4-Methylmorpholine → Methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

HRID 928051Notes

Reaction equation

HRID 928051 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=O)[CH2:28]1)[CH3:26].CN1CCOCC1.[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[S:51]([NH:54][C:55]1[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]2[C:58]([CH:59]3[CH2:69][CH:60]3[CH2:61][O:62]2)=[CH:57][CH:56]=1)(=[O:53])=[O:52]>CN(C=O)C.O>[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:42][CH2:43][C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[S:51]([NH:54][C:55]2[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]3[C:58]([CH:59]4[CH2:69][CH:60]4[CH2:61][O:62]3)=[CH:57][CH:56]=2)(=[O:52])=[O:53])=[O:34])[CH2:28]1)[CH3:26]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 28064096(S)-1-ethylpyrrolidine-3-carboxylic acid2×HCID 86713343methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate2×

Product 1

HCID 71006923Methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylateYield 58.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

HATU (0.234 g) was added to a mixture of (S)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 189, 0.089 g) and NMM (0.068 mL) in DMF (4 mL) and the mixture was stirred for 15 minutes. Methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 102, 0.250 g) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.190 g) as a solid.

Workup

  1. stirringthe mixture was stirred for 20 hours
  2. extractionextracted with ethyl acetate
  3. washThe organic layer was washed with saturated NaHCO3 solution
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customThe filtrate was evaporated to dryness
  7. customthe residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15%

Sources & evidence

ORD record
ord-0cb5ffb0d23d4ef0999889cf55ac6c3a
Source dataset
uspto-grants-2016_03
Patent number
US09290472B2

Reaction notes

Loading…