Water → ABT-072

HRID 1504923Notes

Reaction equation

HRID 1504923 reaction equation
[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(N(C)C)=O.O.C([SiH](CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 962WaterHCID 12052TriethylsilaneHCID 31374DimethylacetamideHCID 46917481HCID 46917481, compound

Product 1

HCID 57775240ABT-072Yield 88.1%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a vessel N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (5.00 g; 10.69 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.375 g; 5.35 mmol) are charged and the vessel is purged with nitrogen. Nitrogen purged dimethylacetamide (20 ml) and water (0.578 g, 32.1 mmol) are charged to the vessel and the mixture was heated to 70° C. Triethylsilane (2.49 g, 21.4 mmol) was charged over 2 hours at a temperature of 70° C. The mixture was heated at 70° C. for approximately 5 hours and cooled to ambient temperature. The mixture was diluted with tetrahydrofuran (40 g) and extracted with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution. The solids which formed were removed by filtration and washed with tetrahydrofuran (18 g). The aqueous layer was extracted with tetrahydrofuran (18 g). The combined tetrahydrofuran extracts were washed successively with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution and a 2.5% NaHCO3/7% NaCl solution. Methanol (28 g) was charged and the solution concentrated to 28 g. Methanol (28 g) was charged and the product was allowed to crystallize. Methanol (28 g) was charged and the slurry was concentrated to 45 g. Methanol (60 g) was charged and the mixture concentrated to 75 g. The slurry was heated to 60° C. for 30 minutes and then cooled to ambient temperature. The solids were isolated by filtration, washed with methanol (2×8 gm) and vacuum dried at 50° C. to provide 4.42 g of the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H). MS (APCI) m/e 470.1 (M+H)+.

Workup

  1. customthe vessel is purged with nitrogen
  2. additionare charged to the vessel
  3. temperatureThe mixture was heated at 70° C. for approximately 5 hours
  4. temperaturecooled to ambient temperature
  5. extractionextracted with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution
  6. customThe solids which formed
  7. customwere removed by filtration
  8. washwashed with tetrahydrofuran (18 g)
  9. extractionThe aqueous layer was extracted with tetrahydrofuran (18 g)
  10. washThe combined tetrahydrofuran extracts were washed successively with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution
  11. additionMethanol (28 g) was charged
  12. concentrationthe solution concentrated to 28 g
  13. additionMethanol (28 g) was charged
  14. customto crystallize
  15. additionMethanol (28 g) was charged
  16. concentrationthe slurry was concentrated to 45 g
  17. additionMethanol (60 g) was charged
  18. concentrationthe mixture concentrated to 75 g
  19. temperatureThe slurry was heated to 60° C. for 30 minutes
  20. temperaturecooled to ambient temperature
  21. customThe solids were isolated by filtration
  22. washwashed with methanol (2×8 gm) and vacuum
  23. customdried at 50° C.

Sources & evidence

ORD record
ord-6e02b13f37704b20877117204f654649
Source dataset
uspto-grants-2015_12
Patent number
US09216952B2

Reaction notes

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