this inv entio n p o s s es s ther a
p eutic index es whic h a r e ex c ep tio na l in the ?el d o f
a na l g es ic p r o duc ts . '
Thes e new c o mp o unds a r e p r ep a r ed thr o ug h a
metho d o f dir ec t s y nthes is a na l o g o us to tha t des c r ib ed
in US . P a t. N o . 3 , 8 5 7 , 8 5 7 f o r the o - c hl o r o - b enz y l der iv
a tiv e.
This metho d c o mp r is es the f o l l o wing es s entia l s tep s :
( 1 ) P r ep a r a tio n o f R, R( ) di~ s ec . - b uty l a mine:
( a ) R( ) s ec . - b uty l a mine is s ep a r a ted f r o m the r a c e
mic s ec . - b uty l a mine b y mea ns o f L ( +) ta r ta r ic
a c id, a c c o r ding to the p r o c edur e des c r ib ed in
Tho me- B er . 1 9 03 , 3 6 , 5 8 2 .
( b ) The ( - ) s ec . - b uty l a mine thus o b ta ined is tr ea ted
with a r a c emic s ec . - b uty l der iv a tiv e o f the f o r mul a
X - C H( C H3 ) C 2 I- I5 wher ein X is p r ef er a b l y b r o mo
o r c hl o r o , in the p r es enc e o f a p o l a r o r g a nic s o l
v ent.
( c ) The s ep a r a tio n o f the r es ul ting R, R( ) di- s ec ,
b uty l a mine hy dr o b r o mide o r hy dr o c hl o r ide is p er
f o r med b y f r a c tio na l c r y s ta l l iz a tio n f r o m a c eto ne
o r etha no l .
( 2 ) P r ep a r a tio n o f the c hl o r o g l y o x y l - p y r r y l der iv a tiv e:
A b enz y l - p y r r o l e o f the f o r mul a :
4 , 1 4 8 , 9 07
3
m
I
. C H2
wher ein R is ?uo r o o r tr i?uo r o methy l , is tr ea ted
with o x a l y l c hl o r ide in the p r es enc e o f a n iner t,
a nhy dr o us , o r g a nic s o l v ent, a t a temp er a tur e o f
1 5 C . , under s tir r ing . Ther e is thus o b ta ined a
c o mp o und o f the f o r mul a :
U- c o - c o - a
|
C H;
wher ein R ha s the a b o v e- indic a ted mea ning .
( 3 ) P r ep a r a tio n o f the p y r r y l - g l y o x y l a mide:
The c hl o r o g l y o x y l - p y r r y l der iv a tiv e o b ta ined in the
p r ec eding s tep is tr ea ted with R, R( ) di- s ec .
b uty l a mine o r a n a c id a dditio n s a l t ther eo f in a n
iner t o r g a nic s o l v ent, a t a temp er a tur e b el o w 0 C .
a nd in the p r es enc e o f a b a s ic s ub s ta nc e s uita b l e f o r
b l o c k ing the f o r ma tio n o f hy dr o ha l o g enic a c id to
a f f o r d N , N - di- s ec . - b uty l - l - ( o - R- b enz y l ) - 2 - p y r r y l
g l y o x y l a mide.
( 4 ) P r ep a r a tio n o f the a mino - p y r r y l - etha no l der iv a tiv e:
The N , N - di- s ec . - b uty l - l - ( o - R- b nz y D - Z - p y r r y l
g l o x y l a mide o b ta ined a c c o r ding to s tep ( 3 ) a b o v e
is r educ ed b y mea ns o f a meta l l o - o r o r g a no
meta l l o hy dr ide, in the p r es enc e o f a n iner t o r g a nic
s o l v ent a t a temp er a tur e o f b etween a b o ut 2 0 C .
a nd the r e?ux temp er a tur e. Ther e is thus o b ta ined
l - [ l ' - ( o - R- b enz y l ) - 2 - p y r r y l ] - 2 di- s ec . - b uty l a mino
( 1 R+ 1 S ) etha no l .
