Ethyl Acetate → HCID 118195212, compound

HRID 924141Notes

Reaction equation

HRID 924141 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[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]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[F:28])[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 569244444-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine2×HCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 118195212HCID 118195212, compound

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 116 mg, 0.25 mmol) and 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (116 mg, 0.5 mmol) were dissolved in DME (1 mL). A solution of 2 M Na2CO3 (0.375 mL, 0.75 mmol) was added, the mixture was flushed with argon and PdCl2(dppf) (9 mg, 0.013 mmol) was added and the RM was stirred at 120° C. for 1 h. Additional 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80 mg) and PdCl2(dppf) (9 mg, 0.013 mmol) were then added and the RM was stirred at 120° C. for further 45 min. After cooling at RT, the RM was treated with EtOAc, washed with brine dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, 12 g, EtOAc/2% MeOH in EtOAc, gradient 50 to 100% B, EtOAc/MeOH 10%) and treated with Si-Thiol (100 mg) in MeOH. The product was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to afford the title product as a beige foam. HPLC (Condition 4) tR=5.14 min, UPLC-MS (Condition 3) tR=0.98 min, m/z=479.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.94 (m, 2H) 2.89-3.00 (m, 1H) 3.14-3.23 (m, 1H) 3.23-3.42 (m, 3H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.47 (dd, J=9.78, 5.47 Hz, 1H) 7.81-7.90 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.62-8.79 (m, 2H) 8.81 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).

Workup

  1. additionwas added
  2. stirringthe RM was stirred at 120° C. for further 45 min
  3. temperatureAfter cooling at RT
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. customThe solvent was evaporated under reduced pressure
  7. customto give a residue that
  8. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, EtOAc/2% MeOH in EtOAc, gradient 50 to 100% B, EtOAc/MeOH 10%)
  9. additiontreated with Si-Thiol (100 mg) in MeOH
  10. customThe product was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min)

Sources & evidence

ORD record
ord-c2af46ae02034730bc08e50bf8b4b5b4
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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