8/20/2019 Levamisole Synthesis http://slidepdf.com/reader/full/levamisole-synthesis 1/15 METHODS OF SYNTHESIS ND TECHNOLOGY OF PRODUCTION OF DRUGS LEVAMISOLE AND ANALOGS. i. METHODS OF SYNTHESIS (REVIEW) N. N. Romanov, Yu. P. Kovtun, and P. M. Kochergin UDC 615.276.4.012,1 2,3,5,6-Tetrahy dro-6-phenylimida zo [ , l - b ] hiazole hydrochloride (I), abbreviated to tetramisole (DL-I) (correspondingly, the levo-rotating optical isome r- levamisole [L(--)-I] and the dextro-rotating isomer -- dextramisole [D(+)-I]) has been known from the middle of the 1960s, when it was introduced into veterinary practice as a wide spectrum anthelmintic p r e p a r a t ion. L r N N HCI 1 ph I The appearance of these drugs was the result of a concerted.massive research program, in the course of which about 3000 heterocyclic compounds were synthesized and tested for their anthelmintic activity [119]. It should be noted that at approximately the same time, research was also being in- tensively carried out in the USSR on the synthesis of compounds with similar structure [i]. At the beginning of the 1970s the influencewas discovered of levamisole on the mechanism of the immune protection of the organism [138], which made possible the use of this compound for the stimulation of the immune response. As soon as they appeared on the market, tetramisole and levamisole evoked at once great interest for both practicing physicians and research-biologists. According to the data of J. Symoene [140], by 1978, more than 1000 publications had appeared in reputable scientific journals and books on the anthelmintic properties of these preparations, and about 500 on their ~mmune-modulating action. Judging from the undiminishing flow of publications (with a shift of emphasis to immunology), the undoubted interest with respect to these preparations, which were introduced into regular clinical practice, has not slackened. The investigations of the medicobiological properties of levamisole and tetramisole are summarized in a large number of reviews, of which we shall mention only a few which seem to us to be most informative: on helminthology [116, 141], immunology [5, 8, 9, i00, 113, 128- 130, 138, 139], and general pharmacology [7, 99, i01, 108, 118, 131, 134, 136, 140]. At the same time, the quite abundant data on the chemistry of tetramiso!e have not yet been correlated, and descriptions of methods of their preparation are centered mainly in the patent literature. In the present review an attempt was made to examine the methods of synthesis of levamisole, tetramisole and their analogs, and also several other aspects, which could be of interest for chemists and pharmacochemists, concerned with the chemistry of heterocyclic compounds, synthesis and study of immunostimulants, anthelmintic preparations, and also other physiologically active preparations. METHODS OF SYNTHESIS On the basis of the .general principles of constructing condensed heterocyclic systems with a junction nitrogen atom, the existing methods of synthesis of tetrahydroimidazothiazole ean be provisionally divided into three groups: adding the imidazole ring onto the existing thiazo!e ring, adding the thiazo!e ring onto the imidazo!e ring, and synthesis from linear Institute of Organic Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev. S. Ordzhonikidze All-Union Scientific Research Chemical Pharmaceutical Institute, Moscow. Trans lated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 2, pp. 206-217, February, 1989. Original article submitted May 19, 1988. 0091 150X/89/2302 0167512.50 9 1989 Plenum Publishing Corporation 167
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M E T H O D S O F S Y N T H E S I S N D TE C H N O L O G Y O F P R O D U C T I O N O F D R U G S
L E V A M I S O L E A N D A N A L O G S .
i . M E T H O D S O F S Y N T H E S I S ( R E V I E W)
N. N. Romanov, Yu. P. Kovtun,
a n d P . M. K o c h e r g i n
U D C 6 1 5 . 2 7 6 . 4 . 0 1 2 , 1
2 , 3 , 5 , 6 - T e t r a h y d r o - 6 - p h e n y l i m i d a z o [ , l - b ] h i a z o l e h y d r o c h l o r i d e ( I) , a b b r e v i a t e d t o
t e t r a m i s o l e ( D L - I ) ( c o r r e s p o n d i n g l y , t h e l e v o - r o t a t i n g o p t i c a l i s o m e r - l e v a m i s o l e [ L( -- )- I]
a n d t h e d e x t r o - r o t a t i n g i s o m e r -- d e x t r a m i s o l e [ D ( + )- I ] ) h a s b e e n k n o w n f r o m t h e m i d d l e o f
t h e 1 9 6 0s , w h e n i t w a s i n t r o d u c e d i n t o v e t e r i n a r y p r a c t i c e a s a w i d e s p e c t r u m a n t h e l m i n t i c
p r e p a r a t i on .
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T h e a p p e a r a n c e o f t h e s e d r u g s w a s t h e r e su l t o f a c o n c e r t e d . m a s s i v e r e s e a r c h p r o g r a m ,
i n t he c o u r s e o f w h i c h a b o u t 3 0 0 0 h e t e r o c y c l i c c o m p o u n d s w e r e s y n t h e s i z e d a n d t e s t e d fo r
t h e i r a n t h e l m i n t i c a c t i v i t y [ 1 1 9] .
I t s h o u l d b e n o t e d t h a t a t a p p r o x i m a t e l y t h e s a m e t i m e , r e s e a r c h w a s a l s o b e i n g i n -
t e n s i v e l y c a r r i e d o u t i n t h e U S S R o n t he s y n t h e s i s o f c o m p o u n d s w i t h s i m i l a r s t r u c t u r e [ i ] .
A t t h e b e g i n n i n g o f t h e 1 97 0 s t he i n f l u e n c e w a s d i s c o v e r e d o f l e v a m i s o l e o n th e m e c h a n i s m o f t he
i m m u n e p r o t e c t i o n o f t h e o r g a n i s m [ 13 8] , w h i c h m a d e p o s s i b l e t h e u s e o f t h i s c o m p o u n d f o r t h e
s t i m u l a t i o n o f t h e i m m u n e r e s p o n s e .
A s s o o n a s t h e y a p p e a r e d o n t h e m a r k e t , t e t r a m i s o l e a n d l e v a m i s o l e e v o k e d a t o n c e g r e a t
i n t e r e s t fo r b o t h p r a c t i c i n g p h y s i c i a n s a n d r e s e a r c h - b i o l o g i s t s . A c c o r d i n g t o th e d a t a o f
J . S y m o e n e [ 14 0] , b y 19 7 8 , m o r e t h a n 1 0 0 0 p u b l i c a t i o n s h a d a p p e a r e d i n r e p u t a b l e s c i e n t i f i c
j o u r n a l s a n d b o o k s on t h e a n t h e l m i n t i c p r o p e r t i e s o f t h e s e p r e p a r a t i o n s , a n d a b o u t 5 0 0 o n
t h e i r ~ m m u n e - m o d u l a t i n g a ct i o n . J u d g i n g f r o m t h e u n d i m i n i s h i n g f l o w of p u b l i c a t i o n s ( w i th a
s h i f t of e m p h a s i s t o i m m u n o l o g y ) , t h e u n d o u b t e d i n t e r e s t w i t h r e s p e c t t o t h e s e p r e p a r a t i o n s ,
w h i c h w e r e i n t r o d u c e d i n t o r e g u l a r c l i n i c a l p r a c t i c e , h a s n o t s l a c k e n e d .
