ChemicalBook CAS DataBase List Nilotinib

Nilotinib synthesis

8synthesis methods

Product Name:Nilotinib
CAS Number:641571-10-0
Molecular formula:C28H22F3N7O
Molecular Weight:529.52

Nilotinib, also known as AMN107, is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia. Structurally related to imatinib, it was developed based on the structure of the Abl-imatinib complex to address imatinib intolerance and resistance. Nilotinib is a selective Bcr-Abl kinase inhibitor that is 10-30 fold more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl expressing cells. Nolitinib was developed by Novartis and is sold under the trade name Tasigna.

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

ROUTE 4

ROUTE 5

ROUTE 6

ROUTE 7

ROUTE 8

ROUTE 9

ROUTE 10

Ueda, Satoshi; Su, Mingjuan; Buchwald, Stephen L. Completely N1-selective palladium-catalyzed arylation of unsymmetric imidazoles: application to the synthesis of nilotinib. Journal of the American Chemical Society. Volume 134. Issue 1. Pages 700-706. 2012.

641571-11-1 Synthesis

3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

641571-11-1
335 suppliers
$9.00/1g

641569-94-0 Synthesis

4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid

641569-94-0
240 suppliers
$7.00/250mg

641571-10-0
410 suppliers
$21.00/5mg

Yield:641571-10-0 94%

Reaction Conditions:

Stage #1: 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acidwith thionyl chloride in 1-methyl-pyrrolidin-2-one at 60; for 1.25 h;
Stage #2: 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in 1-methyl-pyrrolidin-2-one at 90; for 3 h;Product distribution / selectivity;

Steps:

12

Example 12; Preparation of NilotinibTo 1 L glass reactor was added the compound of formula 4-methyl-3-{[4-(pyridin-3-yl) pyrimidin-2-yl]amino}benzoic acid of formula X (80.0 g, 0.26 mol), and N-Methyl-pyrrolidone (400 mL). The mixture was heated to 60° C., then SOCl₂(24 mL, 0.33 mol) was added during 15 minutes. The resulted mixture was stirred at 60° C. for 1 h. A compound of formula I (69.2 g, 0.29 mol) was added and the reaction mixture was stirred and heated to 90° C. for 3 h. Water (500 mL) was added and the solution was heated to 80° C. NaOH 47% solution (65 mL) was added until pH 11-12. Then, the suspension was cooled to 40° C. and stirred at this temperature for 2 hours, filtered under reduced pressure at 40° C., and washed with 500 mL H₂O to yield a beige solid. This material was slurried in water (1 L) at 40° C. for 1 h, filtered, washed with water (500 mL), and dried under vacuum at 50° C. to obtain 135.25 g of Nilotinib base with 94% yield. (95.8% assay, 99.46% purity).

References:

US2010/16590,2010,A1 Location in patent:Page/Page column 20

641571-11-1 Synthesis

641571-11-1
335 suppliers
$9.00/1g

917392-54-2 Synthesis