Synthesis of Some New N-Mannich Bases Derivatives of Phenytoin

 

Sushil R. Mathapati¹, Vikas B. Suryawanshi²,Abhay S. Bondge³,Jairaj K. Dawale⁴*

¹Department of Chemistry, S. M. P. Mahavidyalaya, Murum-413605, Dist.- Osmanabad, India.

²Department of Chemistry, KMC College, Khopoli, Maharashtra- 410203 India.

³Shivneri College, Shirur Anantpal, Dist. Latur, Maharashtra- -413544, India.

⁴Research Laboratory for Pure and Applied Chemistry, M. M. College, Nilanga, Dist. Latur, MH- 413521, India.

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

5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, a small series of amine derivatives (Mannich bases) were designed containing phenytoin nucleus. For this synthesis we follow green methodology during synthesis of phenytoin from benzyl and urea.

 

 

INTRODUCTION:

Green chemistry is the design of chemical products and process that eliminates the use and generation of hazardous substances [1]. Using green solvent, like water, synthesis of biologically active moiety with high percentage yield as well as high purity is one of the objectives of green chemistry. Purity of few drugs for CNS acting required high profile of purity and safety for pertaining biological activity [2].

 

Phenytoin is one of the most widely used drugs in the therapy of epilepsy. However, its low solubility in water, both as free acid and sodium salt, makes its administration to patients difficult and seldom satisfactory. Phenytoin is given orally as sodium salt in a strong alkaline solution, since it requires a p^H between 10 and 12 to be maintained in solution [3].

 

Phenytoin (5, 5-diphenylimidazolidine-2,4-dione) is the first anticonvulsant agent often cited as a prime example of anticonvulsant acting as a sodium channel blocker [4-5]. Generally, according to reported procedure, it is synthesized by condensation of benzil and urea in presence of base (30% w/v NaOH) using ethanol as solvent which itself acts as CNS stimulant [6]. Removal of solvents after synthesis is most difficult and non-assured process. In case of Phenytoin, transformation in polymorphism plays an important role when solvent other than water is used. About 30% extra cost is calculated if solvent other than water is used. Considering this advantages of water solvent, we synthesis phenytoin derivatives in water solvent. 

 

The Mannich reaction as a powerful C-C bond formation process has wide applications for the preparation of diverse aminoalkyl derivatives [1]. It involves the condensation of a compound capable of supplying one or more active hydrogen atom with aldehyde and primary or secondary amine [2].Mannich bases are physiologically reactive because of the basic function rendering the molecule soluble in aqueous solvent when it is transformed into ammonium salt[3]. Tromontini and Angiolini [4] have reviewed several medicinally useful Mannich bases. Besidesthis, considerable work has been reported on synthesis and pharmacological activities of various Mannich bases for analgesic, antispasmodic, anesthetic and anti-malarial as well as intermediates in drug synthesis [5-14].On the other hand, the first clinically approved antiviral agent N-methylisatin-β-thiosemicarbazone and isatin-β-thiosemicarbazone are active against poxvirus [15]. Antiviral properties of certain thiourea and urea derivatives have been reported in which the antiviral effect is attributed to the presence of an intact NH-C(=S)-NH and NH-C(=O)-NH grouping[16]

 

In our previous work, we report synthesis of Thiophenytoin derivatives by using aryl thiouea. [17].As following last work we try to synthesis of N-alkylating derivatives of phenytoin via mannich bases rather than use of aryl thiourea.   Based on the above observation it is worthwhile to prepare newer compounds for their antimicrobial and antiinflammatory activities. In the view of the varied biological and pharmacological application, we synthesized some new N-mannich base derivatives of Phenytoin. We have prepared first Phenytoin from Benzyl and Urea. Next step was the synthesis of Mannich bases derivatives of Phenytoin using various secondary amine and formaldehyde.

 

In the given optimized conditions all secondary amine gives excellent yield of desired products with phenytoin.  Synthesized moieties are conformed based on physical and spectral study (FT-IR, H¹NMR and C¹³NMR). As results, this method showed 100% conversion of reactant with high yield of respective mannich bases.

