S Y N T H E S I S O F P T E R I N S F R O M

N - A C Y L - ~ - A M I N O K E T O N E S

S. I . Z a v ' y a l o v , T . K . B u d k o v a , a n d N. I . A r o u o v a

UDC 542.91:547.85:547.447.5

As a con t inua t ion of ou r s t u d i e s [1, 2] on the s y n t h e s i s of h e t e r o c y c l i c c o m p o u n d s f r o m N-acy l -o~- amino ke tones (AK) i t w a s shown in the p r e s e n t p a p e r that the AK can be used to s y n t h e s i z e p t e r i n s by s t a r t i n g with 2, 5, 6 - t r i a m i n o - 4 - h y d r o x y p y r i m i d i n e ([)

H • N H s 0)

H2N" "I~ \NH 2

CH~COCHRNHCOCHa R = H (II), CH3(III)

Brz , CHsCOCBr RNHCOCHa

I~ = H (IV), CH3(V)

bl !~" HN~ Y C,H~NHNH,

R 1 =CHs, R~=H (VII1) R 1 = H, R ~ ~ CHa (IX) CHaC(=NNHCsHs)C(=NNHC6Hs)R R 1 = R2=CHa (X) R = H(VI), CHs (VII)

The uns t ab l e b r o m i d e s (IV) and (V) a r e f o r m e d when (II) and (III) a r e b r o m i n a t e d in e i t h e r CH3COOH o r H20 , which when r e a c t e d wi th CsH~NHNH 2 g ive the p h e n y l o s a z o n e s of m e t h y l - and d i m e t h y l g l y o x a l (VI) and (VII). The r e a c t i o n of (IV) and (V) wi th (I) r e s p e c t i v e l y l e a d s to a m i x t u r e of the 6 , and 7 - m e t h y l p t e r - ins (VIII) and (IX) and 6, 7 - d i m e t h y l p t e r t n (X). Judging by the IR s p e c t r a l da ta , (IX) p r e d o m i n a t e s in the m i x t u r e ob ta ined f r o m (I) and (IV). The p r i o r t r e a t m e n t of (IV) wi th NaHSO 3 c a u s e s the d i r e c t i o n of the r e a c t i o n of (I) wi th (IV) to change in f avo r of (VIII). The ana logous e f f ec t of NaHSO 3 i s a l s o o b s e r v e d when (I) is r e a c t e d wi th CH3COCH = NOH (XI) [3]. The AK can be used to s y n t h e s i z e the p t e r i n s by a d i f f e r e n t p r o c e d u r e if the AK, fo r e x a m p l e , (II), a r e r e a c t e d with (CH20)x and p i p e r i d i n e , the i n t e r m e d i a t e m e t h y l - ene ke tone (XII) i s h y d r o l y z e d to the o~-diketone, and the l a t t e r is condensed wi th (I) in known m a n n e r [4]

(CH'0)x HC1/Hz0 (If) ~ CHaCOCNHCOCHa - , CHsCOCOCHa

C~HuN I] CH~

(XII) (XIII)

E X P E R I M E N T A L

Methy lg lyoxa l P h e n y l o s a z o n e (VI). A m i x t u r e of 0.5 g of (II), 0.98 g of CH3COOK , and 0.25 ml of B r 2 in 8 ml of 98% CHaCOOH was hea ted f o r 6 h at 40-45~ a f t e r which 1.72 ml of C~HsNHNH 2 in 15 ml of a l coho l w a s added, and the m i x t u r e was kep t at 20 ~ fo r 5 h, d i lu t ed with w a t e r , and a l lowed to s t and at 20 ~ for 12 h. The p r e c i p i t a t e was f i l t e r e d and w a s h e d with aqueous a l coho l (1 : 1). We ob ta ined 9.65 g (60%) of (VI), mp 138-140 ~ cf. [6]. A m i x t u r e of 2 g of (II) and 1 ml of B r 2 in 25 ml of w a t e r was s t i r r e d fo r 16 h at 45-50 ~ a f t e r which 7.9 g of CGHsNHNH 2 in 50 ml of a l coho l w a s added, and the m i x t u r e was kep t at 20 ~ fo r 12 h and then d i lu ted wi th w a t e r . We ob ta ined 1.34 g (31%) of (VI), mp 136-137 ~

N. D. Z e l i n s k i i In s t i t u t e of Organ ic C h e m i s t r y , A c a d e m y of S c i e n c e s of the USSR. T r a n s l a t e d f r o m I z v e s t i y a A k a d e m i i Nauk SSSR, S e r i y a K h i m t c h e s k a y a , No. 9, pp. 2136-2138, S e p t e m b e r , 1973. O r i g i n a l a r t i c l e s u b m i t t e d F e b r u a r y 8, 1973.

o 1974 Consultants Bureau, a division of Plenum Publishing Corporation, 227 g/est 17th Street, New York, N. Y. 10011. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission of the publisher. A copy of this article is available from the publisher for $15.00.

