Water → HCID 66733965, compound

HRID 1929714Notes

Reaction equation

HRID 1929714 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH:17]=O)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:34]O.C(OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([C:17]#[N:34])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 7918Acetic Anhydride2×HCID 443297Hydroxyamine hydrochlorideHCID 86640827HCID 86640827, compound

Product 1

HCID 66733965HCID 66733965, compound

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution of 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (6.000 g; 13.289 mmol) in pyridine (100 ml) was added hydroxylamine hydrochloride (1.015 g; 14.618 mmol). The resulting mixture was first stirred at rt (4 h), and was then heated to 60° C. for 1 h before acetic anhydride (1.9 ml; 20.099 mmol; 1.5 eq.) was added at this temperature. After further heating at 60° C. (30 min.), the reaction mixture was then heated at 80° C. for 16 h. A second addition of acetic anhydride (0.3 ml; 3.173 mmol) was performed at 60° C., and the resulting mixture was additionally stirred at 80° C. for 10 h. The resulting yellow solution was then allowed to cool to rt before water was added. Extractions with DCM, washing with aq. 2N HCl, drying of the organic layer over magnesium sulfate, filtration, and concentration to dryness under reduced pressure afforded the crude product (yellow oil; 7.50 g). Purification by FC (EA/heptane=4/1) gave the expected pure product 1-cyano-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (5.000 g; 84%). LC-MS: tR=1.09 min.; [M+H]+=449.40 g/mol.

Workup

  1. additionwas added at this temperature
  2. temperatureAfter further heating at 60° C. (30 min.)
  3. temperaturethe reaction mixture was then heated at 80° C. for 16 h
  4. customwas performed at 60° C.
  5. stirringthe resulting mixture was additionally stirred at 80° C. for 10 h
  6. additionwas added
  7. extractionExtractions with DCM
  8. washwashing with aq. 2N HCl
  9. dry with materialdrying of the organic layer over magnesium sulfate, filtration, and concentration to dryness under reduced pressure
  10. customafforded the crude product (yellow oil; 7.50 g)
  11. customPurification by FC (EA/heptane=4/1)

Sources & evidence

ORD record
ord-8c76711a054740438e88e3111453cca9
Source dataset
uspto-grants-2012_05
Patent number
US08188082B2

Reaction notes

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