Sodium Carbonate → HCID 25121259, compound

HRID 1640933Notes

Reaction equation

HRID 1640933 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[C:4](I)[CH:3]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]2[N:30]=[C:29]([C:31]3[S:35][C:34]4[C:36](B5OC(C)(C)C(C)(C)O5)=[CH:37][CH:38]=[CH:39][C:33]=4[CH:32]=3)[C:28]([F:49])=[CH:27][N:26]=2)[CH:21]=[CH:20][N:19]=[N:18]1.[C:50](=[O:53])([O-:52])[O-:51].[Na+].[Na+]>C1COCC1.O.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]>[C:50](=[O:51])([OH:53])[O-:52].[NH4+:7].[N:17]1([CH2:22][CH2:23][NH:24][C:25]2[N:30]=[C:29]([C:31]3[S:35][C:34]4[C:36]([C:4]5[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=5[CH2:8][N:9]5[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]5)=[CH:37][CH:38]=[CH:39][C:33]=4[CH:32]=3)[C:28]([F:49])=[CH:27][N:26]=2)[CH:21]=[CH:20][N:19]=[N:18]1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 66738069HCID 66738069, compoundHCID 66738660HCID 66738660, compound

Product 2

HCID 14013Ammonium BicarbonateHCID 25121259HCID 25121259, compoundYield 52%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

Combine 5-(bromomethyl)-2-fluoro-4-iodopyridine (0.2 g, 0.63 mmol), piperidin-4-ol (0.192 mg, 1.9 mmol), and diisopropylethylamine (0.22 mL, 1.27 mmol) in acetonitrile (3.0 mL). Heat the reaction mixture at 80° C. for 2 h and cool to RT. Remove the organic solvent to give crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol. Combine crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol (0.63 mmol), N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.15 g, 0.32 mmol, sodium carbonate (0.102 g, 0.96 mmol), 2-(di-tert-butylphospho)biphenyl (0.006 g, 0.06 mmol) and Pd(dppf)Cl2 (0.026 g, 0.1 mmol) in THF (3 mL) and water (1 mL). Heat the mixture at 120° C. for 10 min in a microwave reactor. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Purify by reverse phase chromatography (28% isocratic at 85 mL/min for 8 min on a 30×75 mm, 5 mm, C18 ODB MS XBridge™ column, Solvent A: water with 0.01 M ammonium bicarbonate, Solvent B: acetonitrile) to afford the title compound (91 mg, 52%). MS (ES) m/z 549 [M+1]+.

Workup

  1. additionPour the crude
  2. customreaction mixture onto a strong cation exchange (SCX) (10 g) column
  3. washElute the desired product with 2 N methanolic ammonia (40 mL)
  4. concentrationconcentrate
  5. customPurify by reverse phase chromatography (28% isocratic at 85 mL/min for 8 min on a 30×75 mm, 5 mm

Sources & evidence

ORD record
ord-13344fef25174fcab38ac936f0f39ff8
Source dataset
uspto-grants-2012_02
Patent number
US08114872B2

Reaction notes

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