Sulfuric Acid → HCID 71571949, compound

HRID 332844Notes

Reaction equation

HRID 332844 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15]C(=O)[O-])[CH:5]=[N:4][C:3]=1[C:19]#[N:20].[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:30]=[C:31]([N:33]3[N:37]=[CH:36][CH:35]=[N:34]3)[CH:32]=2)[NH2:29])[N:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-:39].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.OS(O)(=O)=O>O1CCOCC1.C(O)(C(F)(F)F)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:6]1[N:7]=[C:2]([NH:29][C:28]2[CH:30]=[C:31]([N:33]3[N:34]=[CH:35][CH:36]=[N:37]3)[CH:32]=[C:26]([N:22]3[N:21]=[CH:25][CH:24]=[N:23]3)[CH:27]=2)[C:3]([C:19]([NH2:20])=[O:39])=[N:4][CH:5]=1

Participants

10

Reactant 5

HCID 1118Sulfuric AcidHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86685625((1S,2R)-2-((6-chloro-5-cyanopyrazin-2-yl)amino)cyclohexyl)carbamateHCID 86685634HCID 86685634, compound

Product 1

HCID 71571949HCID 71571949, compoundYield 15%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6422Trifluoroacetic acidSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

The mixture of tert-tutyl ((1S,2R)-2-((6-chloro-5-cyanopyrazin-2-yl)amino)cyclohexyl)carbamate (90 mg, 0.26 mmol), 3,5-di(2H-1,2,3-triazol-2-yl)aniline (88 mg, 0.39 mmol), powder cesium carbonate (340 mg, 1.04 mmol), BINAP (31 mg, 0.05 mmol), Pd(OAc)2 (12 mg, 0.05 mmol) in 15 mL dioxane was degassed with argon stream. It was stirred in argon atmosphere at 110° C. for 16 h. The mixture was cooled, diluted with 100 mL EtOAc, vigorously stirred, and filtered through celite. The filtrate was concentrated and subjected to silica flash column with 0-55% EtOAc in hexane to isolate the coupling product. It was then stirred in 5 mL TFA and 1 mL conc. H2SO4 at 80° C. for 20 m. It was cooled in ice bath, diluted with water, filtered, and subjected to reverse phase preparative HPLC to isolate the title compound (18 mg). MS found for C21H24N120 as (M+H)+ 461.5. UV: λ=259, 311 nm. 1H NMR: (CD3OD) δ 8.52 (2H, d, J=1.6 Hz), 8.43 (1H, t, J=1.6 Hz), 8.01 (4H, s), 7.61 (2H, s), 4.83 (1H, m), 3.76 (1H, m), 1.93-1.55 (8H, m) ppm.

Workup

  1. customwas degassed with argon stream
  2. temperatureThe mixture was cooled
  3. additiondiluted with 100 mL EtOAc
  4. stirringvigorously stirred
  5. filtrationfiltered through celite
  6. concentrationThe filtrate was concentrated
  7. customto isolate the coupling product
  8. customat 80° C.
  9. temperatureIt was cooled in ice bath
  10. filtrationfiltered

Sources & evidence

ORD record
ord-409913fc08824c00ad21c5111bc44414
Source dataset
uspto-grants-2014_11
Patent number
US08877760B2

Reaction notes

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