Hydrochloric Acid → HCID 71233197, Verbindung

Temperatur

0 °C

To a solution of benzyl (1R,2R)-2-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate (132 mg, 0.283 mmol) in CH2Cl2 (2 mL) cooled at 0° C. was added iodotrimethylsilane (0.058 mL, 0.424 mmol) dropwise. After addition, the orange colored suspension was stirred at 0° C. for 10 min, then at rt for 40 min. LCMS showed little reaction happened. Then more TMSI (0.060 mL) was added and the reaction was stirred for total 2 h. LCMS showed the reaction was about ˜20% completed. More TMSI (0.070 mL) was added and the reaction was stirred at rt for total 7 h. LCMS showed the reaction was about ˜60% completed. Additional amount of TMSI (0.060 mL, total 0.25 mL, 1.84 mmol) was added and the reaction was stirred at rt for total 9 h. LCMS showed the reaction was completed. The reaction was quenched by addition of 1.70 mmol of HCl (0.45 mL of 4N HCl in dioxane) in MeOH (3 mL), and then the mixture was concentrated. The dark reddish residue was partitioned between ether and water. The ether phase was extracted with 0.2 N aqueous HCl (3×). The combined acidic aqueous was cooled at 0° C. and then basified with 1N aqueous NaOH to pH ˜10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified using RP prep-HPLC (Method A). The desired fractions was neutralized and concentrated to give the desired product (1R,2R)—N1-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (23 mg, 0.068 mmol, 24.21% yield) as a yellow oil. Anal. Calcd. for C18H28N4O2 m/z 332.4, found: 333.2 (M +H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2H), 6.83 (d, J=9.34 Hz, 2 H), 3.35-3.46 (m, 1 H), 3.23-3.35 (m, 2 H), 3.16 (d, J=12.64 Hz, 1 H), 2.11-2.26 (m, 2 H), 1.88-2.00 (m, 2 H), 1.85 (ddd, J=8.11, 3.99, 3.85 Hz, 1 H), 1.65-1.75 (m, 4 H), 1.56 (ddd, J=17.31, 8.52, 8.25 Hz, 3 H), 1.21-1.33 (m, 3 H), 1.12 (s, 1 H).

1. additionAfter addition
2. waitat rt for 40 min
3. customreaction
4. stirringthe reaction was stirred for total 2 h
5. stirringthe reaction was stirred at rt for total 7 h
6. stirringthe reaction was stirred at rt for total 9 h
7. concentrationthe mixture was concentrated
8. customThe dark reddish residue was partitioned between ether and water
9. extractionThe ether phase was extracted with 0.2 N aqueous HCl (3×)
10. temperatureThe combined acidic aqueous was cooled at 0° C.
11. extractionThe aqueous phase was extracted with CH2Cl2 (3×)
12. washThe combined CH2Cl2 extracts were washed with saturated aqueous NaCl
13. dry with materialdried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated
16. customto give the crude product
17. customThe crude product was purified
18. concentrationconcentrated

ORD-Eintrag

ord-f74c9bc72bfc45e1b7cdea0d42d5f639

Quelldatensatz

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08815909B2