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D i m c t h y l g l y o x a l P h e n y l o s a z o n e (VII). In a s i m i l a r m a n n e r , the b r o m i n a t i o n of (III) [7] in e i t h e r CH 3 �9 COOH o r w a t e r and s u b s e q u e n t t r e a t m e n t wi th C6HhNHNH2 gave (VII) in r e s p e c t i v e y i e l d s of 54 and 33%, mp 238-23 3 ~ ( f rom benzene ) [8].

M i x t u r e of 6- and 7 - M e t h y l p t e r i n s (VIII) and (IX). A m i x t u r e of 2 g of (II) and I ml of B r 2 in 15 ml of w a t e r was h e a t e d at 50 ~ fo r 12 h, a f t e r which a so lu t ion of 1.92 g of the b i s u l f i t e s a l t of (I) [9] in 38 ml of w a t e r w a s added, and the m i x t u r e w a s s t i r r e d at ,,,80 ~ fo r 30 rain, kept at 10 ~ fo r 12 h, and then NaHCO~ was added to pH 5 -6 . The p r e c i p i t a t e was f i l t e r e d , w a s h e d in s u c c e s s i o n with w a t e r , ace tone , and e t h e r , and d r i e d ~,t 100 ~ We ob ta ined 1.22 g (80%) of a m i x t u r e of (VIII) and (IX), with a p r e d o m i n a n c e of (IX). Rf 0.47 (here and s u b s e q u e n t l y TLC, Si lufol UV-254, 7 : 1 : 2 i s o p r o p a n o l - s a t u r a t e d NH 3 s o l u t i o n - w a t e r , d e t e c t i o n ill UV l ight) .

I n f r a r e d s p e c t r u m of (VIII) (v, cm-1) : 3260 m, 3190 w, 2935 w, 2840 m, 2805 m, 2745 m, 1705 s, 1615 m, 1585 w, 1540 s, 1490 s, 1445 w, 1400 s, 1355 s, 1340 w, 1310 w, 1298 s, 1248 s, 1186 s, 1138 s, 1 0 6 0 w , 1010w, 953 s, 865 s, 828 m, 7 7 0 w , 730 m, 680 m.

I n f r a r e d s p e c t r u m of (IX) (v, c m - i ) : 3265 s, 3070 w, 2855 m, 2760 m, 1730 s, 1690 s, 1640 m, 1550 s, 1524 s, 1 4 7 0 w , 1430 s, 1380w, 1320w, 1293 s, 1243 s , 1183 m, 1133 s, 1040w, 9 8 0 w , 890 m, 823 m, 735 s, 700 m.

A sol.ution of 1.2 g of m i x e d (VIII) and (IX) in 78 ml of 0.1 N KOH so lu t ion was r e f l u x e d fo r 5 min with c a r b o n , f i l t e r e d , the hot so lu t i on w a s a c i d i f i e d wi th CH3COOH to pH ~ 7, coo led , and the p r e c i p i t a t e w a s f i l t e r e d , w a s h e d in s u c c e s s i o n wi th w a t e r , a ce tone , and e t h e r , and d r i e d a t 100 ~ We ob ta ined 0.46 g of p u r e (IX), the IR and UV s p e c t r a of which c o i n c i d e d wi th the s p e c t r a of an au then t ic s a m p l e .

A m i x t u r e of 2 g of (II) and 1 ml of B r 2 in 15 ml of w a t e r w a s h e a t e d at 50 ~ for 12 h, a f t e r which 15.6 ml of a 35~6 NaHSO 3 so lu t ion w a s added, and the m i x t u r e was s t i r r e d at 20 ~ fo r 3 h, m i x e d with a hot s o l u - t ion of 1.91: g of the b i s u l f i t e s a l t of (I) in 38 ml of w a t e r , hea ted at 100 ~ f o r 1.5 h, and NaHCO 3 w a s added to pH 5 -6 . The p r e c i p i t a t e was f i l t e r e d and r e p r e c i p i t a t e d f r o m KOH so lu t ion as d e s c r i b e d above. We ob - t a ined 0.34 g (32%) of a m i x t u r e of (VIII) and (IX).

A m i x t u r e of 1.02 g of (XI) and 2.5 g of the d i h y d r o c h l o r i d e of (I) [10] in 40 ml of w a t e r w a s r e f luxed f o r i h, kep t a t 10 ~ fo r 12 h, and the p r e c i p i t a t e w a s f i l t e r e d and r e p r e c i p i t a t e d f r o m KOH so lu t ion a s d e - s c r i b e d above . We ob ta ined 1.3 g (63%) of (IX). A m i x t u r e of (VIII) and (IX) was f o r m e d when th is r e a c - t ion w a s run with a p r i o r t r e a t m e n t of (XI) wi th NaHSO 3.

