Sodium Hydroxide → (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid

HRID 2037301ノート

反応式

HRID 2037301 の反応式
[OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:33])[C:12]([NH:14][C@@:15]1([C:28]([O:30]CC)=[O:29])[CH2:22][C:19]2([CH2:21][CH2:20]2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:23]([O:25]CC)=[O:24])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:33])[C:12]([NH:14][C@@:15]1([C:28]([OH:30])=[O:29])[CH2:22][C:19]2([CH2:20][CH2:21]2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:23]([OH:25])=[O:24])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]

参加物

3

反応物 2

HCID 14798Sodium HydroxideHCID 86691276Diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylate

生成物 1

HCID 86691269(1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxy carbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1'-cyclopropane]-2,6-dicarboxylic acid収率 78.6%

反応条件

温度
25 °C

実験手順

Charge 2 N NaOH (37 mL, 5.0 equivalents) and diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (6.50 g, 14.81 mmol) to a reactor and allow to stir for at least 12 hours between 20-30° C. until the reaction is complete by HPLC. Transfer the reaction to a separatory funnel and allow it to settle for at least 10 minutes. Separate the phases and return the lower aqueous layer to the reactor. Add ethyl acetate (90 mL, 13.8 volumes) to the mixture, and then add 1 N NaHSO4 until pH reaches 2 to 2.5. Separate layers and wash the organic with water (45 mL, 6.9 volumes). Remove water in organic phase atmospheric distillation with ethyl acetate to remove residual water. Cool the resulting slurry between 20-30° C. over at least 2 hours and allowed to granulate at that temperature for at least 90 minutes. Filter the resulting solids and wash the wet cake with ethyl acetate (3×15 mL, 2.3 volumes). Dry under reduced pressure at 45° C. to provide the title compound as a white solid (4.45 g, 11.64 mmol, 78.6%) 1H NMR (DMSO-d6, 400 MHz, 50° C.): δ 12.01 (s, 2H), 8.22 (s, 1H), 6.49 (bs, 1H), 4.00 (bs, 1H), 2.43 (dd, J=6.5, 2.8, 1H), 1.83 (d, J=14.0, 1H), 1.68-1.62 (m, 2H), 1.42 (dd, J=6.5, 2.8, 1H), 1.36 (s, 9H), 1.15 (d, J=7.1, 3H), 0.67-0.61 (m, 1H), 0.56-0.51 (m, 1H), 0.46-0.36 (m, 2H).

後処理

  1. customTransfer the reaction to a separatory funnel
  2. waitto settle for at least 10 minutes
  3. customSeparate the phases
  4. additionAdd ethyl acetate (90 mL, 13.8 volumes) to the mixture, and then add 1 N NaHSO4 until pH
  5. washSeparate layers and wash the organic with water (45 mL, 6.9 volumes)
  6. distillationRemove water in organic phase atmospheric distillation with ethyl acetate
  7. customto remove residual water
  8. temperatureCool the resulting slurry between 20-30° C. over at least 2 hours
  9. waitto granulate at that temperature for at least 90 minutes
  10. filtrationFilter the resulting solids
  11. washwash the wet cake with ethyl acetate (3×15 mL, 2.3 volumes)
  12. customDry under reduced pressure at 45° C.

出典と根拠

ORDレコード
ord-588a2ef94f2c46d4ae610d2b9bc9572e
出典データセット
uspto-grants-2013_11
特許番号
US08575214B2

反応ノート

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