Sodium Bicarbonate → HCID 71503121, compound

HRID 2370032Notes

Reaction equation

HRID 2370032 reaction equation
[CH:1]12[N:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH3:18][C@:19]1([NH2:34])[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20]1.FC(F)(F)S([N-]S(C(F)(F)F)(=O)=O)(=O)=O.[Li+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:18][C@:19]1([NH:34][C@@H:1]2[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]2[NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20]1

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 3816071Lithium bis((trifluoromethyl)sulfonyl)azanideHCID 71226398HCID 71226398, compoundHCID 71441559Benzyl 7-azabicyclo[4.1.0]heptane-7-carboxylate

Product 1

HCID 71503121HCID 71503121, compoundYield 16.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
45 °C

Procedure

A solution of benzyl 7-azabicyclo[4.1.0]heptane-7-carboxylate (170 mg, 0.733 mmol) in CH2Cl2 (1 mL) was added to a 25 mL flask containing (S)-3-methyl-1-(4-nitrophenyl)piperidin-3-amine (115 mg, 0.489 mmol). Then lithium bis(trifluoromethylsulfonyl)amide (28.1 mg, 0.098 mmol) was added in one portion. The resulting greenish orange mixture was stirred at 45° C. under argon for 3 days. The reaction was cooled to rt and diluted with CH2Cl2. Then saturated aqueous NaHCO3 solution (4 mL) was added to the reaction and the reaction was stirred at rt for 30 min. The separated aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified using ISCO column eluting with a gradient of 50-100% EtOAc/Hex. Two diastereomers were separated. The slower eluting fraction which had shorter Rf was the desired product. The fractions containing the desired product were concentrated to give the title compound, benzyl (1R,2R)-2-((S)-3-methyl-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate (37 mg, 0.079 mmol, 16.2% yield) as a yellow oil. Anal. Calcd. for C26H34N4O4 m/z 466.5, found: 467.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08-7.96 (m, 2H), 7.39-7.29 (m, 5H), 6.75 (d, J=9.34 Hz, 2H), 5.13-5.01 (m, 2H), 3.38-3.28 (m, 1H), 3.24 (d, J=12.64 Hz, 1H), 3.19-3.07 (m, 2H), 2.98 (d, J=12.64 Hz, 1H), 2.43-2.29 (m, 1H), 2.21-2.09 (m, 1H), 2.02-1.91 (m, 1H), 1.88-1.77 (m, 1H), 1.67-1.57 (m, 4H), 1.55-1.44 (m, 3H), 1.35-1.15 (m, 4H), 1.07 (s, 3H).

Workup

  1. temperatureThe reaction was cooled to rt
  2. stirringthe reaction was stirred at rt for 30 min
  3. extractionThe separated aqueous layer was extracted with CH2Cl2 (3×)
  4. washThe combined organic layers were washed with saturated aqueous NaCl
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified
  9. washeluting with a gradient of 50-100% EtOAc/Hex
  10. customTwo diastereomers were separated
  11. washThe slower eluting fraction which
  12. additionThe fractions containing the desired product
  13. concentrationwere concentrated

Sources & evidence

ORD record
ord-901d1b1605804368a5e9580a034d2cd2
Source dataset
uspto-grants-2014_04
Patent number
US08710049B2

Reaction notes

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