2-chloro-4-fluoro-3-methoxybenzaldehyde synthesis

Yield:750586-10-8 46%

Reaction Conditions:

Stage #1: 4-fluoro-3-methoxybenzaldehydewith n-butyllithium;N,N',N'-trimethylenediamine in tetrahydrofuran;hexane at -78 - -42; for 1.5 h;
Stage #2: with hexachloroethane in tetrahydrofuran;hexane at -42 - 20; for 2 h;

Steps:

P78.1 Step 1: Preparation of 2-chloro-4-fluoro-3-methoxybenzaldehyde.

N,N,N'-trimethylethylenediamine (1.77 mL, 13.6 mmol) was dissolved in THF (50 mL) and cooled to -42° C. under a backflow of nitrogen then treated with n-butyllithium (2.5 M in hexanes, 5.45 mL, 13.6 mmol) and allowed to stir at -42° C. for 30 minutes after complete addition.
The reaction mixture was then cooled to -78° C. and treated with a 50 mL THF solution of 4-fluoro-3-methoxybenzaldehyde (2.0 g, 13.0 mmol) and then warmed to -42° C. and stirred for 30 minutes.
The reaction mixture was cooled to -78° C. and treated with n-butyllithium (2.5 M in hexanes, 5.45 mL, 13.6 mmol) and then warmed to -42° C. and allowed to stir for 1 hr.
The reaction mixture was transferred quickly via cannula to 50 mL THF solution of hexachloroethane (6.14 g, 26.0 mmol) at ambient temperature and allowed to stir at ambient temperature for 2 hours.
The reaction mixture was treated with 4.0 M HCl and extracted with Et₂O (2*250 mL).
The organic phases were combined and washed with 1.0 M NaOH (1*100 mL), 1.0 M HCl (1*100 mL), and brine (1*50 mL) and then dried over Na₂SO₄, filtered, and concentrated.
The residue was purified by reverse phase C18 chromatography (water/acetonitrile with 0.1% TFA) and the fractions containing the desired product were combined and partitioned between 4:1 DCM:IPA and saturated NaHCO₃ (1*100 mL), dried over Na₂SO₄, filtered, and concentrated to afford 2-chloro-4-fluoro-3-methoxybenzaldehyde (1.12 g, 46%).
¹H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.70-7.67 (m, 1H), 7.52-7.48 (t, 1H), 3.94 (s, 3H).

References:

US2020/407344,2020,A1 Location in patent:Paragraph 0929; 0930