The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT. Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005. Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin, atorvastatin ; however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.
Clinical trials
A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin. Nine phase III studies were completed.
Early termination of study
On December 2, 2006 Pfizer cut off torcetrapib's phase III trial because of "an imbalance of mortality and cardiovascular events" associated with its use. This was a sudden and unexpected event and as late as November 30, 2006 Jeff Kindler, Pfizer’s chief executive, was quoted, "This will be one of the most important compounds of our generation." In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone. Pfizer recommended that all patients stop taking the drug immediately. Six studies were terminated early. One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further." The drug cost $800m+ to bring into Phase III development.
Synthesis
Dietary cholesterol needs be esterified in order to be absorbed from the gut. The enzyme, cholesterylester transfer protein, then completes the absorption of cholesterol. Drugs that interfere with the action of these peptides would aid in lowering cholesterol levels by complementing the action of the statins that inhibit the endogenous production of cholesterol. The CETP inhibitor torcetrapib proved very effective in lowering cholesterol levels in humans; the drug not only lowered low-density lipoproteins but also raised levels of high density, “good” lipoproteins. This agent, which had only a brief time on the market due to adverse safety reports, is included here to illustrate an unusual method for preparing tetrahydroquinolines. Reaction of the trifluoromethylaniline with propanal in the presence of benzotriazole affords the aminal. Condensation of with the vinyl carbamate yields the tetrahydroquinoline ring with expulsion of the benzotriazole fragment. The ring nitrogen is then protected as its ethyl carbamate by acylation with ethyl chloroformate. The benzyl carbamate function on nitrogen at the 4 position is next removed by reduction with ammonium formate over palladium to afford the primary amine; this compound is then resolved as its dibenzyl tartrate salt to afford the 2R,4S isomer. Reductive amination with the bis-trifuoromethyl benzaldehyde in the presence of sodium triacetoxyborohydride followed by acylation with methyl chloroformate completes the synthesis of torcetrapib.
