Patent Watch

August 11, 2014

Here is an improved process for making efavirenz, a key HIV drug. In 1995, Merck research scientists reported that the retroviral drug that later became known as efavirenz (2 in the figure) strongly inhibits HIV-1 reverse transcriptase. The US Food and Drug Administration approved efavirenz for treating HIV in 1998.

G. P. Singh and co-inventors cite several processes for preparing 2. In each method, the last step is a carbonylation reaction that cyclizes cyclopropylacetylene derivative 1 to form of an oxazinane ring. In one process, 1,1′-carbonyldiimidazole (CDI) is used as to carbonylate the racemic form of 1. The product is a racemic mixture that is resolved to give optically pure 2. In one alternative process, chiral compound 1 is treated with phosgene (COCl2), but phosgene is hazardous, and its use should be avoided.

Improved reaction conditions for the last step of the efavirenz synthesis

The inventors describe a stereoselective process for preparing 2 from chiral 1 that uses any of several carbonylating reagents. When CDI is used, the product is isolated in 92–98% yield and 99.7% purity. The reaction conditions are shown in the figure; THF is tetrahydrofuran.

The process can also be carried out with diphenyl carbonate [(PhO)2CO] or 1,8-diazabicycloundec-7-ene (DBU) at 60 ºC; in both cases, the yield of 2 is 90–98% and the purity is 99.7%. The reaction can also be carried out at –10 ºC with triphosgene to give a 74% yield of pure 2.

The inventors state that CDI can be regenerated and reused, but they give no details. The process provides an efficient method for completing the synthesis of an important drug molecule. (Lupin Ltd. [Mumbai]. US Patent 8,710,218, April 29, 2014; Keith Turner)