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Photochemical Formation of Primidone from 2-Thiophenobarbital.

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343
Photochemical Formation of Primidone
Photochemical Formation of Primidone from 2-Thiophenobarbital
Maria H. Paluchowska and Jacek Bojarski
Department of Organic Chemistry, Nicolaus Copernicus Academy of
Medicine, Dzierzynskiego 14 B str., 30-048 Krakow, Poland
Eingegangen am 15. Oktober 1987
of 5-ethvl-5-~henvl-2-thiobarbituric
acid (1)
The Dhotodearadation
. . . , in alcoholic medium was investigated. The irradiation of 1 in secondary alco1H,5H)-pyrimidinedione, a
hols yielded 5-ethyl-2~dih~dro-5-phen~I-4,6(
well known antiepileptic drug - Primidon.
-
Photochemische Bildune von Primidon aus 2-Thio~henobarbital
Photochemischer Abbau
5~ethyl~5~pheny1~2~thiobarbitursIure
(1) in
1 in sekunalkoholischem ~
dwurde iuntersucht.
~ ~i~~Belichtung
daren Alkoholen gab 5-Ethyl-2-dihydro-5-phenyl-4,6(
1H,SH)-pyrimidindion, das antiepileptische Arzneimittel Primidon.
,
Our earlier studies on the photolysis of 2-thiobarbituric acid derivatives'. *) prompted us to investigate the reactivity of 5-ethyl-2-dihydro-5phenyl-2-thioxo-4,6(1H,5H)-pyrimidinedione (5-ethyl-5-phenyl-2-thiobarbituric acid, I) under the irradiation by UV light in the presence of alcohols. The photochemical degradation of similar 5,5-diethyl-2-dihydro-2thioxo-4,6(lH,5H)-pyrimidinedione (5,5-diethyl-2-thiobarbituric acid) in
primary alcohol medium gave 2-alkoxy derivatives of 5,5-diethyl-2-dihydro-4,6( 1H,5H)-pyrimidinedione2).
It is known that the reduction of 1 with Raney nickel in
prim. alcohols leads to z3'4, but the analogous photoreduction process have not been described. The mechanism of the
photochemical formation of 2 is probably the same as formerly proposed for 2-thiobarbital') and represented in
Scheme 2:
We were interested how the phenyl moiety at the pyrimidine ring and the type of alcohol effect the reaction course. The
following alcohols were used as the reaction medium: primary: ethanol and l-propanol, secondary: 2-propanol and 2butanol, and tertiary: 2-methyl-2-butanol.
The alcoholic solutions of 1 were irradiated with UV light
h = 254 nm (low pressure mercury lamp) and then the main
products of the reaction were isolated (Scheme 1):
Et
QH
's
--<
n-PrOH
e
Et
NH
Ph
0
2a: R = Et
2b: R = n-Pr
'TNY:
U
Ph
U
E,t
0
S---H,
SH
- RCHO
lGXH-OPUR
Ph
i
Ph?flYn
0
H
RCHZOH
Ph
0
0
RCH20H
- HZS
Ph
0
R = CH,
C2Hg
hv. 1 6 h
argon
Ph
0
1
The evolution of H2S detected during the reaction supports this conclusion. The formation of 3 may proceed similarly, with the last step being the splitting of the alkoxy moiety (Scheme 3):
8 - BuOH
i-PrOH
\
Ph
0
3
When the reaction was carried out in the primary alcohols
the 2-alkoxy derivatives, 2s and 2b,of 5-ethyl-2-dihydro-5phenyl-4,6(1H,5H)-pyrimidinedionewere formed with good
yield. This result is analogous to that obtained by photodelH,SH)-pygradation of 5,5-diethyl-2-dihydro-2-thioxo-4,6(
rimidinedione'! However, the formation of pertinent 2-alkoxy derivatives has not been observed when the sec. alcohols were used as solvents, but instead, in 2-propanol and 2butanol, 5-ethyl-2-dihydro-5-phenyl-4,6(
1H,SH)-pyrimidinedione 3, a well known antiepileptic drug - Primidon, was
formed as a main product of the reaction.
Arch. Pharm. (Weinheim) 321,343-344 (1988)
The support for this conclusion comes from the results of
monitoring the reaction course by HPLC: After 1 h irradiation of 1 in ethanol only a single peak of the product was observed (Fig. la). It corresponded with the earlier identified 2ethoxy derivative 2a. In 2-butanol, after the same time of irradiation, two peaks of the products were observed. One of
them was the peak of 3, identical with the standard (Mizodin,
Polfa), accompanied by the smaller peak with tR similar to
that for compound 2a (Fig. Ib):
0 VCH Verlagsgesellschqft mbH, 0-6940 Weinheim, 1988 0365-6233188JO606-0343 S 02.5OlO
344
Paluchowska and Bojarski
3 1
1
I
5-Ethyl-2-dihydro-5-pheny1-2-propoxy-4,4(1
H,5H)-pyrimidinedione (2b)
a)
20
radiated for 16 h. After irradiation the reaction mixture was evaporated
under reduced pressure at 30 "C to a volume of 30 ml and was kept overnight in a refrigerator. The separated colorless crystals were filtered off
(1.16 g, 44 % yield) and recrystallized from ethanol. M. p. 143-145 OC
(lit.3) 182 "C decomp.); m. p. determined in an open capillary 177- 180 "C.
- C,,H,,N,O, (262.3) Calcd. C 64.1 H 6.92 N 10.7 Found C 63.9
H 6.73 N 10.6. - MS (70 eV): m/z = 217 (M+'-C,H,O, 2 %). - IR
(KBr): 3250 (NH), 2990, 2970 (CH), 2940, 2890 (CH), 1690, 1660
(C=O), 1075 cm-' (C-0).
