1,2-Dimethoxyethane → 4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-fluoropyridin-3-yl)benzamide

HRID 924146Notes

Reaction equation

HRID 924146 reaction equation
[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.CCCCCC>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:34]2[CH:33]=[N:32][CH:31]=[C:30]([F:29])[CH:35]=2)[CH2:3]1

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 164142683-Fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 899064294-((3 S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide

Product 1

HCID 899082564-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(5-fluoropyridin-3-yl)benzamide

Reagents, catalysts & solvents 1

HCID 21226440Methylenechloride HexaneSolvent2×

Conditions

Temperature
80 °C

Procedure

4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 245.1, 60 mg, 0.122 mmol), 3-fluoropyridine-5-boronic acid pinacol ester and Na2CO3 (0.183 mL, 0.366 mmol) were added to a vial containing DME (1 mL) under an argon atmosphere. PdCl2(dppf)-(CH2Cl2) (5.98 mg, 7.33 μmol) was added and the RM was stirred at 80° C. for 1.5 h. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, DCM/MeOH, from 98:2 to 8:2). Fractions containing product were combined and the solvent was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane, filtered, washed with n-hexane and were purified by preparative HPLC (Condition 14). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane 1:5 and filtered to afford the title product as a white solid. HPLC (Condition 10) tR=6.01 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=493.1/495.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s, 2H) 2.63-2.74 (m, 2H) 3.12 (br. s, 1H) 3.22-3.31 (m, 2H) 3.74 (br. s, 1H) 4.98 (d, J=3.52 Hz, 1H) 6.93 (d, J=8.60 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78 (d, J=9.77 Hz, 1H) 7.86 (m, J=9.00 Hz, 3H) 7.92 (dd, J=8.80, 2.15 Hz, 1H) 8.50 (s, 1H) 8.56 (d, J=2.74 Hz, 1H) 10.10 (s, 1H).

Workup

  1. filtrationThe RM was filtered through Hyflo®
  2. customthe solvent was evaporated off under reduced pressure
  3. customto give the crude product which
  4. customwas purified by flash chromatography (Silica gel column, DCM/MeOH, from 98:2 to 8:2)
  5. additionFractions containing product
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue which
  8. filtrationfiltered
  9. washwashed with n-hexane
  10. customwere purified by preparative HPLC (Condition 14)
  11. additionFractions containing pure product
  12. additiontreated with sat. aq. Na2CO3
  13. customthe MeCN was evaporated off under reduced pressure
  14. extractionThe aq. residue was extracted with EtOAc
  15. washThe combined extracts were washed with brine
  16. dry with materialdried over Na2SO4
  17. filtrationfiltered
  18. customthe filtrate was evaporated off under reduced pressure
  19. customto give a residue which
  20. filtrationfiltered

Sources & evidence

ORD record
ord-2d4300668890456da25ea01f93fbd05b
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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