T h e i n v e s t i g a t i o n s of t he m e d i c o b i o l o g i c a l p r o p e r t i e s o f l e v a m i s o l e a n d t e t r a m i s o l e a r e
s u m m a r i z e d i n a l a r g e n u m b e r o f r e v i e w s , o f w h i c h w e s h a l l m e n t i o n o n l y a f e w w h i c h s e e m t o
u s t o b e m o s t i n f o r m a t i v e : o n h e l m i n t h o l o g y [ 11 6, 1 4 1 ] , i m m u n o l o g y [ 5, 8, 9 , i 0 0 , 1 1 3, 1 2 8 -
130, 138, 139], and general phar mac olo gy [7, 99, i01, 108, 118, 131, 134, 136, 140].
A t t h e s a m e ti m e , t h e q u i t e a b u n d a n t d a t a o n t h e c h e m i s t r y o f t e t r a m i s o ! e h a v e n o t y e t
b e e n c o r r e l a t e d , a n d d e s c r i p t i o n s o f m e t h o d s o f t h e i r p r e p a r a t i o n a r e c e n t e r e d m a i n l y i n
t h e p a t e n t l i t e r a t u r e . I n t h e p r e s e n t r e v i e w a n a t t e m p t w a s m a d e t o e x a m i n e t h e m e t h o d s o f
s y n t h e s i s o f l e v a m i s o l e , t e t r a m i s o l e a n d t h e i r a n a l og s , a n d a l s o s e v e r a l o t h e r a s p e c t s , w h i c h
c o u l d b e o f i n t e r e s t f o r c h e m is t s a n d p h a r m a c o c h e m i s t s , c o n c e r n e d w i t h t h e c h e m i s t r y o f
h e t e r o c y c l i c c o m p o u n d s , s y n t h e s i s a n d s t u dy o f i m m u n o s t i m ul a n t s , a n t h e l m i n t i c p r e p a r a t i o n s ,
a n d a l s o o t h e r p h y s i o l o g i c a l l y a c t i v e p r e p a r a t i o n s .
M E T H O D S O F S Y N T H E S I S
O n t h e b a s i s o f t h e . ge ne ra l p r i n c i p l e s o f c o n s t r u c t i n g c o n d e n s e d h e t e r o c y c l i c s y s t e m s
w i t h a j u n c t i o n n i t r o g e n a t o m, t h e e x i st i n g m e t h o d s o f s y n t h e s i s of t e t r a h y d r o i m i d a z o t h i a z o l e
e a n b e p r o v i s i o n a l l y d i v i d e d i n t o t h r e e g r ou p s : a d d i n g t h e i m i d a z o l e r i n g o n t o t h e e x i s t i n g
t h i a z o ! e r i n g, a d d i n g t h e t h i a z o ! e r i n g o n to t h e i m i d a z o ! e r i ng , a n d s y n t h e s i s f r o m l i n e a r
I n s t i t u t e o f O r g a n i c C h e m i s t r y , A c a d e m y o f S c i e n c e s o f t h e U k r a i n i a n S S R , K i e v . S .
O r d z h o n i k i d z e A l l - U n i o n S c i e n ti f i c R e s ea r c h C h e m i c a l P h a r m a c e u t i c a l I n s ti t u t e , M o s c o w . T r a n s
l a t e d f r o m K h i m i k o - f a r m a t s e v t i c h e s k i i Z h u r n a l , V o l . 2 3 , N o . 2 , p p . 2 0 6 - 2 1 7 , F e b r u a r y , 1 9 8 9 .
O r i g i n a l a r t i c l e s u b m i t t e d M a y 1 9, 1 98 8 .
0091 150X/89/2302 0167512.50 9 1 9 8 9 P l e n u m P u b l i s h i n g C o r p o r a t i o n 1 6 7
s t r u c t u r e s . T o t he l a t t e r t y p e o f c y c l i z a t i o n s , h a v e b e e n a s s i g n e d t h o s e i n w h i c h i t i s
d i f f i c u l t t o a s c e r t a i n w h i c h o f t h e r i n g s i s f i r s t t o c l o se .
i . A d d i n g on o f t h e I m i d a z o l e R i n g
S
1 .1 <N ~ + C- - C)
A s t h e s t a r t i n g m a t e r i a l i n c o n d e n s a t i o n s o f t h i s t y p e , t h e f a i r l y r e a d i l y a c c e s s i b l e
2 - a m i n o t h i a z o l i n e I I) i s m o s t l y u s e d , w h i c h i s o b t a i n e d b y t he r e a c t i o n of 2 - h a l o e t h y l a m i n e
s a l t s w i t h t h i o u r e a [ ii 0, 1 3 5 ] , o r w i t h a l k a l i m e t a l t h i o c y a n a t e s [ i 0 , 2 6, 1 2 7 ] ,
S
II
A m o d i f i c a t i o n o f t h i s m e t h o d i s t h e s y n t h e s i s o f a m i n o t h i a z o l i n e I I f r o m a z i r i d i n e a n d
t h i o u r e a i n s u l f u r i c a c i d [ 35 ].
A d e t a i l e d s y n t h e s i s o f t e t r a m i s o l e f r o m 2 - a m i n o t h i a z o l i n e h a s b e e n d e v e l o p e d, i n
w h i c h t h e p h e n a c y l r e s i d u e i s i n t r od u c e d , f o l l o w e d b y t h e r e d u c t i o n o f t h e c a r b o n y l g r o u p i n
t h e i n t e r m e d i a t e i m i n o d e r i v a t i v e s I V) a n d V I ) a n d r o f t h e c a r b i n o l s V ) a n d
V I I ) i n t o t h e d e s i r e d e n d p r o d u c t I.
