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
C(NC1C=[C:12]([CH:51]=C(C)C=1)[C:13]([NH:15][C@@H:16]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=[C:80]([C:82]2[O:83][CH:84]=[CH:85][N:86]=2)[CH:79]=[C:78]([C:87]([N:89]2[CH2:93][CH2:92][CH2:91][C@@H:90]2[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O.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:49][C:47]1[CH:48]=[C:43]([CH2:42][C@H:16]([NH:15][C:13](=[O:14])[C:12]2[CH:51]=[C:80]([C:82]3[O:83][CH:84]=[CH:85][N:86]=3)[CH:79]=[C:78]([C:87]([N:89]3[CH2:93][CH2:92][CH2:91][C@@H:90]3[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=2)[C@H:17]([OH:18])[C@H:26]2[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][NH:27]2)[CH:44]=[C:45]([F:50])[CH:46]=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 593468493-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoic acid
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-carboxylate
HCID 67316523(2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate2×Product 1
Reagents, catalysts & solvents 1
Procedure
Step 11 (A): Preparation of (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. To a solution of 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoic acid (Preparation H, 40 mg, 0.12 mmol) in dichloromethane (3 mL) was added Hunig's base (46 mg, 0.36 mmol) to make a clear solution and HATU (60 mg, 0.156 mmol) was then added. After stirring for 20 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), 64 mg, 0.12 mmol) and the reaction mixture was stirred at rt for 16 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 70 mg of the title compound (70% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.84 (9H, s), 0.87 (3H, m), 1.46-1.50 (1H, m), 1.74 (1H, m), 1.92-2.06 (3H, m), 2.17-2.23 (2H, m), 2.66 (1H, m), 2.77-2.81 (2H, m), 2.92 (1H, m), 3.05 (1H, m), 3.29-3.38 (4H, m), 3.48 (1H, m), 3.58 (1H, m), 3.66 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.07-4.09 (1H, m), 4.12-4.14 (1H, m), 4.43 (1H, brd s), 4.61 (1H, m), 6.58 (1H, m), 6.77 (2H, d, J=10 Hz), 7.22 (1H, s), 7.69 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.53 (1H, brd s), 8.64 (1H, s). MS (ESI) (M+H)+ 841.61.
Workup
- additionwas then added
- stirringthe reaction mixture was stirred at rt for 16 h
- customThe crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient)
Sources & evidence
- ORD record
- ord-9e24547e2734411887b79dc135df1012
- Source dataset
- uspto-grants-2010_06
- Patent number
- US07745470B2
Reaction notes
Loading…