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

HRID 1697478노트

반응식

HRID 1697478 반응식
[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

참가 물질

9

반응물 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

생성물 1

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

시약·촉매·용매 3

HCID 6228Dimethylformamide촉매HCID 6342Acetonitrile용매HCID 6344Dichloromethane용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-cd487f84be8c4158bc01d887901f0a03
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08163901B2

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