Potassium Carbonate → 2-(Piperidin-1-yl)aniline

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 (9.8 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3M in cyclohexane, 3.64 mL) dropwise over 3 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (919 mg) in dry tetrahydrofuran (3.9 mL) dropwise over 2 mins and is stirred at -78° C. for 2 hrs. The mixture is then warmed to -20° C. over 1 hr and quenched with saturated aqueous ammonium chloride (5 mL), diluted with water (20 mL), the layers are separated, the aqueous phase is extracted with diethyl ether (20 mL), and the combined organic phase is washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (15 mL) and treated with anhydrous potassium carbonate (544 mg, 3.94 mmol), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with diethyl ether (30 mL), washed with water (20 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 4-hydroxy)piperidinyl benzenamine intermediate (Rf =0.25 by TLC, ethyl acetate/hexane (50/50). A mixture of this intermediate and N,N-dimethylaniline (1.00 mL) in tetrahydrofuran (20 mL) is cooled to -20° C. and treated with benzyl chloroformate (0.59 mL), and the resulting mixture is stirred at -20° C. for 1 hr. The mixture is then diluted with saturated aqueous potassium carbonate (5 mL), water (25 mL) and diethyl ether (25 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with a gradient of ethyl acetate/hexane (25/75-50/50), and those fractions with an Rf =0.47 by TLC (ethyl acetate/hexane, 50/50) are pooled and concentrated to give the title compound, NMR (400 MHz, CDCl3) 7.35, 7.00, 6.92, 5.20, 5.16, 4.10, 3.32, 2.15 and 1.79 δ and Anal. calculated for C27H27FN2O5 : C, 67.77; H, 5.69; N, 5.85. Found: C, 67.44; H, 5.83; N, 5.65.

1. stirringis stirred at -78° C. for 2 hrs
2. temperatureThe mixture is then warmed to -20° C. over 1 hr
3. customquenched with saturated aqueous ammonium chloride (5 mL)
4. additiondiluted with water (20 mL)
5. customthe layers are separated
6. extractionthe aqueous phase is extracted with diethyl ether (20 mL)
7. washthe combined organic phase is washed with saline (10 mL)
8. dry with materialdried over anhydrous sodium sulfate
9. concentrationconcentrated under reduced pressure
10. dissolutionThe residue is dissolved in methanol (15 mL)
11. stirringthe mixture is stirred at ambient temperature for 30 mins
12. concentrationconcentrated under reduced pressure
13. additiondiluted with diethyl ether (30 mL)
14. washwashed with water (20 mL) and saline (10 mL)
15. dry with materialdried over anhydrous magnesium sulfate
16. concentrationconcentrated under reduced pressure

ORD record

ord-98e73ed79a6d48f59da9fea4e0b6bf6f

Source dataset

uspto-grants-1999_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05968962