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 572738ノート

反応式

HRID 572738 の反応式
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

参加物

6

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-7afeb4b069df43b3a8ded8e4f426732d
出典データセット
uspto-grants-2015_05
特許番号
US09029374B2

反応ノート

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