UBC Theses and Dissertations

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UBC Theses and Dissertations

A general synthesis of 6-azasteroids Johnson, Roy Allen 1961

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A GENERAL SYNTHESIS OF 6-AZASTEROIDS by Roy A l l e n Johnson B. Chem., The U n i v e r s i t y of M i n n e s o t a , 1959 A t h e s i s s u b m i t t e d i n p a r t i a l f u l f i l m e n t of the r e q u i r e m e n t s f o r t h e degree of MASTER OF SCIENCE i n t h e Department of C h e m i s t r y We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o the r e q u i r e d s t a n d a r d The U n i v e r s i t y of B r i t i s h Columbia September, 1961 In presenting t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree tha t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s representatives. It i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The U n i v e r s i t y of B r i t i s h Columbia, Vancouver 8, Canada. Date ^ ^ f m i ^ 7, ABSTRACT The o z o n i z a t i o n of 7 - k e t o c h o l e s t e r y l a c e t a t e has y i e l d e d 5-keto-5.» 7 ~ s e c o - 6 - n o r - 3 - c h o l e s t e n - 7 - o i c a c i d , an i n t e r m e d i a t e u s e f u l In t h e p r e p a r a t i o n o f 6 - a z a c h o l e s t a n e . C a t a l y t i c h y d r o g e n a t i o n c o n v e r t e d t h i s I n t e r m e d i a t e t o 5-keto-5,7- s e c o - 6 - n o r c h o l e s t a n - 7 - o i c a c i d w h i c h , upon t r e a t m e n t w i t h "benzyl amine, gave N-benzyl-6 -aza-4 -cholesten - 7-one. C a t a l y t i c r e d u c t i o n of t h i s e n o l - l a c t a m y i e l d e d N - b e n z y l - 6 - a z a c h o l e s t a n -7-one w h i c h was reduced w i t h l i t h i u m aluminum h y d r i d e t o N - b e n z y l - 6 - a z a c h o l e s t a n e . The g e n e r a l i t y of t h i s r o u t e was shown when i t was a p p l i e d t o compounds of t h e a n d r o s t a n e s e r i e s . O z o n i z a t i o n of 3 / 3 ,17/?-dihydroxy-5-androsten - 7-one d i a c e t a t e gave 17^-hydroxy-5-keto-5^ 7-seco- 6-nor- 3-androsten - 7-oic a c i d w h i c h was hydrogenated c a t a l y t i c a l l y t o 17 / 2-hydroxy-5-keto-5,7-seco-6-n o r a n d r o s t a n - 7 - o i c a c i d . T h i s s a t u r a t e d a c i d r i n g — c l o s e d w i t h b e n z y l amine t o y i e l d 17^-hydroxy-N-benzyl-6-aza-4-a n d r o s t e n - 7 - o n e . C a t a l y t i c h y d r o g e n a t i o n of t h i s e n o l -l a c t a m gave 17/,-hydroxy~N-benzyl-6-azandrostan - 7-one w h i c h • was reduced w i t h l i t h i u m aluminum h y d r i d e t o N-benzyl-6-azaandrostan-17/?-ol. A m i l d chromic a c i d o x i d a t i o n con-v e r t e d the a l c o h o l t o the k e t o compound, N-benzyl-6-a z a a n d r o s t a n - 1 7 - o n e . ACKNOWLEDGEMENT The time spent w o r k i n g on t h i s t h e s i s under the guidance of Dr. James P. Kutney has been a v e r y v a l u a b l e e x p e r i e n c e ; the w r i t e r e x p r e s s e s h i s a p p r e c i a t i o n o f t h i s t o Dr. Kutney. F i n a n c i a l a i d from the N a t i o n a l R e s e a r c h C o u n c i l Canada and the N a t i o n a l I n s t i t u t e s of H e a l t h Grant No. CY-5037 and a g i f t of d e h y d r o e p i a n d r o s t e r o n e from the Upjohn Company i s g r a t e f u l l y acknowledged. TABLE OF CONTENTS Page I n t r o d u c t i o n . . . . . . 1 N - B e n z y l - 6 - a z a c h o l e s t a n e . 8 N-Benzyl-6-azaandrostan-170-01 17 C o n c l u s i o n 23 E x p e r i m e n t a l 25 B i b l i o g r a p h y 46 LIS T OP TABLES I . The nomenclature of some common s t e r o i d s . . . . 2 LIST OF FIGURES No. 1 C h o l e s t e r o l and the numbering system of s t e r o i d s 3 2 C o r t i s o n e and i t s s t e r e o c h e m i s t r y 3 3 A z a s t e r o i d s y n t h e s i s u s i n g the Beckmann rearrangement . . . . . . . . . . . . . . . 7 4 A z a s t e r o i d s y n t h e s i s u s i n g the r i n g c l o s u r e o f a k e t o - a c i d 7 5 T h e o r e t i c a l r o u t e t o i n t e r m e d i a t e k e t o - a c i d . . 9 6 E p o x i d a t i o n r e a c t i o n s 9 7 Attempted r o u t e t o i n t e r m e d i a t e k e t o - a c i d . . . 11 8 Compounds c o n t a i n i n g e n o l - l a c t a m chromophore . . 11 9 S y n t h e t i c r o u t e t o N-benzyl-6-azacholestane.. . . 14 10 P r o t e c t i o n of oxygen f u n c t i o n s of a n d r o s t e n o l o n e 18 11 S y n t h e t i c r o u t e t o N - b e n z y l - 6 - a z a a n d r o s t a n -17)B-ol 20 INTRODUCTION ^ The s t e r o i d a l compounds of n a t u r e , l i k e o t h e r n a t u r a l p r o d u c t s , have p r o v i d e d c h e m i s t s w i t h the s u b j e c t s f o r many f a s c i n a t i n g s t r u c t u r a l d e t e r m i n a t i o n s as w e l l as a number of complex s y n t h e s e s . T h e i r u s e f u l n e s s t o the chemist has not stopped a t t h i s p o i n t , however, and the s t e r o i d s have been used as a b a s i s f o r a l a r g e number of c h e m i c a l s t u d i e s . Among the s e are d e t e r m i n a t i o n of a b s o r p t i o n s of t y p i c a l f u n c t i o n a l groups and chromophores i n i n f r a r e d and u l t r a - v i o l e t s p e c t r a , c o n f o r m a t i o n a l a n a l y s i s s t u d i e s , u t i -l i z a t i o n of o p t i c a l r o t a t o r y d i s p e r s i o n as a means of d e t e r -m i n i n g c o n f i g u r a t i o n s of asymmetric carbons, and use as p h a r m a c e u t i c a l agents i n the f i e l d of m e d i c i n e . Today, t h e i r u s e f u l n e s s c o n t i n u e s t o occupy the i n t e r e s t of c h e m i s t s . The I n i t i a l work on s t e r o i d s was q u i t e n a t u r a l l y concerned w i t h t h e i r s t r u c t u a l e l u c i d a t i o n and c h e m i s t s used the e a s i l y i n t e r r e l a t e d b i l e a c i d s , c h o l e s t e r o l , and e r g o s t e r o l as a b a s i s of s t u d y . The c o r r e c t s t r u c t u r e of d e s o x y c h o l i c a c i d was p r o posed i n 1932 ( 2 ) ( 3 ) and t h i s l e d t o the immediate f o r m u l a t i o n of c h o l e s t e r o l as I . (see f i g u r e l ) In the f o l l o w i n g y e a r s the sex hormones and the a d r e n a l c o r t i c a l hormones were i s o l a t e d and t h e i r s t r u c t u r e s q u i c k l y d e t e r m i n e d . Table I i l l u s t r a t e s the more common s t e r o i d t y p e s . 2 The s t r u c t u r a l e l u c i d a t i o n s of the s t e r o i d s were e s s e n t i a l l y completed by 19^-0. The nex t decade found the major r e s e a r c h e f f o r t s d i r e c t e d toward d e t e r m i n a t i o n of the s t e r e o c h e m i s t r y of the s t e r o i d s and a t the end of t h i s p e r i o d , c o r t i s o n e , f o r example, c o u l d be r e p r e s e n t e d as i n f o r m u l a I I . (see f i g u r e 2) The s u b s t i t u e n t s a t the asymmetric carbons of a s t e r o i d a r e d e s i g n a t e d as c< (below the p l a n e of t h e m o l e c u l e as drawn) o r ft (above the p l a n e of the m o l e c u l e ) . The nomen-c l a t u r e of s t e r o i d s depends on the c o n f i g u r a t i o n of carbon atom f i v e ; t a b l e I g i v e s the nomenclature of some common s t e r o i d s . T a b l e I THE NOMENCLATURE OF SOME COMMON STEROIDS R R C o n f i g u r a t i o n of C S t e r o i d Name C h o l e s t a n e Coprostane CH n CH -CH CH=CHCH C H ( C H 3 ) 2 E r g o s t a n e CH I A l l o c h o l a n e Cholane Androstane -H Testane -H E s t r a n e Pregnane A l l o p r e g n a n e Figure 2. Cortisone and i t s stereochemistry 4 The d i s c o v e r y of the g r e a t p h y s i o l o g i c a l a c t i v i t i e s of c e r t a i n s t e r o i d s ( s u c h as the sex hormones and the a d r e n a l c o r t i c o hormones) when a d m i n i s t e r e d t o a n i m a l s as w e l l as t o humans has s t i m u l a t e d much r e s e a r c h d e s i g n e d towards s y n t h e s i s of t h e s e hormones and of analogous s t e r o i d a l compounds w h i c h may have s i m i l a r p h y s i o l o g i c a l e f f e c t s . T h i s has l e d t o the s y n t h e s i s of many d i f f e r e n t t y p e s of a l t e r e d s t e r o i d m o l e c u l e s , some of w h i c h have e x h i b i t e d r emarkable p h y s i o l o g i c a l a c t i v i t y . The f i r s t hormone a n a l o g s w h i c h had g r e a t e r a c t i v i t y than the p a r e n t compounds were d i s c o v e r e d a c c i d e n t a l l y when some 9-halogenated C o r t i s o l i n t e r m e d i a t e s were i n c l u d e d i n t e s t s f o r p h y s i o l o g i c a l a c t i v i t y and were found t o be h i g h l y a c t i v e . (4) A l l the 9°<-halogen d e r i v a t i v e s of C o r t i s o l and c o r t i s o n e were p r e p a r e d and t h e d e c r e a s i n g s i z e of the halogen s u b s t i t u e n t was found t o i n c r e a s e g l u c o c o r t i c o i d ( l i v e r g l y c o g e n d e p o s i t i o n ) p r o p e r t i e s of the c o r t i s o n e g r e a t l y . (5) Thus, 9°<-fluorocortisone a c e t a t e was found t o be n i n e t i m e s as a c t i v e as c o r t i s o n e a c e t a t e . F o l l