The mix tur e o f the two dia s ter eo is o mer s thus o b
ta ined is tr ea ted with p - hy dr o x y b enz o ic a c id to a f f o r d
the c o r r es p o nding p - hy dr o x y b enz o a tes a nd thes e a r e
s ep a r a ted b y f r a c tio na l c r y s ta l l iz a tio n f r o m a p o l a r o r
g a nic s o l v ent, p r ef er a b l y , a c eto ne. .
B y r ep ea ting the c r y s ta l l iz a tio n f r o m a c eto ne, the
two dia s ter eo is o mer s a r e o b ta ined a t p r a c tic a l l y 1 00%
o p tic a l p ur ity . Al tho ug h it is no t p o s s ib l e to s ta te whic h
_ o f the two is o mer s ha s the ( R) c o n?g ur a tio n a nd whic h
p o s s es s es the ( S ) c o n?g ur a tio n, nev er thel es s , the two
is o mer s ha v e b een is o l a ted a nd identi?ed. -
Onl y o ne o f s a id is o mer s , identi?ed her eina f ter a s the
o ne whic h p r ec ip ita tes up o n c o o l ing the dia s ter eo is o
mer ic s o l utio n in b o il ing a c eto ne, is c r itic a l to this in
v entio n.
The a b s o l ute s p a c e c o n?g ur a tio n o f thev a s y mmetr ic
c a r b o n a to ms indic a ted with a n a s ter is k in the f o r mul a
( I) , is de?ned a c c o r ding to J UP AC Tenta tiv e Rul es f o r
the Mo nenc l a tur e o f Or g a nic C hemis tr y 1 9 7 0, 3 5 ,
2 8 4 9 - 2 8 6 9 .
1 5
2 0
3 0
5 0
5 5
6 5
4
The a b s o l ute c o n?g ur a tio n o f di- s ec . - b uty l a mine is
b a s ed o n the a b s o l ute c o n?g ur a tio n o f s ec . - b uty l a minc
( s ee A. Kj a er , S . E. Ha us en, Ac ta C hemic a l S c a ndina v ia
1 9 5 7 , II - 1 8 9 8 ) . '
The is o mer s o f l - [ l - ( o - R- b enz y l ) - 2 ' - p y r r y l ) ] - 2 - di
s ec . - b uty l a mino ( 1 R+' 1 S ) etha no l , whic h ha v e s ho wn a
s ur p r is ing a na l g es ic a c tiv ity a nd whic h a r e thus the
o b j ec t o f the p r es ent inv entio n, a r e identi?ed her eina f
ter in uneq uiv o c a l ma nner thr o ug h their p hy s ic a l c ha r
a c ter is tic s .
Is o mer A:
[ 1 1 1 9 2 0 ( in metha no l c =l %) : 3 l C . i3 C .
[ 0. 1 9 2 0 ( in metha no l c =2 %) : 2 9 C . : i: 3 C .
[ 1 1 1 4 3 6 2 0 ( in metha no l C = 1 %) : - 5 9 C . - _ t- 3 C .
[ ( 1 1 4 3 6 2 0 ( in metha no l c =2 %: 5 8 C . - _ l - 3 C .
Is o mer B :
l - [ l ' - ( o - tr i?uo r o methy l b enz y l - 2 ' - p y r r y l ] - 2 - di- ( R, R)
s ec . - b uty l a mino etha no l : m. p . o f p - hy dr o x y b enz o a te:
1 4 8 l 5 0 C .
[ 0. 1 02 0 ( in metha no l c = 1 %) : 2 7 C . i3 C .
[ ( 1 1 02 0 ( in metha no l c =2 %) : 2 6 C . : L - 3 C .
