Sodium Carbonate → 2-(3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5'-fluoro-[3,3'-bipyridine]-5-carboxamide

HRID 924133Notes

Reaction equation

HRID 924133 reaction equation
Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:40][CH2:41][CH:42]1[CH2:46][NH:45][CH2:44][CH:43]1[OH:47].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:40][CH2:41][CH:42]1[CH:43]([OH:47])[CH2:44][N:45]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:46]1

Participants

6

Reactant 4

HCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 148395874-(Aminomethyl)pyrrolidin-3-ol dihydrochlorideHCID 722015872-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5'-fluoro-[3,3'-bipyridine]-5-carboxamide

Product 1

HCID 1181952582-(3-(Aminomethyl)-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5'-fluoro-[3,3'-bipyridine]-5-carboxamide

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 80 mg, 0.183 mmol) and DIPEA (0.224 mL, 1.282 mmol) were added to a vial containing iPrOH (2 mL) and 4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 267.1, 37.1 mg, 0.192 mmol) was added under an argon atmosphere. The RM was stirred at 80° C. for 3 days. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to give the crude product was purified by preparative HPLC (Condition 14). Fractions containing product were treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The resulting aq. residue was extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered and evaporated. The residue was suspended in DCM/Et2O/n-hexane. The obtained solid was filtered off, washed with Et2O, n-hexane and dried to afford the title product as a white solid. HPLC (Condition 10) tR=5.74 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=508 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.41-3.33 (m, 7H) 3.92-4.21 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.03-8.11 (m, 1H) 8.47-8.54 (m, 1H) 8.59 (m, J=2.70 Hz, 1H) 8.77 (m, J=2.30 Hz, 1H) 10.19 (s, 1H).

Workup

  1. additionwas added under an argon atmosphere
  2. extractionextracted with EtOAc
  3. washThe combined extracts were washed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated to dryness under reduced pressure
  7. customto give the crude product
  8. customwas purified by preparative HPLC (Condition 14)
  9. additionFractions containing product
  10. additionwere treated with sat. aq. Na2CO3
  11. customthe MeCN was evaporated off under reduced pressure
  12. extractionThe resulting aq. residue was extracted with EtOAc
  13. dry with materialthe combined extracts were dried over Na2SO4
  14. filtrationfiltered
  15. customevaporated
  16. filtrationThe obtained solid was filtered off
  17. washwashed with Et2O, n-hexane
  18. customdried

Sources & evidence

ORD record
ord-2f06bc02f52c4950a4e68454769bc516
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

Loading…