o w i n g t h i s d i s c o v e r y , many o t h e r c o r t i s o n e a n a l o g s were q u i c k l y p r e p a r e d . C e r t a i n m e t h y l a t e d C o r t i s o l s and c o r t i s o n e s a l s o show g r e a t e r a n t i - i n f l a m m a t o r y p r o p e r t i e s than do the n a t u r a l hormones. The compounds, 2<tf-methyl-Cortisol and i t s 9°(-fluoro d e r i v a t i v e , have such p r o p e r t i e s but a l s o have g r e a t l y enhanced m i n e r a l o c o r t i c o i d ( s a l t and water r e t e n t i o n ) a c t i v i t y . (6) However, 6<*-methyl-prednisolone ( l - d e h y d r o c o r t i s o l ) 5 e l i m i n a t e s t h i s u n d e s i r a b l e s a l t and water r e t e n t i o n w h i l e m a i n t a i n i n g a h i g h l e v e l o f g l u c o c o r t i c o i d a c t i v i t y . (7) Combination o f s e v e r a l s u b s t i t u e n t s i n the same hormone a n a l o g may g i v e a d d i t i v e or complementary p h y s i o -l o g i c a l p r o p e r t i e s . Some C ^ g - h y d r o x y l a t e d C o r t i s o l s i n com-b i n a t i o n w i t h a 9°(-fluoro atom have h i g h g l u c o c o r t i c o i d a c t i v i t y as w e l l as g r e a t l y r e d u c e d s a l t r e t e n t i o n . (8) These h y d r o x y l a t e d s t e r o i d s i l l u s t r a t e a t h i r d type of hormone a n a l o g . I n c o n t r a s t t o the a d d i t i o n of a s u b s t i t u e n t t o the hormone m o l e c u l e , the p r e p a r a t i o n of c e r t a i n n o r s t e r o i d s ( t h o s e i n w h i c h carbon atoms have been removed from the normal s t e r o i d s k e l e t o n ) has a l s o l e d t o compounds of i n c r e a s e d b i o l o g i c a l a c t i v i t y . F o r example, 1 9 - n o r p r o g e s t e r o n e (9) has 4 - 8 t i m e s t h e a c t i v i t y of p r o g e s t e r o n e whereas 17«-ethynyl - 1 9-*nortestosterone has about f i v e t i m e s the p r o g e s t a t i o n a l a c t i v i t y of 1 7 ( X - e t h y n y l t e s t o s t e r o n e . (10) A n o t h e r mode of a l t e r a t i o n of the s t e r o i d m o l e c u l e has been t h e i n t r o d u c t i o n of n i t r o g e n i n t o the s t e r o i d r i n g system t h e r e b y p r o d u c i n g a h e t e r o c y c l i c s t e r o i d a n a l o g . S e v e r a l methods have been used i n the s y n t h e s i s of t h e s e a z a - s t e r o i d s . The f i r s t and more common of t h e s e i s the u t i l i z a t i o n o f the Beckmann rearrangement of an oxime i n w h i c h the s i z e of the h e t e r o c y c l i c r i n g i n the p r o d u c t has been i n c r e a s e d by one atom. (11-20) (see f i g u r e 3) A s i m i l a r 6 method i s the Schmidt r e a c t i o n i n w h i c h the rearrangement of an a z i d e t o an amine has been u t i l i z e d t o p r e p a r e an a z a s t e r o i d . ( 1 2 , 2 0 - 2 2 ) A t h i r d method of p r e p a r a t i o n o f a z a s t e r o i d s has u t i l i z e d t h e r i n g c l o s u r e of a k e t o - a c i d t o a l a c t a m hy r e a c t i o n w i t h bases such as ammonia or amines. (14, 2 3 - 3 1 ) T h i s method must y i e l d a h e t e r o c y c l i c r i n g p o s s e s s i n g one more atom t h a n th e s t a r t i n g k e t o - a c i d . Thus, i f a h e t e r o -c y c l i c six-membered r i n g A, B, C or five-membered D r i n g i s d e s i r e d , a carbon atom must f i r s t be e l i m i n a t e d from t h a t r i n g of the s t e r o i d used as s t a r t i n g m a t e r i a l . Such an e l i m i n a t i o n has been a c c o m p l i s h e d i n r i n g A of the s t e r o i d s by o z o n i z a t i o n of an o f , ^ - u n s a t u r a t e d k e t o n e . ( 2 3 , 2 7 - 3 2 ) (see f i g u r e 4) The p r e p a r a t i o n of 6 - a z a s t e r o i d s was u n d e r t a k e n s i n c e such a s y n t h e s i s would p r o v i d e a s t e r o i d m o l e c u l e w i t h the u s u a l f u n c t i o n a l groups a t and C-^-j, a c o n d i t i o n i m p o r t a n t t o the p h y s i o l o g i c a l a c t i v i t y of most s t e r o i d a l compounds, i n a d d i t i o n t o a b a s i c n i t r o g e n i n t h e B r i n g . These p r o p e r t i e s had not been combined i n any a z a s t e r o i d r e p o r t e d b e f o r e I 9 6 0 ; however, s i n c e t h a t t i m e , Jacobs and B r o w n f i e l d (28) have p r e p a r e d 6 - a z a c h o l e s t a n e and L e t t r e and Knof (21) have p r e p a r e d 6 - a z a c h o l e s t e r o l . P r e l i m i n a r y r e p o r t s have suggested t h a t c e r t a i n 4 - a z a s t e r o i d s e x h i b i t b i o l o g i c a l a c t i v i t i e s (33) and t h a t 6 - a z a - 3 , 5 - c h o l e s t a d i e n e has a c y t o t o x i c a c t i v i t y . (21) F i g u r e 4. A z a s t e r o i d s y n t h e s i s u s i n g the r i n g c l o s u r e of a k e t o - a c i d 8 N-BENZYL-6-AZACHOLESTANE The i n i t i a l r e q u i r e m e n t of the s y n t h e s i s of a 6- a z a s t e r o i d i s t h e removal of Cg f r o m t h e s t e r o i d B r i n g . The u n s a t u r a t i o n of c h o l e s t e r o l a t r e n d e r s t h a t r i n g v u l n e r a b l e t o v a r i o u s methods of a t t a c k w h i c h may be used t o open the r i n g and remove Cg. Thus c h o l e s t e r y l a c e t a t e , r e a d i l y p r e p a r e d by the a c e t y l a t i o n of c h o l e s t e r o l , was used as a s t a r t i n g m a t e r i a l i n t h e s y n t h e s i s of N-benzyl-6-a z a c h o l e s t a n e . Chromic a c i d o x i d a t i o n o f c h o l e s t e r y l a c e t a t e was the f i r s t method of a t t a c k a t t e m p t e d s i n c e t h i s l e a d s t o the o x i d a t i o n of r i n g B t o the k e t o - a c i d , I I I , i n a d d i t i o n t o f o r m a t i o n of 7 - l c e t o c h o l e s t e r y l a c e t a t e , I V . (34) The k e t o -a c i d , I I I , has been c o n v e r t e d t o the l a c t o n e , V, w h i c h upon h e a t i n g goes t o 3-acetoxy-B-norcholest - 5~ene, V I . (35) (see f i g u r e 5) V a r i o u s o x i d a t i v e r e a c t i o n s c o u l d t h e n be a p p l i e d t o V I i n o r d e r t o o b t a i n the k e t o - a c i d , V I I . However, the number of s t e p s r e q u i r e d , many of o n l y moder-ate y i e l d s , p l u s f u r t h e r work u s i n g d i f f e r e n t approaches on 7- k e t o c h o l e s t e r y l a c e t a t e causedvus t o abandon t h i s r o u t e t o a k e t o - a c i d . S e v e r a l a t t r a c t i v e a l t e r n a t i v e s u t i l i z i n g 7-k e t o c h o l e s t e r y l a c e t a t e , IV, as an i n t e r m e d i a t e i n t h e e l i m i n a t i o n of C^ were c o n s i d e r e d i n view of the f a c t t h a t 6 t h i s m a t e r i a l can be p r e p a r e d i n h i g h e r y i e l d . (36) One 9 Figure 5 . Theoretical route to intermediate keto-acid 10 method of approach i n v o l v e d e p o x i d a t i o n o f the double bond. S i n c e b o t h c h o l e s t e n o n e , V I I I , (37) and 3 - h y d r o x y e s t r a - l , 3 , 5 ( 1 0 ) , l 6 - t e t r a e n - 2 0 - o n e , IX, (38) r e a d i l y undergo e p o x i d a t i o n when t r e a t e d w i t h 3 0 - 3 5 $ hydrogen p e r o x i d e i n an a l k a l i n e s o l u t i o n , (see f i g u r e 6) t h e s e c o n d i t i o n s were atte m p t e d w i t h 7 ~ k e t o c h o l e s t e r t j l a c e t a t e . However, e p o x i d a t i o n d i d not o c c u r and 7 - k e t o c h o l e s t e r o l (39) was r e c o v e r e d i n good y i e l d . F o l l o w i n g a p r o c e d u r e u s i n g p e r o x y t r i f l u o r o a c e t i c a c i d ( 4 0 ) , t h e e p o x i d a t i o n was a c h i e v e d i n 33$ y i e l d a f t e r chromatography of the p r o d u c t on s i l i c i c a c i d - c e l i t e . ( 4 l ) I t was a l r e a d y known t h a t p e r i o d i c a c i d i s an e x c e l l e n t h y d r o l y t i c agent f o r 5 , 6 - e p o x y c h o l e s t e r o l s (42) g i v i n g the d i o l s i n h i g h y i e l d . I t was t h e r e f o r e assumed t h a t t h e epoxy ketone, X, v i a the i n t e r m e d i a t e d i o l , X I , would r e s u l t d i r e c t l y i n t h e k e t o -a c i d , V I I , when t r e a t e d w i t h p e r i o d i c a c i d , (see f i g u r e 7) S e v e r a l a t t e m p t e d c l e a v a g e s of t h e e poxide w i t h p e r i o d i c a c i d gave no w e l l d e f i n e d p r o d u c t s and i n view of the subsequent s u c c e s s f u l o z o n l z a t i o n of 7 - k e t o c h o l e s t e r y l a c e t a t e , t h i s a pproach was not f u r t h e r s t u d i e d . O z o n l z a t i o n of an <x",t3-unsaturated ketone system i n r i n g A of compounds such as c h o l e s t e n o n e g i v e s good y i e l d s of t h e S - k e t o - a c i d s . (32) When 7 - k e t o c h o l e s t e r y l a c e t a t e , IV, was t r e a t e d w i t h ozone a t room temperature I n an a c e t i c a c i d s o l u t i o n f o l l o w e d by o x i d a t i v e d e c o m p o s i t i o n of the o z o n i d e w i t h hydrogen p e r o x i d e and w a t e r , a p p r o x i m a t e l y 50$ o f the m a t e r i a l was e x t r a c t a b l e w i t h base. Chromatography on a 11 F i g u r e 7. Attempted r o u t e t o i n t e r m e d i a t e