Field of the invention This invention relates to a process for the synthesis of barbituric/thio barbituric acid and derivatives thereof. More particularly, the present relates to a process for the preparation of barbituric/thio barbituric acid and its derivatives of general formula.
(Figure Removed)
Background and prior art of the invention
The barbituric acids and their thioanalogues are important industrial chemicals used as intermediates in the synthesis of a number of clinically used hypnotic drug of the Barbiturates class e.g. Veronal, Seconal and Phenobarbltal antiviral drug e.g. Acuracil, highly selective HIV-1 inhibitor agent HEPT. Moreover barbituric acids are most useful precursors for the synthesis of a number of fused uracil of biological importance e.g. pyrano pyrimidines, pyrazolopyrimidines, pyridopyrimidines, pyrimidopyrimidines etc.
Reference may be made to E. Fisher and J. R. Moring, Ther. Ggw, 44, 97,(1903) wherein therapeutic value of barbital as a hypnotic agent is reported.
Another reference may be made to W.J.Doran, Med. Chem., 4, 1 (1959) wherein general information on the chemistry and pharmacology of barbiturates are reported.
Still another reference may be made to R.Ya. Levina and F.K. Velichks, Russ. Chem. Rev. (Engl. Franch), 9,437(1980) wherein the synthesis, properties and reactivity of barbituric acid are described.
Still another reference may be made to B. Bobranski, Wiad. Chem., 31, 231 (1977) wherein, the structure and structure-activity relationship of barbiturates are described.
One more reference may be made to J. T. Bojaroki, J. L. Mokrooz, H. J. Barton, M. H. Paluchewska, Adv. In Heterocyclic Chemistry, vol. 38, 229, Ed. A. R. Katritzky,1985 wherein some important recent development in barbituric acids is described.
The compound of the formula 1 of most interest in the invention bear either oxygen or sulphur atom (X= 0 or S) without any substituent at nitrogen atoms /N-3 alkyl (e.g. methyl, benzyl) substituted/N, N-dialkyl (methyl, benzyl) substituent.
The methods hitherto employed for the synthesis of un-substituted or N-alkyl derivatives of barbituric acids and thiobarbituric acids was the technique of condensing malonic acid and urea or N-alkyl urea or thiourea using acetic anhydride in the presence of excess acetic acid as solvent. The reactions were performed under thermolytic conditions for several hours which may be represented by the following reaction scheme.
Reference may be made to H, Biltz, H. Wittek, Ber, 54B, 1035 (1921).The said method suffers from a number of drawbacks e.g. use of acetic acid as solvent, long reaction times (5-7 hrs), gives highly coloured and impure products. In case of the synthesis of N-substituted barbituric acids it produces 5-acetyl derivatives along with the barbituric acids. It takes long reaction time, needs complicated work-up procedure and gives poor yield of the product ( <50 %).
A reference for a modified procedure may be made to A. Stein, H. P. Gregor, P. E. Spoerri, J.Am.Chem.Soc., 78, 6185 (1956), wherein 3-methyl barbituric acid was synthesized from malonic acid and N-methyl urea in the
presence of acetic anhydride. The procedure needs excessive acetic acid as solvent and long reaction time (5 hrs) to afford 50% yield of the product.
Another reference may be made to J. W. Clark-lewis, J. Chem. Soc., 1628 (1959) wherein N,N-dimethyl barbituric acid was synthesised from N,N-dimethyl urea, malonic acid using acetic anhydride as dehydrating agents. The method requires acetic acid as solvent and takes 7 hrs to give 68% overall yield of the barbituric acid.
One more reference may be made to Organic Synthesis, Col. Vol. 2, Ed. A. H. Blatt, 60, 1943.( J. Michael, Prakt. Chem., (2)35, 456 (1887); Tafel and Weinschenk, Ber. 33, 3383 (1900); Gabriel and Colman, Bar. 37, 3657 (1904) wherein the synthesis of barbutiric acid by sodium alkoxide catalysed reaction of malonic ester with urea is described which takes long reaction times (7 hrs. at 110°C) and work-up procedure to yield 72-78 % of the product.
Still another reference may be made to H. Plaut, in Organic Sulfur Compounds, edited by N. Kharasch, vol. I, Ch. 40, Pergamon Press, (1961) wherein, the chemistry and pharmacology of thiobarbituric acid is reviewed.Novelty of the present invention lies in the production of barbituric acids and thiobarbituric acids under microwave irradiation in solvent free condition producing high yield of the products in a short time .
Summary of the invention
The present invention provides a process for the preparation of barbituric acid or their derivatives, which comprises reacting urea or substituted urea (formula 1) with malonic acid (formula 2) in the presence of acetic anhydride, under microwave irradiation at a temperature ranging between 60-95°C, for a period of 5-10 minutes, and removing any traces of acetic acid formed under reduced pressure, cooling down the above said reaction mixture to a temperature of 20-30°C, and isolating the resultant product by adding ethanol, followed by filtration and re-crystallization in ethanol, to obtain the desired product barbituric acid (formula 3) or its derivative.
