Method of preparing glucosylceramide synthase inhibitors
The invention relates to a method of preparing inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.
1. A method of preparing the compound of Formula VIII
comprising reacting a compound of Formula IX
with quinuclidinol.
2. A method according to claim 1 , further including reacting the compound of Formula XI
with imidazole to form the compound of Formula IX
3. A method according to claim 1 , further including heating to reflux the compound of Formula XI
to form the compound of Formula X
4. A method according to claim 1 , further including reacting, while heating to reflux, the compound of Formula XI
with imidazole to form the compounds of Formula IX and Formula X
5. A method according to claim 2 , further including reacting the compound of Formula XII
with N, N′-carbonyldiimidazole to form the compound of Formula XI
6. A method according to claim 5 , further including reacting the compound of Formula XIII
with N, N′-carbonyldiimidazole and hydroxylamine to form the compound of Formula XII
7. A method according to claim 6 , further including reacting the compound of Formula XIV
with potassium tert-butoxide and methyl iodine followed by reacting the ethyl ester so formed with lithium hydroxide to form the compound of Formula XIII.