O-Methylhydroxylamine hydrochloride → N-[4-[(1R,3R,4E,5S)-3-amino-4-methoxyimino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

HRID 705285ノート

反応式

HRID 705285 の反応式
Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[N:18]=[C:17]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[C@H:28]2[CH2:33][C@@H:32]([NH:34]C(=O)OC(C)(C)C)[C:31](=O)[C@@H:30]([CH3:43])[CH2:29]2)=[O:20])[CH:16]=[CH:15][C:14]=1[F:44]>CCO.N1C=CC=CC=1>[NH2:34][C@@H:32]1[CH2:33][C@H:28]([C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:21][C:19](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([F:44])=[C:13]([C:7]3[C:6]([F:5])=[CH:11][CH:10]=[CH:9][C:8]=3[F:12])[N:18]=2)[CH2:29][C@H:30]([CH3:43])/[C:31]/1=[N:4]\[O:2][CH3:3]

参加物

4

反応物 2

HCID 521874O-Methylhydroxylamine hydrochlorideHCID 86705245tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate

生成物 1

HCID 90055958N-[4-[(1R,3R,4E,5S)-3-amino-4-methoxyimino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide収率 16%

試薬・触媒・溶媒 1

HCID 21975839Pyridine ethanol溶媒

実験手順

A solution of methoxylamine-HCl (1.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3 (sat.). The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and the residue was pumped on for 5 minutes, dissolved in CH2Cl2 and neutralized with TEA. The volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5S,E)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 16% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.64 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.25 (broad doublet, J=4.0, 2H), 8.20 (t, J=8.0, 1H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 4.04-4.08 (m, 1H), 3.79 (s, 3H), 3.23-3.29 (m, 1H), 2.39-2.45 (m, 1H), 2.11 (d, J=8.0, 1H), 2.10 (d, J=8.0, 1H), 1.90 (q, J=12, 1H), 1.40 (q, J=12, 1H), 1.01 (d, J=4.0, 3H); and N-(4-((1R,3R,5S,Z)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 27% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.66 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 8.08 (broad singlet, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 3.88-3.92 (m, 1H), 3.80 (s, 3H), 3.22-3.28 (m, 1H), 2.51-2.58 (m, 1H), 2.25 (d, J=12.0, 1H), 1.86 (d, J=12.0, 1H), 1.70 (q, J=12, 1H), 1.62 (q, J=12, 1H), 1.34 (d, J=4.0, 3H).

後処理

  1. waitleft
  2. customThe volatiles were removed in vacuo
  3. customthe residue was partitioned between EtOAc and Na2CO3 (sat.)
  4. washThe organic layer was washed with NaCl(sat)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe Boc group was removed with 25% TFA/CH2Cl2
  9. waitAfter 45 minutes
  10. customthe volatiles were removed in vacuo
  11. customwas pumped on for 5 minutes
  12. dissolutiondissolved in CH2Cl2 and neutralized with TEA
  13. customThe volatiles were removed in vacuo
  14. dissolutionwas dissolved in DMSO
  15. custompurified by RP-HPLC

出典と根拠

ORDレコード
ord-cc25ee697c62464db4b31545cb6227f3
出典データセット
uspto-grants-2015_11
特許番号
US09173883B2

反応ノート

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