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 879199노트

반응식

HRID 879199 반응식
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]

참가 물질

4

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 21975839Pyridine ethanol용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-9254484eefc24f47b77964b08434b737
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08987457B2

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