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

HRID 715526Notes

Reaction equation

HRID 715526 reaction equation
CN1C(=O)CCC1.[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[N:15][CH:16]=1)[CH3:9].CC(C)([O-])C.[K+].[CH3:29][C@:30]1([CH2:38][N:39]2[C:43]3[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:37]CC[C@:32]2(O[CH2:33]2)[CH2:31]1>CC(O)C.O>[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([N:17]2[CH2:21][C@@:20]3([CH2:33][CH2:32][CH2:31][C@@:30]([CH2:38][N:39]4[C:43]5[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=5[N:41]=[CH:40]4)([CH3:29])[CH2:37]3)[O:19][C:18]2=[O:22])=[N:15][CH:16]=1)[CH3:9]

Participants

6

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 23665647Potassium tert-butoxideHCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrileHCID 86717589Ethyl (5-ethoxypyrazin-2-yl)carbamate

Product 1

HCID 712276751-(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

Reagents, catalysts & solvents 1

HCID 21889133Propan-2-ol--water (1/1)Solvent

Procedure

To a 10 mL flask was added NMP (7.11 mL), ethyl (5-ethoxypyrazin-2-yl)carbamate (0.863 g, 4.09 mmol) and potassium tert-butoxide (0.399 g, 3.55 mmol) at RT. After stirring for ˜5 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (1 g, 3.55 mmol) was added. The solution was then heated to 70° C. (oil bath) and stirred for 7 h. At 7 h, the temperature was taken to 80° C., then at 8 h, it was taken to 90° C. The mixture was allowed to stir at 90° C. for 16 h. The resulting solution was cooled to RT and added dropwise to a 50 mL solution of IPA/Water (1:1) that contained a small crystalline seed. The mixture was allowed to stir at RT overnight. The next day, the slurry was filtered, and the solids slurried in MeCN overnight. The next day, the solids were filtered off, dried under reduced pressure to give 1-(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a very light yellow solid (968 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=1.25 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=1.51 Hz, 1H), 7.83 (d, J=8.53 Hz, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 4.32 (q, J=7.03 Hz, 2H), 4.16 (s, 2H), 3.80-3.88 (m, 2H), 1.98 (d, J=13.80 Hz, 1H), 1.88 (d, J=14.31 Hz, 1H), 1.64-1.73 (m, 3H), 1.49-1.53 (m, 2H), 1.34-1.38 (m, 2H), 1.32-1.38 (t, J=8.0 Hz, 2H), 1.07 (s, 3H). MS (m/z) 447.2 (M+H+).

Workup

  1. temperatureThe solution was then heated to 70° C. (oil bath)
  2. stirringstirred for 7 h
  3. waitAt 7 h
  4. customwas taken to 80° C.
  5. waitat 8 h
  6. customwas taken to 90° C
  7. stirringto stir at 90° C. for 16 h
  8. temperatureThe resulting solution was cooled to RT
  9. stirringto stir at RT overnight
  10. filtrationThe next day, the slurry was filtered
  11. waitthe solids slurried in MeCN overnight
  12. filtrationThe next day, the solids were filtered off
  13. customdried under reduced pressure

Sources & evidence

ORD record
ord-1d62d78f16994fbabb5501bde799687a
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

Loading…