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

HRID 1766783Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1766783
[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]

Komponenten

6

Edukt 2

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

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

Versuchsvorschrift

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).

Aufarbeitung

  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/THF
  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

Quellen und Nachweise

ORD-Eintrag
ord-c6341b5fa9ff4a459e41a59189c1338e
Quelldatensatz
uspto-grants-2007_06
Patentnummer
US07230099B2

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