[ 01 1 4 3 6 2 0 ( in metha no l c = 1 %) : ~ 5 0 C . : 3 C . I
[ 0. 1 4 3 6 2 0 ( in metha no l c =2 %) : - 4 8 C . i3 C . The
a na l g es ic a c tiv ity ( ED s o ) o f is o mer s A a nd B ha s
b een deter mined v ia the ho t p l a te tes t o n mic e
( N /. B Eddy et C o l l . J . P ha r ma c o l . 9 8 , 1 2 1 , 1 9 5 0)
a nd v ia the ta il ?ic k tes t o n r a ts ( D Amo ur a nd
S mith; J . P ha r ma c o l . 1 9 4 1 , 7 2 , 7 4 ) . The r es ul ting
v a l ues a r e s et f o r th in the f o l l o wing Ta b l e a nd
c o mp a r ed with the v a l ues g iv en under identic a l
c o nditio ns f o r V IMIN OL O a nd the R2 C o m
p o und r ef er r ed to her eina b o v e ( P ha r ma c o l o g ic a l
Res ea r c h C o mmunic a tio ns 8 , 1 1 1 ( 1 9 7 6 ) ) .
The a c ute to x ic ity v a l ues ( L D 5 0) ha v e b een deter
mined b y the metho d o f L itc h?el d a nd Wil c o x s o n ( J .
P ha r ma c o l . 1 9 4 9 , 9 6 , 9 9 ) b o th f o r the new c o mp o unds
o f this inv entio n a nd f o r V IMIN OL O a nd the R2
C o mp o und. .
ED 5 0 mg /k g ED 5 Q mg /k g L D 5 0
ho t p l a te Ta il Fl ic k mg /k g
C o mp o und s . c s . c . i. p . T. l .
Is o mer A 0. 6 5 0. 4 4 3 8 4 8 7 2
Is o mer B 0. 6 0 0. 3 8 3 5 8 9 4 2
R2 C o mp o und 1 . 1 5 0. 7 1 2 3 0 3 2 4
V IMIN OL O 1 2 . 5 1 6 7 1 3 . 3 6
Fr o m the a b o v e da ta it is ev ident tha t the a na l g es ic
a c tiv ity o f the new c o mp o unds A a nd B R+nea r l y
twic e tha t o f the C o mp o und R2 whic h in tur n wa s
s ur p r is ing l y mo r e a c tiv e tha n V IMIN OL O.
It is a l s o a p p a r ent tha t the L D 5 0 is muc h hig her f o r
new c o mp o unds A a nd B , tha t is , they a r e muc h l es s
to x ic tha n the C o mp o und R2 a nd V IMIN OL O. The
s up er io r ity o f new C o mp o unds A a nd B is a l s o ev ident
f r o m the ther a p eutic index es whic h ha v e b een c a l c u
l a ted a s a r a tio o f L D 5 0/ED 5 0' ta k ing a s the ED 5 0 v a l ue
tha t whic h is o b ta ined b y the ta il ?ic k tes t.
The new c o mp o unds o f this inv entio n c a n b e a dminis
ter ed p er 0s , a nd b y inj ec tio n. The p r es ent c o mp o unds
a r e us ef ul in tr ea ting a numb er o f dis ea s es whic h c a nno t
b e s a tis f a c to r il y tr ea ted with a na l g es ic s a dminis ter ed
4 , 1 4 8 , 9 07
5
p er 0s a nd whic h a r e thus s l o wl y a s s umed b y the o r g a n
is m.
This inv entio n wil l no w b e des c r ib ed b y r ef er enc e to
s p ec i?c ex a mp l es . Ho wev er , it is to b e under s to o d tha t
thes e ex a mp l es a r e il l us tr a tiv e o nl y a nd no t l imita tiv e.
Ther ef o r e, a ny s ub s titutio n o f eq uiv a l ent ma ter ia l s o r
mo di?c a tio n in the r ea c tio n c o nditio ns is c o ns ider ed a s
b eing within the s c o p e o f this inv entio n a nd no t a dep a r
tur e ther ef r o m.
EX AMP L E 1
l - [ l - ( o - Fl uo r o b enz y l ) - 2 ' - P y r r y l ] - 2 - D i- ( R, R) - S ec .