 

EXPERIMENTAL WORK:

General

All the chemicals used for synthesis were of LR (Laboratory Reagent) grade and used after further purification. All solvents were obtained from commercial sources and were distilled from appropriate agents prior to use it. All the melting points of prepared compounds were determined in open capillary tubes and are uncorrected. The IR spectra (in cm^-1) were recorded on a Perkin-Elmer spectrophotometer in KBr pellets. ¹HMR spectra were recorded on Varian Gemini (200 MHz) spectrometer using DMSO-d₆ as solvent and TMS as internal standard.¹³C-NMR spectra recorded on50 MHz in DMSO-d₆ solvent, in δ ppm. All chemical shifts values are reported in δ scale downfield from TMS. Homogeneity of the compound was checked by TLC on silica gel plates.

 

 

 

 

 

General procedure for the synthesis of Mannich bases of Phenytoin (5,5-diphenyl-2 Imidazolidine-4-one).

Step I: Synthesis of Phenytoin (5,5-diphenyl-2- Imidazolidine-4-one) using Benzyl and urea.

Benzyl (0.025 mol) and Urea (0.05 mol), 15 ml of 30% w/v sodium hydroxide solution and 40 ml of water was placed in a 250 ml round bottom flask and heated at 80 to 90^oC temperature. The progress of reaction was traced by TLC. After completion of the reaction (monitored by TLC; CH₂Cl₂ and ethyl acetate (70:30)). After completion of the reaction, stand the resulting reaction mixture to attained room temperature, and then poured into 100 ml of water with stirring. It was allowed to stand for 15 minutes and filtered under suction to remove the insoluble by-product. The filtrate thus obtained was cooled and acidified by using concentrate hydrochloric acid. The precipitates obtained were separated by filtration. The crude product obtained was washed with cold water.

 

 

 

Step II: Synthesis of novel N-Mannich bases of phenytoin (6a-e).

To a solution of phenytoin 3 (0.1 mole) in DMF, formaldehyde (0.1 mole) 4 was added under stirring. The reaction-mixture was stirred at RT for 0.5 hr to complete the reaction of formaldehyde and to yield methylol derivative of 3. To this, solution of secondary amines 5a-e (0.1 mole) in DMF was added drop wise and refluxed for reported time. Completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured into ice cold water and filtered off and washed with hot water. Finally, it was dried and purified by recrystallization from chloroform to give 6a-e.

 

 

 

 

Spectral analysis of synthesized compounds (6a-h)

2-((2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl) isoindoline-1,3-dione (6a): ¹H NMR (in δ ppm): 10.2 (s, 1H, NH), 5.22(s, 2H), 7.23–7.33 (m, 10 H), 7.80-7.83 (m, 4 H).¹³C NMR(in δppm):170.5, 165.2,158.7,139.8,132.7, 128.5, 126.2, 123.7, 73.7, 50.4; IR (in cm^–1): 3160, 2940, 2830, 1772, 1732, 1715.

3-(morpholinomethyl)-5,5-diphenylimidazolidine-2,4-dione (6b):  ¹H NMR (in δ ppm): 9.29 (s, 1H, NH), 2.62 (t, 4H) 3.72(t, 4H), 5.1 (s,2H), 7.21–7.35 (m, 10 H).¹³C NMR(in δppm): 163.3, 158.2, 140.2, 129.4, 128.3, 124.7, 73.5, 67.4, 65.2, 52.4; IR (in cm^–1): 3224, 2912, 2840, 1770, 1725and 1710.

 

3-((diethylamino)methyl)-5,5-diphenylimidazolidine-2,4-dione (6e): ¹H NMR (in δ ppm): 9.81 (s, 1H, NH), 1.14 (t, 6H) 2.74(q, 4H), 4.32 (s, 2H), 7.25–7.38 (m, 10 H).¹³C NMR(in δppm): 163.2, 158.9, 140.7, 131, 129.5, 127.1, 75.4, 65.1, 48.2, 15; IR (in cm^–1): 3322, 2902, 2848, 1766, 1720and 1695.

 

3-((diphenylamino)methyl)-5,5-diphenylimidazolidine-2,4-dione (6g):¹H NMR (in δ ppm): 10.2 (s, 1H, NH),5.10 (s, 2H),6.75(t, 2H),7.24–7.36 (m, 18 H).¹³C NMR(in δppm): 163.4, 158.6, 150.5, 140.2, 130.3, 128.7, 126.8, 122.2, 120.6, 73.8, 72.4; IR (in cm^–1): 3280, 2962, 2860, 1752, 1719and 1692.

