1,2-Dichloroethane → tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamate

HRID 705299

Reaktionsgleichung

Reaktionsgleichung von HRID 705299
C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([OH:60])=[O:59])[CH:55]=[CH:54][C:53]=1[F:61]>CN(C=O)C.O>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@@H:22]2[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@H:24]([CH3:43])[CH2:23]2)=[O:59])[CH:55]=[CH:54][C:53]=1[F:61].[F:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([F:44])[C:46]=1[C:52]1[N:57]=[C:56]([C:58]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C@H:22]2[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([O:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C@@H:24]([CH3:43])[CH2:23]2)=[O:60])[CH:55]=[CH:54][C:53]=1[F:61]

Komponenten

8

Edukt 4

HCID 111,2-DichloroethaneHCID 181649HOAtHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 86705263tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexyl)carbamate

Produkt 2

HCID 90056052tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamateAusbeute 48 %HCID 90056064tert-butyl (1S,2R,3R,5S)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamateAusbeute 48 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

EDC (2.0 equiv.) and HOAt (2.0 equiv.) were added to a solution of (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.08 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (50% MeOH, 100 mL/min, IC column) to yield tert-butyl (1S,2R,3R,5S)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl)ethoxy)cyclohexylcarbamate (48% yield, 99% ee) and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(2-(methylsulfonyl) ethoxy)cyclohexylcarbamate (48% yield, 99% ee). LC/MS (m/z)=663.2 (MH+), Rt=0.88 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.95 (d, J=6.75 Hz, 3 H), 1.45 (s, 8 H), 1.50-1.84 (m, 5 H), 2.80-2.95 (m, 1 H), 3.08 (s, 3 H), 3.14-3.29 (m, 1 H), 3.32-3.45 (m, 1 H), 3.56 (br. s., 1 H), 3.63-3.77 (m, 1 H), 3.95-4.08 (m, 1 H), 4.12 (q, J=7.12 Hz, 1 H), 5.36 (d, J=8.56 Hz, 1 H), 7.04-7.18 (m, 3 H), 7.50 (tt, J=8.47, 6.35 Hz, 1 H), 7.77 (t, J=8.56 Hz, 1 H), 8.33-8.46 (m, 2 H), 9.26 (s, 1 H), 9.81 (s, 1 H).

Aufarbeitung

  1. extractionextracted with ethyl acetate
  2. washThe combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by ISCO SiO2 chromatography
  7. customPurification

Quellen und Nachweise

ORD-Eintrag
ord-f6a56c6b211a4f8899c179264418e138
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09173883B2

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