k e t o - a c i d H xv CH, XVI X V I I F i g u r e 8. Compounds c o n t a i n i n g e n o l - l a c t a m chromophore s i l i c a g e l column gave the d e s i r e d k e t o - a c i d i n 1 8 - 2 2 $ y i e l d s as w e l l as a more p o l a r f r a c t i o n w h i c h was not c h a r a c t e r i z e d . I f the e x t r a c t i o n of the a c i d i c components b e f o r e chromatography was done w i t h aqueous p o t a s s i u m carbonate the 3 - a c e t o x y group was r e t a i n e d i n t h e m o l e c u l e as shown by an e s t e r c a r b o n y l band a t 1730 cm.""1' and a C -0 s t r e t c h i n g band a t 1250 cm." 1 i n i t s i n f r a r e d spectrum. (4-3) Treatment of t h i s compound w i t h 5$ aqueous sodium h y d r o x i d e caused e l i m -i n a t i o n of a c e t i c a c i d t o g i v e 5~keto - 5 , 7~seco - - 6-nor~ 3 -c h o l e s t e n - 7 - o i c a c i d , X I I . T h i s compound was a l s o o b t a i n e d by d i r e c t sodium h y d r o x i d e e x t r a c t i o n of the o z o n i z a t i o n p r o d u c t . The i n f r a r e d a b s o r p t i o n maxima a t 1726 cm. - 1, — 1 - 1 1675 cm. , and 1655 cm.'" are c h a r a c t e r i s t i c of a c a r b o x y l and an - u n s a t u r a t e d c a r b o n y l system as demanded by s t r u c t u r e X I I . The p r e s e n c e of the u n s a t u r a t e d ketone system i s f u r t h e r shown by the u l t r a - v i o l e t spectrum o f t h i s com-pound ( X I I ) w h i c h has a maximum a t 227 ny*. The e x p e c t e d p o s i -t i o n of the u l t r a - v i o l e t maximum f o r t h i s compound as c a l -c u l a t e d by Woodward's r u l e s i s a l s o a t 227 nyx. (44) The n e u t r a l i z a t i o n e q u i v a l e n t of the compound showed the p r e s e n c e of one c a r b o x y l group w h i c h , a l o n g w i t h a n a l y t i c a l d a t a , c o n f i r m e d s t r u c t u r e X I I . The k e t o - a c i d , X I I , d i d not r e a c t when t r e a t e d w i t h ammonia i n a benzene s o l u t i o n a t room temperature a l t h o u g h t h e s e c o n d i t i o n s were s u f f i c i e n t t o form a r i n g A l a c t a m f r o m t h e c o r r e s p o n d i n g k e t o - a c i d . (27) The f a i l u r e of 13 the r i n g B k e t o - a c i d t o f o r m the l a c t a m w i t h ammonia i s not unexpected s i n c e the two r e a c t i v e c e n t e r s are on d i f f e r e n t r i n g s and so w i l l t e n d t o be f u r t h e r s e p a r a t e d than i n t h e r i g i d r i n g A k e t o - a c i d . Such a s i t u a t i o n has been w e l l i l l u s t r a t e d when e x c e p t i o n s t o t h e B l a n c r u l e ( 4 5 ) of c y c l o -pentanone and a n h y d r i d e f o r m a t i o n from s i x carbon and f i v e carbon d i a c i d s ( r e s p e c t i v e l y ) were f o u n d . ( 3 , 4 6 ) The s i x carbon "B r i n g " d i a c i d , t h i l o b i l i a n i c a c i d , was found t o form a seven membered c y c l i c a n h y d r i d e more e a s i l y than the p r e -d i c t e d c y c l o p e n t a n o n e . The a n g u l a r m e t h y l group a t C-^Q i n thes e s i t u a t i o n s w i l l r e a c t s t e r i c a l l y w i t h the a d j a c e n t r i n g when the r e a c t i v e c e n t e r s a re brought t o g e t h e r as i n form-a t i o n o f the l a c t a m or the c y c l o p e n t a n o n e . When r e f l u x e d w i t h b e n z y l amine ( 2 4 ) , the k e t o -a c i d , X I I , gave an u n c h a r a c t e r i z e d o i l w h i c h had an u l t r a -v i o l e t a b s o r p t i o n maxima a t 293 nyi w h i c h i s p r o b a b l y due t o a 2 , 4 d i e n e i n c o n j u g a t i o n w i t h the B r i n g l a c t a m . Jacobs and B r o w n f i e l d s u b s e q u e n t l y r e p o r t e d t h a t 6 - a z a - 2 , 4 - c h o l e s t a d i e n -7-one has an u l t r a - v i o l e t maximum a t 299 ityL* (28) The a c i d r e t a i n i n g the 3 - a c e t o x y f u n c t i o n was a l s o t r e a t e d w i t h b e n z y l amine and y i e l d e d an o i l y p r o d u c t h a v i n g the same u l t r a -v i o l e t spectrum as d e s c r i b e d above. T h i s c o u l d e a s i l y r e s u l t f r o m a c e t i c a c i d e l i m i n a t i o n i n t h e b a s i c b e n z y l amine s o l u -t i o n f o l l o w e d by c y c l i z a t i o n of t h e k e t o - a c i d w i t h the amine. The k e t o - a c i d , X I I , was r e a d i l y c o n v e r t e d t o t h e c o r r e s p o n d i n g s a t u r a t e d k e t o - a c i d , X I I I , by c a t a l y t i c 14 Figure 9. Synthetic route to N-benzyl-6-azacholestane 15 h y d r o g e n a t i o n . The s u c c e s s of the h y d r o g e n a t i o n was e v i d e n c e d by a s h i f t of the ketone c a r b o n y l a b s o r p t i o n t o 1700 cm.-"'" i n the i n f r a r e d and by d i s a p p e a r a n c e of any a b s o r p t i o n i n the u l t r a - v i o l e t spectrum. R e a c t i o n of the s a t u r a t e d k e t o - a c i d , X I I I , w i t h b e n z y l amine a t r e f l u x temperature gave the n e u t r a l e n o l -l a c t a m , XIV, as a c r y s t a l l i n e p r o d u c t . A g a i n , c h a r a c t e r i z a t i o n of t h i s compound was made by c o n s i d e r a t i o n of i t s s p e c t r a l p r o p e r t i e s and i t s e l e m e n t a l a n a l y s i s . I t s i n f r a r e d spectrum had a l a c t a m c a r b o n y l band a t 1640 cm."^ and an o l e f i n i c band a t 1662 cm.'^j t h a t t h e o l e f i n band i s a t the h i g h e r wave number was shown by i t s d i s a p p e a r a n c e upon h y d r o g e n a t i o n . I f t he amide was the r e s u l t of the r e a c t i o n of o n l y the c a r b o x y l group w i t h b e n z y l amine, the compound would be ex p e c t e d t o have no u l t r a - v i o l e t spectrum o t h e r than t h a t of the b e n z y l group. However, the u l t r a - v i o l e t maximum of XIV a t 237 nyl i s v e r y s i m i l a r t o tho s e of analogous e n o l - l a c t a m chromophores 8 such as 4 a-phenyl- A. - o c t a h y d r o - 2 - q u i n o l o n e ( X = 231 m/x), max . Q XV, N -methyl - 4 a-phenyl- A - o c t a h y d r o - 2 - q u i n o l o n e , XVI, (X = 233 mo-) (47) > and f o r 4 - a z a c h o l e s t - 5 - e n - 3 - o n e , max * ( X V I I ) , ( A m a x = 233 rryt). (27) (see f i g u r e 8) C a t a l y t i c h y d r o g e n a t i o n of the e n o l - l a c t a m , XIV, y i e l d e d t h e l a c t a m , X V I I I , h a v i n g a l a c t a m c a r b o n y l band i n the i n f r a r e d a t 1644 cm."'1' and h a v i n g an u l t r a - v i o l e t spectrum c h a r a c t e r i s t i c of the b e n z y l amine group, (211 mjx) . R e d u c t i o n of the e n o l -l a c t a m , XIV, w i t h l i t h i u m aluminum h y d r i d e gave an u n s t a b l e o i l as a p r o d u c t . I t e x h i b i t e d an I n f r a r e d band a t 1634 cm., w h i c h i s p r o b a b l y due t o the o l e f i n . The l a c t a m , X V I I I , was the compound d e s i r e d f o r the p r e p a r a t i o n o f the a z a s t e r o i d and was s u c c e s s f u l l y c o n v e r t e d t o N - b e n z y l - 6 - a z a c h o l e s t a n e , XIX, by r e d u c t i o n w i t h l i t h i u m aluminum h y d r i d e i n a r e f l u x i n g e t h e r s o l u t i o n . The a z a s t e r o i d was a c r y s t a l l i n e compound w h i c h had no c a r b o n y l bands i n the i n f r a r e d spectrum but w h i c h r e t a i n e d the a b s o r p t i o n bands a t t r i b u t a b l e t o the a r o m a t i c r i n g . R e d u c t i o n of t h e l a c t a m , X V I I I , over p l a t i n u m i n an a c e t i c a c i d - H C l s o l u t i o n gave a compound showing a m e l t i n g p o i n t d e p r e s s i o n when mixed w i t h s t a r t i n g m a t e r i a l , a l t h o u g h each had s i m i l a r m e l t i n g p o i n t s . I t a l s o r e t a i n s an amide i n f r a r e d band w h i c h when t a k e n w i t h i t s a n a l y s i s s u g gests t h a t t h e compound may be N - a c e t y l - 6 - a z a c h o l e s t a n e , XX. 17 N-BENZYL- 6- AZAANDROSTAN-170- OL The s u c c e s s f u l u t i l i z a t i o n of c h o l e s t e r o l as a s t a r t i n g m a t e r i a l i n the s y n t h e s i s of N - b e n z y l - o - a z a c h o l e s t a n e p r o v i d e d a s y n t h e t i c sequence w h i c h i t was hoped would be u s e f u l i n t h e p r e p a r a t i o n of 6-aza s t e r o i d a l hormones from s t a r t i n g m a t e r i a l s h a v i n g a 5 , 6 double bond. D e h y d r o e p i -a n d r o s t e r o n e ( a n d r o s t e n o l o n e ) , i s such a compound and i s of the a n d r o g e n i c f a m i l y of hormones; thus i t was used as a s t a r t i n g m a t e r i a l i n a s y n t h e s i s of N - b e n z y l - 6 - a z a a n d r o s t a n -17£-ol and N - b e n z y l - 6 - a z a a n d r o s t a n - 1 7 - o n e . I t was f i r s t n e c e s s a r y t o p r o t e c t the oxygen f u n c t i o n s a t and C^^ of a n d r o s t e n o l o n e , X X I , s i n c e t h e s e would b o t h be a f f e c t e d by subsequent r e a c t i o n s i f l e f t un-p r o t e c t e d . A l t h o u g h the h y d r o x y l group a t i s l o s t d u r i n g subsequent r e a c t i o n s , i t must be p r o t e c t e d d u r i n g the a l l y l i c o x i d a t i o n of Cj. L i k e w i s e , t h e C-^ k e t o n i c f u n c t i o n must be p r o t e c t e d d u r i n g r e a c t i o n s w i t h amines. The h y d r o x y l group a t was f i r s t c o n v e r t e d t o the known f o r m a t e , X X I I , and the ketone t h e n r e d u c e d t o an a l c o h o l , X X I I I , w i t h sodium b.oro-h y d r i d e . (48) The a l c o h o l was a c e t y l a t e d and the r e s u l t i n g compound, XXIV, o x i d i z e d w i t h t - b u t y l chrornate (36) t o g i v e t h e d e s i r e d 7-keto - 5-androsten - 3 ^ > 17^ 6-diol 3 - f o r m a t e 17-a c e t a t e , XXV. An e q u a l l y s u c c e s s f u l r o u t e i n v o l v i n g one l e s s s t e p t o an o z o n i z a b l e compound r e s u l t e d when a n d r o s t e n o l o n e XXVII o II XXII XXIII AczO o O C C H 3 XXIV 0 OCCM3 XXV Figure 1 0 . Protection of oxygen functions of androstenolone was r e d u c e d w i t h sodium b o r o h y d r l d e t o 5~androsten -3/?