Dichloromethane → 2,2-dichloro-N-[(1S,2R)-2-{4-[6-(2-cyanoethyl)pyridin-3-yl]phenyl}-1-(fluoromethyl)-2-hydroxyethyl]acetamide

HRID 1500303Notes

Reaction equation

HRID 1500303 reaction equation
ClCCl.CC1(C)C(C)(C)OB([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[N:16][CH:17]=2)O1.[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@H:29]([OH:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:23][CH:24]([Cl:40])[C:25]([NH:27][C@H:28]([CH2:38][F:39])[C@@H:29]([C:30]1[CH:31]=[CH:32][C:33]([C:12]2[CH:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:34][CH:35]=1)[OH:37])=[O:26]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 683504732,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamideHCID 867131913-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propanenitrile

Product 1

HCID 736036212,2-dichloro-N-[(1S,2R)-2-{4-[6-(2-cyanoethyl)pyridin-3-yl]phenyl}-1-(fluoromethyl)-2-hydroxyethyl]acetamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (30.2 mg, 0.037 mmol) is added to a degassed mixture of the product of step 1, Example 21 along with 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (150 mg, 0.369 mmol), and cesium carbonate (482 mg, 1.48 mmol) in N,N-dimethylformamide (2.76 mL) at room temperature. The reaction mixture is heated at 60° C. for 4 hours. After cooling to room temperature the reaction mixture is concentrated under high vacuum, and the residue slurried in ethyl acetate. The slurry is filtered through solka floc washing the cake with ethyl acetate. The combined filtrates were concentrated and the brown residue purified by chromatography on silica gel eluting with a gradient of 50-80% ethyl acetate in hexanes to afford the title compound (72.5 mg): 1H NMR (300 MHz, DMSO-d6) δ 2.92-2.97 (m, 2H), 3.08-3.13 (m, 2H), 4.23-4.28 (m, 1.5 H), 4.41-4.46 (m, 0.5H), 4.54-4.58 (m, 0.5H), 4.69-4.74 (m, 0.5H), 4.89-4.92 (m, 1H), 5.98 (d, 1H), 6.53 (s, 1H), 7.42-7.49 (m, 3H), 7.79 (d, 2H), 8.03-8.06 (dd, 1H), 8.62 (d, 1H), 8.83-8.84 (m, 1H). MS (ESI+) m/z of 410.0/412.0 [M+H].

Workup

  1. temperatureAfter cooling to room temperature the reaction mixture
  2. concentrationis concentrated under high vacuum
  3. filtrationThe slurry is filtered through solka floc
  4. washwashing the cake with ethyl acetate
  5. concentrationThe combined filtrates were concentrated
  6. customthe brown residue purified by chromatography on silica gel eluting with a gradient of 50-80% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-fb23e13f6c1c49e4810580efd4adca79
Source dataset
uspto-grants-2015_12
Patent number
US09206126B2

Reaction notes

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