Dimethylformamide → HCID 71008483, compound

HRID 1025608Notes

Reaction equation

HRID 1025608 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:39][OH:40])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:37]=[CH:36][C:35](Cl)=[CH:34][N:33]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:70][N:71](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:39][OH:40])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[C:25]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:70]#[N:71])=[CH:34][N:33]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 71008571HCID 71008571, compound

Product 1

HCID 71008483HCID 71008483, compoundYield 91%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
150 °C

Procedure

Take up 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide (prepared in example 23, above) (31 mg, 55.2 μmol), zinc cyanide (51.8 mg, 441 μmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6 mg, 14.6 μmol) in 1.5 ml of dry dimethylformamide in a small capacity microwave tube and thoroughly degas with argon. Add tris(dibenzylideneacetone)dipalladium(0) (7 mg, 7.6 μmol) and degas again. The mixture was heated in a microwave reactor at 150° C. for 60 minutes. The solvent was stripped (rotary evaporator/pump) and the remainder was taken up in ethyl acetate (25 ml) and water (25 mL) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×20 ml). The organic phase was combined, dried from magnesium sulfate, filtered and stripped. The crude was purified by preparative thin layer chromatography (1 plate, eluting with 9.5% methanol in dichloromethane). The product band was collected, providing semi-pure desired product (21 mg, 91% pure). For greater purity the material was again loaded onto 1 preparative thin layer chromatography plate and eluted with 7% methanol in dichloromethane. Re-develop the plate with 7% and then 8.5% and finally 9% methanol in dichloromethane, at which point a more polar impurity was separated. The less polar product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-cyano-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide as an off-white solid (17 mg, 56%). LC/MS calc'd for C29H25FN8O3 (m/e) 552.57, obs'd 553 (M+H, ES+).

Workup

  1. customthoroughly degas with argon
  2. custom(rotary evaporator/pump)
  3. customThe organic phase was collected
  4. extractionthe aqueous phase was back extracted with ethyl acetate (2×20 ml)
  5. dry with materialdried from magnesium sulfate
  6. filtrationfiltered
  7. customThe crude was purified by preparative thin layer chromatography (1 plate, eluting with 9.5% methanol in dichloromethane)
  8. customThe product band was collected

Sources & evidence

ORD record
ord-61e13563c9a0400896da6f5ce9ce80d7
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

Loading…