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-methylbenzamide
Reaction equation
[Si]([O:8][C@H:9]([C@H:32]1[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][N:33]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[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.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C)C=C(C(N2[CH2:82][CH2:81][CH2:80][C@@H:79]2[CH2:83][O:84][CH3:85])=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:103](OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=C(C)C=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.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.COC[C@H]1CCCN1>ClCCl.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([CH3:103])[CH:25]=[C:24]([C:28]([N:29]3[CH2:82][CH2:81][CH2:80][C@@H:79]3[CH2:83][O:84][CH3:85])=[O:30])[CH:23]=2)[C@H:9]([OH:8])[C@H:32]2[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][NH:33]2)[CH:17]=[C:16]([F:18])[CH:15]=1Participants
Reactant 6
HCID 81531Diisopropylethylamine
HCID 671216(2R)-2-(Methoxymethyl)pyrrolidine
HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)
HCID 593468483-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid
HCID 67315032(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate
HCID 67316677(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylateProduct 1
Reagents, catalysts & solvents 2
Procedure
Step 8 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 28 mg, 0.038 mmol) in dichloromethane (1 mL) was added Hunig's base (14 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (65 mg, 0.057 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 30 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 0.88 (3H, t, J=5 Hz), 1.48-1.54 (11H, m), 1.73 (1H, m), 1.92-2.09 (5H, m), 2.18 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.96 (1H, m), 3.05 (1H, m), 3.26-3.39 (5H, m), 3.47 (1H, m), 3.58 (1H, m), 3.68 (1H, m), 3.76 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.14 (1H, m), 4.41 (1H, brd s), 4.56 (1H, m), 6.59 (1H, m), 6.76 (1H, s), 6.77 (1H, s), 7.43 (1H, s), 7.72 (1H, s), 7.74 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 788.61.
Workup
- additionwas then added
- stirringthe reaction mixture was stirred at rt overnight
- washthe mixture was washed with Brine, H2O
- customdried
- concentrationconcentrated
Sources & evidence
- ORD record
- ord-863a97789005496785d13f2011133345
- Source dataset
- uspto-grants-2011_07
- Patent number
- US07981913B2
Reaction notes
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