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

HRID 1697478Notes

Reaction equation

HRID 1697478 reaction equation
[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

Participants

9

Reactant 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

Product 1

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

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-cd487f84be8c4158bc01d887901f0a03
Source dataset
uspto-grants-2012_04
Patent number
US08163901B2

Reaction notes

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