Oxalyl chloride → (R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide

HRID 1697478ノート

反応式

HRID 1697478 の反応式
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[O:7][C@@H:8]([C:11]([OH:13])=O)[CH2:9][O:10][C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([C@H:34]([NH2:36])[CH3:35])=[CH:31][CH:32]=2)[CH:27]=[N:26]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C(#N)C>[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([C@H:34]([NH:36][C:11]([C@@H:8]3[O:7][C:6]4[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:4][C:5]=4[O:10][CH2:9]3)=[O:13])[CH3:35])=[CH:31][CH:32]=2)[CH:27]=[N:26]1

参加物

9

反応物 5

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 58125504(R)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acidHCID 66944155(R)-1-(1H-Indazol-5-yl)ethylamine hydrochloride

生成物 1

HCID 44194765(R)-6-Trifluoromethyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [(R)-1-(1H-indazol-5-yl)-ethyl]-amide収率 44.7%

試薬・触媒・溶媒 3

HCID 6228Dimethylformamide触媒HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒

実験手順

A stirred solution of (R)-6-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid (55 mg, 0.22 mmol) in anhydrous DCM (6 mL) was cooled to 0° C. DMF (1 drop) was added, followed by oxalyl chloride (26 μL, 0.3 mmol). The reaction was allowed to warm to room temperature and stirred for 30 minutes, then evaporated to dryness. A solution of (R)-1-(1H-Indazol-5-yl)ethylamine hydrochloride (40 mg, 0.2 mmol) in acetonitrile (6 mL) was added, followed by N,N-diisopropylethylamine (53 μL, 0.3 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated NaHCO3 solution (5 mL) and extracted with EtOAc (3×5 mL). The combined organics were washed with brine (2×5 mL), dried (MgSO4), filtered and evaporated to dryness. Flash chromatography (0 to 4% MeOH in DCM over 30 minutes) gave the product (35 mg) as a solid. 1H NMR (400 MHz; DMSO-d6) 13.0 (1H, s), 8.63 (1H, dd), 8.04 (1H, s), 7.69 (1H, s), 7.50 (1H, d), 7.37-7.33 (2H, m), 7.23-7.18 (2H, m), 7.07 (1H, d), 5.09-5.05 (1H, m), 4.93-4.90 (1H, m), 4.47-4.43 (1H, m), 4.35-4.32 (1H, m), 1.43 (3H, d).

後処理

  1. customevaporated to dryness
  2. stirringthe reaction was stirred at room temperature for 1 hour
  3. extractionextracted with EtOAc (3×5 mL)
  4. washThe combined organics were washed with brine (2×5 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customevaporated to dryness

出典と根拠

ORDレコード
ord-cd487f84be8c4158bc01d887901f0a03
出典データセット
uspto-grants-2012_04
特許番号
US08163901B2

反応ノート

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