Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)
A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's first-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...
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Published in | Organic process research & development Vol. 1; no. 2; pp. 106 - 116 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Chemical Society
01.03.1997
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Online Access | Get full text |
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Summary: | A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's first-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 MeOH to drive the amine/imidate equilibrium to imidate) followed by reduction with DIBAL (2.27 equiv, toluene, <−10 °C). In the second step, the N-ethyl derivative is heated in 5.13 equiv of piperazine at ∼170 °C in a closed system under moderate pressure (∼10 psig) to give 3-(N-ethylamino)-2-(1-piperazinyl)pyridine, which is purified by crystallization from water. An X-ray crystallographic study revealed that the crystal contains five molecules of water per molecule of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine. The molecules pack in an interesting way, with two layers of piperazinylpyridine molecules sandwiched between layers of water molecules, as in the lipid 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-carboxylic acid (MICA; 1.07 equiv of CDI, CH2Cl2, 30 °C, 2−3 h; then add 1.06 equiv of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine, CH2Cl2, 30 °C) to give atevirdine free base, which is converted into the mesylate salt (1.01 equiv of MeSO3H, methanol, 25 °C) and crystallized. The yield of the third step is 83.3% (overall from MICA; average of eight plant runs). The bulk drug typically contains <0.1% total impurities (by HPLC). This process was used to produce multiton quantities of bulk drug used in phase II clinical trials. |
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ISSN: | 1083-6160 1520-586X |
DOI: | 10.1021/op9600318 |