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

HRID 1897588Notes

Reaction equation

HRID 1897588 reaction equation
[Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:29])[C:25]=1[CH:26]([OH:28])[CH3:27].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([F:29])[C:25]=2[CH:26]([OH:28])[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 579261132-Chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 699379091-(3-Bromo-5-Fluoro-pyridin-4-yl)-ethanol

Product 1

HCID 710875962-Chloro-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrileYield 49.9%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To the solution of 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (263 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, the combined extracts were concentrated and purified by ISCO 12 g (0-30% EtOAc/Hep) to give 2-Chloro-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (138 mg, 49%) as a white solid; ESI-MS m/z: 276 [M+1]+, Retention time 1.15 min. 1H-NMR (CDCl3, 400 MHz) δ 1.53 (d, J=6.8 Hz, 3H), 4.76 (q, J=6.8 Hz, 1H), 7.28 (dd, J=8.0, 2.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.46 (d, J=2.0 Hz, 1H). The racemate was separated by chiral HPLC (ChiralPak IA-H, 40% EtOH/Heptane, v/v) and yielded 2-Chloro-4-[5-fluoro-4-((R)-1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile 16-(enantiomer-1) (retention time: 5.24 min) and 2-Chloro-4-[5-fluoro-4-((S)-1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile 16-(enantiomer-2) (retention time: 13.69 min).

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 with DCM
  5. concentrationthe combined extracts were concentrated
  6. custompurified by ISCO 12 g (0-30% EtOAc/Hep)

Sources & evidence

ORD record
ord-09a6f20fd9ae4686be6256cc92cf219e
Source dataset
uspto-grants-2013_08
Patent number
US08519134B2

Reaction notes

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