Water → 2-[1-(Hydroxymethyl)cyclopropyl]-3-(methoxymethoxy)-6-methyl-phenol

Temperature

50 °C

To a solution of ethyl 1-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]cyclopropanecarboxylate (Intermediate 153, 300 mg, 0.93 mmol) in ethanol (10 ml) HCl 6N in water (0.4 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at 50° C. Combined solvents were removed under reduced pressure. The residue was suspended in dry toluene (10 mL) and the solvent evaporated. The obtained residue was dissolved in dry tetrahydrofuran (10 ml), the mixture was cooled to 0° C. and NaH (60% dispersion in mineral oil) (80 mg, 2 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. MOM-Cl (0.083 mL, 1.1 mmol) was then added and the reaction mixture was stirred for 1 hour at 0° C. LiAlH4 (1M in THF, 1.2 ml, 1.2 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 (20 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 (70 mg) as a white solid.

1. customCombined solvents were removed under reduced pressure
2. customthe solvent evaporated
3. dissolutionThe obtained residue was dissolved in dry tetrahydrofuran (10 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 1 hour 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 (20 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-167ca1336a614ac28f8d8d2f3565dd50

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346790B2