Water → 2-[1-(Hydroxymethyl)cyclopropyl]-3-{[(methyloxy)methyl]oxy}phenol

Temperature

50 °C

To a solution of ethyl 1-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)cyclopropanecarboxylate (Reference Intermediate 211, 490 mg) in ethanol (10 ml) HCl 2N in water (0.789 mL, 1.579 mmol) was added and the reaction mixture was stirred overnight at 50° C. Toluene (20 mL) was added and the combined solvents were removed under reduced pressure. The residue was re-suspended in toluene (20 ml) and the solvent evaporated. The obtained residue was dissolved in dry tetrahydrofuran (20 ml), the mixture was cooled to 0° C. and NaH 60% dispersion in mineral oil (126 mg, 3.16 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. MOM-Cl (0.120 mL, 1.579 mmol) was then added and the reaction mixture was stirred for 2 hours at 0° C. LiAlH4 (1 M in THF, 1.579 ml, 1.579 mmol) was added and the reaction mixture was further stirred for 1 hour at the same temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (10 ml) and extracted with ethyl acetate (2×50 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound as a colourless oil (191 mg).

1. customthe combined solvents were removed under reduced pressure
2. customthe solvent evaporated
3. dissolutionThe obtained residue was dissolved in dry tetrahydrofuran (20 ml)
4. temperaturethe mixture was cooled to 0° C.
5. stirringthe reaction mixture was stirred for 30 minutes at the same temperature
6. stirringthe reaction mixture was stirred for 2 hours at 0° C
7. stirringthe reaction mixture was further stirred for 1 hour at the same temperature
8. customThe reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml)
9. additiondiluted with water (10 ml)
10. extractionextracted with ethyl acetate (2×50 ml)
11. dry with materialCombined organic layers were dried over sodium sulphate
12. filtrationfiltered
13. customevaporated
14. customthe residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents

ORD record

ord-095a95619418444fa300c6440a7154c9

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216967B2