Sulfuric Acid → HCID 86685633, compound

HRID 2200517Notes

Reaction equation

HRID 2200517 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[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:33]=1)[NH2:30].C(=O)([O-])[O-:41].[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:30][C:29]2[CH:28]=[C:27]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:33]=[C:32]([C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:39]=3)[CH:31]=2)[C:3]([C:19]([NH2:20])=[O:41])=[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 86685631HCID 86685631, compound

Product 1

HCID 86685633HCID 86685633, compoundYield 58.7%

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 (60 mg, 0.24 mmol), 3,5-di(pyrimidin-2-yl)aniline (85 mg, 0.24 mmol), powder cesium carbonate (326 mg, 1.00 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 2.5 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 0-90% 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 30 m. It was cooled in ice bath, diluted with water, filtered, and subjected to reverse phase preparative HPLC to isolate the title compound (68 mg). MS found for C25H26N10O as (M+H)+483.5. UV: λ=254, 315 nm. 1H NMR: (CD3OD) δ 9.05 (1H, t, J=1.6 Hz), 8.83 (4H, d, J=5.2 Hz), 8.75 (2H, d, J=1.6 Hz), 7.48 (1H, s), 7.35 (2H, t, J=4.8 Hz), 4.71 (1H, m), 3.60 (1H, m), 1.82-1.39 (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-5192ca502f9c49afa794cc6eb488249b
Source dataset
uspto-grants-2016_06
Patent number
US09359308B2

Reaction notes

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