1,2-Dichloroethane → tert-Butyl ((S)-1-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamate

HRID 527749Notes

Reaction equation

HRID 527749 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.Cl.[CH3:36][Si:37]1([CH3:55])[CH2:41][C@@H:40]([C:42]([NH:44][C@H:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47][CH2:46]2)=[O:43])[NH:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:36][Si:37]1([CH3:55])[CH2:41][C@@H:40]([C:42](=[O:43])[NH:44][C@H:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47][CH2:46]2)[N:39]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:38]1

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 2755956(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(4-iodophenyl)propanoic acidHCID 131735602(R)-3,3-dimethyl-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide HCl

Product 1

HCID 131735601tert-Butyl ((S)-1-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-(4-iodophenyl)-1-oxopropan-2-yl)carbamateYield 88.8%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (0.77 g, 2.0 mmol) in DMF (4 mL) was added EDC (0.53 g, 2.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, followed by addition of 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.22 g, 1.6 mmol) and a solution of (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide HCl (0.53 g, 1.6 mmol) in DMF (3 mL) and DIEA (0.8 mL, 4.6 mmol). The resulting mixture was then stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (0.94 g, 87%). 1H NMR (CDCl3) δ 7.76-7.45 (m, 2H), 7.22-7.05 (m, 3.5H), 6.89 (d, J=8.1 Hz, 2H), 6.50 (d, J=8.1 Hz, 0.5H), 5.27-5.06 (m, 3H), 4.96-4.71 (m, 1H), 3.10 (d, J=13.4 Hz, 0.5H), 2.96-2.45 (m, 4.5H), 2.16-1.98 (m, 1H), 1.85 (dd, J=11.3, 5.8 Hz, 3H), 1.44-1.16 (m, 10H), 0.98 (dd, J=14.7, 10.1 Hz, 1H), 0.44 (s, 3H), 0.27 (s, 3H); MS(ESI+) m/z 662.4 (M+H)+.

Workup

  1. stirringThe resulting mixture was then stirred at rt for 1 h
  2. customThe organic layer was separated
  3. washwashed with aq. NaHCO3 solution
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe resulting oil was purified by flash chromatography (eluting with 20% EtOAc/DCM)

Sources & evidence

ORD record
ord-02d3bc875be34697bf9e063e209d6bd7
Source dataset
uspto-grants-2016_05
Patent number
US09345740B2

Reaction notes

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