8/13/2019 Synthesis of Dl-sparteine

1/3

P a t e n t e d J u l y 2 4 , 1 9 5 1 2,561,326

UNITED S T A T E S PATENT O F F I C EN e l s o n J . Lecnard;Urbana, I l l .

N o D r a w i n g . A p p l i c a t i o n M a r - c h 2 2 , 1 9 4 9 ,S e r i a l No. 8 2 . 9 0 3

4 C l a i m s . ( C l . 2 6 0 ~ . - 2 9 3 )1My nvention r e l a t e s t o d l - s p a r t e i n e a n d mo r ep a r t i c u l a r l y t o t h e s y n t h e s i s t h e r e o f .S p a r t e i n e , otherwise known s l u p i n i d i n e , h a si n t h e p a s t been o b t a i n e d b y t h e a p p l i c a t i o n o f

extractive processes to pl a n t sources s u c h asSpartium s c o p a r z u m L . , a n d A n a g y r i s f o e ' t z ' d a L:A o n v e n i e n t l y a p p l i c a b l e s y n t h e s i s o f t h e drugi s d e s i r a b l e s i n c e the e x t r a c t i v e processes are i ne f ? c i e n t , time-consuming a n d l a b o r i o u s , b u t h i t he r t o a l l attempts a t s y n t h e s i s h a v e been unsucc e s s f u l .

I h a v e d i s c o v e r e d that the s y n t h e s i s o f d ls p a r t e i n e i s r e a d i l y a c c o m p l i s h e d i n good y i e l d byreduction or reductive ring c l o s u r e o f a pyridinecompound, such a s z / i - b i s - ( a - p y r i d y l ) - g l u t a r i ce s t e r , l l - k e t o - 3 - ( u - p y r i d y l ) - - p y r i d o c o l i n e - 1 - c a rb o x y l i c a c i d e s t e r s , 4 - k e t o - 3 - ( a - p i p e r i d y l ) - o c t ah y d r o p y r i d o c o l i n e - l - c a r b o x y l i c a c i d e s t e r , 2 , 4b i s - ( a - p i p e r d y l ) - g l u t a r i c e s t e r , d i o x o s p a r t e i n e ,a n d o x o s p a r t e i n e .

T h e above l i s t e d c ompo u n d s , w h i c h f o r p u rposes o f conv eni ence are herei n c a l l e d pyridinec o m p o u n d s a n d w h i c h s e r v e as s t a r t i n g materialsf o r my y n t h e s i s o f d l - s p a r t e i n e , are known o t hea r t a n d adequate d i r e c t i o n s f o r t h e i r p r o d u c t i o na r e t o be found i n the f o l l o w i n g p u b l i c a t i o n s :Clemo, M o r g a n and R a p e r , J . Chem. S o c . , 1 0 2 5( 1 9 3 6 ) a n d S o r m a n d K e i l , C o l l e c t i o n o f Czechos l o v . C h em. C o m m u n s , 1 2 , 6 5 5 ( 1 9 4 7 ) .For the purpose o f c o n v e n i e n c e , th e ch emicalformulas of the c o m p o u n d s w h i c h s e r v e as s t a r ting m a t e r i a l s f o r my y n t h e s i s o f d l - s p a r t e i n e aregiven b e l o w . I n the formulas R r e p r e s e n t s ine a c h c a s e an s t e r i f y i n g r a d i c a l , s u c h a s for e xample, a lower a l k y l g r o u p .2 , 4 - b i s - ( a - p y r i d y l ) - gl u t a r i c e s t e r

000Ro ri f i n/ROOC4-ke t o -3-(a- p yr i dyl)- p yr i do co l i n e - 1 -carboxylica c i d e s t e r

000R

1 5

i )

10

1 5

2 V4 - k e t o - 3 - v ( a , - p i p e r id y l ) - octahydropyridocoline-lc a r b o x y l i c a c i d ester.

2 , 4 - b i s - a - p i p e r id y l ) - g l u t a r i c e s t e rH2 H2C 000R

2 0 D i o xo s p a r t e i n e I I ,

30

35

3 4 5

5 5

C B 1

1 1 2 0 /

T h e hydrogenation d e s i r a b l y i s c a r r i e d out i na , l i q u i d d i s p e r s i n g m e d i u m t o a i d i n promotinga n intimate contact o f the c a t a l y s t w i t h the subs t a n c e heing hydrogenated. T h e d i s p e r s i n g medium c a n b e a solvent or s i m p ly a s u s p e n d i n ga g e n t . I l l u s t r a t i v e examples o f su i t a b l e d i s p e r si n g m e d i a . a r e t h e h i g h e r b o i l i n g e t h e r s , d i o x a n e ,e t h a n o l , m e t h y l c y c l o h e x a n e , a n d t h e l i k e . T h emedium e m pl oy e d i s o f co urse o n e w h i c h i s una f f e c t e d by t h e hydrogen a n d t h e c a t a l y s t , a n dmany u i t a b l e med i a w i l l r e a d i l y be apparent t oo n e s k i l l e d i n the a r t .The t e m p e r a t u r e a n d p ressure at w h i c h t h eh y d ro g e n a t i o n i s c a r r i e d out are c r i t i c a l so f a r

