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 715523Notes

Reaction equation

HRID 715523 reaction equation
CN1C(=O)CCC1.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].[CH3:30][C@:31]1([CH2:39][N:40]2[C:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=3[N:42]=[CH:41]2)CCC[C@:33]2(OC2)[CH2:32]1>CC#N>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[CH2:21][C@@:19]3([CH2:20][CH2:33][CH2:32][C@@:31]([CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=5[N:42]=[CH:41]4)([CH3:30])[CH2:22]3)[O:18][C:17]2=[O:23])=[CH:12][CH:11]=1

Participants

6

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 2763103tert-Butyl (6-methoxypyridin-3-yl)carbamateHCID 23665647Potassium tert-butoxideHCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile

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 34%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a 4 mL vial was added NMP (1997 μL), tert-butyl (6-methoxypyridin-3-yl)carbamate (448 mg, 1.997 mmol) and potassium tert-butoxide (213 mg, 1.898 mmol) at RT. After stirring for ˜1 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (281 mg, 0.999 mmol) was added. The solution was then heated to 55° C. and stirred for 17 h. The resulting solution was cooled to RT, diluted with 2 mL of MeCN, then purified on HPLC: 20-60% MeCN/Water over 14 min, Sunfire C-18 column, 0.1% TFA. Fractions containing product were added to a separatory funnel, diluted with DCM and saturated NaHCO3. DCM layer was separated, passed over a phase separator and concentrated to give 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 (145 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=4, 12 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.58 (dd, J=4 Hz, 1H), 6.80 (d, J=12 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 3H), 3.66 (q, J=8 Hz, 2H), 2.14-2.18 (m, 1H), 1.94-2.00 (m, 2H), 1.66-1.77 (m, 2H), 1.51 (d, J=16 Hz, 1H), 1.36-1.44 (m, 2H), 1.33 (s, 3H). MS (m/z) 432.2 (M+H+).

Workup

  1. temperatureThe solution was then heated to 55° C.
  2. stirringstirred for 17 h
  3. temperatureThe resulting solution was cooled to RT
  4. custompurified on HPLC
  5. wait20-60% MeCN/Water over 14 min
  6. additionFractions containing product
  7. additionwere added to a separatory funnel
  8. additiondiluted with DCM and saturated NaHCO3
  9. customDCM layer was separated
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-9e5f62eb3bb24b3c826e313f1bd5dd84
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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