B uty l a mino ( 1 R+ 1 S ) Etha no l , p - Hy dr o x y b enz o a te
S tep A: R, R( ) D i- S ec . - B uty l a mine Hy dr o b r o mide
R( ) s ec . - b uty l a mine is dis s o l v ed in a b s o l ute etha no l
a nd to this s o l utio n is a dded ( R+S ) 2 - b r o mo b uta ne in
ex c es s a nd the r es ul ting mix tur e is then r e?ux ed o v er
a b o ut 6 0 ho ur s .
Fo l l o wing r e?ux the s o l utio n is ho t ?l ter ed a nd the
?l tr a te is c o o l ed a nd then k ep t a t 1 5 C . o v er a b o ut 4 8
ho ur s . The r es ul ting R, R( ) di- s ec . - b uty l a mine hy dr o
b r o mide is s ep a r a ted b y ?l tr a tio n a nd then p ur i?ed b y
s uc c es s iv e c r y s ta l l iz a tio n f r o m a c eto ne.
S tep B : l - ( o - Fl uo r o b enz y l ) - 2 - P y r r y l g l y o x y l ic Ac id
C hl o r ide
A s o l utio n o f o x a l y l c hl o r ide in a nhy dr o us p enta ne is
p ut into a ?a s k p r o v ided with a s tir r er , ther mo meter ,
r e?ux c o o l er a nd tub e f o r nitr o g en b ub b l ing . The s o l u
tio n is ma inta ined under a nitr o g en a to mo s p her e a t
- 1 5 C .
A s o l utio n o f l - ( o - ?uo r o b enz y l ) p y r r o l e in a nhy dr o us
p enta ne is then dr o p p ed into the ?a s k with s tir r ing .
The r a tio b etween the r ea c ta nts is o n the o r der o f
a b o ut 1 . 5 mo l es o f o x a l y l c hl o r ide p er mo l e o f l - ( o
?uo r o b enz y l ) p y r r o l e.
The temp er a tur e o f the mix tur e is ma inta ined a t 1 5
C . f o r a f ew minutes a f ter the a dditio n o f the l - ( o
?uo r o b enz y l ) p y r r o l e is c o mp l eted. Then the temp er a
tur e is s l o wl y r a is ed to 4 0 C . under a s l ig ht v a c uum a nd
under a nitr o g en s tr ea m to c o mp l etel y r emo v e ex c es s
o x a l y l c hl o r ide a nd s o l v ent.
Ther e is thus o b ta ined a p r ec ip ita te o f l - ( o - ?uo r o b en
z y l ) - 2 - p y r r y l g l y o x y l ic a c id c hl o r ide.
S tep C : N , N - D i- S ec . - B uty l a mide o f l - ( o - Fl uo r o b en
z y l ) - 2 - P y r r y l g l y o x y l ic Ac id
1 - ( o - Fl uo r o b enz y l ) - 2 - p y r r y l g l y o x y l ic a c id c hl o r ide
( 2 6 . 5 g . ) is dis s o l v ed in c hl o r o f o r m ( 2 00 ml . ) a nd the
r es ul ting s o l utio n, c o o l ed a t 1 5 C . , is a dded dr o p wis e
to a s o l utio n o f R, R( ) di- s ec . ' b uty l a mine hy dr o b r o
mide ( 2 1 g . ) a nd tr iethy l a mine ( 2 1 g . ) in c hl o r o f o r m
( 2 00 ml ) .
The mix tur e is hea ted s l o wl y up to 5 0 C . , s tir r ing is
ma inta ined f o r o ne ho ur a nd the mix tur e is then c o o l ed
a nd wa s hed s uc c es s iv el y with wa ter , s o dium c a r b o na te
a nd wa ter .
The o r g a nic l a y er is r emo v ed, dr iedv o v er s o dium
s ul p ha te a nd then ev a p o r a ted to dr y nes s .
