Advanced Materials Research Vols 518-523 (2012) pp 3917-3920
© (2012) Trans Tech Publications, Switzerland
doi:10.4028/www.scientific.net/AMR.518-523.3917
Online: 2012-05-14
Green synthesis of Phenytoin Sodium
Du Tingting 1, a, Li Jingfen 1, b* , Min Lijing 1, c
1
School of Life Science, Huzhou Teachers College, Huzhou, China
a
714716887@qq.com, b*ljfljf@hutc.zj.cn, cminlijing@hutc.zj.cn
*corresponding author
Keywords: phenytoin sodium; supersonic wave; vitamin B1; FeCl3 • 6H2O
Abstract. In this study, benzaldehyde was reacted with benzoin condensation, oxidation and cyclization reaction to product phenytoin sodium under the supersonic wave radiation. In the condensation reaction, non-toxic vitamin B1 was used as a reactor instead of highly toxic cyanide on pH=9
at 70 oC. After that, FeCl3 • 6H2O was used as oxidant instead of concentrated nitric acid under the
mild conditions. The results were that the yield of phenytoin sodium was up to 56.8%. There were
many advantages in this improved synthesis method such as shorter reaction time, higher product
purity, lower environmental pollution and higher product yield.
Introduction
Phenytoin sodium (5,5-diphenylhydantoin sodium) was also named as dilantin sodium and commonly used in antiepilepsy, antiarrythmia, antitrifacial neuralgia, anti-mild hypertension [1]. Traditionally, the benzaldehyde was used as a raw material through the condensation, oxidized and the
pass link condensation to give the product phenytoin sodium [2-4]. However, in this method, some
reagents were hypertoxic and corrosive, and the yield of product was lower. Based on that, in this
study, benzaldehyde was reacted with benzoin condensation, oxidation and cyclization reaction to
product phenytoin sodium under the supersonic wave radiation [5, 6]. And specifically, the improvement styrax's condensation reaction led to the increase of the yield. And Vitamin B1 was used
as catalyst in the styrax condensation reaction, which was mild, non-toxic, and yield high. And
moreover, FeCl3•6H2O was used as oxidant instead of concentrated nitric acid, which reduced the
environmental pollution.
Experimental
Principle. Fig. 1 showed the synthetic route of phenytoin sodium.
O
C
2
H
O
C
VB 1,OH
OH
O
O
CH
C
C
USI
H 2 NCONH 2
NaO
NH
N
O
Fig.1 The synthetic route of phenytoin sodium
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Advances in Environmental Science and Engineering
Materials. KQ3200DB Ultrasonic cleaning device was bought in Kunshan Ultrasonic
Instrument Co., Ltd. SHZ-D Circulating water pumps was bought in Gongyi Yingyu Yuhua
Instrument Factory. HicoLET5700 Infrared spectrometer was bought in Shanghai Analytical
Instrument Factory. ATC-15 Set thermostat was bought in Xinhua Medical Instrument Factory.
Methods
Synthesis of benzoin. 1.8007g Vitamin B1, 6 mL distilled water and 15 mL 95% ethyl alcohol were
added in the 100 mL round flask. And then 5 mL cold NaOH solution and the benzaldehyde were
added in the mix solution above and shake fully. The reaction was completed in the ultrasonic wave
instrument at 70 oC for 90min under 60% ultrasonic frequency. The mixture was cooled and crystal-lized. The crystal was washed by 30 mL deionized water and dried to give the product benzoin.
In other two round flasks (100 mL), no Vitamin B1 and 0.9005g Vitamin B1 were added into the
react-ive solution, respectively. The following step was the same as above. Record whether there
was be-nzoin finally. The product benzoin was added in 70 mL 80% ethylalcohol (there was some
activete-d carbon) and in circumfluence for 90-120min. Then the mixture was cooled, crystallized,
filtrate-ed and dried to give the purified crystal benzoin. In this experiment, all the operation was
followed the step above except from operation with 1.8007g Vitamin B1 under 80% ultrasonic frequency. Record the weight of crystal benzoin. As the operation, the ultrasonic frequency was fixed
in 100% and the backflow time was 30 min and 90 min. The affect of reaction time on the yield of
benzoin was record.
Preparation of 1,2-diphenyl ethanedione. 4.3006 g benzoin, 12.5 mL acetic acid, 2g sodium
nitrate and 2.5 mL 2% copper sulfate were added in round bottom flask and stirred in circumfluence
for 1.5 h. The mixture was cooled to 50-60 oC and then in ice water bath to separate out
1,2-diphenyl ethanedione. The crystal was filtrated and dried. The weight of crystal was recorded.
Synthesis of phenytoin sodium. 2.1088g 1,2-diphenyl ethanedione, 0.6103g urea and 5 mL water were added in 50 mL flask and stirred at 98 oC. Then, 6 mL 30%NaOH was added into the reactor in circumfluence for 1 h. After that, 10 mL water was added and the mixture was discolored. The
filtrate was adjusted to pH 5-6 at 45 oC to obtain the precipitation, which was washed by water to
give 5,5 - phenyl hydantoin (diphenylhydantoin). Diphenylhydantoin was adjusted the pH 11-11.5
by 30% NaOH and discolored at 70-80 oC for 0.5 h. The solution was filtrated and dried to give the
product phenytoin sodium.
Infrared spectra. Infrared spectra were measured by a HicoLET5700 Infrared spectrometer with
KBr disks.
Results and discussion
Table 1-3 showed the results of synthesis of benzoin under different condition.
