N-Methylpropylamine → N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-methyl-N3-propylisophthalamide

HRID 1014877

Reaktionsgleichung

Reaktionsgleichung von HRID 1014877
[NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:3]([C@H:12]1[CH2:16][C@@H:15]([O:17][CH2:18][CH2:19][CH3:20])[CH2:14][N:13]1C(OC(C)(C)C)=O)[O:4][Si](C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:46]([NH:56][C:57](=[O:67])[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([C:64](=[O:66])N)[CH:59]=1)[CH2:47][C:48]1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:84](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.CNCCC>ClCCl.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH2:28][C@H:2]([NH:1][C:64](=[O:66])[C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:57]([N:56]([CH3:84])[CH2:46][CH2:47][CH3:48])=[O:67])[CH:59]=2)[C@H:3]([OH:4])[C@H:12]2[CH2:16][C@@H:15]([O:17][CH2:18][CH2:19][CH3:20])[CH2:14][NH:13]2)[CH:30]=[C:31]([F:36])[CH:32]=1

Komponenten

9

Edukt 6

HCID 12315N-MethylpropylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67315032(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316024(2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 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 acid

Produkt 1

HCID 11848524N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-methyl-N3-propylisophthalamideAusbeute 85 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

Step 2 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)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), 60 mg, 0.088 mmol) in dichloromethane (2 mL) was added Hunig's base (34 mg, 0.267 mmol) to make a clear solution and HATU (45 mg, 0.12 mmol) was then added. After stirring for 20 min, the reaction mixture was added N-methylpropan-1-amine (13 mg, 0.178 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 55 mg of the title compound (85% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.71-0.76 (1H, m), 0.83 (9H, s), 0.87 (3H, m), 0.91-1.00 (2H, m), 1.40-1.53 (12H, m), 1.60-1.67 (1H, m), 2.01-2.05 (1H, m), 2.17-2.20 (1H, m), 2.64 (1H, m), 2.89-3.04 (4H, m), 3.17 (1H, brd s), 3.27-3.36 (3H, m), 3.48 (1H, brd s), 3.74 (1H, m), 3.97 (1H, m), 4.04-4.11 (2H, m), 4.58 (1H, m), 6.58 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.48 (2H, m), 7.86 (2H, s), 8.13 (1H, brd s).

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-2a48000e7b894c5889c634b74135dc77
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07981913B2

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