PRODUCTION SCALE SYNTHESIS OF THE NONNUCLEOSIDE REVERSE-TRANSCRIPTASEINHIBITOR ATEVIRDINE MESYLATE (U-87,201E)

A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's fir st-generation non-nucleoside reverse transcriptase (RT) inhibitor for treatment of AIDS, is described. The route consists of three steps, In the first Step, the starting material, 3-amino-2-chloropyridine, is N -ethylated by conversion into the acetimidate (1.25 equiv of trimethyl orthoacetate, 0.003 equiv of HOTs . H2O, neat; then distill off the M eOH to drive the amine/imidate equilibrium to imidate) followed by red uction with DIBAL (2.27 equiv, toluene, <-10 degrees C), In the second step, the N-ethyl derivative is heated in 5.13 equiv of piperazine at similar to 170 degrees C in a closed system under moderate pressure ( similar to 10 psig) to give 3-(N-ethylamino)-2-(1-piperazinyl)pyridine , which is purified by crystallization from water. An X-ray crystallog raphic study revealed that the crystal contains five molecules of wate r per molecule of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine. The mole cules pack in an interesting way, with two layers of piperazinylpyridi ne molecules sandwiched between layers of water molecules, as in the l ipid bilayer structure of the biological cell membrane, The yield for the first two steps is 79.2% (overall, average of six plant runs). In the third step, the pentahydrate is coupled with 5-methoxyindole-2-car boxylic acid (MICA; 1.07 equiv of CDI, CH2Cl2 30 degrees C, 2-3 h; the n add 1.06 equiv of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine CH2Cl2, 30 degrees C) to give atevirdine free base, which is converted into t he mesylate salt(1.01 equiv of MeSO3H, methanol, 25 degrees C) and cry stallized, The yield of the third step is 83.3% (overall from MICA; av erage of eight plant runs). The bulk drug typically contains <0.1% tot al impurities (by HPLC). This process was used to produce multiton qua ntities of bulk drug used in phase II clinical trials.