Dimethylformamide → HCID 25263815, compound

HRID 2194852Notes

Reaction equation

HRID 2194852 reaction equation
[CH3:1][N:2](C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[CH3:24])[CH3:21])=[N:14]2)=[CH:9][CH:8]=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:31][C:27]1[CH:26]=[C:25]([C@H:23]([NH:22][CH:20]([C:15]2[CH:16]=[C:17]([O:18][CH3:19])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:1]#[N:2])=[CH:8][CH:9]=3)[N:14]=2)[CH3:21])[CH3:24])[CH:30]=[CH:29][CH:28]=1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 67320793HCID 67320793, compound

Product 1

HCID 25263815HCID 25263815, compound

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A 20 mL vial was charged with Pd(PPh3)4 (0.159 g, 0.138 mmol), zinc cyanide (0.243 g, 2.07 mmol), 3 mL of DMF, and 1-[1-(4-bromophenyl)-5-methoxy-1H-pyrazol-3-yl]-N—[(1R)-1-(3-chlorophenyl)ethyl]ethanamine 85 (0.600 g, 1.38 mmol) as a >20:1 mixture of diastereomers. The reaction mixture was heated to 100° C. After 3 d, an additional 10 mol % of Pd(PPh3)4 and 2 equivalents of ZnCN2 were added. The reaction mixture was heated in a microwave to 180° C. for 15 min. The reaction mixture was cooled to room temperature, dissolved in EtOAc, washed with water and brine, dried, and concentrated. Purification by flash column chromatography on silica gel (2% MeOH in DCM) gave 443-(1-{[(1R)-1-(3-chlorophenyl)ethyl]amino}ethyl)-5-methoxy-1H-pyrazol-1-yl]benzonitrile 96 as a >20:1 mixture of diastereomers. Mass spectrum: calculated for C2H21ClN4O 380.1; found 381.2 (M++1).

Workup

  1. temperatureThe reaction mixture was heated in a microwave to 180° C. for 15 min
  2. temperatureThe reaction mixture was cooled to room temperature
  3. washwashed with water and brine
  4. customdried
  5. concentrationconcentrated
  6. customPurification by flash column chromatography on silica gel (2% MeOH in DCM)
  7. customgave 443-(1-{[(1R)-1-(3-chlorophenyl)ethyl]amino}ethyl)-5-methoxy-1H-pyrazol-1-yl]benzonitrile 96
  8. additionas a >20:1 mixture of diastereomers

Sources & evidence

ORD record
ord-4aa5534ff3834081ab68435ddeb42d2c
Source dataset
uspto-grants-2012_12
Patent number
US08334317B2

Reaction notes

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