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

반응식

HRID 705299 반응식
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]

참가 물질

8

반응물 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

생성물 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)cyclohexylcarbamate수율 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)cyclohexylcarbamate수율 48%

시약·촉매·용매 2

HCID 962Water용매HCID 6228Dimethylformamide용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-f6a56c6b211a4f8899c179264418e138
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09173883B2

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