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CH2COPh CH2CH OH) Ph
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A c c o r d i n g t o t h i s s ch e m e , t e t r a m i s o l e w as o b t a i n e d f o r t he f i r s t t ~ e i n [ 1 1 9] ; s u b s e -
q u e n t l y m a n y m o d i f i c a t i o n s o f t h e m e t h o d s f o r e a c h s t a g e h a v e b e e n d e ve l o p e d . I n i t i a ll y ,
t h e r e d u c t i o n o f s a l t I II ) w a s c a r r i e d ou t a f t e r p r e l i m i n a r i l y p r o t e c t i n g t h e i m i n o g r o u p b y
a c y l a t i o n w i t h a c et i c a n ~ d r i d e i n p y r i d i n e [ 2 8 , 1 2 5] . T h e i n t r o d u c t i o n of t h e p r o t e c t i n g
g r o u p i s d e t e ~ i n e d p o s s ~ l y , b y t wo f a c t o r s : f ir s t l y , i t is k n o ~ t h a t s a l t I II c y c l i z e s
f a i rl y r e a d il y ~ t o 2 , 3 - d i h y d r o ~ i d a z o t h ~ z o l e V II I) [ 13 ] ;
\ P h
V I I I
s e c o n d l y , d e r i v a t i v e s o f t y p e V a r e p ~ s i o l o g i c a l l y a c t i v e c o m p o u n d s , w h i c h w e r e t e s t e d i n
p a r a l l e l w i t h t h e d e s i r e d e n d p r o d u c t s , a n d t h e r e f o r e t h e y a r e o f i n d e p e n d e n t ~ t e r e s t [ 1 1 9 ,
1 4 2 ] . S h o r t l y a f t e r w a r d s i t w a s s h o w n t h a t t h e r e d u c t i o n o f t h e c a r b o n y l g r o u p c a n a l s o b e
c a r r i e d o u t w i t h o u t p r e l i m i n a r y p r o t e c t i o n o f t he i m i n o g r o u p - i n b a s e V I [ 3 4 , 3 6 ] .
I n t h i s s c h e m e , t h e c y c l i z a t i o n s t a g e o f c a r b i n o l V I I w a s f o u n d t o b e c o m p l e x a n d c u m b e r
s o m e. I t i s c a r r i e d ou t i n c o n c e n t r a t e d s u l f u r i c o r p o l y p h o s p h o r i c a c i d , a n d t h e c a r b i n o l
i s u s e d i n t h e f o r m o f a b a s e [ 3 6 ] o r s a l t s [ 27 , 6 1] . T h e c o m p l e x i t y i n t h e i s o l a t i o n o f
t e t r a m i s o l e ( n e u t r a l i z a t i o n o f a l a r g e a m o u n t o f a c i d , u s e d a s a r e a g e n t a n d s o l v e n t ) i s c o m -
p e n s a t e d f o r b y i t s g o o d y i e l d a n d q u a l i t y .
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T h e s y n t h e s i s o f t e t r a m i s o l e w a s a l s o c a r r i e d o u t b y t he s u b s t i t u t i o n o f t h e h y d r o x y l
g r o u p b y h a l o g e n , f o l l o w e d b y c y c l i z a t i o n i n a n a l k a l i n e m e d i u m [ 14 ]. T r e a t m e n t o f s a l t s o f
c a r b i n o l V I I ( I X ) b y h a l o g e n a t i n g a g e n t s ( SO C1 2, P C 1 3 , P B r~ , P O C I 3 ) , w i t h s u b s e q u e n t c y c l i -
z a t i o n o f t h e h a l o g e n d e r i v a t i v e f o r m e d b y t h e a c t i o n o f a l k a l i i s t e c h n o l o g i c a l l y c o n v e n i e n
b u t i n t h i s c a s e , a l r e a d y a t t h e s t a g e of t h e r e p l a c e m e n t o f t h e h y d r o x y l g r o u p a c o n s i d e r -
a b l e a m o u n t ( up t o 5 ) o f i m p u r i t y i s f o r m e d o f a h i g h l y t o x i c a n d d i f f i c u l t l y s e p a r a b l e t r a n s
styr yl (XI) o
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T h i s c o m p o u n d c a n b e o b t a i n e d i n a p u r e s t a t e b y h e a t i n g s a l t X in D M F A i n t h e p r e s e n c e
o f L i C I [ 13 7] . T h e s t y r y l X I i m p u r i t y i s a l s o f o r m e d , a l t h o u g h t o a l e s s e r e x t e n t a t t h e
s t a g e o f c y c l i z a t i o n o f s a l t X o r i t s a c y l a t e d d e r i v a t i v e , e s p e c i a l l y , w h e n t h e r e a c t i o n i s
c a r r i e d o u t i n a c o n c e n t r a t e d s o l u t i o n . T o d e c r e a s e t h e a m o u n t o f t h e s t y r y l X I i m p u r i t y ,
s p e c i a l m o d i f i c a t i o n s o f t he m e t h o d o f r e p l a c e m e n t o f t h e h y d r o x y l g r o u p b y t h e h a l o g e n a t o m
h a v e b e e n p ro p o s e d . T h u s, b y t r e at i n g t h e c h l o r i d e o r t o l u e n e - s u l f o n a t e I X s u c c e s s i v e l y b y
s u l f u r y l c h l o r i d e [ 40 , 8 4 ] , h y d r o c h l o r i c a c i d [ 47 , 8 7 ] , c h l o r o s u l f o n l c a c i d [ 5 2 , 8 8 ] , o r a
m i x t u r e o f h y d r o c h l o r i c a n d s u l f u r i c a c i d s [ 54 ], t h e c o n t e n t o f t h e i m p u r i t y i n t h e t e t r a -
m i s o l e f o r m e d d o e s n o t e x c ee d 1 . A m e t h o d h a s a l s o b e e n d e v e l o p e d f o r r e m o v i n g s t y r y l X I
f r o m t e tr am if fo le , b y t a k i n g a d v a n t a g e o f t h e b e t t e r e x t r a c t a b i l i t y o f i t s s a l t s w i t h a l k y l -
s u l f o n i c a c i d s d e r i v e d f r o m h i g h e r p a r a f f i n s [ 15 ].
C h a r a c t e r i z i n g t h e a b o v e d e s c r i b e d s y s t e m o n t he w h o le , w e s h o u l d n o t e i t s m u l t i s t a g e
c h a r a c t e r ( a l t h o u g h t h e y i e l d s a t e a c h s t a g e a r e f a i r l y h i g h ) a n d t h e n e e d t o u s e h a l o a c e t o -
p h e n o n e s , w h i c h a r e t o x ic c o m p o u n d s w i t h l a c h r y m a t o r y p r o p em t i e s .
T o s im p l if y t h e s y n t h e s i s of t o l u e n e s u l f o n a t e I X, a r e a c t i o n h a s b e e n d e v e l o p e d o f 2 ~
a m i n o t h i a z o l i n e w i t h t h e i n e x p e n s i v e a n d t h e r e a d i l y a v a i l a b l e s t y r e n e o x i d e [ 17 , 27 , 38 ].
T h e p r o c e s s i s c a r r i e d o u t a t r o o m t e m p e r a t u r e i n t h e c o u r s e o f 2 d a y s . S u c h m i l d c o n -
d i t i o n s a r e p r o b a b l y u s e d t o a v o i d t h e p o s s i b i l i t y o f f o r m a t i o n o f b y - p r o d u c t s , w h i c h , w e m a y
a s s u m e , i n c l u d e t h e i s o m e t r i c p r o d u c t s o f t h e a d d i t i o n o f s t y r e n e o x i d e t o a n e x o c y c l i c
n i t r o g e n a t o m ( a s h a s b e e n o b s e r v e d i n t h e c a s e o f 2 - a m i n o p y r i d i n e [ 6] ). T h e y i e l d o f s a l t
I X h a s n o t b e e n s t a t e d , b u t j u d g i n g f r o m t h e a m o u n t s o f t h e r e a g e n t s u s e d , i t c a n n o t e x c e e d
50%.