16
12
e
4
t [min]
Fig. 1: HPLC separations of the photolysates after 1 h irradiation: a photolysis of 1 in ethanol, b - photolysis of 1 in 2-butanol. Peaks
are marked by numbers of the respective compounds.
This last peak disappeared after further irradiation and
only product 3 was observed. The evolution of H2S was detected also in the case of reaction in sec. alcohols, what is in
agreement with the proposed reaction course.
Photoreduction of 1 was not observed when tert. 2-methyl-2-butanol was used as a medium of the reaction. Therefore, one can conclude that the presence of an a-hydrogen
atom in the molecule of the alcohol is necessary for the reduction of 2-thiophenobarbital under the reaction conditions
employed.
Experimental Part
Materials and apparatus: S-ethyl-5-phenyl-2-thiobarbituric
acid 1 (Polfa,
1 H,5H)-pyrimidinedione 3 (MiPoland), S-ethyl-2-dihydro-5-phenyl-4,6(
zodin, Polfa). All other reagents were of analytical reagent grade. The alcohols were dried over molecular sieves (3br or 4A) and distilled before
use. - Uncorrected m. p. s: Boetius apparatus (VEB Analytik, Dresden). HPLC: Chromatograph Liquochrom OE 307 (Labor MIM, Budapest). IR spectra: spectrophotometers UR-10 and Specord 75-IR (VEB Carl
Zeiss, Jena). - 'H-NMR spectra: Tesla BS 567A, 100 MHz. - Mass spectra: LKB 9005 instrument. - Elemental analyses: Regional Laboratory of
Physico-Chemical Analyses, Poznan.
2-Ethoxy-5-ethyl-2-dihydro-5-phenyl-4,6(1
H,SH)-pyrimidinedione(2a)
2.48 g (0.01 mol) of 1 was dissolved in 230 ml of ethanol. The solution was
placed in the photoreactor tube (height 58 cm. diameter 5.5 crn. thickness
of irradiated layer 2.5 mm) equipped with a cooling jacket and a low pressure Hg lamp (TUV 30 W, Philips) protected by the quartz tube. The solution was thermostated at 22 "C and bubbled with argon for 1 h and then ir-
2.48 g (0.01 mol) of 1 in 230 ml of 1-propanol was irradiated as described
above. After irradiation the reaction mixture was evaporated to dryness
and the residue was dissolved in 30 ml of ethanol and cooled. The separated precipitate was filtered off and dried. The yield of 2b was 1.47 g
(52 %), m. p. after recrystallization from ethanol 156-157 "C (lit?)
158 "C). - C,,H,,N,O, (276.3) Calcd. C 65.2 H 7.30 N 10.1 Found
C 64.8 H 7.1 1 N 10.3. - IR (nujol): 3230 (NH), 1700, 1660 (C=O), 1070
cm-I (C-0).
1.24 g (0.005 mol) of 1 was dissolved in 230 ml of 2-propanol or 2-butanol
and irradiated as described above. The solvent was evaporated and the residue was dissolved in ethyl acetate. After cooling 0.44 g (32 %) and 0.61 g
(42 %), respectively, of 3 were obtained. Recrystallization from ethyl acetate yielded crystals with m.p. 283-285 OC (lit?) 281 "C). - C,,H,,N,O,
(218.2) Calcd. C 66.0 H 6.47 N 12.8 Found C 65.9 H 6.50 N 12.8. - IR
(KBr): 3200,3100 (NH), 2990,2975 (CH), 2845 (CH), 1700, 1660 cm-I
(C=O). - MS (70 eV): m/z = 218 (M+., 2 %). - 'H-NMR (CDCI,):
6 (ppm) = 1.00 (t, J = 7.0 Hz, CH,), 2.22 (q, J = 7.0 Hz, CH,), 4.38 (b. s,
N-CH,-N), 7.37 (s, C,H,), 8.51 (b. S, NH), 11.21 (b. S, NH).
Microscale photolysis and HPLC experiments: 10 4 of alcoholic solutions (ethanol or 2-butanol) of 1 (c = 4.4 . 10-3 mol/l) was irradiated at
room temp. in quartz capillary tubes placed in the merry-go-round photoreactor with the low pressure Hg-lamp (TUV 6 W, Philips).
At appropriate time intervals samples of 2 fi volume were withdrawn and
checked by HPLC; column diameter 4.6 mm, length 250 mm, Chromsil
C 18, 10 pm; mobile phase: 30 % MeOH in H,O containing Na,HPO,
(0.0075 mol/l) and NaH,PO, (0.0025 mol/l); flow rate: 1.44 ml/min, UV
detector (h= 225 nm). Retention times: tR 2a = 15.4 min, tR3 = 8.8 min.
Acknowledgment: Work supported by the Polish Academy of Sciences,
project CPBP 01.13.1.11.
References
J. Mokrosz and J. Bojarski, Pharrnazie 37. 768 (1980).
M. Paluchowska and J . Bojarski. Pol. J. Chern. 60. 825 (1986).
W. B. Whalley, E. L. Anderson, F. Du Gan, J. W. Wilson, and G. E.
Ullyot, J. Am. Chem. SOC.77, 745 (1955).
W. R. Boon, H. C. Carrington, N. Greenhalgh, and C. H. Vasey, J.
Chem. SOC.1954,3263.
[Ph 4151
Arch. Pharm. (Weinheim) 321,343-344 (1988)
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thiophenobarbital, formation, photochemical, primidone
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