Experiment 2 Synthesis of Nifedipine Purpose • Be familiar with the general process of pharmaceutical API preparatio n
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Purpose • Be familiar with the general process of pharmaceutical API preparatio n • Be familiar with intermediate control methods in drug preparation pr ocess • Understand the synthesis of dihydropyridine compounds and the appl ication of Hanstzch reaction in the production of dihydropyridine cardi ovascular drugs
Background • Nifedipine is first generation 1,4-dihydropyridine calcium antagonist. I t is widely used drug for the treatment of hypertension and stenocard ia. • Nifedipine is sparingly soluble in water solution Molecular Formula Molecular Weight Flash Point Exact Mass C,H,O, 346.335 241.2428.7 °C 346.116486 110.45000 2.97 PSA LogP
Experimental principles • Nifedipine was synthesized by condensation of ethyl acetoacetate, o-n itrobenzaldehyde and ammonia CH3COCH_COOCH3 + NH3 + CHO CH,00C HC- -NO -COOCH -CH3 NO2
Mechanism • Nifedipine is a dihydropyridine derivative in structure. It can be synthe sized from 2 Molecular ketoacids, 1 molecular aldehydes and 1 molec ular ammonia by hanstzch reaction. The mechanism is as follows: COCH.COM ROCCORD SCHOOR SH A 2010 ROCH.COM.CO CO ROC CH CR ROC CO ROOC ROOC ROOC
Reagents and specifications • O-nitrobenzaldehyde CP or AR 2 98% • molecular weight 151.12, light yellow acicular crystal, melting point 44 - 46 °C, boiling point 153 °C / 3.06 kPa, slightly soluble in water, soluble in alcoho 1, ether and benzene • methyl acetoacetate C.P. or AR 97% . molecular weight 116.11, colorless transparent liquid, boiling point 169 ~ 171 °C, n 1.418, D 1.0785, colorless transparent liquid, aromatic, slightly soluble i n water and easily soluble in organic solvents. • Ammonia C.P. or AR 25 ~ 28% • Methanol C.P. or AR
Experimental procedures • 100ml pear shaped bottle equipped with a reflux condenser and electromagnetic stir rer • 7.6g (0.05mol) of o-nitrobenzaldehyde, 13ml (0.12mol) of methyl acetoacetate, 15ml of methanol and 6ml (0.08mol) of ammonia (25 - 28%,D 0.91) successively added to the reaction bottle • Heat slowly under stirring, and then reflux after 0.5h • After 2h of reaction, take a little mixture reactant and check the reaction by TLC chro matography. Until the reactant reaction is complete, the whole reflux process takes a bout 3h. Cool to 5 °C, precipitate yellow crystals, keep heat for 1h, filter with funnel, wash wit h a small amount of ice methanol to obtain crude products, dry them as much as pos sible and weigh
Experimental procedures • The crude product is recrystallized by 7-8 times the volume (ml/g) of methanol • If necessary, it can be filtered while hot, standing, cooled (~ 5 °C), filte red, washed with a little ice methanol, and dried at 75 °C, to obtain 1 0 - 12g light yellow crystals • Measure the melting point (171 - 175 °C) and nuclear magnetic reson ance (solvent: CDC13). • Calculate the yield.
Final Report Template: 1. Abstract 2. Keywords 3. Introduction and Purpose 4. Experimental Procedures 5. Result and Discussion 6. Conclusion 7. Reference
Final Report Template: 1. Abstract 2. Keywords 3. Introduction and Purpose 4. Experimental Procedures 5. Result and Discussion 6. Conclusion 7. Reference