3-(4-fluorophenyl)-5-methylisoxazole-4-carboxylic acid → (3-(4-Fluorophenyl)-5-methylisoxazol-4-yl)methanol

Temperature

25 °C

A suspension of 448 g of tetrahydrofuran and 95 g (0.70 mol) of zinc chloride was stirred at 20-30° C. for 1 h. 23.6 g (0.62 mol) of sodium borohydride were added in portions at 20-38° C. and the mixture subsequently stirred at 60-65° C. for 3 h. A solution of 69 g (0.31 mol) of 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid in 220 g THF was added dropwise and the resulting mixture stirred at 60-65° C. for 16 h. The reaction was then quenched by the drop wise addition of mixture of 93 g of HCl in 202 g of water at 5-10° C. The mixture was stirred at this temperature for 2 h to dissolve the solids completely. The solvent was removed under reduced pressure with a jacket temperature of 35-40° C. To the residue were added 510 g of water. The resulting suspension was cooled to 20-30° C. and the crystals were filtered off and washed with water. The crude wet product was stirred for 1 h in a mixture of 150 g of water, 31 g of HCl and 419 g of MTBE. The lower aqueous phase was removed and organic phase was dried with 25 kg of anhydrous sodium sulfate, stirred for 0.5 h and filtered under nitrogen. The filtrate was almost completely concentrated under reduced pressure at 40-45° C. The residue was treated at 20-25° C. with 100 g of MTBE. The mixture was stirred at 55-60° C. for 2 h, cooled to 0° C. and subsequently stirred at this temperature for additional 2 h. The crystals were filtered off and dried at 45-50° C. in vacuum over night to afford 42 g (66% yield) of the title alcohol as an off-white solid with a purity of 99.9% (HPLC).

1. stirringthe mixture subsequently stirred at 60-65° C. for 3 h
2. stirringthe resulting mixture stirred at 60-65° C. for 16 h
3. customThe reaction was then quenched by the drop wise addition of mixture of 93 g of HCl in 202 g of water at 5-10° C
4. stirringThe mixture was stirred at this temperature for 2 h
5. dissolutionto dissolve the solids completely
6. customThe solvent was removed under reduced pressure with a jacket temperature of 35-40° C
7. additionTo the residue were added 510 g of water
8. temperatureThe resulting suspension was cooled to 20-30° C.
9. filtrationthe crystals were filtered off
10. washwashed with water
11. stirringThe crude wet product was stirred for 1 h in a mixture of 150 g of water, 31 g of HCl and 419 g of MTBE
12. customThe lower aqueous phase was removed
13. dry with materialorganic phase was dried with 25 kg of anhydrous sodium sulfate
14. stirringstirred for 0.5 h
15. filtrationfiltered under nitrogen
16. concentrationThe filtrate was almost completely concentrated under reduced pressure at 40-45° C
17. additionThe residue was treated at 20-25° C. with 100 g of MTBE
18. stirringThe mixture was stirred at 55-60° C. for 2 h
19. temperaturecooled to 0° C.
20. stirringsubsequently stirred at this temperature for additional 2 h
21. filtrationThe crystals were filtered off
22. customdried at 45-50° C. in vacuum over night

ORD record

ord-f5daf92343884df19d80cfa4419d7616

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08975397B2