A o n e - s t a g e s y n t h e s i s o f t e t r a m i s o l e f r o m 2 - a m i n o t h i a z o l i n e h a s b e e n c a r r i e d o u t t h r o u g h
i t s r e a c t i o n w i t h d i b r o m o e t h y l b e n z e n e
II -{-- PhCH(Br)CH~B r I.
T h e r e a c t i o n p r o c e e d s u n d e r r i g o r o u s c o n d i t i o n s - - p r o lo n g e d b o i l i n g i n t h e p r e s e n c e o f
s o d i u m a m i d e [ 66 ]. T h e y i e l d o f t h e p r o d u c t h a s a l s o n o t b e e n s t a t e d , b u t i t i s r a t h e r
l o w, s i n c e b o t h t h e s t a r t i n g m a t e r i a l s a n d t h e p r o d u c t a r e u n s t a b l e u n d e r t h e r e a c t i o n
c o n d i t i o n s .
T h e a b i l i t y o f a m i n e s t o a d d t o t h e a c t i v a t e d C = C b o n d w a s t a k e n a d v a n t a g e o f f o r t h e
p r e p a r a t i o n o f t e t r a m i s o l e a n a l o g s [ 10 4] a c c o r d i n g t o t he s c h e m e :
II q- A r--CH=CH (Br)CO=Et
I E t 3 N
S
Ar \ r
XII
T h i s p a t h o f b u i l d i n g u p t h e r in g o f t e t r a h y d r o i m i d a z o t h i a z o l e i s p r o m i s i n g , a l t h o u g h
t h e y i e l d i s l o w i n t h i s c a s e ( ~ 3 0% ) .
I t c a n b e s e e n t h a t a l s o t h i s m e t h o d d o e s n o t s o l v e t h e b a s i c g e n e r a l p r o b l e m o f t h e
s y n t h e s i s o f t e t r a m i so l e . T h e r e f o r e , m e t h o d s h a v e b e e n i n t e n s i v e l y d e v e l o p e d f or t h e
p r e p a r a t i o n o f e a r b i n o l V I I a n d i t s s a l t s I X f r o m t h e c o n d e n s a t i o n p r o d u c t o f s t y r e n e o x i d e
w i t h a z i r i d i n e [ 11 5]
H N < -~ P h C H ~ C H 2
O
PhCH(OH)CH2N# ~) SCN- >. VII, IX.
6) =C(NH2)2
XII I
I t w a s f o u n d t h a t t h e d e s i r e d e n d p r o d u c t s a r e r e a d i l y f o r m e d i n t h e r e a c t i o n o f 1 - ( 2 -
h y d r o x y - 2 - p h e n y l e t h y l ) a z i r i d i n e ( X II I ) w i t h t h i o c y a n a t e s o r w i t h t h i o u r e a [ 14 , 16 , 2 4, 2 5 ,
3 9 , 4 1 , 4 4 , 5 1, 6 5 , 1 0 3 , 1 37 ] . T h e s a m e m e t h o d w a s u s e d f o r t h e p r e p a r a t i o n o f a n a l o g s o f
t e t r a m i s o l e b y i n t r o d u c i n g s u b s t i t u e n t s a t t a c h e d t o th e a z i r i d i n e c a r b o n a t o m s i n t o t he
a r y l r e s i d u e o f s t y r e n e o x i d e , a n d a l s o f o r t h e s y n t h e s i s of t e t r a m i s o l e w i t h a r a d i o a c t i v e
3 S S t r a c e r [4 ] f r o m t h e c o r r e s p o n d i n g l a b e l e d t h i o u r e a .
A n i n t e r e s t i n g v a r i a n t o f t h i s m e t h o d , b u t p r o b a b l y l a c k i n g p a r t i c u l a r a d v a n t a g e s , w a s
p r o p o s e d b y J a p a n e s e a u t h o r s : a z i r i d i n e X I I I i s o p e n e d b y s o d i u m t h i o s u l f a t e , w h i l e t h e
c l o s u r e o f t h e t h i a z o l e r i n g t a k e s p l a c e b y t r e a t m e n t w i t h c y a n i d e s [ 94 ].
XIII -b Na2S~Oa -- ~
PhCH(OH)CH2NHCH2CH2SSO~H
V I I .
NaCN
>
T h e m a i n d i s a d v a n t a g e o f t h e m e t h o d s f o r t h e s y n t h e s i s o f t e t r a m i s o l e f r o m s u b s t i t u t e d
a z i r i d i n e X I I I c o n s i s t s i n t h e n e e d o f w o r k i n g w i t h e t h y l e n i m i n e , w h i c h i s a h i g h l y t o x i c a n d
m u t a g e n i c c o m p o u n d . T o o b t a i n t h e o p t i m a l y i e l d o f p r o d u c t X I I I in t h e r e a c t i o n o f s t y r e n e
o x i d e w i t h e t h y l e n i m i n e , i t s t h r e e f o l d e x c e s s i s r e q u i r e d [ 11 5] . T h e p u r i f i c a t i o n o f t h e
p r o d u c t b y d i s t i l l a t i o n u n d e r h i g h v a c u um , f o l l o w e d b y r e c r y s t a l l i z a t i o n , w h i c h i s p r o b a b l y
n e c e s s a r y b e c a u s e o f t h e r e a d y p o l y m e r i z a b i l i t y o f t h e s t a r t i n g c o m p o n e n t s , i s a l s o t e c h n o l o g -
i c a l l y i n c o n v e n i e n t .
P o s s i b l y b e c a u s e o f t h i s , a m e t h o d h a s b e e n d e v e l o p e d f o r t h e p r e p a r a t i o n o f c a r b i n o l
X I I I b y r e d u c i n g l - p h e n a c y l a z i r i d i n e X I V ) [ 70 ].
P h C O C H 2 N / I
Nail,A1
OCH_*CH_~OCH~)._,
X I I I .
l y
l
W e s h o u l d n o t e t h a t a z i r i d i n e X I V i s a l s o u s e d f o r t he s y n t h e s i s o f p h e n a c y l t h i a z o l i d i n e
VI [69] :
X I V K S C N V I .
I n t h e p r e p a r a t i o n o f c a r b i n o l V I I f r o m s t y r e n e o x i d e , e t h y l e n i m i n e c a n b e r e p l a c e d b y
m o n o e t h a n o l a m i n e . F o r t h is , b o t h th e p r e f e r e n t i a l l y f o r m e d s u b s t i t u t e d b e n z y l a l c o h o l X V)
[ 1 1 2 ] a n d i t s i s o m e r X VI ) a r e u s e d a f t e r r e p l a c i n g t h e t e r m i n a l h y d r o x y l g r o u p by a h a l o g e n
a t o m o r a s u l f o g r o u p [ 3 7 , 4 3 ] ) .
