Derivatives of N-phenyl-2-pirimidineamines 2 are valuable intermediates in manufacturing of biologically active compounds. For example, they are used in synthesis of tyrosine kinase inhibitors such as Imatinib, which is approved to treat a rare cancer called Chronic Myeloid Leukemia (CML). On XLVIII Meeting of Polish Chemical Society we revealed improved methods of compound 1 obtaining. Now we would like to show further steps, which lead to polymorphic α form of Gleevec^®.
We developed such process conditions, which guaranteed high yields of all synthetics steps as well as simple methods of products' isolation and purification. In our procedure compound 1 is catalytically reduced to amino-derivative using aqueous hydrazine solution. [1] Then compound 2 undergoes reaction with 4-chloromethylbenzoyl chloride in the presence of base, followed by condensation of obtained product 3 with N-methylpiperazine. Resulting reaction mixture is diluted with water or organic solvent chosen from lower aliphatic alcohols or ketones and optionally neutralized with aqueous solution of inorganic base. Precypitated product 4 is then filtered. [2,3] Finally compound 4 free base is converted into methanesulphonic acid salt and crystallized from proper solvent to give desired product in polymorphic form α.[4]

Literatura:
[1] Sposób wytwarzania N-(5-amino-2-metylofenylo)-4-(3-pirydylo)-2-pirymidynoaminy P-377984
[2] Sposób wytwarzania pochodnych N-fenylo-2-pirymidynoamin P-376691
[3] Process for preparation of imatinib base PCT/PL/2005/000088
[4] Process for preparation of imatinib monomesylate crystalline Form α PCT/PL2005/000024

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