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2-chloro-3-hydroxy-Benzaldehyde is a versatile building block used in the preparation of positional isomers of NOSH-aspirin a dual nitric oxide and hydrogen sulfide releasing hybrid pharmaceutical.

Under stirring conditions, tBuOCl (20 mL, 176 mmol) was slowly added dropwise to a suspension of 3-hydroxybenzaldehyde (20.12 g, 160 mmol) in HOAc (40 mL). The reaction solution gradually changed to a clarified solution with significant exothermic phenomenon. The reaction mixture was cooled and stirred continuously for 16 h, during which a white precipitate was generated. The solid product was collected by filtration, washed with deionized water and dried to afford 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55% yield), which was analyzed by GCMS (EI) showing m/z 156,158 (M+). Subsequently, 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) was dissolved in DMF (30 mL), and K2CO3 (4.8 g, 34.9 mmol) and MeI (2.7 mL, 43.6 mmol) were added sequentially, and the reaction was stirred for 16 h at room temperature. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the residue was dissolved with ethyl acetate, washed with water and saturated saline in turn, dried over anhydrous Na2SO4 and concentrated. Purification was carried out by silica gel column chromatography with ethyl acetate/hexane (1:5) as eluent to obtain 2-chloro-3-methoxybenzaldehyde 3a (4.68 g, 94% yield) as a colorless oil, which was solidified after standing.GCMS (EI) analysis showed m/z 170,172 (M+).

[1] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[2] Australian Journal of Chemistry, 2005, vol. 58, # 8, p. 565 - 571
[3] Patent: WO2005/7164, 2005, A1. Location in patent: Page 30-31
[4] Patent: WO2005/7165, 2005, A1. Location in patent: Page 46
[5] Patent: WO2005/7633, 2005, A1. Location in patent: Page 33