Potassium Carbonate → 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide

HRID 600509ノート

反応式

HRID 600509 の反応式
[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1

参加物

5

反応物 3

HCID 11430Potassium CarbonateHCID 111829543-Bromo-1-methylpyrrolidin-2-one2 回HCID 536296993-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide2 回

生成物 1

HCID 249519403-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide収率 76%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (385 mg, 2.2 mmol) (Intermediate 4) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue was partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (187 mg, 33%) which eluted before its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+

後処理

  1. customThe DMF was evaporated
  2. customthe residue was partitioned between ethyl acetate (90 mL) and water (20 mL)
  3. customThe organic layer was separated
  4. washwashed with brine
  5. dry with materialdried (MgSO4)
  6. customevaporated
  7. customto give an oil which
  8. customwas purified by chromatography on silica eluting with 0-6% methanol in DCM

出典と根拠

ORDレコード
ord-e3e0c5b0cfec4720a85f41a1f0957873
出典データセット
uspto-grants-2011_03
特許番号
US07902200B2

反応ノート

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