 

2-((2,5-dioxo-4,4-diphenylimidazolidin-1yl)(phenyl) methyl) isoindoline-1,3-dione (6h): ¹H NMR (in δ ppm):  9.7 (s, 1H, NH), 6.51 (s, 1H), 7.25- 7.46 (m, 15H),7.82–7.87 (m, 4H).¹³C NMR(in δppm): 170.2, 163.2, 158, 145.7, 140.2, 132.7, 129.9, 129.2, 126.3, 122.9, 75.7, 70.2; IR (in cm^–1): 3360, 2950, 2888, 1740, 1723 and 1712.

 

RESULTS AND DISCUSSION:

Derivatives of Phenytoin have importance in the field of pharmaceuticals. The compounds reported in this research work ie. Derivatives of N-mannich bases of Phenytoin and synthesized compounds in two steps.  N-mannich bases derivative of phenytoin were final compounds and prepared due to its biological activity. For this synthesis, we used different secondary amines, also used formaldehyde and benzaldehyde with phenytoin.

 

Initially, we start with synthesis of phenytoin moiety from benzyl and urea, for this transformation, we used water as solvent.  Water play a vital role, which reported considerable yield of phenytoin. Use of green solvent as water is the key point of this work, it’s an ecofriendly process. After that, we carried out work on synthesis of mannich bases of phenytoin, for this transformation, we have used various secondary amines with formaldehyde, observed results were summarized in Table I. Primarily, we performed reaction with phthalamide, an equimolar amount of phenytoin with phthalamideand formaldehyde (Entry 1) were refluxed in DMF solvent, its results 100% conversion with 90% yield in 4 hr. Afterwards same reaction carried out with morpholine  in DMF it gives 92% yield of 3-(morpholinomethyl)-5,5-diphenylimidazolidine-2,4-dione(Entry 2) within short reaction time 2 hr.

 

Additionally, we have reported mannich bases derivatives that were synthesized from pipyridine and piperazine, it shows successful conversion with 90% and 83% yield respectively (Entry 3 and 4).  We have synthesis 3-((diethylamino)methyl)-5,5-diphenylimidazolidine-2,4-dione from phenytoin by reacts it with diethyl amine in DMF. This shows 100% of reactant with 85% yield of respective product in 2.4 hr(Entry 5). Entry 6and 7 shows, Dimethyl amine and Diphenylamine were also reported respectable 88 % yield. Furthermore, when we replace formaldehyde to benzaldehyde for the same reaction under prescribed reaction condition. Equimolar amount of phenytoin with Benzaldehyde and Phthalamide reflux for 4.2 hr. in DMF solvent, it shows 100% with satisfactory 84% yield of  2-((2,5-dioxo-4,4-diphenylimidazolidin-1 yl)(phenyl)methyl) isoindoline-1,3-dione (Entry 8).

 

Present method report simple and efficient synthesis of N-mannich bases of phenytoin. Use of water as solvent, which follows principles of green chemistry. We synthesized newer derivatives of mannich bases to avoid the side effects of phenytoin molecule under anticonvulsant and antiarrhythmic screening.

 

CONCLUSION:

In conclusion, we have developed a simple and efficient method for the synthesis of N-mannich bases derivatives using phenytoin under mild reaction conditions with competitive and high yield. The advantages of the present technique are the operational simplicity, high efficiency, no side products formation, easy of workup procedure, less reaction time, thus suitable for large-scale production of N-mannich bases derivatives of phenytoin. Various synthesized moieties are important pharmacophores in the field of anticonvulsant and antiarrhythmic drug.

 

 

 

 

 

 

 

 

 

 

 

Table I: Synthesis of N-mannich bases from phenytoin and various secondary amines under optimized reaction conditions.

 

 

 

 

 

 

 

 

 

 

ACKNOWLEDGEMENT:

Authors are thankful to the managements and Principals of their respective colleges for encouragement and assistance. They are also thankful to the IICT Hyderabad for providing spectral data.

 

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Received on 10.03.2018         Modified on 26.03.2018

Accepted on 16.04.2018         © AJRC All right reserved