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Dichloromethane → 2-Methoxy-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile

HRID 1897589
Notes
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Reaction equation

HRID 1897589 reaction equation
[CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=1[CH:27]([OH:29])[CH3:28].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=2[CH:27]([OH:29])[CH3:28])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 595783882-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 699379091-(3-Bromo-5-Fluoro-pyridin-4-yl)-ethanol

Product 1

HCID 711123412-Methoxy-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrileYield 52.2%

Reagents, catalysts & solvents

2
HCID 178477754HCID 178477754, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To the solution of 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (259 mg, 1.00 mmol), 1-(3-Bromo-5-Fluoro-pyridin-4-yl)-ethanol (220 mg, 1.00 mmol) and PdCl2(dpPf). CH2Cl2 adduct (65 mg, 0.08 mmol) in DMF (4 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and sat. NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (0-30% EtOAc/Heptane, v/v) to give 2-Methoxy-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (142 mg, 52%) as a white solid; ESI-MS m/z: 273 [M+1]+, Retention time 1.09 min. 1H-NMR (CDCl3, 400 MHz) δ 1.61 (d, J=6.8 Hz, 3H), 3.96 (s, 3H), 4.83 (q, J=6.8 Hz, 1H), 6.93 (d, J=1.2 Hz, 1H), 6.95 (dd, J=8.0, 1.2 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.51 (d, J=2.8 Hz, 1H)

Workup

  1. temperatureAfter letting cool to room temperature
  2. customsolvent was removed in vacuo
  3. dissolutionThe resulting residue was dissolved in DCM
  4. extractionAfter extraction
  5. customwith DCM and separation
  6. concentrationthe combined extracts were concentrated
  7. custompurified by ISCO 12 g (0-30% EtOAc/Heptane, v/v)

Sources & evidence

ORD record
ord-967cc5c03b4f4e9e8ec862d4d08c608a
Source dataset
uspto-grants-2013_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08519134B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes