Chinese Journal of Chemistry, 2007, 25, 382384

Full Paper

Novel Synthesis of Barbiturates

ASHNAGAR, Alamdar*
a b

,a

GHARIB NASERI, Nahid

SHEERI, Behrang

School of Pharmacy, Ahwaz Jundi Shapour University of Medical Sciences, Ahwaz 61739-44871, Iran Ahwaz Faculty of Petroleum Engineering, Petroleum University of Technology, Ahwaz 61739-44871, Iran

Knovenagel reaction of barbituric acid with different aldehydes were used to synthesize new barbiturates. This is a novel method which can be used to synthsis various types of new generation of barbiturates which are different from the previously reported. Keywords barbiturate, barbituric acid, Knovenagel reaction, 5-(indol-3-ylmethylidene)barbituric acid, 5-(thien-2ylmethylidee)barbituric acid

Introduction
Barbituric acid results from the condensation of malonic acid and urea. The derivatives of barbituric acid (2,4,6-trioxypyrimidine) are today called barbiturates, and many of them are the most widely used sedativehypnotic drugs. The first physiologically active drug, barbital or Veronal, was introduced in 1903. Condensation of dialkyl- or alkylaryl diethylmalonate with urea gives barbiturate, 5,5-dialkyl/alkylarylbarbituric acid. Both hydrogens of diethylmalonate ester must be replaced by alkyl or alkyl and aryl groups for the compounds to show sedative-hypnotic character as a drug. Chemists have synthesized many of these drugs, and pharmacologists have tested their activity. The barbiturates exhibit a wide variety of responses in the body, depending mainly on the identity of the substituting groups. Some generalizations can be made. Increasing the length of an alkyl chain up to 5 or 6 carbon atoms in the 5 position, enhances the sedative action and decreases depressant action decreases, and the drugs become more effective as anticonvulsants for control of epileptic seizures. Branched or unsaturated chains in the 5 position generally produces a briefer duration of action. Barbiturates are classified into four categories, which are based on the time required for them to take effect and the duration of their activity: long-acting, intermediate-acting, short-acting and ultra short-acting. Compounds with phenyl or ethyl groups in the 5 position seem to have the longest duration. The medical and physiological use of barbiturates depends on the dose size. In small doses, the drugs are mild sedatives, acting to relieve tension and anxiety. At 35 times the sedative dose, sleep is produced. In large doses, barbiturates act as anesthetics. High levels of barbiturates cause death. Barbiturates act by depressing the activity of the central nervous system and, in high doses, also depress the respiratory system, which accounts for

their toxicity. Barbiturate use can also lead to addiction and chronic intoxication. Most barbituric acid derivatives are prepared and sold as their sodium salts.1-4 On the other hand, certain substituted 2-thiobarbituric acids have long been used as intravenous anesthetics5 and as intermediates in the preparation of dyes.6 More recently there has been interest in 2-thiobarbituric acids as anticonvulsants,7 immunotropic and anti-inflammatory compounds,8 antineoplastic agents,9 and as platforms in the synthesis of other biologically active compounds.10 Barbituric acid derivatives also exert important action on the central nervous system (CNS) and recently have found totally new biomedicinal applications in fields such as cancer and AIDS therapy. Regarding the therapeutic efficacy and diversity of barbiturates, we decided to synthesize a few of the well established barbiturates and elucidate their structures with spectroscopic techniques. And beside the general approach (Scheme 1), a new synthetic strategy to synthesize barbiturates through Knovenagel reaction (Eqs. 1, 2) was developed.

Experimental
Methods and materials NMR spectra were recorded on a Varian 400 Unity Plus at 400 MHz (1H) and 100 MHz (13C) using TMS as internal standard. Mass spectra were measured on QP-1000 Shimadzu mass spectrometer. Infra-red spectra were recorded using a Jasco, IR700 Infrared spectrophotometer, as KBr pellets. UV-Vis spectra were recorded using a Jasco, 810-UV, spectrophotometer. Anhydrous diethyl malonate, urea, piperidine, barbituric acid, thiophene-2-carboxaldehyde, indole-3-carboxaldehyde, absolute ethanol and anhydrous sodium sulphate were purchased from Merck.

