124 and thiophene s e r i e s , r e c e n t l y s y n t h e s i z e d i n the h e t e r o c y c l i c compounds l a b o r a t o r y of the I n s t i t u t e of O r g a n i c C h e m i s t r y of the AS USSRo m o s t of t h e s e aldehydes having a CHO group a t the fl p o s i t i o n i n the r i n g . A c c o r d i n g to s o m e r e s u l t s [1], p r e c i s e l y s u c h d e r i v a t i v e s of thiophene o r f u r a n , with a f u n c t i o n a l group in the fl p o s i t i o n , have v a l u a b l e p h a r m a c o l o g i c a l properties. The i s o n i a z o n e s a r e o b t a i n e d by r e f l u x i n g t o g e t h e r i n ethanol s o l u t i o n , f o r 1 - 2 h r , e q u i m o l a r a m o u n t s of i s o n i a z i d and aldehyde. The s o l u t i o n was left o v e r night, the i s o n i a z o n e which c r y s t a l l i z e d out f i l t e r e d off, and r e c r y s t a l l i z e d f r o m ethanol. If the i s o n i a z o n e did not s e p a r a t e , the s o l u t i o n was e v a p o r a t e d , o r , i n some c a s e s , d i l u t e d with w a t e r . The compounds p r e p a r e d w e r e t e s t e d in v i t r o f o r a n t i t u b e r c u l a r b a c t e r i o s t a t i c a c t i v i t y on 2 s t r a i n s of m i c r o b a c t e r i a of h u m a n type t u b e r c u l o s i s : A c a d e m i a and H 37 RV. The t e s t s w e r e c a r r i e d out u s i n g a s e m i synthetic n u t r i e n t m e d i u m , and the s a m e m e d i u m p l u s 10% blood s e r u m . All the compounds i n v e s t i g a t e d w e r e highly effective, stopping the growth of A c a d e m i a s t r a i n at d i l u t i o n s of 1 in 1 6 - 3 2 m i l l i o n (see table). The a c t i v i t i e s of the c o m p o u n d s w e r e cut 2 - 8 - f o l d i n n u t r i e n t c o n t a i n i n g blood s e r u m , but a c t i v i t y was s t i l l at a high level. Of the compounds i n v e s t i g a t e d , the m o s t effective w e r e the i s o n i a z o n e s of 5 - c t h y l m e r c a p t o f u r f u r a l ( p r e -

KH

rYA G E T E R O T S I K U C H E S K I K H

SOEDINENII

viously d e s c r i b e d and t e s t e d [5]) and 2 - e t h y l m e r c a p t e 5 - n - p r o p y l - 3 - f u r a n a l d e h y d e . The in v i t r o e f f e c t i v e n e s s of t h e s e c o m p o u n d s c o n s i d e r a b l y exceed that of the c l i n i c a l a n t i t u b e r c u l o s i s compound l a r u s a n , f u r f u r y l i d e n a c e t o n e isoniazone [4]. REFERENCES 1. E. E. C a m p a i g n e , J. Am. P h a r m . A s s o c . , 46, 129, 1957; V. L e u t n e r , A r z n e i m i t t e l - F o r s c h u n g , 7, 505, 1960. 2. Ya. L. G o l ' d f a r b , Ya. L. D a n y u s h e v s k i , and M. A. V i n o g r a d o v , DAN, 151, 2, 332, 1963. 3. Ya. L. G o l ' d f a r b , Yu. B. V o l ' k e n s h t e i n , and B. V. L o p a t i n , ZhOKh, 34, 969, 1964. 4. E. C h e r t k o v a , P r o b l . t u b e r k . , 3, 92, 1957. 5. L. H o e n e n , H. Sous, and H. MUckter, F e d e r a l G e r m a n R e p u b l i c p a t e n t no. 1023042, 1958; RZhKh, 14, 50 784, 1959.

6 January1966

Z e l i n s k i i I n s t i t u t e of O r g a n i c C h e m i s t r y , AS USSR, Moscow; Ordzhonikidze All-Union Scient i f i c R e s e a r c h C h e m i c a l and P h a r m a c e u t i c a l I n s t i t u t e , Moscow; Akrikhin Works

THE SCHMIDT REACTION WITH PYRIDLNE CARBOXYLIC ACIDS V. L. Z b a r s k i i , G. M. Shutov, V. F . Z h i l i n , and E. Yu. O r l o v a K h i m i y a G e t e r o t s i k l i e h e s k i k h S o e d i n e n i i , Vol. 3, No. 1, pp. 178, 1967 UDC 547. 826 The Schmidt reaction in oleurn is used to prepare 2, 3-and 4-aminopyridines. Up to the p r e s e n t a c o n v e n i e n t m e t h o d of p r e p a r i n g p y r i d i n e a m i n e s has not b e e n a v a i l a b l e , s i n c e a p p l i c a t i o n of the C h i c h i b a b i n r e a c t i o n is l i m i t e d to 2 - and 2 , 6 - a m i n o d e r i v a t i v e s [1]. The H o f m a n n a n d C u r t i u s r e a c t i o n s a r e p r i m a r i l y u s e d f o r p r e p a r i n g 3- and 4a m i n o p y r i d i n e s [1]; b u t the s t a r t i n g m a t e r i a l s a r e not v e r y a c c e s s i b l e . It w a s r e c e n t l y shown [2] that 100% s u l f u r i c a c i d m u s t b e u s e d to effect the S e h m i d t r e a c t i o n s u c c e s s f u l l y with b e n z o i c a c i d s c o n t a i n i n g electron-accepting substituents. However aminopyrid i n e s a r e not o b t a i n e d e v e n u n d e r t h o s e c o n d i t i o n s . We have now shown that all the m o n o a m i n o p y r i d i n e s c a n be p r e p a r e d by the S c h m i d t r e a c t i o n when 20-30% o l e u m is u s e d . EXPERIMENTAL 24 g NaNI was sprinkled into a solution of 38 g (0.3 mole) nicotinic acid in 165 ml 30% oleum at 0-5 ~ over a period of 3 hr (faster addition is not recommended, becauge of risk of explosion). Then the temperature was gradually railed to 95" over a period of 6 hr, held there for

3 hr, cooled to 10", and the products poured onto 500 g ice and neutralized with 40% NaOH, temperature not exceeding 30*. Seven extractions with ether (about 500 ml) gave 28.8 g moist product. Two recrystallizations from benzene gave 14.71 g (50.4%) 3-arninopyridine mp 61-62" (the literature gives [3] mp 62"), while the mother liquors gave 5.47 g (18.7%) material mp 53-57*. Mixed mps confirmed that the two materials were identical, and identical with authentic 3-aminopyridine. The picrate and perohlorate of 3-aminopyridine were prepared. Under the above conditions the yields of 2- and 4-arninopyridine did not exceed 30%.

REFERENCES 1. P y r i d i n e a n d i t s D e r i v a t i v e s , I n t e r n . P u b l i c . , New Y o r k - L o n d o n , 3, 1962. 2. A. I. M c N a m a r a and I. B. S t o t h e r s , Can. J . C h e m . , 42, 2354, 1964. 3. D i c t i o n a r y of O r g a n i c C o m p o u n d s [ R u s s i a n t r a n s l a t i o n ] , I L , M o s c o w , 1, 123, 1949.

10 J a n u a r y 1 9 6 6

M e n d e l e e v Moscow I n s t i t u t e of C h e m i s t r y and T e c h n o l o g y , Moscow