1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 2-[4-(benzyloxy)phenyl]-N-[2-(2-piperidin-1-ylethyl)-2H-indazol-4-yl]acetamide

HRID 1825819Notes

Reaction equation

HRID 1825819 reaction equation
[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=2)([O-])=O.[Cl-].[NH4+].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.[Fe].C(O)C.O>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:1][C:4]2[C:5]3[C:9]([CH:10]=[CH:11][CH:12]=2)=[N:8][N:7]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=3)=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1

Participants

10

Reactant 6

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 810334-Benzyloxyphenylacetic acidHCID 81531DiisopropylethylamineHCID 221389114-nitro-2-(2-piperidin-1-ylethyl)-2H-indazole

Product 1

HCID 111555962-[4-(benzyloxy)phenyl]-N-[2-(2-piperidin-1-ylethyl)-2H-indazol-4-yl]acetamide

Reagents, catalysts & solvents 3

HCID 23925IronCatalystHCID 6228DimethylformamideSolventHCID 19096565Water ethanolSolvent

Procedure

4-Nitro-2-(2-piperidin-1-yl-ethyl)-2H-indazole (0.160 g, 0.583 mmol), iron powder (0.326 g, 5.84 mmol) and ammonium chloride (0.0185 g, 0.346 mmol) was suspended in a 4:1 ethanol/H2O solution and heated to reflux for 3 hours. The mixture was cooled to room temperature, the solvents removed in vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 5 mL). The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4) and the filtrate was concentrated to provide a pale white solid. The solid (40.0 mg, 0.164 mmol) was dissolved in 3 mL of N,N-dimethylformamide and (4-benzyloxy-phenyl)-acetic acid (0.0470 g, 0.194 mmol), PS-EDCI (1.30 mmol/g, 0.378 g, 3 equiv), N-Hydroxybenzotriazole (0.0330 g, 0.244 mmol) and diisopropylethylamine (0.0850 mL, 0.488 mmol) were added and the reaction vessel was placed on a shaker table for 6 hours. The mixture was concentrated under vacuo and the residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.37 (m, 2 H) 1.46 (m, 4 H) 2.39 (m, 4 H) 2.79 (t, J=6.61 Hz, 2 H) 3.68 (s, 2 H) 4.51 (t, J=6.61 Hz, 2 H) 5.08 (s, 2 H) 6.92 (m, 2 H) 7.14 (m, 1 H) 7.39 (m, 9 H) 8.47 (m, 1 H) 10.02 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.

Workup

  1. temperatureheated
  2. temperatureto reflux for 3 hours
  3. customthe solvents removed in vacuo
  4. filtrationThe mixture was filtered through a plug of silica gel
  5. washrinsed with triethylamine/ethyl acetate (1/4)
  6. concentrationthe filtrate was concentrated
  7. customto provide a pale white solid
  8. concentrationThe mixture was concentrated under vacuo
  9. dissolutionthe residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol
  10. custompurified by preparative reverse-phase HPLC

Sources & evidence

ORD record
ord-583ee32a49db426786eed246c35507d8
Source dataset
uspto-grants-2006_05
Patent number
US07049307B2

Reaction notes

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