The r es idue c o ns is ts o f c r ude ( - ) N , N - di- s ec . - b uty l a
mide o f l - ( o - ?uo r o b enz y l ) - 2 - p y r r y l g l y o x y l ic a c id.
S tep D : l - [ l ' - ( o - Fl uo r o b enz y l ) - 2 - P y r r y l ] - 2 - D i- ( R, R)
S ec . - B uty l a mino ( 1 R=1 S ) Etha no l , p - Hy dr o x y b enz o
a te
The ( ) N , N - di- s ec . - b uty l a mide o f l - ( o - ?uo r o b en
z y l ) ~ 2 - p y r r y l g l y o x y l ic a c id o b ta ined a s a n imp ur e p r o d
6
- no t in S tep C , is dis s o l v ed in a nhy dr o us to l uene ( 3 00
1 0
2 0
2 5
4 0
4 5
5 0
5 5
6 5
ml ) . a nd the r es ul ting s o l utio n is intr o duc ed dr o p wis e,
with s tir r ing , into a s o l utio n o f L iAl H4 a nd tetr a hy dr o
f ur a n in to l uene. The L iAl H4 c o ns titutes a b o ut a 3 0%
mo l a r ex c es s o v er the a mide r ea c ta nt.
The r ea c tio n mix tur e is ma inta ined a t 2 5 3 0 C . until
the a dditio n o f the r ea c ta nts is c o mp l eted a nd the mix
tur e is then r e?ux ed f o r o ne ho ur .
The mix tur e is then c o o l ed, ex c es s hy dr ide is dec o m
p o s ed with wa ter a nd s o dium hy dr o x ide ( V . M.
Mic o v ic a nd M. C . J . Miha il o v ic J . Or g . C hem. 1 9 5 3 ,
1 1 9 0) a nd the s o l v ent is el imina ted b y ev a p o r a tio n.
An o il y r es idue is o b ta ined ( 2 4 . 5 g . ) a nd this is dis
s o l v ed in methy l ethy l k eto ne ( 2 00 ml . ) a nd then tr ea ted
with a s o l utio n o f p - hy dr o x y b eno ic a c id ( 1 4 g . ) in meth
y l ethy l k eto ne ( 5 0 ml . ) .
The mix tur e is a l l o wed to r es t o v er nig ht a nd the
r es ul ting p r ec ip ita te is ?l ter ed with a wa ter v a c uum
p ump .
Ther e is thus o b ta ined 2 9 . 5 g r a ms o f l - [ 1 - ( o
?uo r o b enz y l ) - 2 ' - p y r r y l ] - 2 - di- ( R, R) - s ec . - b uty l a mino
( 1 R+1 S ) etha no l , p - hy dr o x y b enz o a te ( m. p . : l 2 8 - 1 4 2
C . with dec o mp o s itio n) .
The mix tur e o f dia s ter eo is o mer s thus o b ta ined is dis
s o l v ed in a s tr o ng ex c es s o f b o il ing a c eto ne under s tir
r ing .
Up o n c o o l ing the a c eto nic s o l utio n to r o o m temp er a
tur e a c r y s ta l l ine p r o duc t p r ec ip ita tes r ic h in o ne o f the
two dia s ter eo is o mer s , na mel y , the is o mer identi?ed a s
A in this s p ec i?c a tio n.
Up o n c r y s ta l l iz ing the p r ec ip ita te thr ee times , a nd
up o n c o o l ing the b o il ing a c eto ne s o l utio n, the c o m
p o und A is o b ta ined in the f o r m o f a p ur e p - hy dr o x
y b enz o a te ha v ing a m. p . o f l 4 4 ~ l 4 5 C .
The s p ec i?c r o ta to r y p o wer o f the c o mp o und A with
dif f er ent p o l a r iz ed l ig hts a nd a t v a r io us c o nc entr a tio ns
a r e s et f o r th her eina b o v e.
