Water → (R)-5'-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-6'-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

HRID 923870Notes

Reaction equation

HRID 923870 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:4][C:3]=1[F:34].[CH3:35]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)[CH:6]=[N:7][C:2]=1[CH3:35]

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 574072TrimethylboroxineHCID 118195366(R)-6'-Chloro-5'-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

Product 1

HCID 118195112(R)-5'-Fluoro-2-(3-hydroxypyrrolidin-1-yl)-6'-methyl-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

(R)-6′-Chloro-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 53, 139 mg, 0.28 mmol) and trimethyl-boroxine (34.4 mg, 0.274 mmol) were dissolved in dioxane (1.5 mL). K2CO3 (104 mg, 0.756 mmol) was added, the RM was flushed with argon and Pd(PPh3)4 (32.4 mg, 0.028 mmol) was added. The RM was heated overnight at 110° C. After cooling to RT, the RM was dissolved in EtOAc treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH). Further purification by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10 to 41% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH and evaporated under reduced pressure to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 7) m/z=477.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.42-2.56 (m, 3H) 2.87 (d, J=11.73 Hz, 1H) 3.14-3.28 (m, 2H) 3.33-3.43 (m, 1H) 4.18 (br. s, 1H) 4.84 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.71 (dd, J=10.17, 1.56 Hz, 1H) 7.79-7.90 (m, 2H) 8.02 (d, J=2.35 Hz, 1H) 8.34 (s, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.15 (s, 1H).

Workup

  1. additionwas added
  2. temperatureAfter cooling to RT
  3. extractionextracted with EtOAc
  4. dry with materialThe combined extracts were dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)
  7. customFurther purification by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10 to 41% MeCN+0.1% formic acid)
  8. extractionextracted with EtOAc
  9. dry with materialThe combined organic phases were dried over Na2SO4
  10. customevaporated
  11. dissolutionThe residue was dissolved in MeOH
  12. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-4fc279b756354f4eb0ce3f577f3390cf
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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