Synthesis of ribociclib

Ribociclib is an orally available, small molecule inhibitor of cyclin-dependent kinases 4 and 6 that is used in combination with aromatase inhibitors in the therapy of postmenopausal women with metastatic breast cancer that is positive for the estrogen hormone receptor (ER+), but negative for human epidermal growth factor receptor 2 (HER2-).[1]

Uses

Ribociclib is used in combination with another medication to treat a certain type of hormone receptor–positive (depends on hormones such as estrogen to grow) advanced breast cancer that has spread to other parts of the body or has not improved or has worsened after treatment with other therapies. Ribociclib is also used in combination with another medication to treat a certain type of hormone receptor–positive, early breast cancer in people who have already been treated with surgery, radiation, and/or chemotherapy.

Side effects

The most common side effects of Ribociclib include infections, low levels of white blood cells, headache, cough, nausea, vomiting, diarrhoea, constipation, tiredness, hair loss and rash.[5] The most common severe side effects include infections, low levels of red and white blood cells, vomiting, abnormal blood tests for liver function and low levels of phosphate in the blood (hypophosphataemia).

Synthesis

A process for preparation of Ribociclib is disclosed. The Ribociclib is prepared with 2,6-dichloro-5-bromo-pyrimidine and cyclohentylamine via substitution, coupling, cyclization, oxidative amidation, substitution, and hydrolysis in six steps to generate the product. The process avoids the use of noble metal catalysts or toxic sodium cyanide reagents, and has mild reaction conditions, few synthesis steps, good selectivity, high overall yield, high liquid-phase purity and greatly reduced product impurity.

Reference

[1]LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].