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

HRID 20968Notes

Reaction equation

HRID 20968 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:98]1[CH2:102][C@@H:101]([O:103][CH2:104][CH2:105][CH3:106])[CH2:100][N:99]1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:97])[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][CH:94]([CH3:96])[CH3:95])[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+].IC(C)C>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:97])[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][CH:94]([CH3:96])[CH3:95])[CH:82]=2)[C@H:68]([OH:67])[C@H:98]2[CH2:102][C@@H:101]([O:103][CH2:104][CH2:105][CH3:106])[CH2:100][NH:99]2)[CH:76]=[C:75]([F:77])[CH:74]=1

Participants

8

Reactant 5

HCID 6362Isopropyl 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 67315974(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-isopropoxy-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 11848637N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Step 14 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-isopropoxy-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, 38 mg, 0.05 mmol) in DMF (1 mL) were added cesium carbonate (29 mg, 0.09 mmol) and 2-iodopropane (42 mg, 0.25 mmol) and the reaction mixture was microwaved at 60° C. for 2 h. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 40% EtOAc/Hexane step gradient) to give 21 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.07 (3H, s), 0.86 (9H, s), 0.88 (3H, m), 1.32 (6H, d, J=5 Hz), 1.46-1.54 (11H, m), 2.03-2.21 (4H, m), 2.59 (2H, m), 2.62 (1H, dd, J=10, 15 Hz), 2.94 (1H, m), 3.26-3.36 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.84-3.91 (2H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.13 (1H, m), 4.55 (1H, m), 4.63 (1H, m), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.20 (1H, s), 7.33 (1H, s), 7.71 (1H, s), 7.99 (1H, d, J=10 Hz). MS (ESI) (M+H)+ 775.45.

Workup

  1. customthe reaction mixture was microwaved at 60° C. for 2 h
  2. washthe mixture was washed with Brine, H2O
  3. concentrationconcentrated under vacuum
  4. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 40% EtOAc/Hexane step gradient)

Sources & evidence

ORD record
ord-97ebccc795704f82925e1472f65c12c0
Source dataset
uspto-grants-2010_06
Patent number
US07745470B2

Reaction notes

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