Methanesulfonyl chloride → (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate

HRID 705255Notes

Reaction equation

HRID 705255 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:41][S:42]([O:38][C@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]

Participants

4

Reactant 2

HCID 31297Methanesulfonyl chlorideHCID 86705216tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate

Product 1

HCID 72551166(1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonateYield 45%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in pyridine (0.12 M) was added MsCl (7.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 45% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.60 min.

Workup

  1. waitthe homogeneous solution was left
  2. waitstanding at rt for 16 hrs
  3. customThe volatiles were removed in vacuo
  4. customthe residue was partitioned between EtOAc and H2O
  5. washThe organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat), NaCl(sat)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. custompurified by ISCO chromatography
  10. additionThe Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles
  11. customwere removed in vacuo
  12. dissolutionthe residue was dissolved in DMSO
  13. custompurified by RP-HPLC

Sources & evidence

ORD record
ord-80e5d9c821924522bbc5bd776f916cb1
Source dataset
uspto-grants-2015_11
Patent number
US09173883B2

Reaction notes

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