Dihydro-3(2H)-thiophenone → 3-Fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine

Temperature

-78 °C

A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at −78° C. under N2 is treated with see-butyllthium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at −78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at −78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf=0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf=0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.

1. customdropwise over 2 mins
2. stirringis stirred at −78° C.
3. waitto expire over 4 hrs
4. customThe mixture is then quenched with saturated aqueous ammonium chloride (25 mL)
5. additiondiluted with water (25 mL)
6. customthe layers are separated
7. washthe combined organic phase is washed with saline (20 mL)
8. dry with materialdried over anhydrous sodium sulfate
9. concentrationconcentrated under reduced pressure
10. dissolutionThe residue is dissolved in methanol (16 mL)
11. additiontreated with anhydrous potassium carbonate (1.09 g)
12. stirringthe mixture is stirred at ambient temperature for 30 mins
13. concentrationconcentrated under reduced pressure
14. additiondiluted with water (20 mL)
15. extractionextracted with diethyl ether (2×20 mL)
16. washThe combined organic phase is washed with saline (10 mL)
17. dry with materialdried over anhydrous magnesium sulfate
18. concentrationconcentrated under reduced pressure

ORD record

ord-eb38b24eb4b34c13affd36aa4be07ff8

Source dataset

uspto-grants-2001_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06313307B1