> 17/-d i o l , XXVI. A c e t y l a t i o n of the d i o l f o l l o w e d by a l l y l i c o x i d a t i o n w i t h t - b u t y l chromate gave 7 - k e t o - 5 - a n d r o s t e n ~ 3^,17/?-diol d i a c e t a t e . X X V I I (36) The u n s a t u r a t e d k e t o - a c i d , 1 7 ^ - h y d r o x y - 5 - k e t o - 5 , 7 -s e c o - 6 - n o r - 5 - a n d r o s t e n - 7 - o i c a c i d , X X V I I I , was o b t a i n e d f r o m o z o n i z a t i o n of e i t h e r ' X X V I I or XXV f o l l o w e d by sodium h y d r o x i d e e x t r a c t i o n . The r e s u l t s of the o z o n i z a t i o n r e a c t i o n were not c o n s i s t e n t f r om experiment t o e x p e r i m e n t , however, and the c ourse of t h e r e a c t i o n has not been c o m p l e t e l y worked o u t . I n a d d i t i o n t o the k e t o - a c i d , X X I , c h a r a c t e r i z e d by i t s s p e c t r a l c h a r a c t e r i s t i c s , on one o c c a s i o n a c r y s t a l l i n e s o l i d was i s o l a t e d d i r e c t l y from th e e x t r a c t o f the a c i d i c m a t e r i a l o f the o z o n i z a t i o n r e a c t i o n . T h i s m a t e r i a l was u n i q u e i n t h a t i t was c r y s t a l l i z a b l e f r om hot w a t e r . I t i s a compound r e t a i n i n g f i v e oxygens and h a v i n g no u l t r a - v i o l e t s pectrum. I t s i n f r a r e d spectrum showed the p r e s e n c e of a l c o h o l i c , k e t o n i c , and a c i d i c f u n c t i o n s and the absence of any a c e t a t e group. I t may be s p e c u l a t e d t h a t t h i s m a t e r i a l has the s t r u c t u r e XXIX or XXX. A t h i r d r e a c t i o n p r o d u c t was o b t a i n e d i n t h e form of an o i l h a v i n g a moderate u l t r a - v i o l e t a b s o r p t i o n c o r r e s p o n d i n g t o t h a t of the u n s a t u r a t e d k e t o -a c i d , X X V I I I . T h i s o i l a l s o had an a c e t o x y a b s o r p t i o n band i n i t s i n f r a r e d spectrum and upon chromatography t h i s o i l s e p a r a t e d i n t o two f r a c t i o n s , b o t h r e t a i n i n g s i m i l a r s p e c t r a l c h a r a c t e r i s t i c s . C a t a l y t i c h y d r o g e n a t i o n of t h i s o i ] y p r o d u c t 21 r e s u l t e d i n uptake of 0.5-0.7 of a mole of hydrogen. Treatment of the hydroge n a t e d o i l w i t h r e f l u x i n g b e n z y l amine gave the e n o l - l a c t a m , X X X I I , d e s c r i b e d below, and i n a d d i t i o n i t gave^ a g l a s s y p r o d u c t when the a c i d e x t r a c t of the p r o d u c t was b a s i f i e d . T h i s p r o d u c t has an i n f r a r e d a b s o r p t i o n s i m i l a r t o t h a t of the e n o l - l a c t a m , X X X I I , w i t h peaks a t 1657 and 1690 cm.-"'" b u t , i n a d d i t i o n , i t has a s t r o n g a b s o r p t i o n a t 1505 cm.-"1'. The u l t r a - v i o l e t spectrum of t h i s m a t e r i a l has a maximum a t 248 mji s u g g e s t i n g e i t h e r a d i f f e r e n t chromophore i n the m o l e c u l e o r a f u r t h e r c o n j u g a t i o n of the e n o l - l a c t a m system. The d e s i r e d k e t o - a c i d , X X V I I I , was a c r y s t a l l i n e s o l i d r e t a i n i n g e i t h e r o r g a n i c s o l v e n t s o r wat e r v e r y t e n a c i o u s l y and r e q u i r i n g d r y i n g a t 100°C. T h i s d r y i n g had a marked e f f e c t on the p o s i t i o n of the u n s a t u r a t e d ketone c a r b o n y l a b s o r p t i o n i n the i n f r a r e d spectrum, s h i f t i n g i t from 1637 cm. - 1 t o 1660 cm. - 1. The h y d r o l y s i s of the 17-acetoxy group e i t h e r d u r i n g the o z o n l z a t i o n o r the work up I s shown by t h e h y d r o x y l band a t 3580 cm."*"'" and the absence o f t h e a c e t o x y C-O-band a t 1250 cm.""'" i n t h e i n f r a r e d . The u l t r a -v i o l e t s p ectrum has a maximum a t 227 ny/ c o r r e s p o n d i n g t o an o<,f-unsaturated ketone system. C a t a l y t i c h y d r o g e n a t i o n of the k e t o - a c i d , X X V I I I , gave t h e s a t u r a t e d k e t o - a c i d , XXXI, as e v i d e n c e d by i t s i n f r a r e d spectrum. C y c l i z a t i o n of the k e t o - a c i d , XXXI, w i t h b e n z y l amine proceeded as i n t h e c h o l e s t e r o l s e r i e s of 22 compounds t o g i v e t h e e n o l - l a c t a m , X X X I I . L i k e w i s e c a t a l y t i c h y d r o g e n a t i o n o f t h e e n o l - l a c t a m y i e l d e d t h e l a c t a m , XXXV, h a v i n g s p e c t r a s i m i l a r t o t h o s e o f t h e c o r r e s p o n d i n g l a c t a m , XIV, i n t h e c h o l e s t e r o l s e r i e s . L i t h i u m a l u m i n u m h y d r i d e r e d u c t i o n o f t h e l a c t a m , XXXV, y i e l d e d c r y s t a l l i n e N - b e n z y l - 6 - a z a a n d r o s t a n - 1 7 / ? - o l , XXXVI. O x i d a t i o n o f XXXVI u s i n g t h e m i l d c o n d i t i o n s o f chromium t r i o x i d e i n a c e t o n e y i e l d e d N - b e n z y l - 6 -a z a a n d r o s t a n - 1 7 - o n e , X X X V I I . The a p p e a r a n c e o f t h e c h a r a c t e r -i s t i c c y c l o p e n t a n o n e c a r b o n y l a t 1730 c m . " 1 i n t h e I n f r a r e d s p e c t r u m o f t h i s compound c o n f i r m e d t h e s u c c e s s o f t h e o x i d a t i o n . 23 CONCLUSION A g e n e r a l s y n t h e s i s o f 6 - a z a s t e r o i d s has been de v e l o p e d u s i n g c h o l e s t e r o l as a model s t a r t i n g compound. The s y n t h e s i s i n c l u d e s r e a c t i o n s g i v i n g good y i e l d s of p r o d u c t s w i t h the e x c e p t i o n of the o z o n i z a t i o n . I t seems l i k e l y t h a t a t h o r o u g h s t u d y of c o n d i t i o n s f o r the o z o n i z a t i o n r e a c t i o n would improve t h e y i e l d of t h i s s t e p . The s y n t h e s i s has the d i s -advantage of the l o s s o f the f u n c t i o n a l group a t C^. The use of b e n z y l amine i n t h e c y c l i z a t i o n of t h e s a t u r a t e d k e t o -a c i d s p r o v i d e s , i n the e n o l - l a c t a m , a compound w h i c h may be u s e f u l i n f u r t h e r s t u d i e s d e s i g n e d t o r e - i n t r o d u c e the C^ oxygen f u n c t i o n s i n c e the t e r t i a r y n i t r o g e n w i l l p r e v e n t double bond m i g r a t i o n s w h i c h have been shown t o o c c u r i f the n i t r o g e n of the e n o l - l a c t a m i s s e c o n d a r y . (28) I t has been r e p o r t e d t h a t N-bromosuccinimide s u b s t i t u t e s a bromine a t the o l e f i n i c C^ p o s i t i o n (28), however f u r t h e r s t u d i e s of both, a l l y l i c b r o m i n a t i o n and a l l y l i c o x i d a t i o n r e a c t i o n s on t h e e n o l - l a c t a m system may l e a d t o r e - i n t r o d u c t i o n of the C^ oxygen f u n c t i o n . The h y d r o g e n o l y s i s of N - b e n z y l I s w e l l known (50) and i f a p p l i e d t o N - b e n z y l - 6 - a z a s t e r o i d s i t would p r o v i d e a r o u t e t o the 6 - a z a s t e r o i d s . The p r e p a r a t i o n of N-benzyl - 6-azaandrostan-17 - o l and N-benzyl - 6-azaandrostan-17-one p r o v i d e s the f i r s t known examples of r i n g B aza s t e r o i d a l hormones and demonstrates the 2 4 g e n e r a l i t y o f t h e s y n t h e t i c s e q u e n c e . A m o r e t h o r o u g h s t u d y o f t h e o z o n l z a t i o n s t e p h e r e i s r e q u i r e d , h o w e v e r , i n o r d e r t o d e f i n e t h e s e v e r a l p r o d u c t s o b t a i n e d a n d t h e c o n d i t i o n s u n d e r w h i c h t h e y r e s u l t . 25 EXPERIMENTAL The m e l t i n g p o i n t s were d e t e r m i n e d on a F i s h e r -Johns m e l t i n g p o i n t b l o c k and a r e u n c o r r e c t e d . A l l u l t r a -v i o l e t s p e c t r a were r e c o r d e d on a Cary 11 r e c o r d i n g s p e c t r o -photometer I n s o l u t i o n s o f 95$ e t h a n o l . R o t a t i o n s were de t e r m i n e d i n c h l o r o f o r m s o l u t i o n s . I n f r a r e d s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r 21 s p e c t r o p h o t o m e t e r . A n a l y s e s were performed by A.'