The synthesis of dofetilide, a drug to combat erratic heartbeat

The synthesis of dofetilide, a drug to combat erratic heartbeat 

The chapter ends with a complete synthesis of an important new drug. Cardiac arrhythmia (erratic and inefficient heart action) is a major problem in the modern world causing poor lifestyle (exhaustion) and death by blood clots. A new drug dofetilide (Tikosyn ) is being introduced by Pfizer to treat this problem. It works by blocking the passage of potassium ions out of heart muscle and so delays the onset of an irregular beat until the next normal beat takes over. 

We are going to do a little more than simply give the reactions that eventually made up the synthesis of dofetilide. We are going to put ourselves in the place of the chemists who invented the synthesis and try to see what led them to the reactions they chose. First, we should inspect the structure of the molecule. There are two sulfonamides, one at each end. We have seen how to make sulfonamides earlier in this chapter when saccharin was being discussed. The usual way is to react the amine with a sulfonyl chloride. In this case we shall need to react methane sulfonyl chloride (MeS02Cl or MsCl) with the aromatic amines. This is a well-known reaction and should work well here. The other functional groups— tertiary amine and alkyl aryl ether—should not interfere so no protection is needed. 

So we need to make the required aromatic diamine. We might guess from what we did earlier in this chapter as well as from Chapter 22 that this is likely to be achieved by nitration and reduction so we should check that double nitration of our proposed starting material will occur in the right positions (regioselectivity). Remember that at this stage we are just making proposals—we can only predict whether the reactions will actually occur or not. 

Then we could make the amino alcohol by adding an amine to an epoxide N-CH2-CH2-OH group looks as though it comes from ethylene oxide and an amine. 

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