ethyl 2-(4-broMophenyl)-2-Methylpropanoate

Uses

Ethyl 2-(4-Bromophenyl)-2-methylpropanoate is an intermediate of Alectinib (C183360), a highly selective and potent anaplastic lymphoma kinase (ALK) inhibitor capable of blocking the resistant gatekeeper mutant, which results in reduced cell growth.

Synthesis

Example 13A Synthesis of ethyl 2-(4-bromophenyl)-2-methylpropanoate: 2.0 g (8.2 mmol) of ethyl p-bromophenylacetate was dissolved in 50 mL of DMF, and 0.7 g (18 mmol) of a suspension of 60% sodium hydride mineral oil was added slowly at room temperature. The mixture was stirred at room temperature for 30 min before 2.9 g (20.6 mmol) of iodomethane was added. The reaction mixture was continued to stir overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and extracted sequentially with water and saturated sodium chloride solution. The organic phase was separated, dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by preparative HPLC [Reprosil C18, 10 μm, 250 mm × 40 mm, gradient elution (30% methanol/70% water to 100% methanol), run time 25 min]. After HPLC analysis, the fractions containing the target product were combined and concentrated to give 1.75 g (78% yield) of the product as an oil. The product was characterized by GC-MS [Method 5] and 1H-NMR (400 MHz, DMSO-d6): GC-MS: Rt = 5.10 min; MS (ESIpos): m/z = 270/272 [M+]; 1H-NMR: δ [ppm] = 1.11 (t, 3H), 1.48 (s, 6H), 4.06 (q, 2H ), 7.24-7.29 (m, 2H), 7.50-7.54 (m, 2H).

References

[1] Patent: US2016/318866, 2016, A1. Location in patent: Paragraph 0639; 0640; 0641
[2] Patent: WO2011/44187, 2011, A1. Location in patent: Page/Page column 94
[3] Patent: WO2013/40790, 2013, A1. Location in patent: Page/Page column 60
[4] Patent: WO2013/43624, 2013, A1. Location in patent: Page/Page column 59; 60
[5] Patent: EP3239143, 2017, A2. Location in patent: Paragraph 0339