Tetrahydrofuran → 3-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-(4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]propionamide

HRID 1453977Notes

Reaction equation

HRID 1453977 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.[CH2:30]1C[O:33][CH2:32][CH2:31]1.C([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])C.CN([P+](ON1N=N[C:55]2[CH:56]=C[CH:58]=[CH:59][C:54]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O>[CH2:40]1[C:41]2[C:56](=[CH:55][CH:54]=[CH:59][CH:58]=2)[CH2:39][CH2:38][N:37]1[CH2:30][CH2:31][C:32]([NH:28][CH:15]1[CH2:14][CH2:13][C:12]2([CH3:29])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)([CH2:18][CH2:19][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:16]1)=[O:33]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 68827565N-(3-Phenylpropyl)-6-amino-4a-(3-methoxyphenyl)-8a-methyloctahydroisoquinoline

Product 1

HCID 688280413-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-(4a-(3-methoxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]propionamideYield 80%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To compound 24 (80 mg, 0.203 mmol) dissolved in anhydrous THF (15 mL) 3-(3,4-dihydro-1H-isoquinolin-2-yl)-propioinic acid hydrochloride (73 mg, 0.305 mmol), and triethylamine (0.142 mL, 1.01 mmol) was added, and the reaction mixture was stirred at room temperature for 15 min. After this time BOP reagent (99 mg, 0.22 mmol) was added, 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 layer was washed with 1 N NaOH (30 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 94 mg (80%) of 25b as a shiny white solid: LCMS (ESI): m/z 580.9 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 8.29 [d, J=6 Hz, 1H], 7.03-7.31 [m, 12H], 6.70-6.73 m, 1H], 4.23 [m, 1H], 3.80 [s, 1H], 3.68 [s, 2H], 2.94 [t, J=6 Hz, 2H], 2.77-2.82 [m, 4H], 2.62-2.67 [m, 3H], 2.42 [t, J=6 Hz, 2H], 2.25-2.35 [m, 2H], 1.74-1.87 [m, 7H], 1.19-1.34 [m, 3H], 1.14 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 171.9, 159.2, 148.8, 142.8, 134.4, 134.1, 129.1, 128.9, 128.7, 128.6, 127.4, 126.9, 126.8, 126.3, 126.1, 122.1, 116.2, 110.8, 62.1, 58.2, 55.6, 54.1, 51.1, 50.5, 45.6, 44.0, 37.9, 36.8, 36.7, 35.3, 34.0, 33.0, 29.7, 29.2, 28.3, 26.8.

Workup

  1. stirringto stir at room temperature for 1.5 h
  2. customReaction progress
  3. washwashed with saturated aqueous NaHCO3 (25 mL)
  4. extractionThe aqueous layers were back extracted with EtOAc (2×20 mL)
  5. washThe combined organic layer was washed with 1 N NaOH (30 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated under reduced pressure
  8. customto afford crude amide
  9. customThe crude product was purified by flash chromatography (30% CMA 80 in CH2Cl2)

Sources & evidence

ORD record
ord-d3542c9a789e4473a584f8b51018ab34
Source dataset
uspto-grants-2009_01
Patent number
US07476679B2

Reaction notes

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