N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-(oxazol-2-yl)-N3,N3-dipropylisophthalamide → N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamide

HRID 20966Notes

Reaction equation

HRID 20966 reaction equation
[Si](O[C@H]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.FC1C=C(C[C@H](NC(=O)C2C=C(C3OC=CN=3)C=C(C(N(CCC)CCC)=O)C=2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)C=C(F)C=1.[Si]([O:102][C@H:103]([C@H:138]1[CH2:142][C@@H:141]([O:143][CH2:144][CH2:145][CH3:146])[CH2:140][N:139]1C(OC(C)(C)C)=O)[C@@H:104]([NH:114][C:115](=[O:137])[C:116]1[CH:121]=[C:120]([C:122]2[O:123][CH:124]=[CH:125][N:126]=2)[CH:119]=[C:118]([C:127]([N:129]2[CH2:133][CH2:132][CH2:131][C@@H:130]2[CH2:134][O:135][CH3:136])=[O:128])[CH:117]=1)[CH2:105][C:106]1[CH:111]=[C:110]([F:112])[CH:109]=[C:108]([F:113])[CH:107]=1)(C(C)(C)C)(C)C>Cl.O>[F:112][C:110]1[CH:111]=[C:106]([CH2:105][C@H:104]([NH:114][C:115](=[O:137])[C:116]2[CH:121]=[C:120]([C:122]3[O:123][CH:124]=[CH:125][N:126]=3)[CH:119]=[C:118]([C:127]([N:129]3[CH2:133][CH2:132][CH2:131][C@@H:130]3[CH2:134][O:135][CH3:136])=[O:128])[CH:117]=2)[C@H:103]([OH:102])[C@H:138]2[CH2:142][C@@H:141]([O:143][CH2:144][CH2:145][CH3:146])[CH2:140][NH:139]2)[CH:107]=[C:108]([F:113])[CH:109]=1

Participants

6

Reactant 3

HCID 11848583N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-(oxazol-2-yl)-N3,N3-dipropylisophthalamideHCID 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-carboxylateHCID 68558510(2R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate

Product 1

HCID 11498228N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamide

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 313Hydrochloric AcidSolvent

Procedure

Step 12 (B): Preparation of N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-(oxazol-2-yl)-N3,N3-dipropylisophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-(oxazol-2-yl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (step 12 (A), 110 mg) in HCl (4.0 M solution in dioxane, 2 mL) was added 4 drops of H2O and the mixture was stirred at rt for 2 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 42-82% methanol/H2O/0.1% TFA) to give the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.74 (3H, m), 0.97 (3H, m), 1.03 (3H, m), 1.57 (1H, dd, J=5, 15 Hz), 1.63 (1H, m), 1.76 (2H, dd, J=5, 15 Hz), 2.19 (1H, m), 2.54 (1H, m), 2.90 (1H, dd, J=10, 15 Hz), 3.21 (2H, m), 3.35-3.53 (7H, m), 3.85 (1H, m), 4.08 (1H, dd, J=5, 10 Hz), 4.23-4.30 (2H, m), 6.75 (1H, m), 6.92 (2H, m), 7.37 (1H, s), 7.71 (1H, m), 8.06 (1H, s), 8.13 (1H, m), 8.39 (1H, m). MS (ESI) (M+H)+ 613.27.

Workup

  1. customThe solvent was removed
  2. customthe mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 42-82% methanol/H2O/0.1% TFA)

Sources & evidence

ORD record
ord-b58f8c1aaf4946398b8338f84d39cf74
Source dataset
uspto-grants-2010_06
Patent number
US07745470B2

Reaction notes

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