Triethylamine → 2''-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-N,N,2-trimethyl-4''-(trifluoromethyl)-1,1':3',1''-terphenyl-4-carboxamide

HRID 2093218Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2093218
[F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=CC(C(O)=O)=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.CNC.Cl.[CH3:56][N:57]([CH3:66])[CH2:58][CH2:59][CH2:60]N=C=NCC.O.N1([OH:77])C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:60][C:59]([C:58]([N:57]([CH3:56])[CH3:66])=[O:77])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:50])[F:49])[CH:8]=1

Komponenten

8

Edukt 5

HCID 8471TriethylamineHCID 10473Dimethylamine, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 250105732''-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-2-methyl-4''-(trifluoromethyl)-1,1':3',1''-terphenyl-4-carboxylic acid

Produkt 1

HCID 250091602''-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4'-methoxy-N,N,2-trimethyl-4''-(trifluoromethyl)-1,1':3',1''-terphenyl-4-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (EXAMPLE 30, 300 mg, 0.42 mmol), N-methylmethanamine hydrochloride (41 mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (86 mg, 0.56 mmol) and triethylamine (146 μL, 1.05 mmol) were stirred in DCM (5 mL) at room temperature for 1.5 hours. LCMS of aliquot at this time indicated formation of the desired product and complete consumption of starting material. Crude mixture was diluted with MeCN and purified by reversed phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with (acetonitrile+0.1% v/v TFA)/(water+0.1% v/v TFA) (10% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min) to give a solid foam. This solid foam was dissolved in EtOAc and washed with NaHCO3 (sat., aq) and then with water. Aqueous layers were separated from the extracts. The combined aqueous phases were back extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and then concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=738.21; found=739.41 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atropisomers): δ 7.85 (s, 0.5H), 7.71 (s, 0.5H), 7.69 (s, 1H), 7.67-7.62 (m, 2.5H), 7.44 (d, J=8 Hz, 0.5H), 7.41 (d, J=8.5 Hz, 0.5H), 7.36 (t, J=7.5 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.25 (s, 0.5H), 7.23 (s, 1H), 7.19 (d, J=8 Hz, 0.5H), 7.12 (t, J=2 Hz, 1H), 7.07 (d, J=7 Hz, 0.5H), 7.05 (d, J=7 Hz, 0.5H), 5.58 (d, J=8 Hz, 0.5H), 5.30 (d, J=8 Hz, 0.5H), 4.96 (d, J=16 Hz, 1H), 4.16 (d, J=16 Hz, 0.5H), 3.97 (d, J=15.5 Hz, 0.5H), 3.86 (s, 3H), 3.81-3.73 (m, 1H), 3.11 (s, 3H), 3.02 (s, 3H), 2.33 (s, 1.5H), 2.27 (s, 1.5H), 0.54 (d, J=6.5Hz, 1.5H), 0.41 (d, J=6.5 Hz, 1.5H).

Aufarbeitung

  1. customformation of the desired product and complete consumption of starting material
  2. additionCrude mixture was diluted with MeCN
  3. custompurified by reversed phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm)
  4. washeluting with (acetonitrile+0.1% v/v TFA)/(water+0.1% v/v TFA) (10% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min)
  5. customto give a solid foam
  6. washwashed with NaHCO3 (sat., aq)
  7. customAqueous layers were separated from the extracts
  8. extractionThe combined aqueous phases were back extracted with EtOAc
  9. dry with materialThe combined extracts were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-04d668e4b8944ffbb72384410075c410
Quelldatensatz
uspto-grants-2013_05
Patentnummer
US08440702B2

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