Acetic Acid → Tert-butyl 3-(2-(2-bromo-3-methylphenylamino)-2-oxoethyl)piperazine-1-carboxylate

HRID 1035293Notes

Reaction equation

HRID 1035293 reaction equation
[C:1]([OH:4])(=[O:3])C.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[Br:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C(N([CH:26]([CH3:28])[CH3:27])CC)(C)C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl[CH2:36]Cl>CN(C)C=O.O1CCCC1>[Br:11][C:12]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:5](=[O:9])[CH2:6][CH:31]1[NH:32][CH2:33][CH2:34][N:29]([C:1]([O:4][C:26]([CH3:28])([CH3:36])[CH3:27])=[O:3])[CH2:30]1

Participants

9

Reactant 6

HCID 176Acetic AcidHCID 4837PiperazineHCID 6344DichloromethaneHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 6037812-Bromo-3-methylaniline

Product 1

HCID 67248813Tert-butyl 3-(2-(2-bromo-3-methylphenylamino)-2-oxoethyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.00 g, 6.43 mmol) in dichloromethane (50 mL) with N,N-dimethylformamide (2 drops) was added oxalyl chloride (1.13 mL, 12.9 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 hour, and then it was concentrated. The concentrate is taken up in tetrahydrofuran (50 mL) and 2-bromo-3-methyl aniline (1.33 g, 7.07 mmol) was added in tetrahydrofuran (5 mL) and diisopropylethylamine (5.62 mL, 36.2 mmol). The solution is heated to 70° C. for 2 hours. The mixture was then cooled to 50° C. and piperazine (1.66 g, 19.3 mmol) was added. The reaction mixture stirred for 16 hours before concentration onto silica gel. Purification via flash chromatography (0-20% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54-7.71 (m, 1H), 7.06-7.31 (m, 2H), 3.62-3.98 (m, 2H), 2.26-3.45 (m, 10H), 0.87-1.05 (m, 9H); MS (APCI+) m/z 412, 414 (M+H)+.

Workup

  1. concentrationit was concentrated
  2. temperatureThe solution is heated to 70° C. for 2 hours
  3. temperatureThe mixture was then cooled to 50° C.
  4. stirringThe reaction mixture stirred for 16 hours before concentration onto silica gel
  5. customPurification via flash chromatography (0-20% methanol/dichloromethane)

Sources & evidence

ORD record
ord-da377a8e51914bf1947178bcbd970674
Source dataset
uspto-grants-2013_10
Patent number
US08546377B2

Reaction notes

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