Water → HCID 71208632, compound

HRID 1887915Notes

Reaction equation

HRID 1887915 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.Br[C:25]1[CH:53]=[CH:52][C:28]([C:29]([NH:31][CH2:32][C:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][C:38]([Cl:44])=[CH:39][CH:40]=3)[N:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:34]=2)=[O:30])=[CH:27][N:26]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:44][C:38]1[CH:37]=[C:36]2[C:41]([C:42](=[O:43])[C:33]([CH2:32][NH:31][C:29](=[O:30])[C:28]3[CH:52]=[CH:53][C:25]([C:9]4[CH:13]=[N:12][NH:11][CH:10]=4)=[N:26][CH:27]=3)=[CH:34][N:35]2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:51])=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 962WaterHCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 71811132HCID 71811132, compound

Product 1

HCID 71208632HCID 71208632, compoundYield 7.6%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

While purging with argon, a small microwave tube was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.0 mg, 0.155 mmol), K3PO4.H2O (53 mg, 0.230 mmol), and PdCl2(dppf) (9.3 mg, 0.013 mmol). 6-Bromo-N-[7-chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (Example I-101) (50 mg, 0.099 mmol) in DMF (0.50 mL) was added followed by water (0.05 mL). The reaction mixture was heated at 120° C. via microwave irradiation for 15 min. HPLC showed one or two new peaks forming; LC/MS showed one of the new peaks with the product mass. The reaction mixture was heated at 120° C. for another 40 min. After this time, most of the starting material was consumed, as observed by HPLC. The reaction mixture was diluted with H2O, then extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine. The organic phase was dried over Na2CO3, filtered, and concentrated. The crude product was purified using flash chromatography (12 g silica gel column eluting with 100% methylene chloride ramped to 0% methanol in methylene chloride). N-[7-Chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-6-(1H-pyrazol-4-yl)-nicotin-amide (3.7 mg, 7%) was obtained as a light brown solid at 90% purity by reverse-phase HPLC. MS calcd. for C25H17Cl2N5O2 [(M+H)+] 491.0, obsd. 489.9.

Workup

  1. customWhile purging with argon, a small microwave tube
  2. customforming
  3. temperatureThe reaction mixture was heated at 120° C. for another 40 min
  4. customAfter this time, most of the starting material was consumed
  5. additionThe reaction mixture was diluted with H2O
  6. extractionextracted twice with ethyl acetate
  7. washThe combined ethyl acetate layers were washed with brine
  8. dry with materialThe organic phase was dried over Na2CO3
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product was purified
  12. washflash chromatography (12 g silica gel column eluting with 100% methylene chloride ramped to 0% methanol in methylene chloride)

Sources & evidence

ORD record
ord-c2e2f784b6224be6a9e11044deca000b
Source dataset
uspto-grants-2013_08
Patent number
US08501732B2

Reaction notes

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