Synthesis of 2-arylamino substituted 5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ones from arylguanidines

Abstract

A practical protocol was developed for the synthesis of 2-arylamino substituted 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones from α,β-unsaturated esters, malononitrile, and an aryl substituted guanidine via the corresponding 3-aryl-3,4,5,6- tetrahydropyrido[2,3-d]pyrimidin-7(8H)-ones. Such compounds are formed upon treatment of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles with an aryl substituted guanidine in 1,4-dioxane and are converted to the desired 4-aminopyridopyrimidines with NaOMe/MeOH through a Dimroth rearrangement. The overall yields of this three-step protocol are, generally speaking, higher than the multicomponent reaction, previously developed by our group, between an α,β-unsaturated ester, malononitrile, and an aryl substituted guanidine.

4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies

“…We obtained a new family of 4-aminopyrido[2,3-d]pyrimidnes active against NHLs starting from the previously described 4-amino-6-(2,6-dichlorophenyl)-5,6-dihydro-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (12a) [18] which was aromatized to 14a, methylated in the lactam nitrogen to afford 16, brominated in the para position of the 2-phenylamino substituent to yield 18 whose bromine atom was subsequently substituted using the Ullman protocol to give compounds 19, 20, and 21 presenting a tertiary amine in such later substituent [25].…”

“…Among this compounds, 12a (R 1 ¼ C 6 H 3 -2,6-Cl 2 , R 4 ¼ Ph) (Chart 2) [18], obtained starting from methyl 2-(2,6-dichlorophenyl)acrylate (8a, R 1 ¼ C 6 H 3 -2,6-Cl 2 ) and phenylguanidine carbonate (11a, R 4 ¼ Ph) and which precisely contains the 2,6-dichlorophenyl substituent present in several biologically active pyrido [2,3-d]pyrimidines previously reported [19,20], showed a promising biological activity against two MCL cell lines. Thus, the dose and time response of compound 12a was Chart 1.…”

“…Thus, compound 19 was obtained in 69% yield by treating 18 with 1-methylpiperazine in DMSO in the presence of L-proline, copper(I) iodide, and K 2 CO 3 under microwave irradiation for 16 h at 80 C. Compound 20 (Chart 3) was obtained in 77% yield upon treatment with 4-(aminoethyl)morpholine under the same reaction conditions. Finally, 21 was formed (18%) by using 4-(2-hydroxyethyl)morpholine as solvent in the presence of copper(I) iodide and Cs 2 CO 3 under microwave irradiation for 18 (Table 2) indicate that these compounds target Btk, Lyn, and Syk aa1-635 kinases, being compound 19 the strongest inhibitor. So, 19 is inhibiting the most upstream tyrosine kinases involved in the BCR signaling.…”

“…Unless otherwise mentioned, all solvents and chemicals were purchased from commercial vendors (Fluka, Aldrich, ABCR and ACROS Organics) and used without purification. Compound 12a was prepared as previously described [18]. 1 H and 13 C NMR spectra were recorded on a Varian 400-MR spectrometer that was operating at a field strength of 400 and 100.6 MHz, respectively.…”

“…The overall yields of such two-step protocol are in general higher than the reaction between pyridones 10 and an arylsubstituted guanidine 11 (Scheme 1) [18].…”