Sodium Bicarbonate → HCID 71226830, compound

HRID 715528Notes

Reaction equation

HRID 715528 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:5]([CH3:15])[CH:4]=1.CC(C)([O-])C.[K+].[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)[CH2:30]CC[C@:25]2(O[CH2:26]2)[CH2:24]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]3([CH2:26][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])[CH2:30]3)[O:11][C:10]2=[O:14])=[C:5]([CH3:15])[CH:4]=1

Participants

6

Reactant 4

HCID 516892Sodium BicarbonateHCID 23665647Potassium tert-butoxideHCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrileHCID 86717590HCID 86717590, compound

Product 1

HCID 71226830HCID 71226830, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of ethyl (6-methoxy-4-methylpyridin-3-yl)carbamate (0.593 g, 2.82 mmol) and potassium tert-butoxide (0.275 g, 2.452 mmol) in NMP (4.90 mL) was stirred at RT for 5 min before 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.69 g, 2.452 mmol) was added. The reaction mixture was stirred at 55° C. for 16 h, then at 70° C. for 2.5 h and then at 85° C. for 16 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layer was concentrated and purified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60% MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min). Fractions contained desired products were free based with NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulted foam was crystallized by stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped vial overnight. The resulted cloudy mix was concentrated to ˜2 mL volume and then stirred for 1 h. The resulted light pink solids were collected by filtration and dried on high vacuum for 2 h to yield 1-(((5S,7S)-3-(6-methoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=8.53 Hz, 1H), 7.78 (s, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.93 (s, 3H), 3.52-3.58 (m, 2H), 2.25 (s, 4H), 2.01 (d, J=13.80 Hz, 2H), 1.63-1.77 (m, 2H), 1.60 (s, 1H), 1.50 (d, J=13.80 Hz, 1H), 1.37-1.42 (m, 4H). MS (m/z) 446.2 (M+H+).

Workup

  1. additionwas added
  2. waitat 70° C. for 2.5 h
  3. waitat 85° C. for 16 h
  4. extractionthe mixture was extracted with EtOAc
  5. concentrationThe organic layer was concentrated
  6. custompurified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60% MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min)
  7. extractionextracted with DCM
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe resulted foam was crystallized
  11. stirringby stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped vial overnight
  12. additionThe resulted cloudy mix
  13. concentrationwas concentrated to ˜2 mL volume
  14. stirringstirred for 1 h
  15. filtrationThe resulted light pink solids were collected by filtration
  16. customdried on high vacuum for 2 h

Sources & evidence

ORD record
ord-f978ee7c8a87435888b28ba1b4a2cfae
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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