Application - Isentress Synthesis

Raltegravir potassium, or Isentress (1), was the first FDA-approved inhibitor of HIV integrase.

Isentress

A number of carbonyl addition and carbonyl "like" addition reactions are utilized in the medicinal chemistry and industrial routes to Isentress.  They both begin with acetone cyanohydrin.  Acetone cyanohydrin is reacted with ammonia (NH3) in what is know as the Strecker reaction to form the α-aminonitrile.  We will discuss the Strecker synthesis in a later chapter as means to prepare aminoacids.  The amino group is then protected as the cbz (carboxybenzyl) group.  Then hydroxylamine is added to the nitrile to yield the amidoxime (i.e. an oxime of an amide).  There are many steps left to get to Isentress.  Imagine how much work this is and how much it costs to develop a drug.  In 2007, 33 million people worldwide were infected with HIV and more than 2,000,000 people died of HIV complications.

1) Although the acetone cyanohydrin is likely purchased by the manufacturer of Isentress (Merck), somebody had to make it.  Can you propose a method to synthesize acetone cyanohydrin?

2) Propose a mechanism for the third reaction above in which hydroxylamine (NH₂OH) reacted with the cbz-protected nitrile above?  (Hint:  A nitrile will behave much like a aldehyde's or ketone's carbonyl in an addition reaction).

3) The structure of cbzCl (benzylchloroformate) is shown below.  Propose a mechanism for the cbz protection of the amino group in the second step.