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.
® Identification is based on ir and nmr spectra and on Rt values. b Not identified.compound was irradiated for 60 min under the same conditions as described above. A multitude of products was obtained on tic, but acetophenone was not detected.
Seven series of as‐triazino[4,3‐a] [1,4]benzodiazepines were prepared which differed in the degree of unsaturation or the nature and position of oxygen function on the triazino ring. These were prepared by closing the triazino ring of appropriately substituted hydrazones from 2‐hydrazinobenzodiazepines or by condensing substituted hydrazines with 2‐thiobenzodiazepines. Most of these represent new ring systems. They were tested in a battery of tests designed to uncover central nervous system activities. Most of the activity was found in tests thought to be indicative of anxiolytic, hypnotic or sedative potential. Five of the series contained members more active than the standard, diazepam, and a few of the compounds were among the most potent benzodiazepines known. Some of the intermediate benzodiazepine hydrazones were also active.
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