(Figure Removed)
Detailed description of the invention
Accordingly, the present invention provides a process for the preparation of barbituric acid or their derivatives, which comprises reacting urea or substituted urea (formula 1) with malonic acid (formula 2) in the presence of acetic anhydride, under microwave irradiation at a temperature ranging between 60-95°C, for a period of 5-10 minutes, and removing any traces of acetic acid formed under reduced pressure, cooling down the above said reaction mixture to a temperature of 20-30°C, and isolating the resultant product by adding ethanol, followed by filtration and re-crystallization in ethanol, to obtain the desired product barbituric acid (formula 3) or its derivative.
(Figure Removed)
In an embodiment of the invention, the substituted urea used is selected from N, N-dimethyl urea, N-methyl urea and thiourea.In yet another embodiment of the invention, the reactions are performed in a solvent free condition.In yet another embodiment of the invention, the reaction temperature used is inthe range of 70-90°C.In yet another embodiment of the invention, the power of microwave irradiation used is in the range of 40-70%.In still another embodiment of the invention, the yield of product obtained is in the range of 60-90%.The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of N, N-dimethyl barbituric acid:1.06g (0.012 moles) of N, N-dimethyl urea was thoroughly mixed with 1.24g (0.0119 moles) of malonic acid and then added 3ml (0.0317 moles) of acetic anhydride. The whole reaction mixture was exposed to microwave irradiation (in a Synthewave 402 Monomode Reactor from Prolabo) at 40% power for 7 minutes keeping the temperature around 70°C. After that the small amount of acetic acid formed in the reaction was removed under reduced pressure. The remaining part was allowed to come to room temperature and added 10 ml of ethanol. Filtered off the light yellowish needle like solid compound and recrystallised from ethanol as white crystalline solid. Melting Point 121- 122°C. (Lit. 121°C- 123°C), yield 1.45g (78%).
EXAMPLE 2
Preparation of 3-methyl barbituric acid:
1.00g (0.0135 moles) of N-methyl urea was mixed thoroughly with 1.25g (0.012 moles) of malonic acid and then added 3 ml (0.0317 moles) of acetic anhydride. The whole reaction mixture was exposed to microwave irradiation (in a Synthewave 402 Monomode Reactor from Prolabo) at 50% power for 10 minutes keeping the temperature around 90°C. Then, the small amount of acetic acid formed was removed under reduced pressure. The remaining part was allowed to come to room temperature and added 10 ml ethanol. The light yellow solid which appeared was filtered and recrystallised from ethanol as whitish crystalline solid, mp 129-131°C (Lit. 130-131°C). Yield 1.357g (75%).
EXAMPLE 3
Preparation of barbituric acid:
1.24g (0.02 moles) of urea was mixed well with 2.1g (0.02 moles) of malonic acid. Added 4 ml (0.0425 moles) of acetic anhydride to the reaction mixture and then allowed to react under microwave irradiation (in a Synthewave 402 Monomode Reactor from Prolabo) at 70% power for 5 minutes keeping the temperature around 90°C. When the reaction mixture was allowed to come to room temperature, instantly a whitish solid compound separated out. The compound was recrystallised from ethanol, mp 253-254°C (Lit. 253-254°C). Yield 2.47g (95%).
EXAMPLE 4
Preparation of thiobarbituric acid:
1.00g (0.0131 moles) of thiourea was mixed thoroughly with 1.40g (0.0134 moles) of malonic acid and then added 3 ml (0.0317 moles) of acetic anhydride. The whole reaction mixture was allowed to react under microwave irradiation (in a Synthewave 402 Monomode Reactor from Prolabo) at 40% power for 5 minutes, keeping temperature around 70°C. Then, the small amount of acetic acid formed, was removed under reduced pressure and the residue was allowed to come to room temperature. A light yellow needle like solid which separated out, was recrystallised from water as whitish crystalline solid, mp 232-134°C (Lit. 235°C). Yield 1.13 (60%).

We claim
1. A process for the preparation of barbituric acid or its derivatives, which
comprises reacting urea/thiourea or substituted urea of formula 1 with malonic
acid of formula 2, in the presence of acetic anhydride, under microwave
irradiation, at a temperature ranging between 60-95°C, for a period of 5-10
minutes, and removing any traces of acetic acid formed under reduced
pressure, cooling down the above said reaction mixture to a temperature of
20-30°C, and isolating the resultant product by known methods, followed by
filtration and re-crystallization in ethanol, to obtain the desired product
barbituric acid or its derivative of formula 3.
(Figure Remove)
2. A process as claimed in claim 1, wherein the substituted urea used is selected
from N, N-dimethyl urea and N-methyl urea.
3. A process as claimed in claim 1, wherein the reaction is performed in a solvent
free condition.
4. A process as claimed in claim 1, wherein the reaction temperature used is in
the range of 70-90°C.
5. A process as claimed in claim 1, wherein the power of microwave irradiation
used is in the range of 40-70%.
6. A process as claimed in claim 1, wherein the yield of product obtained is in the
range of 60-90%.
7. A process for the production of barbituric acid or their derivatives as
substantially herein described with reference to the examples.