Hydrochloric Acid → 1,3-Dioxo-8a-pridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo [1,5-a]pyrazine-7-carboxylic acid tert-butyl ester

HRID 394844Notes

Reaction equation

HRID 394844 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]Cl.Cl.C([O-])(O)=O.[Na+].N12CCN(CC1)CC2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:16](=[O:17])[C:10]2([CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 9237DabcoHCID 11430Potassium CarbonateHCID 23393Picolyl chlorideHCID 516892Sodium BicarbonateHCID 3251421Potassium bis(trimethylsilyl)amideHCID 111867551,3-Dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester

Product 1

HCID 113163151,3-Dioxo-8a-pridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo [1,5-a]pyrazine-7-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

In flame-dried glassware, 1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 4, 10.11 g, 30 mmol) was dissolved in 150 mL of DMF/30 mL of THF and cooled to −78° C. Potassium bis(trimethylsilyl)amide (KHMDS, 0.5 M solution, 90 mL, 45 mmol) was added dropwise and allowed to stir for 1 h at −78° C. In separate glassware, 2-picolyl chloride.HCl (14.76 g, 90 mmol) was reacted with saturated aqueous NaHCO3 (150 mL), extracted with CH2Cl2 (3×150 mL), dried with MgSO4, evaporated and added 50 mL of dry THF with some molecular sieves. The resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe and allowed to warm to room temperature overnight. The toluene and THF were evaporated and resulting DMF solution was partitioned with 150 mL of H2O/150 mL of IPE. 1,4-Diazabicyclo[2,2,2]octane (7.3 g, 65 mmol) and K2CO3 (12 g, 90 mmol) were added to the solution and the solution was stirred for one hour to remove excess 2-picolyl chloride. The organic solvents were separated and were removed by evaporation to give 11.45 g (89%) of essentially pure title compound.

Workup

  1. extractionextracted with CH2Cl2 (3×150 mL)
  2. dry with materialdried with MgSO4
  3. customevaporated
  4. additionadded 50 mL of dry THF with some molecular sieves
  5. additionThe resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe
  6. temperatureto warm to room temperature overnight
  7. customThe toluene and THF were evaporated
  8. customresulting DMF solution
  9. customwas partitioned with 150 mL of H2O/150 mL of IPE
  10. stirringthe solution was stirred for one hour
  11. customto remove excess 2-picolyl chloride
  12. customThe organic solvents were separated
  13. customwere removed by evaporation

Sources & evidence

ORD record
ord-17e5d019a5f24f57ac94a9b50646fdda
Source dataset
uspto-grants-2003_08
Patent number
US06603002B2

Reaction notes

Loading…