Table 1 The results of synthesis of benzoin under different ultrasonic frequency
Ultrasonic
frequency [%]
Time
[min]
Temperature
[℃]
0
90
70
60
90
80
100
90
90
Benzaldehyde
[mL]
Quantity of
Production [g]
Yield
[%]
10
4.1117
39.5
70
10
6.4290
61.8
70
70
10
10
5.3215
5.8651
51.2
56.4
Advanced Materials Research Vols. 518-523
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Table 2 The effect of catalyst on the synthesis of benzoin
Quantity of
catalyst [g]
Ultrasonic
frequency [%]
Time
[min]
Temperature
[℃]
Benzaldehyde
[mL]
Quantity of
production [g]
Yield
[%]
60
90
70
10
0
0
60
60
90
90
70
70
10
10
6.4290
4.3218
61.8
41.6
0
1.8007
0.9003
In this step, Vitamin B1 was used as the catalyst under the alkalinity condition, which urged the
production of carbon anoin, and thus it played the great role to the yield of product. The high pH
could urge the Vitamin B1 to product carbon anoin, which was advantageous to the condensation of
benzaldehyde. But if the pH value is too high, it was easy to have the Cannizzaro disproportionation
under the strong alkali condition resulting to the decrease of product.
Table 3 The effect of ultrasonic and time on the synthesis of benzoin
Ultrasonic
frequency [%]
Time
[min]
Temperature
[℃]
Benzaldehyde
[mL]
Quantity of
production [g]
Yield
[%]
0
90
70
10
4.1117
39.5
100
100
90
30
70
70
10
10
5.3215
4.1454
51.2
39.9
In the IR spectrums of benzoin, 3421.35 cm-1 and 3372.76 cm-1 were assigned to stretching
vibration of OH. 3032.64 cm-1 and 2931.04 cm-1 were assigned to stretching vibration of =C-H on
the aromaticring. 1676.56 cm-1 was assigned to stretching vibration of C=O. 1446.87 cm-1, 1539.63
cm-1 and 1574.97 cm-1 were assigned to skeleton vibration of the aromatic ring. 757.79 cm-1 and
700.37 cm-1 were assigned to bending vibrations outside aromatic ring for list substitution surface.
All the data were consistent with standard infrared spectroscopy of benzoin [7].
In the IR spectrums of 1,2-diphenyl ethanedione, 3050.46 cm-1 and 3001.04 cm-1 were assigned to
stretching vibration of =C-H on the aromaticring. 1710.25 cm-1 was assigned to stretching vibration
of C=O. 1546.43 cm-1, 1498.97 cm-1 and 1529.86 cm-1 were assigned to skeleton vibration of the
aromatic ring. 734.79 cm-1 and 698.74 cm-1 were assigned to bending vibrations outside aromatic
ring for list substitution surface. All the data were consistent with standard infrared spectroscopy of
1,2-diphenyl ethanedione [7].
In the IR spectrums of phenytoin sodium, 3275.58 cm-1 and 3204.91 cm-1 were assigned to
stretching vibration of unsaturated =C-H. 3076.81 cm-1 and 3037.06 cm-1 were assigned to
stretching vibration of =C-H on the aromaticring. 1716.32 cm-1 was assigned to stretching vibration
of C=O. 1654.48 cm-1, 1519.14 cm-1 and 1557.30 cm-1 were assigned to skeleton vibration of the
aromatic ring. 1495.46 cm-1 was assigned to stretching vibration of secondary amine. All the data
were consistent with standard infrared spectroscopy of phenytoin sodium [7].
Conclusion
In this study, VB1 was used as catalyst under ultrasonic wave to synthesize benzoin. After that
FeCl3 • 6H2O was used as oxidant instead of concentrated nitric acid under the mild conditions.
This method was safe, fast and highly effective. Specially, benzoin was synthesized under
ultrasonic wave, which raised the utilization of raw material benzaldehyde and reduced the emission
of benzaldehyde. And simultaneously, the catalyst was halved which was a symbol of green
chemistry. The results indicated that the temperature to synthesize benzoin is 70 oC, the ultrasonic
frequency is 60% and the time is 90 min.
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Acknowledgements
This work was supported by the teaching reform project of new century higher education of
Zhejiang Province (zc2010081), which is about the research and practice of classroom teaching
reform of 《Organic Reactions for Drug Synthesis》in Pharmaceutical Engineering. We are grateful
to Dr. Zhang Zhongshan for his help in this study.
References
[1] W. J. Tian, J. Yuan, R. Zhang, et al: The summarize of clinical application of Phenytoin Sodium.
Strait Pharmaceutical Journal Vol. 11( 2007), p.74-76
[2] J. C. Feng and L.G. Mai: Preparation of Phenytoin Sodium. Journal of Tianjin Normal University (Natural Science Edit ion) Vol. 20( 2000), p.70-72
[3] L. J. Li, J. Zhang and H. L. Chen: The synthesis route improvements of Phenytoin Sodium. Hebei Chemical Engineering and Industry Vol. 6(2004), p.40-41
[4] J. J. Deng, T. T. Li and S. L. You: The synthesis route improvements of Phenytoin Sodium. Inner
Mongol Journal of Traditional Chinese Medicine Vol. 5(2008), p.46-47
[5] Q. Chen, Z. L. Yuan and H. X. Wu: Benzoin condensation with supersonic as promoter.
Shanghai Chemical Industry Vol. 30(2005), p.19-21
[6] J. Nulty Mc, J. A. Steere and S. Wolf: The ultrasound promoted knoevenagel condensation of
aromatic aldehydes . Tetrahedron Letters Vol. 39(1998), p. 8013-8016
[7] Tianjin University: Guide of pharmaceutical engineering experiment (Chemical Industry Press,
Tianjin 2005)
Advances in Environmental Science and Engineering
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Green Synthesis of Phenytoin Sodium
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