Sodium Carbonate → (S)-6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-5-(2-methylthiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525661Notes

Reaction equation

HRID 525661 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.CO.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.O.O1CCOCC1>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[S:31][C:30]([CH3:29])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

9

Reactant 3

HCID 10340Sodium Carbonate2×HCID 457858292-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole2×HCID 86702601(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118045065(S)-6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-5-(2-methylthiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
80 °C

Procedure

(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 16.1, 92 mg, 0.2 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (90 mg, 0.4 mmol), Na2CO3 (53 mg, 0.5 mmol), dioxane (1 mL) and water (0.6 mL). were added to a MW vial, which was sealed and evacuated/purged with argon. Pd(Ph3P)4 (11.56 mg, 0.01 mmol) was added and the RM was stirred at 80° C. for 18 h. The RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue. The residue, 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (90 mg, 0.4 mmol), Na2CO3 (53 mg, 0.5 mmol), dioxane (1 mL) and water (0.6 mL) added to an MW vial which was sealed and evacuated/purged with argon. Pd(Ph3P)4 (11.56 mg, 0.01 mmol) was added and the RM was stirred at 80° C. for 18 h. After cooling the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) followed by reverse phase chromatography (MPLC, Lichroprep® 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 40% MeCN+0.1% formic acid). The fractions containing pure product were combined, treated with excess aqueous NaHCO3 and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in MeOH and the solvent was evaporated off under reduced pressure to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=5.1 min, UPLC-MS (Condition 6) m/z=479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.59 (m, J=7.40 Hz, 1H) 1.85 (m, J=6.30 Hz, 1H) 2.15-2.31 (m, 1H) 2.68 (s, 3H) 3.03-3.19 (m, 1H) 3.21-3.40 (m, 5H) 4.63 (t, J=5.28 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.60 (s, 1H) 7.83 (d, J=8.99 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.73 (m, J=1.00 Hz, 1H) 10.17 (s, 1H).

Workup

  1. additionwere added to a MW vial, which
  2. customwas sealed
  3. customevacuated/purged with argon
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue
  8. customwas sealed
  9. customevacuated/purged with argon
  10. stirringthe RM was stirred at 80° C. for 18 h
  11. temperatureAfter cooling the RM
  12. washwashed with brine
  13. dry with materialdried over Na2SO4
  14. customthe solvent was evaporated off under reduced pressure
  15. customto give a crude product
  16. customwas purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)
  17. additionThe fractions containing pure product
  18. additiontreated with excess aqueous NaHCO3
  19. extractionextracted with EtOAc
  20. dry with materialThe combined extracts were dried over Na2SO4
  21. customthe solvent was evaporated off under reduced pressure
  22. customto give a residue which
  23. customthe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record
ord-d34598082b384c60aecb5023a2c02c70
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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