PhCH OH)CH2NHCH2CH2OHxv
. . . . ~ PhCH(Hal)CH2NHCH'~CH2Hal- -
P h CH ( C H 2O H ) N H C H ~C H tO H ~ P h C H ( C H ~ H a l ) N H C H 2 C H 2 H a l - - ~
X V I
S = C N H , ) ~
H a l C H . o C H z N ~ P h C H ( O H ) C H 2 N H C H ~ C H 2 Y 9
V I I
N p h X V I I
Y H a l , O S 0 3 H .
T h e i n t e r m e d i a t e p r o d u c t X V I I Y = C I) i s p o s s i b l y t h e k e y p r o d u c t i n t he o ri g i n a l ,
a l t h o u g h m u l t i s t a g e s y n t h e s i s [ 2 2 ] o f h y d r o x y i m i n o t h i a z o l i d i n e V I I f r o m t h e i n e x p e n s i v e a n d
r e a d i l y a v a i l a b l e s t a r t i n g m a t e r i a l s -- s t y r e n e t h e s t a r t i n g c o m p o u n d f o r t h e s y n t h e s i s o f
s t y r e n e o x i d e ) a n d s u b s t i t u t e d d e r i v a t i v e s of m o n e t h a n o l a m i n e - - u r e t h a n e X V II I ) or o x a -
zoli dino ne XIX) [Iii]o
O
C I C H 2 C H 2 N H C O 2 E t
~ N ~ O
l
...... H
XVIII XIX
A s i m i l a r p r i n c i p l e w a s u s e d p r e v i o u s l y i n [ 1 02 ] f o r t h e p r e p a r a t i o n o f t e t r a m i s o l e
f r o m s t y r e n e
X V I I I ( X I X )
> > > 2. S----C NH,)~/SCN- II
I
I I I
B r CH~CH Br) h CH~CH OH)Ph
T h e m e t h o d i s b a s e d o n t h e a b i l i t y o f N - b r o m o - s u b s t i t u t e d d e r i v a t i v e s t o ad d t o u n -
s a t u r a t e d c o m p o u n d s
P h C H = C H = + C H 3 C 6 H . S O 2 N C I 2 ,~, C H 3 C ~ H 4 S O ~ N ~ p\
X X
D i c h l o r a m i n e T r e a d i l y a d d s t o s t y r e n e w i t h t h e f o r m a t i o n o f N - t o s y l p h e n y l a z i r i d i n e X X )
w h i c h i s f u r t h e r s u b j e c t e d t o r e a c t i o n w i t h m o n o e t h a n o l a m i n e .
H o w e v e r , t h e o p e n i n g o f t he a z i r i d i n e r i n g p r o c e e d s n o n s e l e c t i v e l y , a n d, a l t h o u g h t h e
f o r m a t i o n o f b y - p r o d u c t X X I I c a n b e p r e v e n t e d b y c a r r y i n g o u t t h e r e a c t i o n i n a n a p r o t i c
s o l v e n t ( o p t i m a l l y i n d i o x a n e ) , t h e y i e l d o f t h e r e q u i r e d p r o d u c t X X I i s n e v e r t h e l e s s l o w.
, . s o c l ,
~
H , S O , . I
X X I 2,
SC~ - <..
N / / ~ N H
CH~CHPhNHTS
XXIII
T h e s u b s e q u e n t s t a g e s a r e f a i r l y c u m b e r s o m e a n d i n t hi s f o r m t h e m e t h o d i s p r o b a b l y
n o t u s e d in t h e i n d u s t r y . H o w e v e r , i t is p r o b a b l e t h a t s p e c i f i c a l l y t h i s e a r l y i n v e s t i -
g a t i o n s t i m u l a t e d t h e i n v e s t i g a t i o n o f t h e s y n t h e s i s o f t h e s t a r t i n g m a t e r i a l s X X I a n d X X I I I .
T h u s , a c y l a n a l o g s o f t h e s u b s t i t u t e d e t h a n o l a m i n e X X I w e r e o b t a i n e d f r o m s u b s t i t u t e d d i -
e t h a n o l a m i n e X V w i t h n i t r i l e s i n c o n c e n t r a t e d s u l f u r i c a c i d , a c c o r d i n g t o t h e R i t t e r r e a c t i o n
[ 1 1 ]
R C N
X V ~ P h C H ( N H C O R) C H , N H C H ~ C H2 Y
XXIV
Y = O H , H a l , OSOsH.
I n t h e r e a c t i o n o f t h e s u l f a t e e s t e r X X I V ( Y = O S O 3 H ) a n d a l s o o f t h e a z i r i d i n e ( XX V)
o b t a i n e d f r o m i t , w i t h t h i o c y a n a t e s o r t h i o u r e a , t h i a z o l i d i n e ( X X VI ) i s f o r m e d , w h i c h g i v e s
t e t r a a m i s o l e b y t r e a t m e n t w i t h s u l f u r i c o r p o l y p h o s p h o r i c a c i d o r b y t h e a c t i o n o f n i t r o u s
a c i d o n a m i n o t h i a z o l i d i n e ( X X V I I) [ 3 1, 4 2 , 6 1 , 8 5 ] ,
I
\ |
Ph
X X V
CH~CH Ph)NHCOR
XXVI
- - S
< ~ / [ ~ N H N~ ~ I
CH,CH NHJPh
XXVI
T h e m a i n d i f f i c u l t y o f t h i s g r o u p o f s y n t h e s i s c o n s i s t s i n t h e l o w a c c e s s i b i l i t y o f t h e
k e y c o m p o u n d X X I V , w h i c h i s o b t a i n e d i n c o n c e n t r a t e d s u l f u r i c a c i d at a t e m p e r a t u r e l o w e r
t h a n 0 ~ a n d i s i s o l a t e d b y t h e e v a p o r a t i o n to d r y n e s s o f t h e n e u t r a l i z e d s o l u t i o n a t a
t e m p e r a t u r e n o t h i g h e r t h a n 5 0 ~
W e s h o u l d n o t e t h a t t h e a m i n o d e r i v a t i v e X X V I I w a s a l so s y n t h e s i z e d b y c a t a l y t i c h y d r o -
g e n a t i o n o f 2 - i m i n o p h e n a c y l t h i a z o l i d i n e o x i m e ( X XV I I I) [ 69 ].
S e v e r a l m e t h o d s o f s y n t h e s i s o f t e t r a m i s o l e a r e b a s e d o n t h e r e a d i l y a v a i l a b l e t h i a z o l i -
d i n e d e r i v a t i v e s : 2 - o x o - ( X X I X ) a n d 2 - t h i o x o t h i a z o - l i d i n e ( X X X ) .
