Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts

Dehydration of primary amides to nitriles in water. Late-stage functionalization and 1-pot multistep chemoenzymatic processes under micellar catalysis conditions

“…Thus, included among the products featured in Scheme 3 are (a) a derivatized 2,4-dichloropyrimidine 11 . In this case, and in other situations listed, use of DMSO (in additon to the THF present) was preferred to assist with emulsification of the highly insoluble starting amide, done by first adding the co-solvent to this educt prior to introduction of the other reagents; (b) tosylated hydroxynitrile 12 was generated in nearly quantitative yield with no observed hydrolysis of the sulfonyl group; (c) derivatized non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen 13 (77%), naproxen 14 (99%), and indomethacin 18 (86%) were formed in high yields with, in the case of 14 , no loss in enantiopurity; (d) substituted quinoline 15 , from a derivative en route to levatinib, 24 was obtained in excellent yield (87%), albeit in this case requiring 20 v/v % DMSO as co-solvent; (e) dinitroaniline 16 was isolated in a surprisingly modest yield (42%). This low yield is most likely due to very poor solubility of the substrate even with the addition of 20 v/v% DMSO, as well as the unprotected nitrogen functionality at the α-position relative to the primary amide in the starting material which is known to affect the equilibrium between the amide and the desired nitrile product.…”

Identification, Synthesis, and Characterization of Novel Baricitinib Impurities

“…The structures of the three new impurities, i.e. BCL, BCD, and BHM, were confirmed by using several analytical methods such as 1 H NMR, 13 C NMR, and MS. For BCL, the structure was confirmed by analyzing with 2D NMR (COSY, HSQC, and HMBC). The NMR comparison of the BCL, BCD, and BHM impurities is shown in Table 1.…”

“…The reaction was kept at room temperature for 12 h. After completion of the starting material, the reaction mixture was evaporated and extracted with DCM (100 mL) to afford 250 mg of the pure compound as an off-white solid. 1 H NMR and 13 C NMR data of BHM impurity are presented in Table 1.…”

“…Furthermore, there are few additional signals at δ 8.30−8.31 (d), δ 7.66−7.67 (d), and δ 9.06 (s) corresponding to the dimerized pyrrolo pyrimidine core unit. In the 13 C NMR spectrum also, we observed peaks at δ C 150.46, 151.18, and 153.89 corresponding to C-28, C-33, and C-35 of the dimerized compounds, respectively. After in-depth analysis, it was confirmed that the synthesized and isolated compounds were the same and was BCD.…”

“…as a solvent at 80 °C for 48 h. The crude BCL was purified by using prep-HPLC to obtain the impurity with good purity. 1 H NMR and 13 C NMR of BCL impurity data are presented in Table 1.…”