Process for the preparation of an orexin receptor antagonist
The present invention is directed to processes for preparing a pyridyl piperidine compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved.
1. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof,
which comprises:
contacting a compound of the formula II:
with a compound of the formula III:
in the presence of a coupling agent, which is selected from the group consisting of: 1-propyl phosphonic anhydride, oxalyl chloride and thionyl chloride;
to give the compound of the formula I, or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 wherein the step of contacting the compound of the formula II with the compound of the formula III is conducted in the presence of a weak organic base.
3. The process of claim 2 wherein the weak organic base is diisopropylethylamine or triethylamine.
4. The process of claim 1 wherein the coupling agent is 1-propyl phosphonic anhydride.
5. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof,
which comprises:
contacting a compound of the formula V:
with 5-fluro-2-hydroxypyridine of the formula VI:
in the presence of cesium carbonate to give the compound of the formula IV:
followed by removal of the protecting group in the compound of the formula IV to give the compound of the formula II:
followed by contacting the compound of the formula II with a compound of the formula III:
in the presence of a coupling agent, which is selected from the group consisting of: 1-propyl phosphonic anhydride, oxalyl chloride and thionyl chloride;
to give the compound of the formula I, or a pharmaceutically acceptable salt thereof.
6. The process of claim 5 wherein the amino protecting group is a BOC protecting group or a CBZ protecting group.
7. The process of claim 5 wherein the step of contacting the compound of the formula II with the compound of the formula III is conducted in the presence of a weak organic base.
8. The process of claim 7 wherein the weak organic base is diisopropylethylamine or triethylamine.
9. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof,
which comprises:
contacting a camphorsulfonate salt of the formula VII:
with 2,5-difluropyridine in the presence of a strong organic base to give the compound of the formula II:
followed by contacting the compound of the formula II with a compound of the formula III:
in the presence of a coupling agent, which is selected from the group consisting of: 1-propyl phosphonic anhydride, oxalyl chloride and thionyl chloride;
to give the compound of the formula I, or a pharmaceutically acceptable salt thereof.
10. The process of claim 9 wherein the strong organic base is sodium t-butoxide.