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

反応式

HRID 705299 の反応式
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]

参加物

8

反応物 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

生成物 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)cyclohexylcarbamate収率 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)cyclohexylcarbamate収率 48%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-f6a56c6b211a4f8899c179264418e138
出典データセット
uspto-grants-2015_11
特許番号
US09173883B2

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