Acetic Acid → HCID 15985540, compound

HRID 1510167Notes

Reaction equation

HRID 1510167 reaction equation
[CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.C(O)(=O)C>C1COCC1>[CH:1]1([N:7]=[C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:27])[CH3:28])[CH:20]=4)[C@@H:14]([CH3:29])[CH2:13]3)[N:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[C:10](=[O:37])[N:9]2[CH3:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 6328Methyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 178458374HCID 178458374, compound

Product 1

HCID 15985540HCID 15985540, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (11-10, 0.5 g, 0.1 mmoles) was dissolved in THF (2 mL) in an oven-dried flask and the solution was cooled under nitrogen to −78° C. in a dry ice/acetone bath. To the cooled reaction was added a 1 M solution of Lithium bis(trimethylsilyl)amide in THF (0.3 mL, 0.3 mmoles) dropwise, and the solution was warmed to −20° C. for 10 min. The solution was cooled to −50° C. and iodomethane (0.014 g, 0.1 mmole) was added and the reaction stirred for 30 min at −50° C. The reaction was then allowed to warm to rt. A drop of acetic acid was added and the volume was reduced. The residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and methylene chloride (5 mL). The organic layer was dried over sodium sulfate, filtered and reduced to a residue which was chromatographed on silica gel eluting with a gradient elution of 100% methylene chloride going to 30% methylene chloride/methanol/10% NH4OH solution over 20 min. The desired fractions were combined and the solvents removed to give the product.

Workup

  1. customTo the cooled reaction
  2. temperaturethe solution was warmed to −20° C. for 10 min
  3. temperatureThe solution was cooled to −50° C.
  4. temperatureto warm to rt
  5. customThe residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and methylene chloride (5 mL)
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. filtrationfiltered
  8. customwas chromatographed on silica gel eluting with a gradient elution of 100% methylene chloride going to 30% methylene chloride/methanol/10% NH4OH solution over 20 min
  9. customthe solvents removed
  10. customto give the product

Sources & evidence

ORD record
ord-0e293cbce3ef4ced82fa5329467f2512
Source dataset
uspto-grants-2012_07
Patent number
US08211904B2

Reaction notes

Loading…