Acetic Acid → tert-butyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamate

HRID 2204551Notes

Reaction equation

HRID 2204551 reaction equation
[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18](C=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].NO.CC(O)=O.[C:28]([O:32][C:33]([NH:35][C:36]12[CH2:43][CH2:42][C:39]([C:44]([OH:46])=O)([CH2:40][CH2:41]1)[CH2:38][CH2:37]2)=[O:34])([CH3:31])([CH3:30])[CH3:29].[CH3:47][N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.C1COCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].[Zn]>[C:28]([O:32][C:33](=[O:34])[NH:35][C:36]12[CH2:43][CH2:42][C:39]([C:44](=[O:46])[NH:48][CH2:47][C:18]3[N:19]=[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=5)(=[O:3])=[O:2])[C:15]4=[N:16][CH:17]=3)([CH2:40][CH2:41]1)[CH2:38][CH2:37]2)([CH3:31])([CH3:30])[CH3:29]

Participants

11

Reactant 5

HCID 176Acetic AcidHCID 787HydroxylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 231507384-{[(Tert-butoxy)carbonyl]amino}bicyclo[2.2.2]octane-1-carboxylic acidHCID 580098835-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde

Product 1

HCID 58010034tert-butyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamateYield 23.1%

Reagents, catalysts & solvents 5

HCID 23994ZincCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×HCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent2×

Conditions

Temperature
40 °C

Procedure

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.49 g, 1.6 mmol, Example #10, Step B) in MeOH (10 mL) was added hydroxylamine (50% in water, 0.199 mL, 3.25 mmol). The reaction mixture was heated to about 40° C. After about 2 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. To a solution of the crude oxime in THF (10 mL) and AcOH (0.93 mL, 16 mmol) was added zinc dust (<10 micron, 0.425 g, 6.50 mmol). After about 4 h at ambient temperature, the reaction mixture was diluted with DCM and saturated aqueous NaHCO3 and filtered through Celite®. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 N in 1,4-dioxane, 1 mL) and concentrated under reduced pressure. To a solution of the crude amine in DCM (10 mL) was added 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (0.48 g, 1.8 mmol, Prime Organics), TEA (0.23 mL, 1.6 mmol) and HATU (0.618 g, 1.63 mmol). After about 4 h at ambient temperature, the reaction mixture was diluted with DCM and saturated aqueous NaHCO3 and filtered through Celite®. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amide was purified by chromatography on silica gel eluting with a gradient of 20-80% EtOAc in DCM to provide tert-butyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamate as a tan solid (0.205 g, 23%). LC/MS (Table 2, Method a) Rt=2.52 min; MS m/z: 554 (M+H)+.

Workup

  1. temperaturethe reaction mixture was cooled to ambient temperature
  2. concentrationconcentrated under reduced pressure
  3. waitAfter about 4 h at ambient temperature
  4. filtrationfiltered through Celite®
  5. customThe layers were separated
  6. dry with materialthe organic layer was dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. additiontreated with HCl (4 N in 1,4-dioxane, 1 mL)
  9. concentrationconcentrated under reduced pressure
  10. waitAfter about 4 h at ambient temperature
  11. filtrationfiltered through Celite®
  12. customThe layers were separated
  13. dry with materialthe organic layer was dried over anhydrous Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure
  16. customThe crude amide was purified by chromatography on silica gel eluting with a gradient of 20-80% EtOAc in DCM

Sources & evidence

ORD record
ord-243c276c70e24bfa9406d6d64ea55fbe
Source dataset
uspto-grants-2016_06
Patent number
US09365579B2

Reaction notes

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