H
S N
[ I 4- Ph b, ~
XX IX, XXX XXXI
S / P h H CI
L N / / J ~ ( ' N > I
XXXII
I n t h e r e a c t i o n o f t h e s e t h i a z o l i d i n e d e r i v a t i v e s w i t h 2 - p h e n y l a z i r i d i n e ( X X X I) , 2 -
a z i r i d i n y l t h i a z o l i n e ( X X X II ) i s f o r m e d , w h i c h b y t h e a c t i o n o f h y d r o c h l o r i c a c i d r e a r r a n g e s
i n t o t e t r a m i s o l e [ 64 ]. T h i s s c h e m e a t t r a c t s a t t e n t i o n n o t o n l y b e c a u s e o f it s h i g h y i e l d
( 95 ) a n d e x p e r i m e n t a l s i m p l i c i t y , b u t a l s o d u e t o t h e p o s s i b i l i t y o f d i r e c t l y o b t a i n i n g
l e v a m i s o l e , i f t h e c o r r e s p o n d i n g o p t i c a l l y a c t i v e a z i r i d i n e X X X I i s u s e d .
F o r t h e p r e p a r a t i o n o f t e t r a m i s o l e , a l s o 3 - s u b s t i t u t e d t h i a z o l i d i n e - 2 - t h i o n e s ( Y~ XX II I)
a r e u s e d [ 3 0 , 4 5, 8 6 ] a c c o r d i n g t o t h e sc h e m e :
X X IV ~ ~ - ~ mx
S
I
CH2CH NHCOR)Ph
XXXIII
--S
CH2CH(NHCOR)Ph
XXXlV
Q u a t e r n a r y s a l t s w i t h t h e s t r u c t u re o f X XX I V a r e c l ea r l y i n t e r m e d i a t e p r o d u c t s i n t h e
s y n t h e s i s o f t e t r a m i s o l e [ 9 8 ] f ro m. a l k y l t h i o t h i a z o l i n e s Y 2 ~ V .
S
l
XXXV
+ PhCH(NH COR)CH ~Hal : I
XXXVI
I n t h e a l k y l a t i o n o f a l k y l t h i o t h i a z o l i n e s X X X V by h a l o g e n d e r i v a t i v e s o f t h e t y p e X X X V I ,
t h e y i e l d o f t e t r a m i s o l e i s 3 0 - 4 0 . T h i s i s p o s s i b l y d u e t o t h e r i g o r o u s r e a c t i o n c o n d i t i o n s
( h e a t i n g a t 1 7 0 ~ f o r 1 .5 h ) , a t w h i c h b o t h t h e d e a l k y l a t i o n o f t h e i n i t i a l l y f o r m e d q u a t e r -
n a r y s a lt X X X I V a n d t h e d e h y d r o h a l o g e n a t i o n o f th e a l k y l a t i n g a g e n t a r e v e r y p r o b a b l e.
N e v e r t h e l e s s , t h is m e t h o d i s p r o b a b l y b e t t e r t h a n t he i n i t i a l l y p r o p o s e d a l t e r n a t i v e s t a g e -
w i s e r e a c t i o n [ 82 ]:
XXXV + PhCH(NH2)CH~OH >
~S I. SOCI,
~NHCH (Ph)CH~OH 2. OH-
O f t h e a b o v e e n u m e r a t e d m e t h o d s , w e c a n s i n g l e o u t t h e m e t h o d s o f t h e p r e p a r a t i o n o f I
f r o m 2 - a m i n o t h i a z o l i n e a n d h a l o a c e t o p h e n o n e s a s t h e p r i n c i p a l o n e s . N a m e l y i n t h i s w a y ,
b e c a u s e o f t h e a v a i l a b i l i t y o f t he v a r i o u s s u b s t i t u t e d d e r i v a t i v e s o f t he s t a r t i ng c o m p o n e n t s
n o t f e w e r t h a n t h o u s a n d s o f t e t r a m i s o l e a n a l o g s w e r e o b t a i n e d w i t h a m o d i f i c a t i o n o f s u b -
s t i t u e n t s a t t h e 6 - p o s i t i o n a l o n e [ 2 8 , 4 8, 5 8 - 6 0 , 9 2 , 9 3, 1 05 , 1 3 2 ] . A m o n g t h e . s y n t h e si z e d
c o m p o u n d s , m a n y w e r e f o u n d h a v i n g a c t i v i t y . c o m m en s u r a bl e w i t h t h a t o f t e t r a m i z o l e o r e ve n
h i g h e r w i t h r e s p e c t t o i n d i v i d u a l p a r a m e t e r s , b u t n o n e of t h e m s u r p a s s e s i t w i t h r e s p e c t t o
t h e b r e a d t h o f t h e s p e c t r u m o f i t s a c t i v i t y .
S e l e n i u m a n a l o g s o f t e t r a m is o l e , w h i c h a r e u n i n t e r e s t i n g f r o m t h e s t a n d p o i n t o f
p h y s i o l o g i c a l a c t i v i t y [ i1 7, 1 2 0] a s w e l l a s t e t r a m i s o l e c o n t a i n i n g a r a d i o a c t i v e c a r b o n
a t o m ( 14 C) a t t h e 6 - p o s i t i o n , u s e d f o r t r a c i n g t h e p a t h s o f m e t a b o l i s m o f t e t r a m i s o l e i n
t h e o r g a n i s m [ 1 2 1] , w e r e o b t a i n e d b y t h e s a m e m e t h o d .
2 . A d d i n g o n t h e T h i a z o l e R i n g
T h e s e c o n d , a l s o f a i r l y n u m e r o u s g r o u p o f m e t h o d s o f s y n t h e s i s o f t e t r a m i s o l e i s b a s e d
o n i n i t i a l l y o b t a i n e d h y d r o g e n a t e d d e r i v a t i v e s o f i m id a z o l e . F o r s o m e o f t h em , 4 - p h e n y l -
i m i d a z o l i d i n e - 2 - t h i o n e ( X XX V II ) [ 11 4] s e r v e s a s t h e s t a r t i n g m a t e r i a l , w h i c h i s a l k y a t e d
b y 1 , 2 - d i h a l o e t h a n e s ( X X X V I I I ) , X I = X 2 = l la l) , f o l l o w e d b y c y c l i z a t i o n i n a l k a l i n e m e d i u m
[29, 125]
- - N H
[ [ + XtCH=C H~X 2 ~-
p h \ N ~ s
I
X X X V I I X X X V I I I
- - N
I I I
p h / l ' N / ~ S C H ~C H ~X2
I
X X X l X
X 1 X 2 = C 1 B r , O H .
I
T h e m e t h o d i s a l s o u s e d f or t h e p r e p a r a t i o n o f t e t r a m i s o l e a n a l o g s w i t h v a r i o u s s u b -
s t i t u e n t s i n t h e i m i d a z o l e r i n g [ 29 ].