* E-mail: aashnagar2003@yahoo.com Received April 24, 2006; revised September 1, 2006; accepted November 13, 2006. 2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Barbiturate Scheme 1 Synthesis of barbituric acid

Chin. J. Chem., 2007 Vol. 25 No. 3 383

washed once with 20 mL of water, once with 30 mL of 5% sodium bicarbonate solution, and finally with 30 mL of water. Ethereal layer was dried over anhydrous sodium sulphate, then filtered. Ether was evaporated and the liquid residue was vacuum distilled (b.p. 120140 /2030 mmHg), a clear colourless liquid was obtained (9.5 g, 44 mmol, 80% yield). IR (neat liquid) : 2962, 2936, 2874 (s, aliphatic CH), 1732 (s, CO), 1463 (s, CH2), 1369 (s, CH3), 10001300 (br s, CO) cm 1. Preparation of 5,5-diethyl barbituric acid (2) In a 250 mL round bottomed flask, piceses of sodium metal (1.1 g, 48 mmol) was added to 50 mL of dry absolute ethanol. When the sodium metal was dissolved completely, 2,2-diethyl malonic acid diethyl ester (1) (9.5 g, 44 mmol) was added. Then, a hot solution (70 ) of anhydrous urea (2.6 g, 43 mmol) in absolute ethanol was added under stirring. The solution was refluxed for 23 h then was acidified with 4 mL of concentrated HCl acid. The solution was concentrated to 50 mL, then cooled in an ice bath for 15 min. Filtration on a Buchner funnel gave a solid material which was recrystallized from water. A white crystalline material was obtained which was kept in an oven (105110 ) for 3 h (7.3 g, 39.7 mmol, 90% yield). m.p. 191193 ; 1H NMR (CDCl3, 400 MHz) : 0.9 (t, 3H, CH3), 1.6 (s, 2H, 2NH), 2.02.1 (q, 2H, CH2); 13C NMR (CDCl3, 100 MHz) : 15 (CH3), 32 (CH2), 58 (C-5), 149 [NCON], 173 (CO); IR (KBr) : 3206 (s, NH), 2980, 2940, 2864 (s, aliphatic CH), 1763, 1715 (s, CO), 1676 (s, NCON), 1240 (s, CN) cm 1; MS (EI) m/z (%): 185 ([MH] , 100), 156 ([MCHO] , 84.7), 141 ([156NH] , 81.6), 112 ([141C2H5] , 20.4). Preparation of 5-(indol-3-ylidene)barbituric acid (5) A mixture of barbituric acid (5 g, 39 mmol) (3) and indole-3-carboxaldehyde (5.66 g, 39 mmol) (4) was refluxed in ethanol (75 mL) for 3 min, then, piperidine (1.0 mL) was added in one portion and the reflux was continued for further 5 h. The reaction mixture was cooled to room temperature and the solid material formed was filtered, washed with cooled ethanol (230 mL) and dried at room temperature. Recrystallization

Preparation of 2,2-diethyl malonic acid diethyl ester (1) In a 250 mL round-bottomed flask, fitted with a refulx condenser, 1.32 g (5.74 mol) sodium metal which was cut into pieces and 25 mL of dry absolute ethanol were added. After the sodium was dissolved and the boiling was subsided, a calcium chloride drying tube was attatched to the top of the reflux condenser. 0.75 g (4.5 mmol) of anhydrous powdered KI was added down the condenser and the mixture was heated until all the solids were dissolved. Then, 8.8 g (55 mmol) of dry diethyl malonate was added and the mixture was stirred gently until the ingredients were mixed. The mixture was heated for further 1020 min. At this stage 8.5 g (54.5 mmol) of ethyl iodide was added in three equal portions down the condenser. The mixture was heated for 45 min, then 1.32 g (5.74 mmol) of sodium dissolved in dry absolute ethanol was added, and was heated at 60 . Again, 0.75 g (4.5 mmol) of anhydrous powdered KI and 8.5 g (54.5 mmol) of ethyl iodide in three equal portions were added down the condenser and the reflux continued for 2 h. The mixture was cooled to room temperature and the liquid was decanted as much as possible away from the inorganic salts formed as a white solid at the bottom of the flask. Ethanol was removed completely from the liquid, 40 mL of water was added then poured into the flask containing the solid material. After all the solids were dissolved and the mixture was cooled, 40 mL of diethyl ether was added and the mixture was transferred to a separatory funnel. The organic layer was separated and

