Microwave Assisted Synthesis and Characterization of Phenytoin

 

Mukesh K. Nagar*, Karishma R. Waghmare², P.N. Dhabale, Pradeep D. Chanekar and Suresh Bhatia

Govt. College of Pharmacy, Karad, Dist: Satara, Maharashtra- 415124, India.

*Corresponding Author E-mail: mukeshnagar26@rediffmail.com

ABSTRACT:

A simple, clean, fast, efficient and economical, microwave-assisted method for the synthesis of Phenytoin has been developed. The antiepileptic drug Phenytoin is synthesized by reaction between Benzil and Urea. The activation of Benzil and Urea is a type of pinacole-pinacolone rearrangement reaction. Comparison of microwave assisted synthesis with the conventional methods of synthesis demonstrates advantages related to shorter reaction time and in some cases better reaction yields. Moreover, microwave activation is a very convenient method for the synthesis of phenytoin resulting in good yield and purity.

 

 

 

INTRODUCTION:

Microwave assisted organic synthesis become an increasingly popular technique in academic and Industrial research laboratories, due to certain advantages, particularly shorter reaction times and rapid optimization of chemical reactions.^1-3 Synthesis of phenytoin requires ethanol as solvent and two hours of reflux in the conventional methods. The synthesis of phenytoin by the reaction of urea with Benzil in presence of aqueous sodium hydroxide in absence of solvent (ethanol) under microwave irradiation is described. The products are obtained in quantitative yields and excellent purities.⁴

 

The imidazolidine-2, 4-dione, or hydantoin nucleus is a common 5-membered ring containing a reactive cyclic urea core. This heterocycle is present in a wide range of biologically active compounds including anticonvulsant⁵ and antitumor⁶ agents.

 

Phenytoin or 5,5 diphenylhydantoin, is a well-known therapeutic drug for the treatment of epileptic seizures, clinically it is most effective in controlling of tonic-clonic, clonic, tonic and partial seizures.⁷

 

Phenytoin acts to damp the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage gated sodium channels. Phenytoin is also used to control arrhythmias (irregular heartbeat) and to treat migraine headaches and facial nerve pain.^8,9

 

Microwave assisted synthesis has emerged as frontier in pharmaceutical research for synthesis of newer drugs. Microwave irradiation is well known to promote the synthesis of a variety of organic compounds, where chemical reactions are accelerated because of selective absorption of microwave by polar molecules.¹⁰

 

EXPERIMENTAL WORK:

Melting points were determined in open capillary tubes, expressed in ⁰C and are uncorrected.

The time required for completion of the reaction was monitored by TLC using precoated Silica gel-G plates using the solvent system chloroform: acetone (4:1) and spots were exposed in iodine chamber¹¹. Identification test was carried out as per Indian pharmacopoeia¹².

 

 

 

TABLE:-1.  METHOD – A, POWER LEVEL-6(420W)

Sample no.	Time (min.)	Yield  (gm)	Melting Point(oC)	TLC (Rf. value)	IR(KBr)cm-1
A1	1	4.01	295	31	1448,1492,1725,3211
A2	2	5.46	296	32	1448,1494,1725,3211
A3	3	6.01	291	32	1448,1496,1720,3209

 

TABLE:-2.  METHOD- B, CONSTANT TIME (2 min.)

Sample no.	Power Level	Yield  (gm)	Melting Point(oC)	TLC (Rf. value)	IR(KBr)cm-1
B1	3(245W)	4.19	294	34	1448,1494,1720,3213
B2	4(280W)	4.93	295	31	1448,1494,1720,3213
B3	5(350W)	5.21	292	32	1448,1494,1720,3209

 

 

 

The IR spectra of the compounds were recorded on Shimadzu IR Affinity FTIR using KBr discs and the values are expressed in cm^-1.

 

Conventional Method for Synthesis of Phenytoin:

Place 5.3 gm of benzil and 3 gm of Urea, 15 ml of 30% Sodium hydroxide, 75 ml ethanol in 250 ml RBF. Attach to reflux condenser and heat the reaction mixture for 2 hours. Cool the flask and pour the content into 125 ml cold water. Filter and render filtrate strongly acidic with concentrated HCl. Filtrate the precipitates and recrystallized by industrial spirit¹³.

 

Microwave Method:

For the synthesis of phenytoin by the microwave method placed 5.3 gm of benzil, 3 gm of urea and 15 ml of 30% sodium hydroxide in the RBF and was irradiated in the microwave at specific power for specific time. The reaction mixture was then cooled to the room temperature then added 100 ml of water and filtered. To the filtrate added concentrated HCl until the solution was strongly acidic. Cooled in the ice water and immediately filtered. Precipitate was then collected, washed with water and recrystallized by industrial spirit. Product from each method was collected and melting point of each was taken.

 

In microwave assisted synthesis two methods were used. In method-A intensity (power) of the wave were kept constant and time for irradiation was varied. In Method-B intensity of the wave was varied and time for the irradiation was kept constant (Tables:- 1 and 2).

 

In all two methods time required for the reaction was reduced and also the reaction can be carried out in the absence of the solvent. The yield was also increased as compared to the conventional method.

 

RESULTS AND DISCUSSION:

The Biltz synthesis is a common way to synthesize phenytoin starting from benzil and urea. The microwave heating effectively reduced the reaction time from (2-20) hours to a few minutes (1-10 minutes). All The six synthesized phenytoin compounds were characterized by their physical, chemical and spectral data.

 

From the results, it was observed that the melting point for sample no. A₁(295 ^oC), A₂(296 ^oC), A₃(291 ^oC), B₁(294 ^oC), B₂(295 ^oC) and B₃(292 ^oC).

IR spectra of synthesized compounds showed the presence of characteristic absorption peaks around 1448 cm^-1, 1494 cm^-1, 1720 cm^-1, 3211 cm^-1.

 

CONCLUSION:

From the above result, it would be concluded that the microwave assisted method is very convenient method due to enhanced reaction rates, higher yields, improved purity, ease of work up after the reaction and eco-friendly reaction conditions compared to the conventional methods. Microwave irradiated synthesis of phenytoin was carried out to get higher yield with less reaction time period as compared to conventional method. The synthesized phenytoin produces yield around 50% (conventional) and 90% (microwave).

 

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Received on 07.12.2010        Modified on 18.12.2010

Accepted on 30.12.2010        © AJRC All right reserved