R . A r i e s h a s d e v e l o p e d a w h o l e s e r i e s o f m o d i f i c a t i o n s o f t h i s m e t h o d . T h u s , b y t h e
r e a c t i o n o f t h i o n e X X X V I I w i t h e t h y l e n e c h l o r o h y d r i n [ 67 ], o r e t h y l e n e o x i d e [ 6 8 ] 2 - h y d r o e t h y
t h i o i m i d a z o l i n e X X X I X ( X = O H ) w a s s y n t h e s i z e d , w h i c h w a s f u r t h e r s u b j e c t e d t o th e a c t i o n o f
h a l o g e n a t i n g a g e n t s a n d c y c l i z a t i o n . I n t h e r e a c t i o n w i t h v i n y l h al i d e s , t e t r a m i s o l e i s
f o r m e d i n o n e s t a g e . [ 7 6 ] :
X X X V I I - -{ -CH ~
=
C H H a l ~ I
T h e s a me a u t h o r p r e p a r e d t e t r a m i s o l e f r o m 2 - h a l o - 4 - p h e n y l - i m i d a z o l i n e X L b o t h b y a o n e -
s t a g e ( in t h e r e a c t i o n w i t h e t h y l e n e t h i o x i d e [ 75 , 7 9] ) , a n d b y a m u l t i s t a g e s y n t h e s i s ,
u s i n g a 2 - m e r c a p t o e t h a n o l [ 71 ], t h e s o d i u m s a l t o f 2 - c h l o r o e t h y l m e r c a p t a n [ 7 3 ] o r a m i x t u r e
o f d i b r o m o e t h a n e a n d s o d i u m s u l f i d e [ 72 ].
N C I C H C H ~ . S N a
N / > X X X I X > I
P h / ~ ~ C l ~ BrCHoCH..Br~_NaoS /
f i I s
X L f , / ~ l
I t s h o u l d b e n o t e d t h a t a l l t h e s e m e t h o d s h a v e t w o s u b s t a n t i a l d r a w b a c k s . F i r s t l y , t h e
k e y c o m p o u n d , l - p h e n y l e t h y l e n e d i a m i n e ( XL I) r e q u i r e d f o r th e s y n t h e s i s o f i m i d a z o l e s
X X X V I I a n d X L, w h i c h i s o b t a i n e d b y t h e r e d u c t i o n o f p h e n y l g l y c i n e n i t r i l e [ 12 3 ], i s d i f f i -
c u l t t o p r e p a r e .
P h C H = O + K C N + N H 4C I - - +
> P h C H ( N H = ) C N L i A I ~~ Ph CH (N H = )CH = N H =
Secondly, the unequivo calit y of the direction of the cycliz ation in the above synth eses
of tetramisole arouses doubts.
In fact, the electron density on the nitrogen at oms in the mole cule of hydroge nated
imidaz oline should be similar, and hence the formatio n of isomers in particu lar during the
alkyla tion or cyclization) is equally probable:
. N H
Ph Ph ,
l
H
r - - - - N / I
Moreover, the phenyl ring in these imidazolines devia tes fro m the plane of the hetero-
cyclic ring. Similarly, the steric environment of the reactio n centers N l and N 3) also
differs.
Studies of the reacti on of 2-mercap toimidaz ole XLII) with dibromoetha ne showed [12~
that also in this case the 5-substitute d isomer XLIII is prefer ential ly formed and not
the tetramisole analog XLIV.
N H
ph [~X.N/ J%S + BrCH~CH2B r >
I
H
X L I I
- - . N N
p h - S s p h s
l
X L I I I X L I V
What is more sur prisin g is that despite these data, a similar behav ior of hydrogena ted
derivat ives was establ ished only in 1981 [107]o It was found that in the synthesis from imi-
d a z o l i n e t h i o n e X X X V I I a n d d i b r o m oe t h a n e , i n a c c o r d a n c e w i t h t h e t he o r y, t e t r a m i s o l e a n d i t s
5-phe nyl-su bstitu ted anal og XLV are formed in a i:i ratio. In the same article, a directed
synthesis of isomer XLV was described this compoun d was found to be inactive as an anthel -
mintic) accordi n~ to a scheme:
PhCH(CN )NHCH ,,CH2O H. LtAIH,>
CS
> PhCH CH2NH2)NHCH2CH2OH
~ N H
P h ~ S
t
CH2CH~OH
N
P h 7 N ~ S . H CI
X L V
T h us , t h e a b o v e d e s c r i b e d m e t h o d s b a s e d o n i m i d a z o l i n e d e r i v a t i v e s a p p a r e n t l y h a v e n o
practic al value because of the probability of formation of by-products.
I t i s i n t e r e s t i n g t h a t c o m p o u n d L c an b e s e p a r a t e d i n t o e n a n t i o m e r s a n d b e u s e d f o r t h e
s y n t h e s i s o f l e v a m i s o l e .
T h e m a i n d r a w b a c k s o f t h e s e m e t h o d s h a v e a l r e a d y b e e n d i s c u s s e d a b o v e : t h e s e a r e t h e
n o n u n e q u i v o c a l i t y o f t h e r i n g o p e n i n g o f s t y r e n e ox i d e , a n d t h e d i f f i c u l t i e s i n v o l v e d i n t h e
i s o l a t i o n o f t h e d e r i v a t i v e s o f t y p e X X I V . I n t h i s c o n n e c t i o n , a n u n u s u a l m e t h o d f o r t he
p r e p a r a t i o n o f d i a m i n e L d i r e c t l y f r o m s t y r e n e h a s b e e n p r o p o s e d i n [ 19 ]:
PhCH----CH2 + CHsCN + XLIX
N/CH2CH~,OMe
OH
Ph Me
T h e i n t e r m e d i a t e f o r m a t i o n o f t h e i m i d a z o l e r i n g i s p r e s u m e d a l s o i n s y n t h e s e s b a s e d o n
b r o m o a c e t o p h e n o n e [ 5 3 , 5 5, 56 , 9 0, 91 , 1 2 6 ] :
T h e k e y s t a g e o f t h i s m e t h o d , t h e h y d r o g e n a t i o n o f i m i d a z o l o n e (L I) c a n b e c a r r i e d o u t
o n c o m p l e x r h o d i u m c a t a l y s t s c o n t a i n i n g o p t i c a l l y a c t i v e l i g a n d s , w h i c h l e a d s t o t h e p r e p a -
r a t i o n o f l e v a m i s o l e . I t i s r e p o r t e d t h a t a t a l l s t a g e s t h e y i e l d s a r e g oo d , a n d a 3 0 %
o p t i c a l p u r i t y o f t h e p r o d u c t i s o b t a i n e d .
3 . S y n t h e s i s f r o m L i n e a r S t r u c t u r e s
A s h a s a l r e a d y b e e n n o t e d , t h i s t y p e o f r e a c t i o n c o v e r s t h o s e i n w h i c h t h e c l o s u r e
o f t he h e t e r o c y c l i c r i n g s o f b o t h t h i a z o l e a n d i m i d a z o l e o c c u r s a t t h e l a s t s t a g e .
F o r e xa m p l e, J a p a n e s e a u t h o r s h a v e o b t a i n e d d e r i v a t i v e s o f i s ot h i o u r e a c o n t a i n i n g a l l
t h e f r a g m e n t s o f t h e e n d p r o d u c t s ( t h e " l i n e a r t e t r a m i s o l e " ) , f r o m w h i c h t e t r a m i s o l e w a s
s y n t h e s i z e d i n o n e s t a g e [ 96 , 9 7] .
