N-methyl-2-pyrrolidone → 2-(2-Chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl ester

HRID 857501Notes

Reaction equation

HRID 857501 reaction equation
[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[CH3:22][N:23]1CCCC1=O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:22]#[N:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]

Participants

6

Reactant 2

HCID 13387N-methyl-2-pyrrolidoneHCID 865967715-Bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester

Product 1

HCID 865967762-(2-Chlorophenylamino)-5-cyano-3,4-difluorobenzoic acid methyl esterYield 52%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (14) (3.01 g, 7.99 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf) (93 mg, 0.162 mmol), Pd2dba3 (73 mg, 0.080 mmol) and Zn(CN)2 (573 mg, 4.78 mmol) in 1-methyl-2-pyrrolidinone (NMP: 4.5 mL) was heated in a sealed tube reactor. After 20 hours, the reaction mixture was cooled to room temperature, quenched by the addition of 8 mL 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and extracted with a mixture of EtOAc:THF. The combined organic extracts were washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (twice: 100% hexanes to 35% CH2Cl2 in hexanes, then 30% CH2Cl2 in hexanes) provided 1.33 g (52%) of the desired product (15).

Workup

  1. temperaturewas heated in a sealed tube reactor
  2. customquenched by the addition of 8 mL 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water
  3. extractionextracted with a mixture of EtOAc
  4. washThe combined organic extracts were washed with 4:1:4 (volume) mixture of saturated NH4Cl, concentrated NH4OH and water, and brine
  5. dry with materialThe organic layer was dried (MgSO4)
  6. concentrationconcentrated
  7. customPurification by flash column chromatography

Sources & evidence

ORD record
ord-47af09c34f1c4fd99e993937a7157dfa
Source dataset
uspto-grants-2006_12
Patent number
US07144907B2

Reaction notes

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