Hydrochloric Acid → HCID 86670345, compound

HRID 1972460Notes

Reaction equation

HRID 1972460 reaction equation
Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)=[NH:40])C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+]>CCOC(C)=O.O1CCOCC1.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].C1COCC1.C1(C)C=CC=CC=1>[NH2:40][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 86670342HCID 86670342, compound

Product 1

HCID 86670345HCID 86670345, compoundYield 57.3%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A 250-mL round-bottomed flask was charged with (2-(2-((2S)-4-((5-bromo-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.00 g, 1.76 mmol), 1,1-diphenylmethanimine (0.382 g, 2.11 mmol), 30 mL of toluene, sodium tert-butoxide (0.405 g, 4.22 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.273 mL, 0.439 mmol, Sigma-Aldrich, St. Louis, Mo.), and tris(dibenzylideneacetone)dipalladium (0) (0.101 g, 0.176 mmol, Strem Chemicals, Newburyport, Mass.). The round-bottomed flask was sealed and heated at 90° C. for 15 h. After that time, the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated to give a brown oil. To this was added 25 mL of THF and 15 mL of 5M HCl in dioxane. After 15 min, 17 mL of 5M NaOH was added and the mixture was extracted with EtOAc. The layers were separated, the organics were dried (MgSO4), filtered, and concentrated to give an orange oil. Purification via column chromatography on silica gel (120 g of silica, 0 to 65% EtOAc in hexanes) gave 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.510 g) as a tan solid. 1H NMR (400 MHz, CD3OD) δ=8.57 (s, 2H), 7.19 (d, J=4.1 Hz, 1H), 6.04 (d, J=4.1 Hz, 1H), 5.10 (br. s., 1H), 4.71 (d, J=13.7 Hz, 1H), 3.71 (d, J=11.7 Hz, 1H), 3.56 (d, J=11.5 Hz, 1H), 3.31-3.23 (m, 1H), 2.61 (dd, J=3.7, 11.5 Hz, 1H), 2.46 (dt, J=3.5, 11.8 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). m/z (ESI, +ve ion) 506.0 (M+H)+. GK-GKRP IC50 (Binding)=0.252 μM; GK-GKRP EC50 (LC MS/MS-2)=0.161 μM.

Workup

  1. customThe round-bottomed flask was sealed
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated
  4. customto give a brown oil
  5. extractionthe mixture was extracted with EtOAc
  6. customThe layers were separated
  7. dry with materialthe organics were dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give an orange oil
  11. customPurification via column chromatography on silica gel (120 g of silica, 0 to 65% EtOAc in hexanes)

Sources & evidence

ORD record
ord-96c0fabd667e446286f5283d9372ddea
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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