Triethylamine → N-(4a-(3-Methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]-3-piperidin-1-yl-propionamide

HRID 1453976Notes

Reaction equation

HRID 1453976 reaction equation
[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:12]([CH3:29])([CH2:13][CH2:14][CH:15]([NH2:28])[CH2:16]3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:17]23[CH2:16][CH:15]([NH:28][C:38](=[O:39])[CH2:37][CH2:36][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:14][CH2:13][C:12]2([CH3:29])[CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]3)[CH:25]=[CH:24][CH:23]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 1177821-Piperidinepropanoic acidHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 68827565N-(3-Phenylpropyl)-6-amino-4a-(3-methoxyphenyl)-8a-methyloctahydroisoquinoline

Product 1

HCID 68826978N-(4a-(3-Methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]-3-piperidin-1-yl-propionamideYield 85.2%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To compound 24 (105 mg, 0.267 mmol) dissolved in anhydrous THF (15 mL) was added 1-piperidinepropionic acid (63 mg, 0.40 mmol), triethylamine (0.17 mL, 1.33 mmol), and BOP reagent (140 mg, 0.32 mmol), and the reaction mixture was allowed to stir at room temperature for 1.5 h. Reaction progress was monitored by TLC (50% CMA 80 in CH2Cl2). The reaction mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (25 mL) followed by water (25 mL). The aqueous layers were back extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (25 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude amide. The crude product was purified by flash chromatography (30% CMA 80 in CH2Cl2) to afford 121 mg (85%) of 25a as a shiny white solid: LCMS (ESI): m/z 532.8 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 8.77 [d, J=6 Hz, 1H], 7.15-7.30 [m, 8H], 6.72-6.75 [m, 1H], 4.24 [m, 1H], 3.82 [s, 3H], 2.76 [br, 1H], 2.65-2.68 [m, 2H], 2.42-2.56 [m, 3H], 2.32-2.37 [m, 6H], 2.07-2.30 [m, 7H], 1.62-1.83 [m, 5H], 1.59-1.61 [m, 4H], 1.48-1.59 [m, 4H], 1.25-1.27 [br, 1H], 1.21 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 172.2, 159.2, 148.8, 142.8, 128.8, 128.7, 128.6, 126.0, 122.2, 116.2, 110.9, 62.4, 58.4, 55.6, 54.9, 54.0, 51.4, 45.5, 44.1, 38.1, 37.0, 36.8, 35.5, 34.0, 32.5, 29.2, 28.4, 26.9, 26.7, 24.6.

Workup

  1. customReaction progress
  2. washwashed with saturated aqueous NaHCO3 (25 mL)
  3. extractionThe aqueous layers were back extracted with EtOAc (2×20 mL)
  4. washThe combined organic layers were washed with 1 N NaOH (25 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customto afford crude amide
  8. customThe crude product was purified by flash chromatography (30% CMA 80 in CH2Cl2)

Sources & evidence

ORD record
ord-72db6bad69844617a6b07186d21a409d
Source dataset
uspto-grants-2009_01
Patent number
US07476679B2

Reaction notes

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