Methyl iodide → N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-methoxy-5-(2-oxopyrrolidin-1-yl)benzamide

HRID 1014889Notes

Reaction equation

HRID 1014889 reaction equation
[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[Si]([O:67][C@H:68]([C@H:96]1[CH2:100][C@@H:99]([O:101][CH2:102][CH2:103][CH3:104])[CH2:98][N:97]1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:95])[C:81]1[CH:86]=[C:85]([N:87]2[CH2:91][CH2:90][CH2:89][C:88]2=[O:92])[CH:84]=[C:83]([O:93][CH3:94])[CH:82]=1)[CH2:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73]([F:78])[CH:72]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(N2CCCC2=O)C=C(O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.C(OCC)(=O)C>[F:78][C:73]1[CH:72]=[C:71]([CH2:70][C@H:69]([NH:79][C:80](=[O:95])[C:81]2[CH:86]=[C:85]([N:87]3[CH2:91][CH2:90][CH2:89][C:88]3=[O:92])[CH:84]=[C:83]([O:93][CH3:94])[CH:82]=2)[C@H:68]([OH:67])[C@H:96]2[CH2:100][C@@H:99]([O:101][CH2:102][CH2:103][CH3:104])[CH2:98][NH:97]2)[CH:76]=[C:75]([F:77])[CH:74]=1

Participants

8

Reactant 5

HCID 6328Methyl iodideHCID 10796Cesium carbonateHCID 59346851(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67315382(2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-methoxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316383(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

Product 1

HCID 11848636N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-methoxy-5-(2-oxopyrrolidin-1-yl)benzamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Step 13 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-methoxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate (Preparation I, 27 mg, 0.037 mmol) in DMF (1 mL) were added cesium carbonate (24 mg, 0.074 mmol) and methyl iodide (25 mg, 0.185 mmol) and the reaction mixture was stirred at 80° C. for 3 h, at rt for 3 days and microwaved at 80° C. for 6 h. Ethyl acetate (100 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% EtOAc/Hexane step gradient) to give 20 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 0.88 (3H, m), 1.46-1.54 (11H, m), 2.02-2.07 (1H, m), 2.10-2.16 (2H, m), 2.20 (1H, m), 2.59 (2H, m), 2.64 (1H, dd, J=10, 15 Hz), 2.92 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.84 (3H, s), 3.88-3.92 (2H, m), 3.98 (1H, m), 4.04-4.13 (2H, m), 4.58 (1H, m), 6.60 (1H, m), 6.78 (2H, d, J=5 Hz), 7.23 (1H, s), 7.34 (1H, s), 7.80 (1H, s), 8.05 (1H, brd s). MS (ESI) (M+H)+ 746.41.

Workup

  1. custommicrowaved at 80° C. for 6 h
  2. washthe mixture was washed with H2O
  3. concentrationconcentrated under vacuum
  4. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% EtOAc/Hexane step gradient)

Sources & evidence

ORD record
ord-750e11c6fdab409f93c818f4a97ba73a
Source dataset
uspto-grants-2011_07
Patent number
US07981913B2

Reaction notes

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