Dasatinib
From The Cure For The Needy
Contents |
Dasatinib (Sprycel)
Effective Against
CML - Chronic myelogenous leukemia
Dasatinib is in a class of medications called protein-tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.
Cost
From LC Laboratories: 89 USD (100mg)
Reported Route of Synthesis
1) Reaction of N-(2-chloro-6-methylphenyl)-2-(6-chloro-2-methylpyrimidin-4-ylamino)-1,3-thiazole-5-carboxamide (I) with 1-(2-hydroxyethyl)piperazine (II) by heating the mixture at 80 (1,2,6), refluxing in dioxane (3) or by means of DIEA in tert-butanol at 118 C (4,5).
Lombardo, L.J.; Lee, F.Y.; Chen, P.; et al.
Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004, 47(27): 6658
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Das, J.; Chen, P.; Norris, D.; et al. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 2006, 49(23): 6819
Cyclic protein tyrosine kinase inhibitors. Bristol-Myers Squibb Co. JP 2002542193, WO 2000062778, US 6596746, EP 1610780, WO 2004085388, US 2004054186, JP 2006523216, US 7125875
Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors. Bristol-Myers Squibb Co. JP 2007521340, WO 2005077945, US 2005215795, EP 1711481, US 2006004067, US 7491725
2) Reaction of 4,6-dichloro-2-methylpyrimidine (X) with 1-(2-hydroxyethyl)piperazine (II) by means of DIEA in CH2Cl2 affords the pyrimidine derivative (XXIII), which is condensed with the 2-aminothiazole derivative (IX) by means of K2CO3, Pd(AcO)2 and BINAP in toluene at 100 C (4,5).
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors. Bristol-Myers Squibb Co. JP 2007521340, WO 2005077945, US 2005215795, EP 1711481, US 2006004067, US 7491725
Cost of Starting Materials and Selected Reagents:
Starting Material 4,6-Dichloro-2-methylpyrimidine from Sigma-Aldrich: 47.4 USD (5g)
Starting Material 1-(2-Hydroxyethyl)piperazine from Sigma-Aldrich: 25.5 USD (100g)
Starting Material 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide pricing not available from Sigma-Aldrich
- 2-Chloro-6-methylaniline from Sigma-Aldrich: 31.4 USD (1g)
N,N-Diisopropylethylamine (DIEA) from Sigma-Aldrich: 65.7 USD (100 mL)
Potassium Carbonate from Sigma-Aldrich: 58.8 USD (500g)
Palladium(II) acetate from Sigma-Aldrich: 69.3 USD (1g)
(R)-BINAP from Sigma-Aldrich: 21.1 USD (100mg)
(S)-BINAP from Sigma-Aldrich: 21.1 USD (100mg)
3) Treatment of 4-amino-6-chloro-2-methylpyrimidine (XVI) with 1-(2-hydroxyethyl)piperazine (II) by means of DIEA in CH2Cl2 affords the pyrimidine derivative (XXIV), which after reaction with benzoyl isothiocyanate (XXV) in CHCl3 followed by hydrolysis with aqueous NaOH in MeOH provides the thiourea intermediate (XXVI). Condensation of compound (XXVI) with N,N-dimethylformamide dimethyl acetal (XXVII) in EtOH at 73 C yields compound (XXVIII) which is finally reacted with 2-chloro-N-(2-chloro-6-methylphenyl)acetamide (XXIX) ( prepared by acylation of the aniline (VII) with chloroacetyl chloride (XXX) by means of NMM in acetone) in refluxing MeOH.
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors. Bristol-Myers Squibb Co. WO 2005076990, US 2005176965
Cost of Starting Materials and Selected Reagents:
Starting Material 6-chloro-2-methylpyrimidin-4-amine pricing not available from Sigma-Aldrich
Starting Material 1-(2-Hydroxyethyl)piperazine from Sigma-Aldrich: 25.5 USD (100g)
Starting Material Chloroacetyl chloride from Sigma-Aldrich: 17.2 USD (100 mL)
Starting Material 2-Chloro-6-methylaniline from Sigma-Aldrich: 31.4 USD (1g)
N,N-Diisopropylethylamine (DIEA) from Sigma-Aldrich: 65.7 USD (100 mL)
Sodium Hydroxide (10M in H2O) from Sigma-Aldrich: 61.6 USD (100 mL)
N-Methylmorpholine pricing not available from Sigma-Aldrich
1-benzoyl-pyrrolidine-2,5-dione from Sigma-Aldrich: pricing not available from Sigma-Aldrich
- N-chlorosuccinimide from Sigma-Aldrich: 8.4 USD (5g)
- Benzoic acid from Sigma-Alrich: 17.9 USD (25g)
N,N-Dimethylformamide dimethyl acetal (derivatization grade) from Sigma-Aldrich: 57.6 USD (5 mL)
Intermediate (I) can be synthesized by several different procedures: a) Protection of ethyl 2-aminothiazole-5-carboxylate (III) with Boc2O and DMAP in THF gives intermediate (IV), which is hydrolyzed with NaOH in THF/MeOH to yield the corresponding carboxylic acid derivative (V). Reaction of compound (V) with oxalyl chloride in THF affords the acyl chloride (VI), which is condensed with 2-chloro-6-methylaniline (VII) by means of TEA in CH2Cl2 to provide the intermediate (VIII). Deprotection of compound (VIII) by means of TFA gives the 2-aminothiazole derivative (IX), which finally reacts with 4,6-dichloro-2-methylpyrimidine (X) by means of NaH in THF (1,2).
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Cyclic protein tyrosine kinase inhibitors. Bristol-Myers Squibb Co. JP 2002542193, WO 2000062778, US 6596746, EP 1610780, WO 2004085388, US 2004054186, JP 2006523216, US 7125875
b) Reaction 2-chlorothiazole (XI) with 2-chloro-6-methylphenylisocyanate (XII) by means of BuLi in THF gives 2-chloro-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (XIII), which is N-protected with 4-methoxybenzyl chloride (XIV) and NaH in THF to yield compound (XV). Reaction of intermediate (XV) with 4-amino-6-chloro-2-methylpyrimidine (XVI) by means of NaH in THF affords the adduct (XVII), which is finally deprotected by means of TfOH/TFA in CH2Cl2 (1,2).
Lombardo, L.J.; Lee, F.Y.; Chen, P.; et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004, 47(27): 6658
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Das, J.; Chen, P.; Norris, D.; et al. 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 2006, 49(23): 6819
c) Condensation of 2-chloro-6-methylaniline (VII) with 2-ethoxyacryloyl chloride (XVIII) by means of pyridine in THF gives the corresponding acrylamide derivative (XIX), which is cyclized with thiourea (XX) by means of NBS in hot dioxane to yield 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (IX). Finally, compound (IX) is condensed with 4,6-dichloro-2-methylpyrimidine (X) by means of t-BuONa in THF (4,5). d) Reaction of 4-amino-6-chloro-2-methylpyrimidine (XVI) with ethyl isothiocyanatoformate (XXI) in THF at reflux followed by hydrolysis in 1M NaOH at 50 C yields the thiourea derivative (XXII), which is finally cyclized with the acrylamide (XIX) by means of NBS in THF/H2O (4,5).
McIntyre, J.A., Castaner, J., Bayes, M. Dasatinib. Drugs of the Future 2006, 31(4): 291
Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors. Bristol-Myers Squibb Co. JP 2007521340, WO 2005077945, US 2005215795, EP 1711481, US 2006004067, US 7491725