.Bernhardt, Mulheim-Ruhr, Germany. C h o l e s t e r y l a c e t a t e . The a c e t y l a t i o n p r o c e d u r e d e s c r i b e d by F i e s e r (51 ) was used . C h o l e s t e r o l , I , (40 g.) was d i s s o l v e d i n p y r i d i n e (40 ml.) and a c e t i c a n h y d r i d e (40 ml.) and hea t e d on a steam b a t h f o r 0 . 5 hour. The s o l u t i o n was then poured i n t o c o l d water and s t i r r e d s e v e r a l h o u r s . The r e s u l t i n g w h i t e s o l i d was f i l t e r e d o f f and d r i e d . R e c r y s t a l l i z a t i o n of the s o l i d f r om acetone y i e l d e d c h o l e s t e r y l a c e t a t e as c o l o r l e s s n e e d l e s , m.p. 1 1 2 - 1 1 4 . 5 ° ; 0 c = 0 1727 cm." 1 (5-79yu) i n KBr and i n N u j o l ; 9 G = c 1470 cm. - 1 ( 6 . 8 0 / i ) i n KBr; \) C _ Q _ 1250 cm." 1 (d.OOjx) i n KBr and i n N u j o l . R e p o r t e d m.p. 1 1 6 ° . (51) 7 - K e t o c h o l e s t e r y l a c e t a t e ( I V ) . The a l l y l i c o x i d a t i o n p r o c e d -u r e of H e u s l e r and W e t t s t e i n (36 ) was used. A s o l u t i o n of c h o l e s t e r y l a c e t a t e ( 5 0 . 0 g., 0 . 1 1 3 mole) i n 240 ml. o f carbon t e t r a c h l o r i d e was heated t o 70°C. and t r e a t e d w i t h 26 275 m l . o f a s o l u t i o n of t - b u t y l chromate i n carbon t e t r a c h l o r i d e mixed w i t h 125 m l . of g l a c i a l a c e t i c a c i d and 50 m l . of a c e t i c a n h y d r i d e . The o x i d i z i n g s o l u t i o n was added t o the r e a c t i o n over a p e r i o d of 0 . 5 hour. The r e a c t i o n m i x t u r e was then warmed t o 7 6 - 7 9 ° w i t h c o n s t a n t s t i r r i n g f o r t e n hours a f t e r w h i c h the d a r k green s o l u t i o n was c o o l e d t o 5 ° i n an i c e b a t h . E i g h t y grams of o x a l i c a c i d i n 4-00 m l . of water were s l o w l y added t o the c o o l e d r e a c t i o n w i t h v i g o r o u s s t i r r i n g . A f u r t h e r 50 g. o f s o l i d o x a l i c were then added and t h e m i x t u r e a l l o w e d t o warm t o room t e m p e r a t u r e . The carbon t e t r a c h l o r i d e l a y e r was s e p a r a t e d and t h e aqueous l a y e r e x t r a c t e d w i t h more carbon t e t r a c h l o r i d e . The o r g a n i c e x t r a c t s were combined and washed w i t h aq. sodium b i c a r b o n a t e and w i t h w a t e r and then d r i e d over magnesium s u l f a t e . The carbon t e t r a c h l o r i d e s o l u t i o n was f i l t e r e d and the s o l v e n t removed under r e d u c e d p r e s s u r e t o y i e l d a g r e e n i s h - y e l l o w s o l i d . C r y s t a l l i z a t i o n from e t h e r y i e l d e d , i n t h r e e c r o p s , 3 1 . 1 g. of 7 - k e t o c h o l e s t e r y l a c e t a t e , m.p. 1 5 0 - 1 5 2 ° , l 6 l - l 6 3 ° C . j 0 c = 0 1 7 3 2 , 1670 cm." 1 (5.77, 5 . 9 9 u ) i n KBr j \) Q _ Q 1640 cm." 1 (6.10/x) i n KBr. R e p o r t e d m.p. 1 5 7 - 1 5 9 ° . (39) 7 - K e t o c h o l e s t e r o l . S a p o n i f i c a t i o n of 7 - k e t o c h o l e s t e r y l a c e t a t e w i t h m e t h a n o l i c sodium h y d r o x i d e f o r t w e l v e hours a t room tem p e r a t u r e gave a w h i t e s o l i d when the r e a c t i o n was d i l u t e d w i t h w a t e r . C r y s t a l l i z a t i o n of the s o l i d from acetone gave s m a l l , c o l o r l e s s n e e d l e s of 7 - k e t o c h o l e s t e r o l , 27 m.p. 1 7 3 - 1 7 ^ ° ; A m a v 236 ma (lfog€ 4 . 1 9 ) . R e p o r t e d m.p. 170-1 7 2 ° , ( 3 9 ) . 3 / ? -Hydroxy- 5 , 6-epoxycholestan - 7 -one 3 - a c e t a t e ( X ) . A. Methods of P l a t t n e r , e t a l . (37) and Z a f f a r o n i , e t a l . ( 3 8 ) . When 7 - k e t o c h o l e s t e r y l a c e t a t e ( l . O g., 2 . 3 mmoles) was t r e a t e d w i t h 4—8 m l . o f 30$ hydrogen p e r o x i d e i n a m e t h a n o l i c sodium h y d r o x i d e s o l u t i o n a t e i t h e r 0°C. or a t room t e m p e r a t u r e , t h e r e was o b t a i n e d 0 . 8 9 g. ( 2 . 2 mmoles, 97$) of a w h i t e s o l i d p r o d u c t . T h i s p r o d u c t was c r y s t a l l i z e d f r o m acetone and had m. p. 1 7 1 - 1 7 3 ° ; mixed m.p. w i t h 7 - k e t o c h o l e s t e r o l , 1 7 1 - 1 7 3 ° . B. Method of Bergmann and Meyers, ( 4 l ) . The , e p o x i d i z i n g r e a g e n t was made up as f o l l o w s : 3 . 0 m l . of t r i f l u o r o a c e t i c a n h y d r i d e i n 5 m l . o f methylene c h l o r i d e was mixed a t 0°C. w i t h s t i r r i n g w i t h a s o l u t i o n of 4 . 5 m l . of 9 8 $ hydrogen p e r o x i d e i n 10 m l . of methylene c h l o r i d e . T h i s r e a g e n t was added by d r o p p i n g over a p e r i o d of f o r t y minutes t o a s o l u t i o n of 1 .0 g. ( 2 , 3 mmole) of d r i e d 7 - k e t o c h o l e s t e r y l a c e t a t e i n 30 m l . of methylene c h l o r i d e over 5 g. of anhydrous sodium hydrogen phosphate a t the r e f l u x t e m p e r a t u r e of methylene c h l o r i d e . The s o l u t i o n was r e f l u x e d a n o t h e r f o r t y m i n u t e s , t h e n c o o l e d and t r e a t e d w i t h 50 m l . of w a t e r . The l a y e r s were s e p a r a t e d , t h e aqueous l a y e r was washed t w i c e w i t h methylene c h l o r i d e , and the combined o r g a n i c e x t r a c t s were d r i e d over magnesium s u l f a t e . F i l t r a t i o n of the d r y s o l u t i o n f o l l o w e d by removal of the s o l v e n t under 28 reduced p r e s s u r e y i e l d e d 1.02 g. of a g l a s s y s o l i d . T h i s m a t e r i a l was chromatographed on a column made of 50 g. of c e l i t e mixed w i t h 50 g. of s i l i c i c a c i d (100 mesh) packed i n hexane. E l u t i o n of t h e column w i t h 50$ gbenzene i n hexane y i e l d e d 0.36 g. of a w h i t e s o l i d . C r y s t a l l i z a t i o n from methanol gave a f i r s t crop o f c r y s t a l s , m.p. 122-129°, a f t e r r e c r y s t a l l i z a t i o n , +77° and a second crop h a v i n g m.p. 127-131° and +99° a f t e r r e c r y s t a l l i z a t i o n . R e p o r t e d m.p. 130-131.5°; [cx]D +78.9° f o r 30-acetoxy-5,6*-epoxy-c h o l e s t a n - 7 - o n e . (4l) P e r i o d i c a c i d o x i d a t i o n of the e p o x i d e , X . A s o l u t i o n of the e p o x i d e , X, (0.040 g.) i n 4 m l . of acetone was added t o a s o l u t i o n o f O.625 g. of p e r i o d i c a c i d In 3 m l . o f wat e r and r e f l u x e d f o r 12 h o u r s . The r e a c t i o n m i x t u r e s l o w l y t u r n e d brown i n c o l o r and upon removing the acetone and c o o l i n g t he s o l u t i o n , a d a r k o i l s e p a r a t e d . T h i s o i l s o l i d i f i e d and was d i s s o l v e d i n acetone and then poured i n t o w ater y i e l d i n g a creamy-white s o l i d . The s o l i d was t a k e n up i n e t h e r and d r i e d a f t e r w h i c h a w h i t i s h s o l i d r e s u l t e d ; max. 234 mju. ( l o g € 4.01); V> c = 0 1730, 1670 cm." 1 (5.78, 599/0 i n N u j o l . 5-Keto-5, 7 - s e c o - 6 - n o r - 3 - c h o l e s t a n - 7 - o i c a c i d (XII) . S o l u t i o n s of 7 - k e t o c h o l e s t e r y l a c e t a t e (25.0 g., O.O565 mole) i n g l a c i a l a c e t i c a c i d (100 ml.) were o z o n i z e d i n f i v e gram p o r t i o n s . 29 Ozonizing conditions using a Welsbach ozonator were: 5 . 5 p . s . i , of oxygen pressure, 110 volts, 0 . 0 6 rotameter setting., 20 minutes, 2 5 ° . The solution became bright yellow during the ozonization. This color slowly disappeared when the ozonide was treated with 10 ml. of 30$ hydrogen peroxide and 50 ml. of water (for each 5 g. lot) and allowed to stand for 15-18 hours. The excess solvent was removed under reduced pressure and the residue was taken up in ether. The ether solution was washed twice with water and then extracted with 5$ aq. sodium hydroxide. The i n i t i a l basic extracts removed the remaining acetic acid; after this the extracts were bright yellow-orange In color with some orange, oily material observed between the aqueous and ether layers which was included in the basic extract. Basic extraction was continued until only slightly yellow extracts were obtained. The basic extract was acidified with d i l . aqueous hydrochloric acid which resulted in the formation of an oily white mixture. The acidic material was taken up in ether and dried over magnesium sulfate. Removal of the ether gave 2 0 . 3 g. of viscous o i l . Chromato-graphy of the o i l on BDH s i l i c a gel (500 g.) gave the keto-acid, XII, as an o i l when eluted with 100$ chloroform. Crystallization fromhexane gave 4 . 8 6 g. ( 0 . 0 1 2 mole, 22$) of colorless crystalline keto-acid, m.p. 1 7 9 - 1 8 3 ° . Three recrystallizations from hexane gave 5-keto-5> 7-seco-6-nor-3-cholesten-7-oic acid as colorless needles, m.p. 1 8 1 - 1 8 4 ° ; 30 \ i a x . 2 2 6 m ^ ( l o g G 3 - 9 3 ) ; +78.9°; \) c = 0 1726, 1677 cm."1 (5.79, 5.9^0 i n N u j o l , 1705, 1675 cm."1 (5.86, 5.97/x) i n CHCL 3; 9 c = c 1655 cm."1 (6.04)u) (shoulder) i n N u j o l . A n a l . C a l c d. f o r Cg 6 H.^ 0 3 (402 . 