1,2-Dichloroethane → (S)-Methyl 2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

HRID 339234Notes

Reaction equation

HRID 339234 reaction equation
[NH2:1][C@@H:2]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:3]([N:5]1[C@H:14]([C:15](=[O:27])[NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:28]([O:30][CH3:31])=[O:29])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[C:36]([O:40][C:41]([N:43]([CH3:49])[C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:36]([O:40][C:41]([N:43]([CH3:49])[C@@H:44]([CH3:48])[C:45]([NH:1][C@@H:2]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:3]([N:5]1[C@H:14]([C:15](=[O:27])[NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:28]([O:30][CH3:31])=[O:29])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 86705868(S)-Methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

Product 1

HCID 86705869(S)-Methyl 2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylateYield 100%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a 0° C. solution of (S)-methyl 2-((S)-2-amino-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (966 mg, 2.02 mmol) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Advanced ChemTech, 411 mg, 2.02 mmol) in DMF (20 mL) was added EDC (465 mg, 2.43 mmol), followed by HOAt (330 mg, 2.43 mmol). NMM (667 μl, 6.07 mmol) was then added, and the resulting reaction mixture was stirred at 0° C. for 30 min, then warmed to room temperature and stirred for 4 h. The reaction mixture was then poured into a separatory funnel containing EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with 1N HCl (2×) and 10% LiCl, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.34 g, 2.02 mmol, 100%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 663.3 (M+H)+.

Workup

  1. customthe resulting reaction mixture
  2. temperaturewarmed to room temperature
  3. stirringstirred for 4 h
  4. additionThe reaction mixture was then poured into a separatory funnel
  5. extractionThe aqueous layer was extracted with EtOAc (3×)
  6. washThe combined organic extracts were washed with 1N HCl (2×) and 10% LiCl
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-adf445424fc646538ee76c3b6d8c837f
Source dataset
uspto-grants-2014_11
Patent number
US08889712B2

Reaction notes

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