Synthesis of some derivatives of acetonylbarbituric acid

73 Pages·03.299 MB·English

by  McAuley, Margaret Louise

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NAME AND ADDRESS DATE

NORTHWESTERN UNIVERSITY
-SYNTHESIS OF SOME DERIVATIVES OF
ACETONYLBARBITIXRIC ACID
A DISSERTATION
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
for the degree
DOCTOR OF PHILOSOPHY
DEPARTMENT OF CHEMISTRY
BY
MARGARET LOUISE McAULEY
EVANSTON, ILLINOIS
August, 1942
ProQuest Number: 10101714
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ACKNOWLEDGMENT
The author wishes to express her
appreciation to Dr. C. D. Hurd for his
constant guidance and encouragement in
carrying out these investigations.
TABLE OF CONTENTS
INTRODUCTION ........................................ 1
Barbituric Acid Derivatives ..................... 1
Dioxolanes and 1,3-Dioxanes ........ . . . . . . 6
Dxazolidines and 1,3-Oxazines ................... 19
Condensation of Aldehydes with Acetonylbarbituric
Acids . ...................................... 23
Reduction of Ethylacetonylbarbituric Acid . . . . 26
Preparation of 5-Ethyl-5-(2-aminopropyl)barbituric
Acid....................................... 29
Oxidation of Ethylacetonylbarbituric Acid with
Hypohalites.............................. 32
EXPERIMENTAL................................... 34
Starting Materials. . ........................... 34
Preparation of 5-Alkyl-5-acetonylbarbituric Acids 37
Preparation of Dioxolanes and 1,3-Dioxanes. . . . 45
Attempted Preparation of Oxazolidines .......... 55
Condensation of Aldehydes with Acetonylbarbituric
Acids..................................... 57
Reduction of Ethylacetonylbarbituric Acid. . . . 59
Attempted Preparation of 5-Ethyl-5-(2-amino-
propyl)barbituric Acid................... . 61
Oxidation of Ethylacetonylbarbituric Acid with
Hypohalites ................................... 63
SUMMARY......................................... 6b
V I T A ........................................... 67
I INTRODUCTION
t.
!;
!| Since 1903, when Fischer and v. Mering1 discovered that
is simple barbituric acid derivatives possess narcotic activity,
!i hundreds of harhituric acid derivatives have been prepared.
S;
ji Nearly all of them have substituents in the 5-position, and
; many have substituents in the 1-position or the 1- and 3-
| positions* Of the derivatives substituted only in the 5-
a
!; position, 5,5-diethylbarbituric acid (Barbital) was found1
j! to be a powerful narcotic. If smaller groups are present,
; the compound has little or no activity, while if the groups
are larger the activity reaches a maximum with dipropyl-
barbituric acid. However, if one of the groups is ethyl,
: maximum hypnotic activity is reached where the other is amyl,
isoamyl (Amytal), or hexyl. Unsaturated radicals have been
\
employed to advantage diallylbarbituric acid (Dial) is
slightly better as an hypnotic than dipropylbarbituric acid,
and 5-(l-cyclohexenyl)-5-ethylbarbituric acid (Phanodorm)
and 5-(l-cyclohexenyl)-l, 5-dimethylbarbituric acid (Epivan)
are in clinical use. Derivatives containing aromatic groups
have been prepared. Ethylphenylbarbituric acid (Phenobarbital)
is an excellent narcotic.
Substitution of the 1-position by alkyl groups gives
more powerful and shorter-acting drugs $ 5-ethyl-l-methyl-5-
phenyl-barbituric acid (Prominal) and l-(3L,3-dibromopropyl)-
Cl) E. Fischer and v. Mering, Therap. d. Gegen. March
(1903)$ Chem. Zentr. (5]2* 1155 (1903).
;j 5,5-diethylbarbituric acid (Diogenal) are examples.
Si
i Many derivatives of thiobarbituric acid are known. Their
j1
|l hypnotic action is generally shorter: and their stability is
|i
jless than that of the oxygen analogs. 5-Ethyl-5-(l-methyl-
butyl)-2-thiobarbituric acid (Pentothal) is an example.2
■j
Ij During the last few years the interest has turned to
! barbituric acid derivatives containing oxygen, nitrogen, halo-
: gen, and sulfur in the substituents at the 1-, 3-, and 5-
! positions. The oxygen-containing radicals include acetonyl,3’4
* £ -hydroxyethyl,5 pinacolyl,6 alkoxyalkyl,7 alkoxyalkoxyalkyl,8
X
9 o
furfuryl, and tetrahydrofurfuryl. The nitrogen-containing
2
.1 12 1
radicals include dialkylaminoalkyl, acetanilido, piperidyl,
(2) G. M. Dyson, The Chemistry of Chemotherapy, Bouverie
House, London, 1928; A. L. Tatum, Physiological Review,
iS, 472 (1939).
(3) A. W. Dox and B. Houston, J. Am. Chem. Soc., 46, 252
(5-924).
(4) A. V. Kirsanov and Y* N. Ivashchenko, J. Gen. Chem.