6 0 ) : C, 77.56; H, 10.51; 0, 11.92. Found: C, 77.82; H, 10.46; 0, 12.09; n e u t r a l i z a t i o n e q u i v a l e n t , 39^; M.W. (Rast), 402. Reported m.p. 164-165°; [<x]D +81 + 1 ° . (28) When the o z o n i z a t i o n was c a r r i e d out as above w i t h the exception t h a t the ba s i c e x t r a c t i o n was done w i t h d i l u t e potassium carbonate, an o i l was obtained which was e l u t e d from a s i l i c a g e l column w i t h 100$ chloroform to y i e l d c r y s t a l s from ether-petroleum ether (30-60°), m.p. 171-177°C. Two f u r t h e r r e c r y s t a l l i z a t i o n s from ether-petroleum ether (30-60°) gave c o l o r l e s s needles, m.p. 173-178°C; V* Q _ Q 17^0, 1730, 1715, and 1702 cm."1 (5.75, 5.78, 5.83, 5.88^.) i n KBr. An a l . Calcd. f o r CggH^gO^ (462.65): C, 72.69; H, 10.02; 0, 17.30. Found: C, 72.08; H, 9.84; 0, 18.02. When t h i s com-pound was taken up i n ether and ex t r a c t e d w i t h 5$ aqueous sodium hydroxide, i t was converted to 5-keto - 5 , 7 - seco -6-nor-3-cholesten~ 7-oic a c i d as shown by appearance of an u l t r a -v i o l e t absorption maxima at 227 myx. and a s i m i l a r melting p o i n t of the s o l i d . 31 5-Keto - 5 , 7 - s e c o ~ 6 - n o r c h o l e s t a n - 7 - o i c A c i d ( X I I I ) . The o(,/?-unsaturated k e t o - a c i d , X I I , (0 .398 g., 0.990 mmole) was hydrogenated over 10$ p a l l a d i u m - o n - c h a r c o a l ( 0 . 4 g.) i n an e t h a n o l s o l u t i o n a t room temperature and a t m o s p h e r i c p r e s s u r e . The hydrogen u p t a k e was complete i n 15 minutes and t o t a l l e d 18.6 c c . ( c a l c u l a t e d volume f o r one mole uptake i s 22 .2 c c ) . The c a t a l y s t was f i l t e r e d o f f and the s o l v e n t removed under r e d u c e d p r e s s u r e l e a v i n g a w h i t e s o l i d . T h i s s o l i d c r y s t a l l i z e d f r om hexane y i e l d i n g 0.237 g. (0.587 mmole, 59$) of s a t u r a t e d k e t o - a c i d , m.p. 1 8 8 - 1 9 3 ° . Three a d d i t i o n a l c r y s t a l l i z a t i o n s from hexane gave 5 - k e t o - 5 , 7 - s e c o - 6 - n o r c h o l e s t a n - 7 - o i c a c i d as c o l o r l e s s n e e d l e s , m.p. 1 9 2 - 1 9 4 ° ; [<*]D + 9 1 . 3 ° ; 0 Q = 0 1715, 1697 cm." 1 ( 5 . 8 3 , 5.89//.) i n KBr, 1722, 1703 cm.""1 ( 5 . 8 1 , 5.87/0 i n N u j o l ; s h o u l d e r a t 1736 cm." 1 (5.76/x) i n KBr, 1745 cm. - 1 (5.73/0 i n N u j o l . A n a l . C a l c d . f o r C^E^O^ ( 4 o 4 . 6 l ) : C, 77.17; H, 1 0 . 9 8 ; 0, 1 1 .86 . Pound: C, 7 6 . 4 0 ; H, 10.84; 0 , 13.11-R e p o r t e d m.p. 1 8 6 . 6 - 1 8 9 . 2 ° ; [<*]D +93 + 2 ° . (28) A mixed m.p. of t h e s e two samples was 189-192° and t h e i r i n f r a r e d s p e c t r a were i d e n t i c a l . N - B e n z y I - 6 - a z a - 4 - c h o l e s t e n - 7 - o n e ( X I V ) . The s a t u r a t e d k e t o -a c i d , X I I I , ( 4 . 0 g., 9 .9 mmole) was d i s s o l v e d i n 10 m l . of .benzyl amine and r e f l u x e d g e n t l y f o r 18 hours i n a n i t r o g e n atmosphere. (24) The c o o l e d y e l l o w r e a c t i o n s o l u t i o n was ta k e n up i n e t h e r and e x t r a c t e d w i t h aqueous h y d r o c h l o r i c a c i d 32 u n t i l the e x t r a c t remained a c i d i c to l i t m u s . I t was then washed once w i t h 5$ aqueous sodium hydroxide and once w i t h a saturated s a l t s o l u t i o n . The n e u t r a l ether l a y e r was d r i e d over magnesium s u l f a t e , f i l t e r e d , and the ether evaporated to y i e l d a l i g h t y e l l o w s o l i d . C r y s t a l l i z a t i o n from methanol y i e l d e d , i n two crops, 3 - 9 3 g.. ( 8 . 3 mmole, 84$) of c o l o r l e s s c r y s t a l s , m.p. 1 3 5 - 1 4 0 ° . Three r e c r y s t a l l i z a t i o n s from methanol gave N~benzyl - 6~aza - 4-cholesten - 7-one as long, f l a t c o l o r l e s s c r y s t a l s , A n a l . Calcd. f o r C^H^NO ( 4 7 5 . 7 3 ) : C, 8 3 . 3 1 ; H, 1 0 . 3 8 ; N, 2 . 9 4 ; 0 , 3 . 3 6 . Pound: C, 8 2 . 4 2 ; H, 1 0 . 3 3 ; N, 3 . 0 1 ; 0 , 3.48. Reported m.p. 1 3 6 . 3 - 1 3 7 . 3 ° ; +107 + 1 ° . (28) Mixed m.p. of the two samples was 1 3 5 - 1 3 7 ° and t h e i r i n f r a r e d spectra were i d e n t i c a l . N-Benzyl~ 6-azacholestan - 7-one ( X V I I I ) . The enol-lactam, XIV, ( 0 . 5 0 0 g., 1 . 0 5 mmole) was hydrogenated i n a c e t i c a c i d (40 ml) over 0 . 0 5 0 g. of pre-reduced platinum oxide at room temperature and atmospheric pressure. The t o t a l uptake of hydrogen was 3 1 . 0 cc. ( c a l c u l a t e d f o r one mole, 24 cc.) and was complete i n one hour. The c a t a l y s t was f i l t e r e d o f f , the a c e t i c a c i d was removed under reduced pressure, and the remaining o i l was placed i n a vacuum d e s i c c a t o r over potassium hydroxide f o r sev e r a l hours. The o i l ( 0 . 4 9 7 g., 1 . 0 4 mmole, 99$) c r y s t a l l i z e d from ether-methanol, m.p. l 4 l - l 4 5 ° . Three r e c r y s t a l l i z a t i o n s from ether-methanol gave an a n a l y t i c a l sample of N-benzyl-6 -azacholestan - 7-one, m.p. l 4 3 - l 4 5°j [oC^ + 6 3 ° ; \) c = z Q 1644 cm."1 (6.08)u) i n N u j o l ; ^ a r o m a t l c 1 5 0 0 , 732 cm."1 ( 6 . 6 7 , 13 .6^) i n N u j o l . Anal. Calcd. f o r C Q Q H C 1 N 0 : C, 8 2 . 9 6 ; H, 1 0 . 7 6 ; 33 51 N, 2 . 9 3 ; 0 , 3 . 3 5 . Found: C, 8 3 . 1 9 ; H, 1 0 . 5 3 ; N, 3 . 1 9 ; 0 , 3 . 5 0 . C a t a l y t i c r e d u c t i o n of N-benzyl - 6-azacholestan - 7-one. A s o l u t i o n of the lactam, XVIII, ( 0 . 1 4 8 g., 0 . 3 0 9 mmole) i n 29 ml. of a c e t i c a c i d and 4 . 8 ml. of IN h y d r o c h l o r i c a c i d was hydrogenated over 0 . 1 2 0 g. of platinum oxide (pre-reduced) f o r 14- hours. The' measured hydrogen uptake was 2 1 . 6 cc. The c a t a l y s t was f i l t e r e d o f f and water was added to the s o l u t i o n which caused a cloudy s o l i d to form. A f t e r 48 hours, small c r y s t a l s had formed. These were f i l t e r e d o f f and d r i e d . They weighed 0 . 1 1 5 g. and had m.p. 1 4 2 - 1 4 5 ° . Two r e c r y s t a l l i z a t i o n s from methanol gave long c o l o r l e s s needles, m.p. 1 5 0 - 1 5 2 ° ; mixed m e l t i n g p o i n t w i t h N-benzyl - 6-azacholestan - 7-one, 130-145°; \ ) Q = Q 1629 cm."1 ( 6 . l 4 y z ) i n KBr. A n a l . Calcd. f o r C 2 QH^ gN0: C, 8 0 . 8 9 ; H, 1 1 . 8 8 ; N, 3 . 3 7 ; 0 , 3 . 8 5 . Found: C, 81.64; H, 1 1 . 8 6 ; N, 3*19; 0 , 3 . 7 1 . 34 N - B e n z y l - 6 - a z a c h o l e s t a n e ( X I X ) . N - B e n z y l - 6 - a z a c h o l e s t a n - 7 -one ( 0 . 5 0 g., 105 mmole) was d i s s o l v e d i n d r y e t h e r and t r e a t e d w i t h l i t h i u m aluminum h y d r i d e (-0.6 g) e x t r a c t e d f rom a S o x h l e t cup w i t h r e f l u x i n g e t h e r f o r 24 h o u r s . The exces s l i t h i u m aluminum h y d r i d e was decomposed w i t h m o i s t e t h e r and wat e r f o l l o w e d by r e f l u x i n g f o r 0 . 5 h o u r . The i n o r g a n i c s o l i d s were f i l t e r e d o f f by s u c t i o n and the ether s o l u t i o n d r i e d over magnesium s u l f a t e . Removal of the e t h e r y i e l d e d 0 . 4 2 3 g. ( 0 . 9 1 5 mmole, 87$) of l i g h t y e l l o w o i l w h i c h c r y s t a l l i z e d f r om e t h e r -methanol, m.p. 6 5 - 6 8 ° . Two f u r t h e r r e c r y s t a l l i z a t i o n s f r om e t h e r - m e t h a n o l y i e l d e d N - b e n z y l - 6 - a z a c h o l e s t a n e as c o l o r l e s s , chunky c r y s t a l s , m . p . 6 7 - 6 9 ° ; A . m x # 210 rajx ( l o g 6 3 . 9 8 ) ; [oC] D + 7 1 ° ; \ ) a r o m a t l c 1 4 9 3 , 736 cm.' 1 ( 6 . 7 0 , 13.6/x) i n KBr. A n a l . C a l c d . f o r 0 ^ ^ ( 4 6 3 . 7 6 ) : C, 85.46; H, 1 1 . 5 2 ; N, 3 . 0 2 . Pound: C, 8 5 . 4 2 ; H, 1 1 . 2 7 ; N, 3 . 3 0 . 3/?~Hydroxyandrost~ 5-en - 1 7-one fo r m a t e ( X X I I ) . The pr o c e d u r e of R i n g o l d , e t a l . , (48) was used t o p r e p a r e the f o r m a t e . D e h y d r o e p i a n d r o s t e r o n e , X X I , ( 5 . 0 0 g., 1 7 . 4 mmole) was d i s s o l v e d i n 60 m l . of 85$ f o r m i c a c i d and heated t o 6 0 - 6 5 ° f o r one hou r . D i l u t i o n of the r e a c t i o n m i x t u r e gave a w h i t e s o l i d w h i c h was f i l t e r e d o f f and d r i e d t o y i e l d 5 . 3 4 g. of crude p r o d u c t , m.p. 1 3 5 - 1 4 0 ° . A sample c r y s t a l l i z e d f r om acetone-hexane gave 3 / 2-hydroxyandrost - 5-en - 1 7-one f o r m a t e , m.p. 143-146°; \ ) c = 0 1 7 0 0 , 1734 cm.' 1 ( 5 . 8 8 , 5.77/4 i n KB.rj $ C_Q_ 1174 cm".1 35 (8.52 / i) in KBr. Reported m.p. 1 4 4 - 1 4 6 ° . (48) Androst-5 -en~3^,17 / -d io l 3-formate (XXIII) . The method des-cribed by Ringold, et a l . (48) was used for the reduct ion . A so lut ion 3 £ - h y d r o x y a n d r o s t - 5 - e n e - 1 7 - ° n e formate, X I I , (5 .3^ g . , 16.9 mmole) i n 100 ml . of tetrahydrofuran was treated with 0 .25 g. of sodium borohydride d isso lved i n 0 . 