A practical synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid—the key precursor toward imatinib

Королева, Е. В.; Kadutskii, A. P.; Фарина, А. В.; Ignatovich, Janna; Ermolinskaya, A. L.; Gusak, K. N.; Kalinichenko, Еlena N.

doi:10.1016/j.tetlet.2012.06.107

Cited by 10 publications

(10 citation statements)

References 18 publications

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“…A previously described synthetic method of the reductive amination [22] was used in the second approach. The reaction between aldehyde 1 and primary amines a – d in the presence of triacetoxyborohydride sodium and acetic acid proceeded at room temperature with the formation of the amines 6a – 6d with high yield (80–95%).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors

et al. 2019

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A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues 11 and 13 with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue 10 showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).

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Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors

et al. 2019

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“…The yield of product 4.2.c (or its methyl ester obtained from the methyl ester of acid 4.2.a) was found to be at the level of 90−99%. 218 2 equiv of NaBH 4 was used in the reaction with an RME of 27% (61 g of the product in the form of methyl ester 4.2.c). Nicolaou et al also described the use of sodium triacetoxyborohydride in the reductive amination of methyl ester of acid 4.2.a.…”

Section: Imatinibmentioning

confidence: 99%

Reductive Amination in the Synthesis of Pharmaceuticals

et al. 2019

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Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C–N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C–N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

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“…4-Methoxycarbonylbenzyl derivatives 17 (R 1 = 4-CO 2 Me) of 4-methylpiperazine, morpholine and pyrrolidine have been obtained in 86% ± 98% yields, and 3-and 4-nitrobenzylpiperazines (R 1 = NO 2 ) have been synthesized in 84% ± 90% yields (Scheme 13). 69,70 Direct reductive alkylation has been used to synthesize secondary amines 18 from primary aromatic amines and methyl 4-for-…”

Section: Scheme 12mentioning

confidence: 99%

“…41 This protocol has been used to synthesize 4-[(4-methylpiperazino)methyl]benzoic acid (24, X = NMe) Ð the key intermediate in the synthesis of anti-leukemia drug imanitib Ð in up to 96% yield in two stages involving the synthesis of methyl 4-[(4-methylpiperazino)methyl]benzoate from 1-methylpiperazine (25, X=NMe, n = 1) and 4-methoxycarbonylbenzaldehyde (R 1 = 4-CO 2 Me) and its acid (HCl) hydrolysis. 70 4-Morpholinomethylbenzoic acid dihydrochloride (24, X = O) has been synthesized in 85% yield in the same way (see Scheme 13).…”

Section: Scheme 12mentioning

confidence: 99%