(USSR), 8, 1576 (1938).
(5) G. S. Skinner, J. Am. Chem. Soc., 59, 322 (1937)* G. S.
Skinner and A. P. Stuart, ibid., 6£, 2993 (1941).
(6) S. M. McElvain and R. F. Taylor, ibid., 63, 2513 (1941).
(7) F. F. Blicke and M. F. Zienty, ibid., 63, 2991 (1941)*
F. C. Whitmore and M. A. Thorpe, U. S. Patent, 2,161,212#*
%
C. A., 33, 7493 (1939).
(8) Y. Prelog and V. Hahn, Coll. Trav. chim. Tch^coslovaquie,
8, 219 (1936)* Chem. Zentr. II, 1544 (1936).
(9) W. R. Kirner and G. H. Richter, J. Am. Chem. Soc., 51,
3131 (1929)* L. Rosenthaler, Pharm. Acta Helv., 13.
359 (1938)* C. A., 33, 9551 (1939).
(10) A. W. Dox and E. G. Jones, J. Am. Chem. Soc., 50, 2033
(1928).
(11) A. W. Dox and L. Yoder, ibid., 45. 1757 (1923).
(12) J. A. Timm, ibid., 52, 1943 (1935;.
(13) I. Y. Zbarskii, Ukrain. Gosudarst. Inst. Eksptl. Farm.
(Kharkov) Konsul1tatsionnye Materialy, 265 (1939)* C. A.,
36, 3160 (1942).
3.
i!,|
p>
|| -picolyl,14 imidazolemethyl,15 and antipyryl.16 Several
jj
j!nitrogen-containing dyes have been prepared*17 Among the
P
!l sulfur-containing radicals are p-toluenesulfonyl,18 thienyl,19
!! 20
land thiazolemethyl. Some of the halogen-containing barbi-
I* turic acid derivatives in particular have been useful as
•! 5 21
9
|idrugs. A few of the radicals used are 0 -bromoethyl,
‘i
•2-chloro(or bromo)-2-propenyl,22 and bromoisobutenyl.23
i In the present work it was considered of interest to
ji prepare barbituric acid derivatives with groups in the 5-
jl position containing oxygen and nitrogen, which could be pre­
pared from 5-alkyl-5-acetonylbarbituric acids. The approach
to these compounds was through the reactivity of the acetonyl
'group.
The first problem was the preparation of the alkyl-
3
! acetonylbarbituric acids. The method of Dox and Houston was
tried, but the yields of alkylacetonylbarbituric acids ob-
tained were much less than they had reported. The method of
' (14) C. S. Kuhn and G. H. Richter, J. Am. Chem. Soc., 57.
1927 (1935).
(15) M. S. Taggert and G. H. Richter, ibid. 55, 1110 (1933).
(16) A. Sonn and W. Litten, Ber. 66, 1512 (1933).
(IV) A. E. Pierce and M. M. Rising, J. Am. Chem. Soc., 58,
1361 (1936) $ A. Mossini, Ann. chim. farm., Dec. 47
(1939)$ C. A., 34, 2175 (1940).
(18) E. L. D’Ouville, F. J. Myers, and R. Connor, J. Am.
Chem. Soc., 61, 2033 (1939).
(19) F. F. Blieke and M. F. Zienty, ibid., 63, 2945 (1941).
(20) F. E. Hopper and T. B. Johnson, ibid. 56, 484 (1934).
: (21) G. S. Skinner, ibid., 59, 322 (1937)$ H. R. Henze and
J. J. SpurlocK, ibid., 63, 3360 (1941).
F. Boedecker and H. Gruber, U.S. Patent 2,080,071$
i; (22)
Chem. Zentr., II, 1047 (1937)$ Y. 0. Gabel, I. Y.
Zbarskii, and R. P. Gvirtsman, Ukrain. Gosudarst. Inst.
Eksptl. Farm. (Kharkov), Konsul1tatsionnve Materialy,
No. 4, 106 (1939); C. A., 36. 3787 (1942).
(23) G. Heilner, Ger. Patent 629,373$ Chem. Zentr. II,
819 (1936).
| Kirsanov and Ivashchenko4 was reported to give satisfactory
yields but required the preparation of bromoacetone. Since
i
chloroacetone is commercially available, it was considered
preferable to develop a method using that compound.
The usual method of preparing 5-alkylbarbituric acids
is by treating ethyl malonate with an alkyl halide in the
24 2 5
presence of sodium ethoxide or magnesium ethoxide, and
condensing the ethyl alkylmalonate with urea.36 This approach
! was tried. Reaction of ethyl malonate and chloroacetone in
ether solution with sodium ethoxide in the presence of a
trace of sodium iodide gave 64 per cent of ethyl acetonyl-
2 7
malonate. Gault and Salomon obtained a 70 per cent yield
using bromoacetone. Attempts to prepare ethyl ethylacetonyl-
malonate from ethyl acetonylmalonate and ethyl iodide, how­
ever, were unsuccessful.
Accordingly, the plans were modified to attach the groups
in the reverse order. With ethyl ethylmalonate and sodium
ethoxide, chloroacetone gave tarry materials from which no
pure compounds were isolated. Dox and Houston3 obtained
similar results. A tarry product w^s also obtained when
ethyl butylmalonate was used. Since the tar resulted by de­
composition of chloroacetone in anhydrous alkaline solution,
an experiment was tried with a derivative of chloroacetone
(24) R. Adams and R. M. Kamm, Organic Syntheses, 4, 11 (1925).
(25) H. Lund, Kong, dansk. Vidensk. Selsk., mat-Fysiske Medd,
13. No. 13 (1935)$ Chem. Zentr., I, 2096 (1936).
(26) E. Fischer and A. Dilthey, Ann. 355. 334 (1908).
(27) H. Gault and T. Salomon, Compt. rend. 174, 754 (1922)$
Ann. chi*., 2, 133 (1924).