5 ml . of water for three hours at room temperature with constant s t i r r i n g . The excess sodium borohydride was decomposed with formic ac id and the inorganic mater ia l was f i l t e r e d off and washed with fresh tetrahydrofuran. The solvent was removed under reduced pressure leaving an o i l y residue which slowly c r y s t a l l i z e d . A sample r e c r y s t a l l i z e d from acetone-hexane had m.p. 157-169°; 9 0 _ H 3460 cm." 1 (2.89JLL) i n KBr j ? c = 6 1698 cm." 1 (5.89/0 i n KBr. Reported m.p. 1 7 0 - 1 7 2 ° . (48) Androst-5 -en-3/,17#-diol 3-formate 17-acetate (XXIV). The procedure of Ringold, et a l . (48) was followed for th i s a c e t y l a t i o n . A so lut ion of androst-5-en-3/3 , 17/—diol 3-formate, XXIII , (5 .35 g . , 0.0168 mole) and I . 8 3 g. of p- to luenesul fonic ac id in 50 ml . of acet ic anhydride was s t i r r e d at room temperature for 15 hours. The c l e a r , brown so lut ion was poured into an aqueous sodium acetate so lut ion and thoroughly s t i r r e d . A yellow s o l i d p r e c i p i t a t e d and was f i l t e r e d off to y i e l d 5".l4 g. (0.0143 mole, 85$) of crude androst-5-en-3/3,17/-d i o l 3-formate 17-acetate. A sample was r e c r y s t a l l i z e d from 36 3/3,17^-Dihydroxyandrost-3-en-7-one 3-formate 17-acetate, The oxidation procedure of Heusler and Wettstein (36) was used to prepare this compound. A solution of androst-5-en-3 ^ 1 7 ^ - d i o l 3-formate 17-acetate, XXIV, ( 5 . 1 3 g., 0.014-3 mole) in 26 ml. of carbon tetrachloride was treated with a mixture of 36 ml. t-butyl chromate solution, 1 2 . 5 ml. of acetic acid, and 5 ml. of acetic anhydride. The reaction was then carried out and worked up in the way described for the preparation of J-ketocholesteryl acetate. Recrystallization of the reaction product from ether gave a total of 2 . 5 5 g. ( 0 , 0 0 6 7 mole, 48$) of crystalline solid, m.p. 1 8 0 - 2 0 5 ° . Two further r e c r y s t a l l i -zations from ether gave 3 ^ , 17^-dih.ydroxyandrost-5-en-7-one 3-formate 17-acetate as shiny, colorless needles, m.p. 2 2 5 -Anal. Calcd. for C22E30°5 (37^.4-6): C, 7 0 . 5 6 ; H, 8.07; 0, 21.37. Found: C, 70.47; H, 7 . 6 8 ; 0, 21.41. -1 Androst-5-en-3/, 1 7^-diol (XXVl). Dehydroepiandrosterone, XXI, ( 5 . 0 0 g., 0 . 0 1 7 mole) was dissolved in 100 ml. of tetrahydro-furan and stirred with 0 . 5 g. of sodium borohydride in 1 .0 ml. 37 of water f o r f o u r h o u r s . F o r m i c a c i d was used t o decompose the excess sodium horoh.yd.ride and the i n o r g a n i c s o l i d s were f i l t e r e d o f f . Removal o f the s o l v e n t under reduced p r e s s u r e y i e l d e d a n d r o s t - 5 - e n - 3 ^ , 1 7 ^ - d i o l as a w h i t e s o l i d . C r y s t a l l i z a t i o n f r om acetone gave the p r o d u c t w i t h m.p. 1 7 3 - 1 7 9 ° ; ^o-H ^ 2 0 0 , 3 3 8 0 , 3450 cm." 1 (3 . .12, 2 . 9 6 , 2.90/Z.) i n KBr. R e p o r t e d m.p. l84°C. ^ ( 5 2 ) A n d r o s t - 5 - e n - 3 ^ j 1 7 ^ - d i o l d i a c e t a t e . The pr o c e d u r e of F i e s e r (51) was used as d e s c r i b e d f o r the a c e t y l a t i o n of c h o l e s t e r o l . The d i a c e t a t e was c r y s t a l l i z e d f r o m hexane and had m.p. 155-1 6 0 ° ; dc=sQ 1727 cm." 1 (5.79/0 i n KBr; ^Q_Q 1248 cm." 1 (8.01/t) i n KBr. R e p o r t e d m.p. l 6 5 - l 6 6 ° C . (53) 3fi, 1 7^-Dihydroxyandrost - 5-en - 7-one d i a c e t a t e ( X X V I I I ) . The pro c e d u r e of H e u s l e r and W e t t s t e i n (36) was used i n a manner i d e n t i c a l t o t h a t d e s c r i b e d f o r the p r e p a r a t i o n o f 7-k e t o c h o l e s t e r y l a c e t a t e , p. 25 . C r y s t a l l i z a t i o n f r om e t h e r gave 3fi, 1 7 ^ - d i h y d r o x y a n d r o s t - 5 - e n - 7 - o n e d i a c e t a t e , m.p. 2 2 0 - 2 2 5 ° ; \ ) c = 0 1730, 1687 cm." 1 ( 5 . 7 8 , 5.93/0 J \ ? c = c 1623 cm." 1 (6.16/x). \ ) c _ 0 1240 cm." 1 (8.06/1) i n KBr. R e p o r t e d m.p. 219-22.1 °C» (36) 38 Ozonization of 3fi, 17yff-dihydroxyandrost-5-en-7-one dlacetate. A. 1 Tfi-Hydroxy-5- ke t o- 5 , 7 - s e c °~ 6- nor- 3-andro sten-7-oic acid (XXVIII). A solution of 3fi, 17^-dihydroxyandrost-5-en-7-one dlacetate (or 3-formate 17-acetate) ( 3 . 4 2 g., 8 . 8 mmole) in glacial acetic acid was treated with ozone from a Welsbach ozonator operating under the conditions: 5 . 5 p . s . i . of oxygen pressure, 110 volts, rotameter setting of 0 . 0 6 , 15 minutes, 2 5 ° . A yellow solution resulted which was treated with 3 ml. of dilute hydrogen peroxide and 15 ml, of water after 20 minutes. The solution became clear as i t stood at room temperature for 20 hours. The excess acetic acid was then removed under reduced pressure leaving an oily residue. The o i l was taken up in ether and extracted with 5$ aqueous sodium hydroxide. This basic extract was yellow-orange in color but became colorless after acidification with dilute hydrochloric acid. The acidic material was extracted five times with 15 ml. portions of ether, the ether extract was dried over magnesium sulfate and then f i l t e r e d . Removal of the solvent yielded 1 . 6 .g. of a glassy material. This was chromatographed on 100 g. of BDH s i l i c a gel packed in benzene. The material was applied to the column in chloroform and elution with 2.\% methanol in chloroform yielded a total of 0 . 9 6 0 g. ( 3 . 1 4 mmole, 36$) of glassy material. This product crystallized from ether-petroleum ether ( 3 0 - 6 0 ° ) and had m.p., l 4 2-l48°C. Exhaustive ether extraction of the acidic aqueous solution yielded a further 1 .2 g. of material. When this was chromatographed on 100 g. of BDH s i l i c a gel, e l u t i o n w i t h 2-|$ methanol i n c h l o r o f o r m f a i l e d t o y i e l d a s i g n i f i c a n t q u a n t i t y of m a t e r i a l . Two r e c r y s t a l l i z a t i o n s of the above s o l i d from e t h e r - p e t r o l e u m e t h e r ( 3 0 - 6 0 ° ) gave s h i n y , chunky c r y s t a l s m e l t i n g 14-5-150°, 1 9 5 - 2 0 0 ° and o n l y a f t e r d r y i n g a t 1 0 0 ° i n h i g h vacuum d i d t h e y have a s h a r p e r m e l t i n g p o i n t . The c r y s t a l s of 1 7 ^ - h y d r o x y - 5 - k e t o - 5 , 7-seco-6 - n o r - 3 - a n d r o s t e n - 7 - o i c a c i d a f t e r d r y i n g were c o l o r l e s s , opaque chunks, m.p. 2 0 0 - 2 0 4 ° ; A. 227 mu ( l o g 6 3 . 9 8 ) ; [oC]D + 8 8 . 2 ° j V 1 ^ 3400 cm." 1 (2.94 / l ) (broad) i n KBr; \ ? Q 1720, 1657 cm." 1 ( 5 . 8 1 , 6.04yi) i n KBr. I n f r a r e d a b s o r p t i o n b e f o r e d r y i n g : ^o_ H 3 5 8 0 , 3200 t o 3400 cm." 1 ( 2 . 7 9 , 2 . 9 4 t o 3.12 / i) (broad) i n KBr; V ? c = 0 1726, 1635 cm." 1 ( 5 . 7 9 , 6.12/0 i n KBr; \^  c = c 1710 cm." 1 (6.21/A) i n KBr. A n a l . C a l c d . f o r C ^ H ^ O ^ ( 3 0 6 . 3 9 ) : C, 7 0 . 5 6 ; H, 8 . 5 5 ; 0 , 2 0 . 8 9 . Found: C, 7 0 . 6 5 ; H, 8 . 5 2 ; 0 , 21 .14. B. " C 1 8 H 2 6 ° 5 a c i d ' " A s o l u t i o n of 3$, 1 7 ^ - d i h y d r o x y a n d r o s t -5-en -7-one d i a c e t a t e ( 2 . 2 9 0 g., 5 . 9 0 mmole) i n 100 ml. of g l a c i a l a c e t i c a c i d was t r e a t e d w i t h ozone from the Welsbach o z o n a t o r f o r 15 minutes a t room temperature under the f o l l o w i n g con-d i t i o n s : 5 . 5 p . s . i . of oxygen p r e s s u r e , 110 v o l t s , and the r o t a m e t e r opened t o 0 . 0 6 . The r e s u l t i n g y e l l o w s o l u t i o n was l e f t a t room tem p e r a t u r e f o r t h i r t y m i n u t e s , then i t was t r e a t e d w i t h 3 m l . of 30$ hydrogen p e r o x i d e and 10 m l . of wat e r and l e f t s t a n d i n g a t room tem p e r a t u r e f o r 18 h o u r s . The exces s s o l v e n t was removed under r e d u c e d p r e s s u r e l e a v i n g an o i l which 40 was taken up in ether and washed twice with water. The ether solution was then extracted three times with 5$ aqueous sodium hydroxide giving a yellow-orange extract. The basic extract was treated with 60 ml. of a dilute hydrochloric acid solution made up of 5 ml. of concentrated hydrochloric acid in 90 ml. of water. This resulted in a clear, colorless solution from which small needles slowly crystallized. The mixture was cooled to aid further crystallization. The crystals were fi l t e r e d off and dried in a vacuum desiccator. The yield of crystalline product was 0 . 5 2 4 g. ( 1 . 6 2 mmole, 28$) having a melting point of 2 1 2 - 2 1 7 ° preceded by a loss of sharp needle form at 1 1 0 ° - 1 2 5 ° . The neutral ether layer from the ozonlzation workup gave, after drying, 0 . 3 8 g. of colorless o i l . Ether extraction of the acidic aqueous solution yielded 0 . 2 g. of colorless o i l . The above crystalline material was recrystal-lized three times from hot water giving shiny colorless needles which became smaller and opaque white upon drying, m.p. 2 3 3 -2 3 4 ° ; A m a x ^ none; 3540 cm."1 (2.83/*) in KBr; \ ? c = 0 1727, 1692 cm."1 ( 5 . 7 9 , 5.91>0 (broad) in KBr. Anal. Calcd. for 0 ^ ^ 0 ^ ( 3 2 2 . 3 9 ) : C, 6 7 . 0 5 ; H, 8 . 1 3 ; 0 , 2 4 . 8 2 ; for C l 8H 2 £ 0 ^ ( 3 2 4 . 4 0 ): C, 66.64; H, 8 . 6 8 ; 0 , 2 4 . 6 8 . Found: C, 6 7 . 0 2 ; H, 8 . 0 0 ; 0 , 2 5 . 0 6 ; neutralization equivalent, 3 0 8 . 4l C. M i x t u r e o f p r o d u c t s . S e v e r a l o z o n i z a t i o n s c a r r i e d out as e i t h e r o f t h o s e d e s c r i b e d above gave as a p r o d u c t an o i l h a v i n g an u l t r a - v i o l e t maximum a t 227 m/A w i t h an e v a l u e of 2 , 0 0 0 - 3 , 0 0 0 . Chromatography of t h i s o i l on s i l i c a g e l gave two f r a c t i o n s , the f i r s t e l u t i n g w i t h 1 0 0 $ c h l o r o f o r m and h a v i n g a s l i g h t l y i n c r e a s e d u l t r a - v i o l e t G v a l u e ( 3 , 0 0 0 - 5 , 0 0 0 ) and t h e second e l u t i n g w i t h 2.