Triethylamine → 4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester

HRID 1772239Notes

Reaction equation

HRID 1772239 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl.O>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:10]([CH:8]2[CH2:7][C:6]3[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9]2)=[O:12])[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 143452tert-Butyl piperazine-1-carboxylateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 131024035-Fluoro-2,3-dihydro-1-benzofuran-2-carboxylic acid

Product 1

HCID 901498584-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl esterYield 52%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

In a 250 ml round-bottomed flask containing a solution of 5-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid (1.8 g, 9.9 mmol) in 100 ml of dichloromethane was added EDAC.HCl (2.85 g, 14.9 mmol, 1.5 eq), HOBt (2.00 g, 14.8 mmol, 1.5 eq), triethylamine (2.00 g, 19.8 mmol, 2.0 eq), and t-butyl piperazine-1-carboxylate (2.20 g, 11.8 mmol, 1.2 eq). The solution was stirred overnight at room temperature before diluting with 50 ml of water. The crude product was then extracted from the mixture using 3×50 ml of dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1.8 grams of the desired amide as a light yellow solid (52%); 1H NMR (300 MHz, CDCl3): δ 6.92 (dd, J=2.4 Hz, 7.8 Hz, 1H), 6.79 (m, 1H), 6.69 (dd, J=4.2 Hz, 8.7 Hz, 1H), 5.40 (dd, J=7.2 Hz, 9.9 Hz, 1H), 3.78-3.91 (m, 3H), 3.46-3.67 (m, 5H), 3.26-3.39 (m, 2H), 1.49 (s, 1H).

Workup

  1. extractionThe crude product was then extracted from the mixture
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under vacuum
  5. customThe crude residue was purified by silica gel chromatography
  6. washto elute
  7. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-267342f9eb884ebdb7666a830c7e7f52
Source dataset
uspto-grants-2016_02
Patent number
US09249102B2

Reaction notes

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