Trifluoroacetic acid → HCID 54671132, compound

HRID 869045Notes

Reaction equation

HRID 869045 reaction equation
C(N(CC)CC)C.[CH:8]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([C:41]#[CH:42])[C:23]([N:26](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:10])[CH3:9].Br[C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH2:49])=[O:48].C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:26][C:23]1[C:22]([C:41]#[C:42][C:44]2[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=2)[C:47]([NH2:49])=[O:48])=[N:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([S:11]([CH:8]([CH3:9])[CH3:10])(=[O:13])=[O:12])=[CH:19][CH:18]=2)=[CH:25][N:24]=1

Participants

10

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 898073-BromobenzamideHCID 59471983N,N-Di(Boc)-3-ethynyl-5-[4-(isopropylsulfonyl)phenyl]pyrazin-2-amine

Product 1

HCID 54671132HCID 54671132, compoundYield 17.5%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
120 °C

Procedure

Triethylamine (151.3 mg, 208.4 μL, 1.495 mmol) was added to a stirred solution of tert-butyl N-[5-(4-(isopropylsulfonyl)phenyl)-3-ethynylpyrazin-2-yl]-N-tertbutoxycarbonyl-carbamate (75 mg, 0.1495 mmol), 3-bromobenzamide (44.85 mg, 0.2242 mmol), copper (I) iodide (3.417 mg, 0.01794 mmol) and PdCl2(PPh3)2 (5.247 mg, 0.007475 mmol) in DMF (1.5 mL) and the reaction was stirred at 120° C. for 5 minutes under fixed power (300 W) microwave conditions. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and 1MHCl/brine (1:1). The layers were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organics extracts washed with brine (×2), dried over (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and TFA (1 mL, 12.98 mmol) was added. The reaction was stirred at ambient temperature for 40 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a beige solid (11 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.45 (sept, 1H), 7.22 (br s, 2H), 7.53 (br s, 1H), 7.57 (t, 1H), 7.91 (d, 2H), 7.94 (d, 2H), 8.10 (s, 1H), 8.24 (d, 2H), 8.29 (d, 1H) and 8.78 (s, 1H) ppm; MS (ES+) 421.1.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with ethyl acetate (×2)
  4. washThe combined organics extracts washed with brine (×2)
  5. dry with materialdried over (MgSO4)
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in DCM (5 mL)
  8. stirringThe reaction was stirred at ambient temperature for 40 hours
  9. customThe solvent was removed in vacuo
  10. customthe residue azeotroped with DCM (×2) and ether (×2)
  11. customThe material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]
  12. customThe fractions were collected
  13. customfreeze-dried

Sources & evidence

ORD record
ord-5dde2c0f367b46d6b84533dc6da545c9
Source dataset
uspto-grants-2015_03
Patent number
US08969356B2

Reaction notes

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