\% methanol i n c h l o r o f o r m and h a v i n g an £ v a l u e o f 2 , 0 0 0 - 3 , 0 0 0 , b o t h maxima o c c u r r i n g a t 227 mju. I n f r a r e d ; \) not d i s t i n c t i n c h l o r o f o r m ; \} 1700 t o 1725 cm." 1 ( 5 . 8 0 t o . 5 .88 / / ) i n c h l o r o f o r m ; \ ) _ c _ 0 1255 cm. - 1 (7.97/>0 i n c h l o r o f o r m . H y d r o g e n a t i o n of the combined f r a c t i o n s above i n e t h a n o l over 10$ p a l l a d i u m - o n - c h a r c o a l r e s u l t e d i n hydrogen up-t a k e c o r r e s p o n d i n g t o 0 . 5 t o 0 . 7 of a: .'.mole. 1 7/?-Hydroxy - 5~keto - 5 , 7- s e c o - 6 - n o r a n d r o s t a n - 7 - o i c a c i d ( X X X I ) . A s o l u t i o n of the u n s a t u r a t e d k e t o - a c i d , X X V I I I , ( 0 . 8 9 6 g., 2 . 9 3 mmole) i n 95$ e t h a n o l was hydrogenated over 0.540 g. of 10$ p a l l a d i u m - o n - c h a r c o a l a t room temperature and a t m o s p h e r i c p r e s s u r e . The c a t a l y s t was f i l t e r e d o f f and the s o l v e n t d i s t i l l e d o f f under reduced p r e s s u r e to. g i v e an o i l ( 0 . 7 5 g.)« Chromatography of t h e o i l on 50 g. of s i l i c a g e l gave the p r o d u c t as an o i l by e l u t i o n w i t h 2^$ methanol I n c h l o r o f o r m . . T h i s o i l . ( 0 . 7 0 g.) s l o w l y c r y s t a l l i z e d and was r e c r y s t a l l i z e d t w i c e f rom hexane t o g i v e IJfi-hydroxy - 5 - k e t o~ 5 , 7 - s e c o - 6 -n o r c h o l e s t a n - 7 - o i c a c i d as chunky, v e r y f a i n t y e l l o w c r y s t a l s , m.p. 2 2 6 - 2 2 9 ° ; + 9 6 . 5 ° ; V ) Q_ H 3450 cm." 1 (2.90/*) i n KBr; )^ C = Q 1 7 2 2 , 1687 cm." 1 ( 5 . 8 1 , 5.93/x) i n KBr. A n a l . C a l c d . f o r C^gHggO^ ( 3 0 8.40): C, 7 0 . 0 9 ; H, 9 . 1 5 ; 0, 2 0 . 7 6 . Pound: C, 6 9 . 6 7 ; H, 9 . 0 1 ; 0, 2 1 . 2 3 . 1 7^-Hydroxy-N-benzyl - 6-aza-4-androsten - 7-one (XXXII). A. Prom c r y s t a l l i n e s a t u r a t e d k e t o - a c i d : A s o l u t i o n o f 5-keto-5 , 7 - s e c o - 6 - n o r a n d r o s t a n - 1 7 - o l - 7 - o i c a c i d , (XXXI), (0 . 5 5 3 g.* I . 80 mmole) i n 10 m l . of b e n z y l amine was r e f l u x e d g e n t l y i n a n i t r o g e n atmosphere f o r 15 h o u r s . The c o o l e d , y e l l o w s o l u t i o n was t a k e n up i n e t h e r and washed w i t h d i l u t e h y d r o c h l o r i c a c i d u n t i l t he e x t r a c t was a c i d i c t o pH p a p e r . The e t h e r s o l u t i o n was washed once w i t h 5$ aqueous sodium h y d r o x i d e and once w i t h w a t e r . A f t e r d r y i n g o v er anhydrous magnesium s u l f a t e , r e m o v a l of the e t h e r y i e l d e d a l i g h t o i l w e i g h i n g O .56 gram. Chromatography o f the o i l on a column o f 50 g. s i l i c a g e l gave 0 . 4 6 0 g. ( l . 2 1 mmole, 68$) of o i l when t h e column was e l u t e d w i t h 50$ c h l o r o f o r m i n benzene. T h i s o i l c r y s t a l l i z e d f r o m ether-n-hexane as heavy, round chunks c o v e r e d w i t h f l u f f y w h i t e n e e d l e s , m.p. 1 0 5 - 1 0 9 ° . Three s i m i l a r r e c r y s t a l l i z a t i o n s gave an a n a l y t i c a l sample of 1 7^-hydroxy-N-benzyl - 6-aza-4-a n d r o s t e n - 7 - o n e as a c o l o r l e s s s o l i d , m.p. 1 0 7 - 1 1 0 ° : \ ' £- \ j f max 238 ma ( l o g G 4 . 0 2 ) , 211 mu ( l o g C 4 0 3 ) ; M D + 1 0 2 o j \) c = 0 1637 cm." 1 (6.11/x) i n KBr; 0 c = c l 6 6 l cm." 1 (6.02/i) i n KBr. A n a l . C a l c d . f o r Cgr-H^NOg ( 3 7 9 . 5 2 ) : C, 7 9 . 1 1 ; H, 8 . 7 6 ; N, 3 . 6 9 ; 0, 8 . 4 3 . Pound: C, 7 9 . 4 9 ; H, 8 . 8 2 ; N, 3 . 7 2 ; 0, 8 . 3 0 . 43 B. From mixture of oily acids. When the reduced acidic material described under the ozonization (part C) of 3fl, 17/-dihydroxy-androst~5-en-7-one was treated with benzyl amine as above, the identical enol-lactam was obtained from the neutral fraction in approximately 50$ yield. In addition, when the acidic extract of the benzyl amine reaction was neutralized with 5$ aqueous sodium hydroxide, a reddish-brown o i l precipitated. This o i l had at 248 mo, (log £ 3 . 8 5 to 3 . 9 8 ) in addition to the max. y usual absorption maximum of the benzyl amine function. This o i l did not readily re-dissolve in dilute aqueous hydrochloric acid. Its infrared spectrum had "v" 1690, 1657, 1505, cm."1. 17/?-Hydroxy-N-benzyl-6-azaandrostan-7-one (XXXV). A solution of 17^-hydroxy-N-benzyl- 6-aza-4-androsten-7-one, XXXII, (0.I85 g., 0.488 mmole) in glacial acetic acid was reduced with hydrogen over platinum for two hours. The hydrogen uptake was 17 cc. (calculated, 11 cc.). The catalyst was fi l t e r e d off and the acetic acid removed under reduced pressure and f i n a l l y under high vacuum to yield 0 . 1 6 8 g, (0.441 mmole, 90$) of o i l . The o i l was chromatographed on 15 g. of s i l i c a gel and the product was eluted in 50$ chloroform in benzene. It may also be chromatographed on alumina (activity III/IV) and elutes with 50$ ether in petroleum ether (3 0 - 6 0 ° ) . The o i l crystallized upon standing a short time and recrystallized from acetone-petroleum ether ( 3 0 - 6 0 ° ) as colorless needles, m.p. 1 3 4 - 1 3 6 ° . Two further recrystallizations yield 17^-hydroxy-N-benzyl-6-azaandrostan-7-one as colorless needles, m.p. 1 3 5 - 1 3 7 ° ; 44 0_ H 3410 cm. - 1 (2.93^0 (broad) i n KBr; \) c = = 0 1630 cm." 1 ( 6 . 1 3 /0 i n KBr; \ ? a r o m a t l c 1495 cm." 1 ( 6 . 6 9/jt).in KBr. A n a l . C a l c d . f o r C^H^NOg ( 3 8 1 . 5 4 ) : C, 7 8 . 6 9 ; H, 9 . 2 5 ; N, 3 . 6 7 ; 0 , 8 3 8 ; a c t i v e H, 0 . 2 6 4 . Pound: C, 7 8 . 7 3 ; H, 9 .6l ; N, 3 . 9 0 ; 0 , 8 . 6 6 ; a c t i v e H, O . 2 7 . N-Benzyl-6 -azaandrostan - 1 7 ^ - 0 1 ( X X X V I ) . 17y?~Hydroxy-N-benzy 1-6-azaandrostan - 7-one, XXXV, ( 0 . 9 0 0 g., 2 . 3 6 mmoles) was d i s -s o l v e d i n anhydrous e t h e r and t r e a t e d w i t h l i t h i u m aluminum h y d r i d e by e x t r a c t i o n of 1 . 0 g. p l a c e d i n a S o x h l e t cup. The t o t a l r e a c t i o n time was 24 hours a t e t h e r r e f l u x temperature and 56 hours a t room t e m p e r a t u r e . The excess l i t h i u m aluminum h y d r i d e was decomposed w i t h an a c e t o n e - e t h e r s o l u t i o n . One m l . of water was added and the m i x t u r e warmed g e n t l y on a steam b a t h f o r 0 . 5 hour. The i n o r g a n i c s a l t s were f i l t e r e d o f f and washed w i t h e t h e r . The combined e t h e r s o l u t i o n s were d r i e d over magnesium s u l f a t e . F i l t r a t i o n and d i s t i l l a t i o n of the e t h e r gave a c o l o r l e s s o i l w h i c h s l o w l y c r y s t a l l i z e d . The y i e l d of s o l i d c r y s t a l l i n e r e d u c t i o n p r o d u c t was 0.843 g. ( 2 , 3 0 mmoles/ 9 7 $ ) . R e c r y s t a l l i z a t i o n of 0 . 2 9 4 g. of t h e s o l i d from p e t r o l e u m e t h e r ( 3 0 - 6 0 ° ) gave a f i r s t crop of 0 . 1 7 0 g. of n e e d l e s , m.p. 1 0 9 - 1 1 1 ° . Two f u r t h e r r e c r y s t a l l i z a t i o n s gave N - b e n z y l - 6 - a z a a n d r o s t a n - 1 7 ^ - o l as c o l o r l e s s , f l a t n e e d l e s , m.p. 1 1 0 - 1 1 2 ° ; t * [ D + 6 6 . 6 ° ; V)Q_H 3340 cm." 1 (330^) (broad) i n KBr; ^ a r o m a t i c 1495 cm." 1 (G.G^) i n KBr. 45 A n a l . C a l c d . f o r C^H^NO ( 3 6 7 . 5 6 ) : C, 8 1 . 6 9 ; H, 1 0 . 1 5 ; N, 3 . 8 1 ; 0 , 4 3 5 . Found: C , 8 1 . 5 7 ; H, 1 0 . 3 4 ; N, 4 . 1 4 ; 0 , 4.51. N - B e n z y l - 6 - a z a a n d r o s t a n - 1 7 - o n e ( X X X V I I ) . N - B e n z y l - 6 -a z a a n d r o s t a n - 1 7 ^ - o l , (XXXVT), ( 0 . 2 6 5 g., O .725 mmole) was d i s s o l v e d i n 10 m l . o f flistilled acetowand c o o l e d t o 10°C. I t was t r e a t e d w i t h 0 . 5 m l . of a s o l u t i o n of 8 N CrO^ i n s u l f u r i c a c i d and w a t e r . (49) W i t h i n a minute a g r e e n i s h p r e c i p i t a t e had formed. A f t e r 15 m i n u t e s , 1 m l . of water was added and a f t e r 45 m i n u t e s , 100 m l . o f wa t e r were added and t h e s o l u t i o n made b a s i c w i t h d i l u t e aqueous sodium c a r b o n a t e . The s o l u t i o n was e x t r a c t e d w i t h e t h e r , t h e e t h e r was d r i e d and a f t e r d i s t i l l a t i o n gave 0 . 2 0 0 g. ( 0 . 5 5 mmole, 76$) of an o i l p r o d u c t . C r y s t a l l i z a t i o n from aqueous methanol gave N - b e n z y l - 6 -azaandrostan - 1 7-one as c o l o r l e s s n e e d l e s , m.p. 1 1 0 - 1 1 2 ° ; BIBLIOGRAPHY 1. Much i n f o r m a t i o n i n c l u d e d i n the i n t r o d u c t i o n was found i n : F i e s e r , L o u i s P. and Mary P i e s e r , S t e r o i d s . New York: R e i n h o l d P u b l i s h i n g C o r p o r a t i o n , 1 9 5 9 . 945 PP. 2 . 0 . Rosenheim and H. K i n g . N a t u r e , 1 3 0 , 315 ( 1 9 3 2 ) ; C h e m i s t r y and I n d u s t r y , 5 1 , 954 ( 1 9 3 2 ) . 3 . H. 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