(S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile → 2-Amino-6-(((3S)-1-(3-methyl-1-oxobutyl)-3-piperidinyl)methoxy)benzonitrile

HRID 332949Notes

Reaction equation

HRID 332949 reaction equation
[CH3:1][CH:2]([CH3:25])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=2[C:16]#[N:17])[CH2:7]1)=[O:5]>C(O)(=O)C.[Fe]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:25])[CH2:7]2)[C:15]=1[C:16]#[N:17]

Participants

4

Reactant 1

HCID 86714279(S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile

Product 1

HCID 867142782-Amino-6-(((3S)-1-(3-methyl-1-oxobutyl)-3-piperidinyl)methoxy)benzonitrile

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile (Example 5c, 43.26 g, ˜18.0 mmol) in glacial acetic acid (35 mL) cooled to 0° C. in an ice bath was added iron powder (2.02 g, 36.1 mmol). The solution was stirred under a N2 balloon at 0° C. for 10 minutes then at room temperature overnight and filtered through a bed of Celite, rinsing well with EtOAc. The EtOAc solution was then washed successively with 2N Na2CO3, water, and brine, dried over Na2SO4, filtered and concentrated to give the crude product as an orange oil. The residue was purified by silica gel chromatography using a 0-60% EtOAc/Hexanes gradient followed by crystallization from EOAc/Hexane to afford the title compound a pale yellow solid (27.01 g, 85.63 mmol, 71% over two steps). 1H NMR (400 MHz, DMSO-d6) 20° C.) δ0.79-0.92 (3×d, J=6.4 Hz, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J=10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 & 6.00 (s & s, 2H), 6.18 (pseudo t, J=8.4 & 9.2 Hz, 1H), 6.32 (pseudo d, J=8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (MH+).

Workup

  1. filtrationat room temperature overnight and filtered through a bed of Celite
  2. washrinsing well with EtOAc
  3. washThe EtOAc solution was then washed successively with 2N Na2CO3, water, and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude product as an orange oil
  8. customThe residue was purified by silica gel chromatography
  9. customfollowed by crystallization from EOAc/Hexane

Sources & evidence

ORD record
ord-0d1bda99029c40e68fa5eafbd5513a6c
Source dataset
uspto-grants-2014_11
Patent number
US08877922B2

Reaction notes

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