Azetidine → 6-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4H-chromen-4-one

HRID 1947353Notes

Reaction equation

HRID 1947353 reaction equation
[B-](F)(F)(F)F.CN(C(O[N:14]1[C:19](=O)[CH2:18][CH2:17]C1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49]([OH:51])=O)[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(C(C)C)C(C)C)C.N1CCC1>C(Cl)Cl.CN(C=O)C>[N:14]1([C:49]([C:34]2[CH:35]=[C:36]3[C:41](=[C:32]([CH:30]([NH:29][C:24]4[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=4)[CH3:31])[CH:33]=2)[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])=[O:51])[CH2:17][CH2:18][CH2:19]1

Participants

7

Reactant 4

HCID 10422AzetidineHCID 81531DiisopropylethylamineHCID 98575222-(2,5-Dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborateHCID 582349718-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid

Product 1

HCID 529137066-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4H-chromen-4-oneYield 61%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (409 mg, 1.36 mmol) was added portionwise to a suspension of the enantiomer 2 of 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid ([α]D20°: −102°, enantiomer 2, see Example 7.0a) (450 mg, 1.05 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.310 mL, 1.78 mmol) in DCM (5 mL) at RT under nitrogen. The resulting mixture was stirred at RT for 4 hrs. Azetidine (0.211 mL, 3.14 mmol) was then added to the mixture and stirring was maintained overnight. The mixture was diluted with DMF and concentrated to remove DCM. The reaction mixture was purified by preparative HPLC on a Waters X-Bridge system. The fractions were evaporated to dryness to afford a white solid 6-(azetidine-1-carbonyl)-8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4H-chromen-4-one (300 mg, 61%). Mass Spectrum: M+H+ 470. [α]D20°: −113° in MeCN. NMR Spectrum (DMSOd6): 1.50 (d, 3H), 2.18-2.28 (m, 2H), 3.50-3.63 (m, 4H), 3.69-3.78 (m, 4H), 3.98-4.07 (m, 2H), 4.09-4.19 (m, 2H), 4.97-5.05 (m, 1H), 5.61 (s, 1H), 6.15 (d, 2H), 6.21 (t, 1H), 7.03 (d, 1H), 7.79 (d, 1H), 8.02 (d, 1H).

Workup

  1. stirringstirring
  2. temperaturewas maintained overnight
  3. concentrationconcentrated
  4. customto remove DCM
  5. customThe reaction mixture was purified by preparative HPLC on a Waters X-Bridge system
  6. customThe fractions were evaporated to dryness

Sources & evidence

ORD record
ord-588ebd1b921e480ab820a94c51ae53cd
Source dataset
uspto-grants-2013_03
Patent number
US08399460B2

Reaction notes

Loading…