a s t h e i r lower l i m i t s are concerned. I h a v e f o u n dt h a t a t e m p e r a t u r e o f a p p r o x i m a t e l y 2 0 0 C . a n da p r e s s u r e o f / a b o u t 200 atmospheres a r e r e q u i r e d ,

8/13/2019 Synthesis of Dl-sparteine

2/3

8/13/2019 Synthesis of Dl-sparteine

3/3

5c o m p r i s e s hydrogenating a t a temperature b et w e e n a b o u t 2 0 0 C. a n d 3 0 0 C . , a n d a pressure o fa t l e a s t 200 atmospheres w ith a c a t a l y s t o f thec l a s s c o n s i s t i n g o f copper chromite a n d z i n cc h r o m i t e , a m e m b e r o f th e group c o n s i s t i n g o f4-keto-3-(a-pyridyl) - p y r i d . o c o l i n e 1 - carboxylica c i d e s t e r a n d 4 - k e t o - 3 - ( a - p i p e r i d y l ) - o c t a h y d r op y r i d o c o l i n e - l - c a r b o x y l i c a c i d e s t e r , a n d i s o l a ti n g t h e d l - s p a r t e i n e w h i c h i s formed.2 . T h e me t h o d o f preparing d l ~ s p a r t e i n e w h i c hcomprises providing a d i s p e r s i o n i n a n i n e r tmedium o f a member o f the group c o n s i s t i n g o f4-keto-3-(apyridyl) - p yr i do co l i n e - 1 - carboxylica c i d e s t e r a n d l i - k e t o - m a - p i p e r i d y l ) - o c t a h y d r op y r i d o c o l i n e - l - c a r b o x y l i c a c i d e s t e r , s u b j e c t i n gsa i d d i sp e r si o n at a t e m p e r a t u r e b e t w e e n a b o u t2 0 0 C . a n d 3 0 0 C . , a n d a pressure o f a t l e a s t2 0 0 atmospheres t o t h e a c t i o n o f h y drogen a n da c a t a l y s t o f the c l a s s c o n s i s t i n g o f copper chromite a n d z i n c c h r o m i t e , a n d i s o l a t i n g t h e d l - s p a rt e i n e .3 . T h e m e t h o d o f preparing d l - s p a r t e i n e w h i c hcomprises treating a dioxane s o l u t i o n o f a lowera l k y l e s t e r o f 4 - k e t o - 3 - ( a - p y r i d y l ) - p y r i d o c o l i n el - c a r b o x y l i c a c i d a t a temperature o f a bo u t 2 5 0

5

1 0

1 5

20

25

2 , 5 8 1 , 3 2 6 6C . a n d a pressure o f about 4 0 0 atmospheres) w i t hhyd r o g e n a n d copper ch romite c a t a l y s t , a n d i s ol a t i n g t h e d l - s p a r t e i n e .4 . T h e m e t h o d o f preparing d l - s p a r t e i n e wh i c hcomprises t r e a t i n g a dioxane s o l u t i o n o f a lowera l k y l e s t e r o f 4 - i e t 0 - 3 - ( a p i p e r i d y l ) - o c t a h y c l r op y r i c l o c o l i n e - l - c a r b o x y l i c a c i d a t a temperatureo f a b o u t 250 C . a n d a p ressure o f a b o u t 400 a t mospheres with h y drogen a n d copper chromitec a t a l y s t , a n d i s o l a t i n g t h e d l - s p a r t e i n e .

NELSON . LEONARD.REFERENCES CITED

T h e f o l l o w i n g r e f e r e n c e s a r e o f record i n the? l e o f t h i s p a t e n t :UNITED STATES PATENTS

Name D a t eP a t i et a 1 ___________ May 7, 1949OTHER REFERENCES

C l em o e t a l . : J o u r . C h e m . S o c . (London), 1 9 3 6 ,p p . 1 0 2 5 - 1 0 2 8 .H e n ry : The P l a n t Alkaloids ( 4 t h ed), TheBlackiston 0 0 . , P h i l a . , 1 9 4 9 , p . 1 3 8 .

Number2 , 4 7 0 , 1 0 8