P h C H ( C 1 ) C H 2 N H C ( = N H ) S C H 2 C H z C 1 N a CO i , I
L I I
T h e y i e l d s a t a l l s t a g e s a r e g o o d, a n d t h e s c h e m e i s f a i r l y w e l l t e c h n o l o g i c a l l y f e a s i -
b l e a n d ca n b e u s e d f o r t h e p r e p a r a t i o n o f t e t r a m i s o l e a n a l o g s d i f f e r i n g i n t h e m o d i f i c a t i o n
of the phe nyl group.
T h e 1 , 2 - d i s u b s t i t u t e d t h i o u re a s , i s o m e ri c w i t h t h e t h i o u r o n i u m d e r i v a t i ve s , a r e
a p p a r e n t l y i n t e r m e d i a t e p r o d u c t s i n t h e s y n t h e s i s o f t e t r a m i z o l e f r o m i s o t h i o c y a n a t e ( L I I I )
[74, 77].
P h C H ( N = C = S ) C H 2 H a I ( N a I N I
. . . . \ H a l C H z C H z N H 2
L I I I
X N a I
A s o m e w h a t m o r e c o m p l e x s c h e m e o f b u i l d i n g t h e i m i d a z o t h i a z o i e s y s t e m s e r v e s a s t he b a s i s
f o r a m e t h o d [ 78 ], a c c o r d i n g t o w h i c h t h e i n i t i a l a d d i t i o n o f an a m i n e t o a n a c t i v a t e d C == C
b o n d i s a s s u m e d ~
P h C H ( N H ~ ) C H 2 H a +
H g ( O O A c ) z
~ H ~ C H N = C = S N a l > I
A n d l a s t l y , a m e t h o d i s k n o w n [ 6 2 ], s i m i l a r t o t h a t p r o p o s e d p r e v i o u s l y ( f r o m 2 - a m i n o -
t h i a z o l i n e a n d d i b r o m o s t y r e n e / , u s i n g t h e i n t e r m e d i a t e p r o d u c t s o f t h e s y n t h e s i s o f 2-
I n g e n e r a l l y c h a r a c t e r i z i n g t h i s g r o u p o f m e t h o d s i n a g e n e r a l m a n n e r , w e s h o u l d n o t e
t h e n o n u n e q u i v o c a l i t y , s i n c e i n m a n y o f t h e m a l t e r n a t i v e p a t h s o f t h e c o u r s e o f t h e r e a c ti o n
a r e a l s o f u l l y p r o b a b l e .
S ~ r i z i n g t h i s b r i e f r e v i e w o f t h e m e t h o d s f o r t h e s y n t h e s i s of t h e c o n d e n s e d r i n g o f
i m i d a z o [ 2 , l - b ] t h i a z o l e s , w e s h o u l d p o i n t o u t t h at a t t h e p r e s e n t t i m e, t h e i r d e v e l o p m e n t h a d
a l r e a d y l e d t o t h e c r e a t i o n o f a w h o l e s e r i e s o f n e w g r o u p s o f h i g h l y a c t i v e a n d s p e c i f i c a l l y
a c t i n g p r e p a r a t i o n s . O f t h e s e , w i t h r e g a r d to t h ei r p h y s i o l o g i c a l a c t i v i t y , w e s h o u l d
p a r t i c u l a r l y c i t e t h e d e r i v a t i v e s o f m - a m i n o p h e n y l - ( L l V ) [ 23 , 4 7 - 5 0 , 5 7 , 6 3 , 83 , 92 , 9 3 , 9 5 ,
1 0 5 , 1 0 6 , 12 5 , 1 3 3 ] , 6 - h e t e r y l - ( L V ) [ 14 , 5 8 - 6 0 , 1 2 4 ] a n d d i - , t r i - t e t r a s u b s t i t u t e d t e t r a -
1 2 5 . A. R a e y m a e k e r s , F . A l l e w i j n , J . V a n d e r b e r k , e t a l . , J . Me d . C h e m . , ~ , No . 4 , 5 4 5 - 5 5 0
1966).
1 26 . S . R a g h u , A. Z w e i g , a n d W . H a n d e r s o n ~ F u n d a m . R e s . H o m o g e n , C a t a l . , ~ , 5 6 5 - 5 7 7 1 9 7 9 ).
127. G. Raiz iss and L. Clem enee , J. Am. Chem. Sor 63, 3124 -31 26 1941).
128. G. Ren oux and M. Renou x, Ann. Immunol., 128C , No. 1-2, 273-2 74 1977).
1 2 9 . G . R e n o u x a n d M . R e n o u x , A n n. l ~ u n o l . , 1 2 8 C , No . 1- 2 , 2 7 5 - 2 7 7 1 9 7 7 ).
130. G. Renou x, Drugs , 20, No. 2, 89-99 1980).
1 3 1 . G . R e n o u x , I n t . E n c y c l . P h a r m a c o l . T h e r . , 1 1 5 , 3 9 3 - 4 1 0 1 9 8 5 ).
132. J. Reyn olds , E xper ient ia, 3-3, No. 2, 154- 155 1977).
133. N. Ronald and R. Bell, So uthw est Vet., 29, No. 3, 217- 218 1976).
134. H. Schn ieden , Int. J. Irmnunopharmacol., 3, No. i, 9-13 1981).
1 3 5 o A . S c h o b e r l a n d G . H a n s e n , C he m. B e r . , 9 1 , 1 2 3 9 - 1 2 4 1 1 9 5 8 ) .
1 36 . H . S i k o r s k a , R e u m a t o l o g i a W a r z a w a ) , 1 7 , N o . 3 , 3 3 9 - 3 4 7 1 9 7 9) .
137. L. Spicer, M. Bull ock , W. Gorb er, et. al., J. Org. Chem., 33, No. 4, 1350 -135 3 1968).
1 3 8 . J . S y m o e n s a n d M . R o s e n t a l , J . R e t i c u l o e n d o t h e l S o c . , 21 , N o. 3 , 1 7 5 - 2 1 1 1 9 7 7 ).
1 3 9 . J . S y m o e n s , M . R o s e n t a l , M . D e B r a b a n d e r , e t a l . , S p r i n g e r S e m i n . , I m m u n o p s t h o l o g y , ~ ,
No. i, 49-6 8 1979).
140. J. Symoens, J. De Cree, W. Van Beve r, et al., Pha rmacol . Bioc hem. , Prep. Drug. Subst.,
2 , 4 0 7 - 4 6 4 1 9 7 9 ) .
1 4 1 . D . T h i e n p o n t , G . V a n p a r i j s , a n d A . R a e m a e k e r s , N a t u r e , 2 0 9 , 1 0 8 4 - 1 0 8 6 1 9 6 6 ).
142. M. Xie, G. Zhong, an d X. Zhon~, Ya ox ue Xu eba o, 18_,No. 2, 147- 150 1983); Chem. Abs tr.,