Investigation of synthesis methods of anti-anginal drug nicorandil and optimization of the selected synthesis method

Abstract

Nicorandil is a nicotinamide nitrate with both vasodilator and potassium channel opener activity used to treat angina, patented in 1976 and approved as a drug in 1983 and Various methods for the synthesis of this drug have been reported, and in this project, we have succeeded in producing this drug by synthesizing all the pharmaceutical intermediates.Objective:The synthetic method was optimized for localizing the production of this drug in the country, considering the potential of the Iranian Chemical and pharmaceutical industry .Method and materials : For the synthesis of Nicorandil , at first the intermediate of ethyl nicotinate was prepared (step:I),then this compound was converted to (3) (step:II). In the next step , the intermediate (3) was converted to (4) (step:III),then with nitration of this compound (4) the finish product (5) is obtained (step:V).Also for the synthesis of (4) is obtained from reaction between 2-chloroethylamine and (2) (step:IV).

Figure 1-1) Optimized method for the synthesis of nicorandil Ι) ethanol, H2SO4, reflux4h, (yield 71%) ΙΙ) Monoethanolamine, 160oc, 1h, (yield 93%) ΙΙΙ) Thiourea, NCS, Dichloromethane, 1h (yield 52%) ΙV) 2-chloroethanolamine, chloroform ,25oc, 120h, (yield 10%) V)NaNO3, acetonitrile, reflux48h, (yield 91%). Overall yield 76.5%

Findings The melting point of nicorandil is reported to be 88-920C, and the melting point of synthesized nicorandil was found to be sharp at 91.50C , and the TLC of that is at one point and the FT-IR and 1HNMR confirms that this compound is made with high purity and Total reaction yield was calculated 76.5%. Conclusion:Elevated efficieny of the reaction stages,eliminated toxic solvents,and inexpensive reactants , reducing the production of industrial wastewater. As a result, we achieved the technical knowledge of producing Nicorandil , which was an optimized, simple, and cost-effective approach .