6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide → 6-(cis-3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 525759Notes

Reaction equation

HRID 525759 reaction equation
Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[NH2:29][CH2:30][C@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[OH:36]>C(Cl)Cl.CCCCCC>[NH2:29][CH2:30][C@H:31]1[C@@H:32]([OH:36])[CH2:33][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1

Participants

4

Reactant 2

HCID 722015896-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamideHCID 89906931cis-4-(Aminomethyl)pyrrolidin-3-ol dihydrochloride

Product 1

HCID 899080066-(cis-3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 1

HCID 21226440Methylenechloride HexaneSolvent

Procedure

The title compound was prepared in an analogous fashion to that described in Example 48 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and cis-4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 80.1). The crude product was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was suspended in DCM/n-hexane, filtered and dried to afford the title product as a beige solid. HPLC (Condition 7) tR=5.38 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=479 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.05 (m, 1H) 2.38-2.86 (m, 2H) 2.88-3.06 (m, 1H) 3.08-3.23 (m, 1H) 3.24-3.37 (m, 2H) 3.91-4.18 (m, 1H) 6.33-6.42 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.68-7.91 (m, J=9.00 Hz, 3H) 7.97-8.06 (m, 1H) 8.68-8.78 (m, 1H) 10.20 (s, 1H) 12.94 (br. s, 1H).

Workup

  1. customThe title compound was prepared in an analogous fashion to
  2. customThe crude product was purified by preparative HPLC (Condition 10)
  3. additionFractions containing product
  4. additiontreated with sat. aq. Na2CO3
  5. customthe MeCN was evaporated off under reduced pressure
  6. customto give an aq. residue which
  7. extractionwas extracted with EtOAc
  8. washThe combined extracts were washed with brine
  9. dry with materialdried over Na2SO4
  10. customthe solvent was evaporated off under reduced pressure
  11. customto give a residue
  12. filtrationfiltered
  13. customdried

Sources & evidence

ORD record
ord-e8b186e889bf4356a52602282ad5c7bd
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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