The metho d des c r ib ed in Ex a mp l e 1 wa s r ep ea ted in
a n identic a l ma nner , ex c ep t tha t l - ( o - tr i?uo r o methy l
b enz y l ) p y r r o l e wa s s ub s tituted f o r the l - ( o - ?uo r o b en
z y l ) p y r r o l e o f S tep B .
Up o n the c o nc l us io n o f this metho d, a f ter s ev er a l
c r y s ta l l iz a tio ns f r o m a c eto ne, a s ing l e o p tic a l l y p ur e
is o mer wa s o b ta ined f r o m the mix tur e o f dia s ter eio s im
er s . This p r o duc t is 1 - [ 1 ' - ( o - tr i?uo r o methy l b enz y l )
Z p y r r y l ] - 2 - di- ( R, R) - s ec . - b uty l a mino etha no l .
The p ur e c o mp o und in the f o r m o f its p - hy dr o x y b en
z o a te ha s a mel ting p o int o f l 4 8 l 5 0 C . This p r o duc t
ha s b een identi?ed uneq uiv o c a l l y thr o ug h its r o ta to r y
p o wer with dif f er ent p o l a r iz ed l ig hts a t v a r io us c o nc en
tr a tio ns .
Wha t is c l a imed is :
1 . An o p tic a l l y a c tiv e is o mer o f the f o r mul a :
U- c no n c u N /
f * 2 \
C H2
R
wher ein R is ?uo r o o r ti?uo r o methy l ; a nd the no n- to x ic
ther a p eutic a l l y a c c ep ta b l e a c id a dditio n s a l ts ther eo f .
7 .
2 . A l - [ l ' - ( o - Fl uo r o b enz y l ) - 2 - p y r r y l ] - 2 - di- ( R, R)
s ec . - b uty l a r nino etha no l a c c o r ding to c l a im 1 o f the f o r
mul a :
U- /C H( C H3 ) C 2 H5
N C HOH- C Hz - N \
( 3 1 2 c mc nnc z ns
the p - hy dr o x y b enz o a te s a l t o f whic h ha s a mel ting p o int 2 0
o f 1 4 4 1 4 5 C . a nd the f o l l o wing v a l ues o f s p ec i?c
r o ta to r y p o wer :
[ c 1 1 9 2 0 ( in metha no l c = 1 %) : 3 1 - _ l - 3 C . 2 5
[ 1 ] D 2 O ( in metha no l c =2 %) : 2 9 i3 0" C .
[ 1 2 1 4 3 6 2 0 ( in metha no l c =1 %) : 5 9 i3 C .
3 0
( R, R) - s ec . - b uty l a mino etha no l a c c o r ding to c l a im 1 o f 3 5
the f o r mul a :
4 5
5 0
5 5
6 5
4 , 1 4 8 , 9 07
8
C H2
C F3
the p - hy dr o x y b enz o a te s a l t o f whic h ha s a mel ting p o int
o f l 4 8 - l 5 0 C . a nd the f o l l o wing v a l ues o f s p ec i?c
r o ta to r y p o wer :
[ ( 1 . ] 9 2 0 ( in metha no l c =1 %) : 2 7 i3 C .
[ 1 1 b 2 0 ( in metha no l c =2 %) : - 2 6 i3 C .
[ a ] 4 3 6 2 ( in metha no l c =1 %) : - 5 0i3 C .
[ a ] 4 3 6 2 ( in metha no l c =2 %) : 4 8 : l : 3 C .
4 . A ther a p eutic c o mp o s itio n ha v ing a na l g es ic a c tiv
ity whic h c o mp r is es a s the a c tiv e ing r edient a n es s en
tia l l y p ur e o p tic a l l y a c tiv e is o mer o f the f o r mul a :
wher ein R is ?uo r o o r tr i?uo r o methy l , o r a no n- to x ic
ther ea p eutic a l l y a c c ep ta b l e a c id a dditio n s a l t ther eo f ; in
c o mb ina tio n with a p ha r ma c o l o g ic a l l y a c c ep ta b l e c a r
r ier .
i i I! l l Il l