Diisopropylethylamine → HCID 58629410, compound

Temperature

0 °C

A solution of 3-hydroxymethyl-3-methyloxetane (1.90 mL, 19.1 mmol) in methylene chloride (6 mL) was added to a solution of nickel (II) chloride hexahydrate (113 mg, 0.476 mmol) in water (2 mL). This mixture was cooled to 0° C. and bleach (127 mL) was added over a 30 min period via addition funnel. After 2 h the ice bath was removed and the reaction mixture was stirred at room temperature for an additional 2 h. 2M HCl (120 mL) was added and the solution was extracted with ether (4×200 mL). The combined extracts were dried over sodium sulfate and concentrated to a clear oil. A portion of this oil (1.00 g, 8.61 mmol) was dissolved in tetrahydrofuran (43 mL) and 4-(N-Boc-amino)-piperidine (2.07 g, 10.3 mmol) was added at room temperature. Propylphosphonic anhydride (6.99 mL, 50 wt. % in ethyl acetate, 11.2 mmol) and N,N-diisopropylethylamine (3.00 mL, 17.2 mmol) were added, and the reaction mixture was stirred for 24 h. The solution was partitioned between ethyl acetate (35 mL) and water (35 mL). The organic portion was washed with 0.2M HCl (10 mL), sat. sodium bicarbonate (35 mL), and brine (35 mL). The solution was then dried over sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel (0% to 100% methylene chloride in ethyl acetate). The resulting amide (213 mg, 0.714 mg) was diluted with methylene chloride (7 mL) and trifluoroacetic acid (1.8 mL) was added at room temperature. After 2 h the solution was concentrated and a 2M sodium hydroxide solution was added. The aqueous solution was extracted with ethyl acetate (3×10 mL). The combined extracts were dried over sodium sulfate and concentrated to give the title compound as a clear oil, (4-aminopiperidin-1-yl)(3-methyloxetan-3-yl)methanone, 68 mg (4% over three steps). 1H NMR (300 MHz, CD3OD) δ 4.95-4.88 (m, 2H), 4.48-4.38 (m, 1H), 4.38-4.31 (m, 2H), 3.19-2.96 (m, 2H), 2.94-2.81 (m, 1H), 2.81-2.66 (m, 1H), 1.93-1.81 (m, 2H), 1.67-1.60 (m, 3H), 1.36-1.15 (m, 2H).

1. additionwas added over a 30 min period via addition funnel
2. customAfter 2 h the ice bath was removed
3. addition2M HCl (120 mL) was added
4. extractionthe solution was extracted with ether (4×200 mL)
5. dry with materialThe combined extracts were dried over sodium sulfate
6. concentrationconcentrated to a clear oil
7. stirringthe reaction mixture was stirred for 24 h
8. customThe solution was partitioned between ethyl acetate (35 mL) and water (35 mL)
9. washThe organic portion was washed with 0.2M HCl (10 mL), sat. sodium bicarbonate (35 mL), and brine (35 mL)
10. dry with materialThe solution was then dried over sodium sulfate
11. concentrationconcentrated
12. customThe crude material was purified by column chromatography on silica gel (0% to 100% methylene chloride in ethyl acetate)
13. additionThe resulting amide (213 mg, 0.714 mg) was diluted with methylene chloride (7 mL) and trifluoroacetic acid (1.8 mL)
14. additionwas added at room temperature
15. concentrationAfter 2 h the solution was concentrated
16. additiona 2M sodium hydroxide solution was added
17. extractionThe aqueous solution was extracted with ethyl acetate (3×10 mL)
18. dry with materialThe combined extracts were dried over sodium sulfate
19. concentrationconcentrated

ORD record

ord-732ad22e57934d9d8e921efe656d3721

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08591943B2