Diethyl Ether → 3-Methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione

HRID 924608Notes

Reaction equation

HRID 924608 reaction equation
Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.ClC([C:21]1([CH:30]=[C:31]=[O:32])[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][CH:22]1[CH3:29])=O.[OH-].[Na+].[CH2:35]([O:37]CC)C>>[CH3:2][O:3][N:4]1[CH2:10][CH2:9][N:8]2[C:35](=[O:37])[CH:30]([C:21]3[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=3[CH3:27])[C:31](=[O:32])[N:7]2[CH2:6][CH2:5]1

Participants

6

Reactant 5

HCID 3283Diethyl Ether2×HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 867199135-Methoxy-[1,2,5]triazepane hydrochloride saltHCID 867199242-(Chlorocarbonyl)-2-mesitylketene

Product 1

HCID 867199153-Methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione

Conditions

Temperature
2.5 °C

Procedure

To a degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (408 mg, 2.0 mmol) and triethylamine (1.115 ml, 810 mg, 8.0 mmol) in diethyl ether (1.0 ml) at 0-5° C. was added a solution of 2-(chlorocarbonyl)-2-mesitylketene [prepared according to Nakanishi's method: S. Nakanishi, K. Butler, Org. Prep. Proced. Int. 7, 155-158 (1975)] (891 mg, 4.0 mmol) in diethyl ether (1.0 ml) dropwise. The suspension was stirred at 0-5° C. for 30 minutes, and at room temperature overnight. The reaction mixture was poured on water (5 ml), the pH made alkaline (pH 14) by addition of aqueous sodium hydroxide, the aqueous layer extracted with ethyl acetate (3×10 ml) and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 5 by addition of a 4N HCl solution and the product thoroughly extracted with ethyl acetate (3×20 ml) and dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient ethyl acetate/cyclohexane 5:1→4 ethyl acetate). Yield: 70 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a pale beige solid, mp 227-229° C.

Workup

  1. customat room temperature
  2. customovernight
  3. additionThe reaction mixture was poured on water (5 ml)
  4. extractionthe aqueous layer extracted with ethyl acetate (3×10 ml)
  5. temperaturewith cooling to pH 5 by addition of a 4N HCl solution
  6. extractionthe product thoroughly extracted with ethyl acetate (3×20 ml) and dichloromethane (3×20 ml)
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography on silica gel (gradient ethyl acetate/cyclohexane 5:1→4 ethyl acetate)

Sources & evidence

ORD record
ord-8a3d7b94fa7a46abbae549377e5a61ae
Source dataset
uspto-grants-2016_03
Patent number
US09282743B2

Reaction notes

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