N-methyl-2-pyrrolidone → 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

HRID 715524Notes

Reaction equation

HRID 715524 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Li]CCCC.[CH3:22][C@:23]1([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=3[N:34]=[CH:33]2)CCC[C@:25]2(OC2)[CH2:24]1.CN1CCCC1=O>O1CCCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@:12]3([CH2:13][CH2:25][CH2:24][C@@:23]([CH2:31][N:32]4[C:36]5[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=5[N:34]=[CH:33]4)([CH3:22])[CH2:15]3)[O:11][C:10]2=[O:16])=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 2763103tert-Butyl (6-methoxypyridin-3-yl)carbamateHCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrileHCID 178418339Butyllithium

Product 1

HCID 712275831-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrileYield 80.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22728543Water ethylacetateSolvent

Procedure

To a solution of tert-butyl (6-methoxypyridin-3-yl)carbamate (5.98 g, 26.7 mmol) in tetrahydrofuran (THF) (20 mL) at −78° C. under N2 was added n-BuLi (2.5M in hexanes) (10.66 mL, 26.7 mmol). The mixture was allowed to warm up to RT and stirred for 20 min, to the mixture was added 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (6.0 g, 21.33 mmol) followed by N-methyl-2-pyrrolidone (NMP) (20.00 mL). The mixture was heated at 75° C. for 2 days and then cooled to RT. The reaction mixture was diluted with EtOAc/H2O and extracted with 3×EtOAc. The organic layers were washed with 2× brine, dried over Na2SO4, filtered and concentrated. To the residue was added 250 mL of i-PrOH, heated to reflux for 2 hours, and then cooled to RT for 2 days. The solid was filtered and air dried to afford 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (7.43 g, 79% yield).

Workup

  1. temperatureThe mixture was heated at 75° C. for 2 days
  2. temperaturecooled to RT
  3. extractionextracted with 3×EtOAc
  4. washThe organic layers were washed with 2× brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additionTo the residue was added 250 mL of i-PrOH
  9. temperatureheated
  10. temperatureto reflux for 2 hours
  11. temperaturecooled to RT for 2 days
  12. filtrationThe solid was filtered
  13. customair dried

Sources & evidence

ORD record
ord-38cf0ca46916414f82d8913fe2b1d6d8
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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