Reverse transcription is a characteristic of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of formula (III):
also known as efavirenz, is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of the compound (III) as a reverse transcriptase inhibitor, economical and efficient synthetic processes for its production need to be developed.
The final step in preparing the compound (III) is the cyclization reaction from compound (I).
This is done commercially using phosgene to prepare efavirenz. Phosgene is a highly toxic gas and it would be advantageous to prepare the compound without the use of phosgene.
U.S. Pat. No. 5,922,864 describes a method for preparing the compound (III) by a cyclization reaction involving alkyl and aryl chloroformates. However, the method using alkyl chloroformates involves isolating the carbamate intermediate.
It would be an advantage to have a cyclization procedure using less toxic ingredients and without having to isolate another intermediate in the cyclization step.
None of the above-cited references describe the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.