Dichloromethane → ((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile

HRID 715496Notes

Reaction equation

HRID 715496 reaction equation
[OH:1][C@@:2]1([CH2:21]O)[CH2:7][CH2:6][CH2:5][C@@:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)([CH3:8])[CH2:3]1.C(Cl)Cl.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[CH3:8][C@:4]1([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:5][CH2:6][CH2:7][C@:2]2([O:1][CH2:21]2)[CH2:3]1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 711161281-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile

Product 1

HCID 86716577((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrileYield 99.9%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 516892Sodium BicarbonateSolvent

Procedure

To a 1 L flask was added 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (21.2 g, 70.8 mmol) and DCM (698 mL) and the temperature was lowered to 5° C. Next DMAP (6.49 g, 53.1 mmol), tosyl-Cl (20.25 g, 106 mmol) and triethylamine (20.23 mL, 145 mmol) were added. The solution was allowed to stir and warm to RT. Stirring was continued for 18 h and then the solution was added to a separatory funnel and diluted with saturated aq NaHCO3 (1 L). The DCM was separated, and washed sequentially with saturated aq NH4Cl, then saturated aq NaHCO3. The DCM was then passed over a phase separator to remove leftover water, concentrated, and taken directly onto the next step. To the yellow residue was added methanol (698 mL) followed by K2CO3 (10.77 g, 78 mmol). The mixture was stirred at RT for 3 h. Following completion, the solution was filtered, and the solids were washed with MeOH. The mixture was then diluted with DCM (500 mL) and saturated aq NaHCO3 (1 L). The solution was added to a 3 L separatory funnel, and the aqueous layer extracted three times with DCM. The combined DCM extracts were washed with brine and then dried over Na2SO4, filtered and concentrated. The crude solid was azeotroped with EtOAc two times to give a yellow residue. The residue was dried under reduced pressure to give 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile as a yellow solid (19.9 g, 95% yield). MS (m/z) 282.2 (M+H+).

Workup

  1. customwas lowered to 5° C
  2. stirringStirring
  3. additionthe solution was added to a separatory funnel
  4. customThe DCM was separated
  5. washwashed sequentially with saturated aq NH4Cl
  6. customto remove leftover water
  7. concentrationconcentrated
  8. additionTo the yellow residue was added methanol (698 mL)
  9. stirringThe mixture was stirred at RT for 3 h
  10. filtrationthe solution was filtered
  11. washthe solids were washed with MeOH
  12. additionThe mixture was then diluted with DCM (500 mL) and saturated aq NaHCO3 (1 L)
  13. additionThe solution was added to a 3 L separatory funnel
  14. extractionthe aqueous layer extracted three times with DCM
  15. washThe combined DCM extracts were washed with brine
  16. dry with materialdried over Na2SO4
  17. filtrationfiltered
  18. concentrationconcentrated
  19. customThe crude solid was azeotroped with EtOAc two times
  20. customto give a yellow residue
  21. customThe residue was dried under reduced pressure

Sources & evidence

ORD record
ord-68c3f8aa76ee42ac9124c53875cd55b5
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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