Synlett 2016; 27(15): 2233-2236
DOI: 10.1055/s-0035-1562498
letter
© Georg Thieme Verlag Stuttgart · New York

A Practical Preparation of Imatinib Base

Xu Zhang
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, P. R. of China   Email: yulei@yzu.edu.cn
,
Jingjing Sun
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, P. R. of China   Email: yulei@yzu.edu.cn
,
Tian Chen
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, P. R. of China   Email: yulei@yzu.edu.cn
,
Chenggen Yang
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, P. R. of China   Email: yulei@yzu.edu.cn
,
Lei Yu*
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002, P. R. of China   Email: yulei@yzu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 28 March 2016

Accepted after revision: 21 May 2016

Publication Date:
23 June 2016 (online)


Abstract

A practical preparation of imatinib base was reported in this article. Compared with reported works, the features of this work were the concise procedures, the industrially available starting materials, the avoidance of expensive or highly toxic transition-metal catalysts or reagents, and the genotoxic impurities 6-methyl-N 1-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The method was scalable to at least 100 mmol, and the products were separated by simple recrystallizations.

Supporting Information

 
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  • 12 General Methods All of the chemicals were industrially pure and directly used without special treatment. Melting points were measured by a WRS-2A digital melting pointing instrument. IR spectra were measured by a Bruker IFS66/S FTIR spectrophotometer. 1H NMR (600 MHz) and 13C NMR NMR (150 MHz) spectra were recorded by using CDCl3 or DMSO-d 6 as the solvent with TMS as the internal standard. Coupling constants (J) are given in Hz. Mass spectra were measured on a Thermo Trace DSQ II spectrometer (EI).
  • 13 Procedure for the Synthesis of 16 3-Bromo-4-methylaniline (10, 1.86 g, 10 mmol), K2CO3 (1.38 g, 10 mmol), and DCE (40 mL) were first added into a 100 mL round-bottom flask and stirred. 4-(Chloromethyl)benzoyl chloride (14, 1.89 g, 10 mmol) was then injected. After 1 h, the product 16 precipitated as yellow crystals and could be isolated by filtration and purified by washing with small amount of DCE. About 3.18 g of 16 were obtained (94% yield). Characterization Data of Compound 16 IR (KBr): 3452, 3284, 2985, 2871, 1641, 1577, 1499, 1441, 1384, 1299, 1137, 1078, 1033, 849, 806, 665 cm–1. 1H NMR (600 MHz, CDCl3, TMS): δ = 7.89 (s, 1 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.75 (s, 1 H), 7.51 (d, J = 7.8 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.63 (s, 2 H), 2.38 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 165.0, 141.4, 136.6, 134.6, 134.2, 130.9, 129.0, 127.5, 124.9, 123.9, 119.2, 45.3, 22.3 ppm. MS (EI, 70 eV): m/z (%) = 339 (10) [M+] (37Cl), 337 (7) [M+] (35Cl), 137 (100). Known compound: CAS Reg. No. 1072105-05-5.7
  • 14 Procedure for the Synthesis of 11 To a 100 mL round-bottom flask, 16 (1.7 g, 5 mmol) and 1-methylpiperazine (56 mL) were added. The mixture was refluxed for 3 h and poured to 100 mL of water after cooling to room temperature. The precipitated crystals were filtrated and washed with water to give 1.57 g of 11 as the brown powder (78% yield). Characterization Data of Compound 11 Mp 140.8–141.3 °C. 1H NMR (600 MHz, DMSO-d 6, TMS): δ = 10.28 (s, 1 H), 8.13 (s, 1 H), 7.90 (d, J = 7.8 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.32 (s, 1 H), 3.52 (s, 2 H), 2.51–2.35 (br s, 8 H), 2.32 (s, 3 H), 2.15 (s, 3 H) ppm. 13C NMR (150 MHz, DMSO-d 6): δ = 165.4, 142.4, 138.4, 133.2, 132.0, 130.8, 128.6, 127.6, 123.6, 123.2, 119.4, 61.6, 54.7, 52.6, 45.7, 21.7 ppm. Known compound: CAS Reg. No. 581076-59-7.4
  • 15 Procedure for the Coupling of 11 To Give Imatinib Base 1 3 mmol Scale Reaction To a 100 mL round-bottom flask, 12 (0.57 g, 3.3 mmol), 11 (1.2 g, 3 mmol), CuI (0.14 g, 0.75 mmol), and K2CO3 (0.83 g, 6 mmol) were added. Under N2 protection, a solution of DMEDA (66 mg) in 1,4-dioxane (45 mL) was injected. The mixture was stirred at 100 °C for 24 h. After cooling to room temperature, it was poured into a mixture of concentrated NH3 (12 mL) and sat. NaCl solution (60 mL) and extracted by EtOAc (3 × 50 mL). The combined organic layer was dried by Na2SO4 and gave 0.92 g of imatinib base 1 as a white crystal (62% yield) after concentration.1 mol Scale Reaction To 20 L autoclave, 12 (189.4 g, 1.1 mol), 11 (402.3 g, 1 mol), CuI (47.8 g, 0.25 mol), and K2CO3 (276.4 g, 2 mol) were added. The autoclave was then charged with N2, and a solution of DMEDA (26.8 mL) in 12 L of 1,4-dioxane was slowly dropped. The mixture was mechanically stirred at 100 °C for 28 h. After cooling to room temperature, it was poured into a mixture of concentrated NH3 (3.5 L) and cold sat. NaCl solution (15 L, 0–5 °C) and extracted by EtOAc (3 × 14 L). The combined organic layer was dried by Na2SO4 and led to white crystal after concentration. The crystal was washed by PE and dried under vacuum overnight to afford 350.5 g of imatinib base 1 in 71% yield.Characterization Data of Compound 1Mp 207.4–209.2 °C. IR (KBr): 3410, 3290, 2967, 2964, 2932, 2801, 1628, 1588, 1532, 1507, 1478, 1450, 1416, 1380, 1346, 1007, 829, 761, 700 cm–1. 1H NMR (600 MHz, DMSO-d 6, TMS): δ = 10.22 (s, 1 H), 9.30 (d, J = 1.8 Hz, 1 H), 9.02 (s, 1 H), 8.71–8.70 (m, 1 H), 8.54–8.50 (m, 2 H), 8.12 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2 H), 7.55–7.44 (m, 5 H), 7.23 (d, J = 8.4 Hz, 1 H), 3.53 (s, 2 H), 2.53–2.33 (br s, 8 H), 2.25 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR (150 MHz, DMSO-d 6): δ = 165.3, 161.6, 161.2, 159.4, 151.3, 148.1, 142.1, 137.8, 137.2, 134.4, 133.7, 132.2, 130.0, 128.6, 127.5, 123.8, 117.2, 116.8, 107.5, 61.6, 54.7, 52.5, 45.7, 17.6 ppm. Known compound: CAS Reg. No. 152459-95-5.3
  • 16 Maiti D, Fors BP, Henderson JL, Nakamura Y, Buchwald SL. Chem. Sci. 2011; 2: 57