Diisopropylethylamine → 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
Reaction equation
[Si]([O:8][C@H:9]([C@H:44]1[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][N:45]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:43])[C:22]1[CH:27]=[C:26]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)[CH:25]=[C:24]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:40][O:41][CH3:42])=[O:34])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.C(NC1C=C(C=C(C2OC=CN=2)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)C1C=CC=CC=1.C(N(CCC)C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O)CC.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:43])[C:22]2[CH:27]=[C:26]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)[CH:25]=[C:24]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@@H:36]3[CH2:40][O:41][CH3:42])=[O:34])[CH:23]=2)[C@H:9]([OH:8])[C@H:44]2[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][NH:45]2)[CH:13]=[C:14]([F:19])[CH:15]=1Participants
Reactant 5
HCID 81531Diisopropylethylamine
HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)
HCID 210628933-(Dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid
HCID 67315981(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
HCID 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-carboxylate2×Product 1
Reagents, catalysts & solvents 1
Procedure
Step 12 (A): Preparation 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. To a solution of 3-(dipropylcarbamoyl)-5-(oxazol-2-yl)benzoic acid (WO 2002/02512), 45 mg, 0.14 mmol) in dichloromethane (2 mL) was added Hunig's base (54 mg, 0.42 mmol) to make a clear solution and HATU (65 mg, 0.17 mmol) was then added. After stirring for 30 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 81 mg, 0.154 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 20% to 30% to 40% EtOAc/Hexane step gradient) to give 110 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.03 (3H, s), 0.06 (3H, s), 0.69 (3H, m), 0.82 (9H, s), 0.87 (3H, m), 0.96 (3H, m), 1.21-1.28 (2H, m), 1.47-1.51 (11H, 1.68 (2H, m), 2.01 (1H, m), 2.18 (1H, d, J=15 Hz), 2.68 (1H, dd, J=10, 15 Hz), 2.88 (1H, dd, J=5, 15 Hz), 3.14 (2H, m), 3.26-3.36 (3H, m), 3.44 (2H, m), 3.74 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.08-4.11 (2H, m), 4.64 (1H, dd, J=10, 15 Hz), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.22 (1H, s), 7.68 (1H, s), 7.97 (1H, s), 8.14 (1H, s), 8.64 (2H, m).
Workup
- additionwas then added
- stirringthe reaction mixture was stirred at rt for 6 h
- customThe crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 20% to 30% to 40% EtOAc/Hexane step gradient)
Sources & evidence
- ORD record
- ord-a6c795ae764f49dd903c9c4649927c94
- Source dataset
- uspto-grants-2010_06
- Patent number
- US07745470B2
Reaction notes
Loading…