2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

384 Chin. J. Chem., 2007, Vol. 25, No. 3 with ethanol afforded a dark yellow powdered material (8.85 g, 89% yield). m.p. 250252 . UV (EtOH) max (A): 212 (0.4), 257 (0.578), 419 (0.496) nm; 1H NMR (DMSO-d6, 400 MHz) : 7.17 (m, 2H, H-4H-5), 7.61 (d, H-2), 7.94 (d, H-7), 8.88 (s, NH-indole), 9.57 (s, HC), 11.15 (br s, 2H, NH-barbituric); 13C NMR (DMSO-d6, 100 MHz) : 111.5 (C-3), 113.3 (C-3a), 117.8 (C-2), 122.8 (C-7), 123.8 (C-4a), 129 (C-6), 136.5 (C-5), 140 (C-4), 143.4 (C-7a), 150.5 [NCON], 163.3 (CO), 164.7 (CO); IR (KBr) : 3356 (m, indole ring NH), 3274, 3156 (m, NH), 3022 (m, aromatic CH), 3022 (m, olefinic CH), 1721, 1683 (s, CO), 1639 (s, NCON) cm 1; MS (EI) m/z (%): 255 (M , 100), 238 ([MOH] , 2.24), 212 ([238CN] , 2.45). Preparation of 5-(thien-2-ylmethylidene)barbituric acid (7) A mixture of barbituric acid (2.82 g, 22 mmol) (3) and thiophene-2-carboxaldehyde (2.5 g, 22 mmol) (6) was refluxed in ethanol (50 mL) for 3 min, then, piperidine (0.5 mL) was added in one portion and the reflux was continued for further 2 h. The reaction mixture was cooled to room temperature and the solid material formed was filtered, washed with cooled ethanol (220 mL) and dried at room temperature. Recrystallization from ethanol afforded a yellow powdered material (4.6 g, 94% yield). m.p. 220222 . UV (EtOH) max (A): 219.5 (0.420), 255 (0.222), 368.5 (0.607) nm; 1 H NMR (DMSO-d6, 400 MHz) : 7.25 (m, H-4), 8.00 (d, H-3), 8.15 (d, H-5), 8.6 (s, HC), 11.3 (m, 2H, NH-barbituric); 13C NMR (CHCl3DMSO-d6, 100 MHz) : 111.2 (CCH), 128.04 (C-2a), 136.5 (C-2), 141.6 (C-3), 145.6 (C-4), 146.6 (C-5), 150.3 [NCON], 162.9 (CO), 163.5 (CO); IR (KBr) : 3204 (m, N H), 3050 (s, aromatic CH), 1746, 1694 (s, CO), 1652 (s, NCON) cm 1; MS (EI) m/z (%): 222 (M , 100), 194 ([MCO] , 2.04), 179 ([194NH] , 9.2).

ASHNAGAR , GHARIB NASERI & SHEERI

This is a general approach and works quite well. However, based upon the fact that the two acidic hydrogen atoms at position 5 of the barbituric acid must be replaced by substituents in order to show therapeutic efficacy, we decided to take advantage of the well known Knovenagel condensation reaction. Therefore, two different relatively complex aldehydes were chosen, i.e. indole-3-carboxaldehyde (4) and thiophene-2-carboxaldehyde (6) as model aldehydes and their reactions with barbituric acid (3) were investigated. The reactions were proceeded in the presence of a small amount of piperidine in a relatively short period of time. The products were collected as crystalline material and their structures were elucidated on the basis of their various spectra. Therefore, it can be concluded that, this is a general procedure for the preparation of a vast number of new generation of barbiturates and thiobarbiturates in a rather simple method and short time. Of course, more work is needed to evaluate therapeutic and pharmacological efficacy of these barbiturates.

References
1 2 Foye, W. O. Principles of Medicinal Chemistry, Lea & Febiger, Philadelphia, 1974, pp. 165171. Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, Hypnotics and Sedatives. I. The Barbiturates, Chap. 9, 4th ed., Ed.: Sharpless, S. K., Macmillan, New York, 1970. Kauffman, G. B. J. Chem. Educ. 1980, 57, 222. Ray, O. S. Drugs, Society, and Human Behavior, Chap. 11, Ed.: Mosby, C. V., St. Louis, 1972. Doran, W. J. In Barbituric Acid Hypnotics, Vol. 4, Eds: Blicke, F. F.; Cox, R. H., John Wiley and Sons, New York, 1959, p. 5. Dass, J. N.; Dutt, S. Indian Acad. Sci, 1938, 8A, 145. (a) Vasey, C. H. Br 741097, 1955 [Chem. Abstr. ]. (b) Dhasmana, A.; Barthwal, J. P.; Pandey, B. R.; Ali, B.; Bhargava, K. P.; Parmer, S. S. J. Heterocycl. Chem. 1981, 18, 635. Zawisza, T.; Matczak, H.; Kowalczyk-Bronisz, S. H.; Jakobiec, T. Pol. Arch. Immunol. Ther. Exp. 1981, 29, 235. Singh, S.; Behl, C. K. Indian J. Chem. Sect. B 1980, 19B, 625. Bogue, J. Y.; Carrington, H. C. Br. J. Pharmacol. 1953, 230.

3 4 5

6 7

Results and discussion

The starting material available was diethyl malonate. First, 2,2-diethyl malonic acid diethyl ester was synthesized, then the product purified was condensed with urea to afford 5,5-diethylbarbituric acid as the final product as outlined in Scheme 1. 2,2-Diethyl malonic acid diethyl ester can be condensed with any substituted urea, thiourea or substituted thiourea to obtain various types of barbiturates with different therapeutic effects.
8 9 10

(E0604243

ZHAO, C. H.; ZHENG, G. C.)

2007 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim