Processes for the preparation of a BACE inhibitor
This invention provides an improved processes for the preparation of verubecestat (Compound of Formula (I)), a potent inhibitor of BACE-1 and BACE-2.
1. A process for the preparation of a compound of Formula (I):
comprising:
combining an amine
with a weak base;
then reacting said mixture with a cyanating agent followed by treatment with a Brønsted base to form the compound of Formula (I).
2. The process of claim 1 , wherein the weak base is sodium bicarbonate or potassium phosphate dibasic.
3. The process of claim 2 , wherein the weak base is sodium bicarbonate.
4. The process of claim 3 , wherein amine (7) is dissolved in a solvent prior to the addition of the weak base.
5. The process of claim 4 , wherein the solvent is a mixture of an organic solvent and water.
6. The process of claim 5 , wherein the cyanating agent is selected from the group consisting of cyanogen, cyanogen bromide, cyanogen fluoride, cyanogen chloride, cyanogen iodide, 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate, and bisphenol A cyanate.
7. The process of claim 6 , wherein the cyanating agent is cyanogen bromide.
8. The process of claim 7 , wherein the reaction temperature is from 45 to 50° C.
9. The process of claim 8 , wherein the Bronsted base is sodium hydroxide.