Sodium Bicarbonate → HCID 118195187, compound

HRID 923907Notes

Reaction equation

HRID 923907 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].[F:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][CH2:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:35][CH:36]=1

Participants

7

Reactant 3

HCID 516892Sodium BicarbonateHCID 59534948HCID 59534948, compoundHCID 86702601(S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118195187HCID 118195187, compound

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 92 mg, 0.2 mmol) and 2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (prepared as described in US20090571601) (316 mg 30% ig, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was heated for 2 h at 90° C. After cooling at RT, the RM was dissolved in EtOAc and water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was first purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), treated with Si-Thiol (100 mg) in MeOH and further purified by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 38% 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 to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.96 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=491.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.29 (m, 1H) 2.92-3.02 (m, 1H) 3.07-3.38 (m, 4H) 3.42-3.53 (m, 2H) 4.60 (t, J=5.08 Hz, 1H) 5.47 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.58 (d, J=7.82 Hz, 1H) 7.77-7.92 (m, 3H) 8.02 (d, J=2.35 Hz, 1H) 8.64 (d, J=1.56 Hz, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.16 (s, 1H).

Workup

  1. customthe RM was flushed with argon
  2. temperatureThe RM was heated for 2 h at 90° C
  3. temperatureAfter cooling at RT
  4. extractionwater, and extracted with EtOAc
  5. dry with materialThe combined extracts were dried over Na2SO4
  6. customevaporated to dryness under reduced pressure
  7. customThe crude product was first purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)
  8. additiontreated with Si-Thiol (100 mg) in MeOH
  9. customfurther purified by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 38% MeCN+0.1% formic acid)
  10. extractionextracted with EtOAc
  11. dry with materialThe combined organic phases were dried over Na2SO4
  12. customevaporated

Sources & evidence

ORD record
ord-4aa01b5f1cab41fa91fac8b562af9bce
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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