Triethylamine → (1-Cyanocyclopropyl)-2-hydroxymethyl-cyclohexane-carboxamide

HRID 2222939Notes

Reaction equation

HRID 2222939 reaction equation
[C:1]1(=[O:11])[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3](=[O:10])O1.Cl.N[C:14]1([C:17]#[N:18])[CH2:16][CH2:15]1.C([N:21](CC)CC)C.[BH4-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.C(OCC)(=O)C>[C:17]([C:14]1([C:4]2([C:3]([NH2:21])=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:1][OH:11])[CH2:16][CH2:15]1)#[N:18]

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 10942665trans-Cyclohexane-1,2-dicarboxylic anhydrideHCID 145863631-Amino-1-cyclopropanecarbonitrile hydrochloride

Product 1

HCID 69114725(1-Cyanocyclopropyl)-2-hydroxymethyl-cyclohexane-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of trans-hexahydroisobenzofuran-1,3-dione (2.62 g, 17.01 mmol) and 1-amino-cyclopropanecarbonitrile hydrochloride (2.00 g, 17.01 mmol, (see O'Donnell, M. J., et al., Synthesis, 1984, 127-128) in dichloromethane (100 mL) at −10° C. was added triethylamine (5.22 mL, 37.43 mmol). The reaction mixture was allowed to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (80 mL), and cooled to −10° C. Isobutyl chloroformate (2.21 mL), 17.01 mmol) was added. After 15 min., the solution was filtered (20 mL tetrahydrofuran wash) and the filtrates were poured slowly into a solution of NaBH4 (1.28 g, 34.02 mmol) in water (100 mL) at 0° C. The reaction mixture was stirred for 1 h and then saturated aqueous sodium hydrogen carbonate (100 mL) and ethyl acetate (150 mL) were added. The reaction mixture was stirred vigorously for 1 h. The organic phase was separated, washed with brine, the aqueous phases were combined, extracted with ethyl acetate, then the combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was recrystallized from ethyl acetate/hexane to give (1-cyanocyclopropyl)-2-hydroxymethyl-cyclohexane-carboxamide.

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue was dissolved in tetrahydrofuran (80 mL)
  3. temperaturecooled to −10° C
  4. additionIsobutyl chloroformate (2.21 mL), 17.01 mmol) was added
  5. filtrationthe solution was filtered
  6. wash(20 mL tetrahydrofuran wash)
  7. stirringThe reaction mixture was stirred vigorously for 1 h
  8. customThe organic phase was separated
  9. washwashed with brine
  10. extractionextracted with ethyl acetate
  11. dry with materialthe combined organics were dried over anhydrous magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was recrystallized from ethyl acetate/hexane

Sources & evidence

ORD record
ord-f5a2eda888b342f49406015c1a125d41
Source dataset
uspto-grants-2008_05
Patent number
US07371747B2

Reaction notes

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