1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 8-(1-(3,5-difluorophenylamino)ethyl)-6-((S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one

HRID 572738Notes

Reaction equation

HRID 572738 reaction equation
CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40](O)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1.[NH:43]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]1.OP=O>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40]([N:43]3[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]3)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 22497phosphenous acidHCID 2733874(3S)-pyrrolidin-3-olHCID 582349718-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid

Product 1

HCID 582350078-(1-(3,5-difluorophenylamino)ethyl)-6-((S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-oneYield 95%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

EDCI (102 mg, 0.53 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino) ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 2 ([α]D20°−102°, described as a starting material in Example 7.0a), (S)-pyrrolidin-3-ol (0.043 mL, 0.53 mmol) and HOPO (47.1 mg, 0.42 mmol) dissolved in DCM (2 mL) in a screwcap vial. The resulting solution was stirred at RT for 5 min then 50° C. for 30 min. More EDCI (˜50 mg) was added to complete the reaction. The solution was washed with a 10% aq. citric acid solution, water, brine and dried over magnesium sulfate. The solvent was evaporated and the crude product purified by flash chromatography on silica gel (40 g) eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-((S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (95%) as a off-white foam. Mass Spectrum: M+H+ 500. NMR Spectrum (CDCl3): 1.60 (d, 3H), 1.89-2.11 (m, 1H), 2.54 (bs, 0.5H), 2.81 (bs, 0.5H), 3.29-3.43 (m, 2H), 3.51 (bs, 4H), 3.64-3.78 (m, 2H), 3.79-3.91 (m, 5H), 4.42 (bs, 0.5H), 4.54 (bs, 0.5H), 4.59 (bs, 0.5H), 4.70 (bs, 0.5H), 4.87-4.95 (m, 1H), 5.54 (bs, 1H), 5.89-6.01 (m, 2H), 6.09 (dd, 1H), 7.85 (s, 0.5H), 7.87 (s, 0.5H), 8.18 (bs, 0.5H), 8.25 (bs, 0.5H).

Workup

  1. wait50° C. for 30 min
  2. customthe reaction
  3. washThe solution was washed with a 10% aq. citric acid solution, water, brine
  4. dry with materialdried over magnesium sulfate
  5. customThe solvent was evaporated
  6. customthe crude product purified by flash chromatography on silica gel (40 g)
  7. washeluting with 0 to 10% MeOH in DCM
  8. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-7afeb4b069df43b3a8ded8e4f426732d
Source dataset
uspto-grants-2015_05
Patent number
US09029374B2

Reaction notes

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