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)benzamide

HRID 20953

Reaktionsgleichung

Reaktionsgleichung von HRID 20953
[Si]([O:8][C@H:9]([C@H:39]1[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][N:40]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][O:36][CH3:37])=[O: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.C(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=CC=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.CN(C=O)C.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][O:36][CH3:37])=[O:29])[CH:23]=2)[C@H:9]([OH:8])[C@H:39]2[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][NH:40]2)[CH:17]=[C:16]([F:18])[CH:15]=1

Komponenten

9

Edukt 5

HCID 81531DiisopropylethylamineHCID 671216(2R)-2-(Methoxymethyl)pyrrolidineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673161403-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acidHCID 67316242(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

Produkt 1

HCID 59346852N-((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)benzamideAusbeute 79 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

Step 1 (D): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)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)benzoic acid (Step 1 (C), 50 mg, 0.074 mmol) in dichloromethane (2 mL) and DMF (5 mL) was added Hunig's base (28 mg, 0.222 mmol) to make a clear solution and HATU (36 mg, 0.0962 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (17 mg, 0.148 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 45 mg of the title compound (79% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.83 (9H, s), 0.86-0.89 (3H, m), 1.48-1.51 (11H, m), 1.72 (1H, m), 1.91-2.07 (4H, m), 2.18 (1H, d, J=15 Hz), 2.64 (1H, dd, J=10, 15 Hz), 2.90-2.94 (1H, m), 3.02 (1H, brd s), 3.28-3.38 (6H, m), 3.48 (1H, m), 3.55 (1H, m), 3.67 (1H, m), 3.74 (1H, m), 3.98 (1H, m), 4.04-4.12 (2H, m), 4.42 (1H, m), 4.59 (1H, m), 6.57-6.60 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.44 (1H, m), 7.60-7.62 (1H, m), 7.88 (1H, d, J=5 Hz), 7.96 (1H, s), 8.08 (1H, brd s). MS (ESI) (M+H)+ 774.40.

Aufarbeitung

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt overnight
  3. washthe mixture was washed with Brine, H2O
  4. customdried
  5. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-c0932e2aaacb4e24b2c1bda7a58d733c
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745470B2

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