6, 7 - D i m e t h y l p t e r i n (X). A m i x t u r e of 0.5 g of (III), 0.68 g of Br2, and 0.09 g of CaCO 3 in 7 ml of w a t e r w a s s t i r r e d at 45-50 ~ fo r 19 h, fo l lowed by the add i t i on of NaHCO 3 to pH 7 and 0.91 g of 2 - m e r c a p - toe thano l (iYiE), a f t e r which a hot so lu t ion of 0.65 g of the su l f a t e of (I) [10] and 0.7 ml of ME in 65 ml of w a t e r w a s added, and the m i x t u r e w a s hea t ed at 100 ~ fo r 2 h, kep t a t 10 ~ f o r 12 h, and the p r e c i p i t a t e w a s f i l t e r e d . We ob ta ined 0.2 g (39%) of (X). Rf 0.48. U l t r a v i o l e t s p e c t r u m (in 0.1 N KOH so lu t ion) : ).max 250 and 363 nm. The au then t i c (X), ob ta ined by the r e a c t i o n of (XIII) wi th (I) [4], had the s a m e p h y s i c o - c h e m i c a l c h a r a c t e r i s t i c s . Compound (X) w a s i s o l a t e d in l o w e r y i e l d when the r e a c t i o n of (I) wi th (V) w a s run in the a b s e n c e of the ME.

D i m e t h y l g l y o x a l (XIII). A m i x t u r e of 0.6 g of (II), 0.16 g of (CH20)x , and 0.8 ml of p i p e r i d i n e in 10 ml of a l coho l was kep t a t 20 ~ fo r 170 h, e v a p o r a t e d in vacuo , and the r e s i d u e was c h r o m a t o g r a p h e d on a co lumn con t a in ing Al203 (II ac t iv i ty ) . E lu t ion wi th b e n z e n e gave 0.26 g (40%) of (XII), mp 47-48 ~ ( f rom c y - c lohexane ) . Rf 0.59 (Silufol UV-254, 1 : 1 b e n z e n e - a c e t o n e ) . U l t r a v i o l e t s p e c t r u m (in a l coho l ) : )-max 206 and 258 nm. Found : C 56.52; H 7.05; N 10.97%. C6HgNO 2. C a l c u l a t e d : C 56.68; H 7.14; N 11.02%.

The h y d r o l y s i s of (XII) wi th d i lu t e HCI so lu t ion (2 h, 100 ~ gave (XIII) in 50% y ie ld , wh ich w a s i d e n - t i f i ed as th~ p h e n y l o s a z o n e , mp 239 ~

We e x p r e s s o u r g r a t i t u d e to K. B. S t o r m (USA) and W. P f l e i d e r e r (Germany) fo r g r a c i o u s l y s u p p l y - ing the s a m p l e s of c o m p o u n d s (VIII) and (IX).

C O N C L U S I O N S

1. The r e a c t i o n of 2, 5, 6 - t r i a m i n o - 4 - h y d r o x y p y r i m i d i n e with the b r o m i n a t i o n p r o d u c t s of N - a c e t y l - a m i n o a c e t o n e and N - a c e t y l - 3 - a m i n o - 2 - b u t a n o n e r e s p e c t i v e l y gave a m i x t u r e of the 6- and 7 - m e t h y l p t e r i n s and 6, 7 - d i I a e t h y l p t e r i n .

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2. The reaction of N-acetylam[noacetone with paraform and pipertdine leads to the formation of N- acetyl-2-amino-l-buten-3-one, which on acid hydrolysis gives dimethylglyoxal.

L I T E R A T U R E C I T E D

1. S . I . Zav'yalov, N. I. Makhova, N. I. Aronova, and I. F. Mustafaeva, Izv. Akad. Nauk SSSIt, Set. Khim., 2826 (1971).

2. S . I . Zav'yalov, N. [. Aronova, and I. F. Mustafaeva, Izv. Akad. Nauk SSSR, Set. Khim., 1674 (1972).

3. W. Pfleiderer, H, Zondler, and It. Mengel, Liebigs Ann. Chem., 483, 259 (1930). 4. T. Sachs and G. Meyerheim, Bet . , 41, 3965 (1908). 5. S . I . Zav'yalov, M. P. Unanyan, G.'V. Kondrat'eva, and V. V. Filtppov, Izv. Akad. Nauk SSSIt,

Ser. Khim., 1792 (1967). 6. H .V. Pechmann, Ber . , 20, 2543 (1887). 7. S . I . Zav'yalov, N. I. Ar-'onova, and N. N. Makhova, ItIMIOS, Vol. 22, Khimiya (1971), p. 18. 8. It. Fitttg, C. Daimler, and H. Keller, Ltebigs Ann. Chem., 249, 203 (1888) 9. C . K . Cain, M. F. Mallette, and E. C. Taylor, J. Am. Chem. Soc., 68, 1996 (1946).

10. V.M. Berezovskii and L. I. Strel'china, Tr. Vses. Nauchn. Issled. Vitamin. Inst., 5, 28 (1954).

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