Sulfuric Acid → HCID 86685630, compound

HRID 332840Notes

Reaction equation

HRID 332840 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]([NH2:33])[CH:30]=[N:31][CH:32]=1.C(=O)([O-])[O-:35].[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:33][C:29]2[CH:30]=[N:31][CH:32]=[C:27]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:28]=2)[C:3]([C:19]([NH2:20])=[O:35])=[N:4][CH:5]=1

Participants

10

Reactant 5

HCID 1118Sulfuric AcidHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 69284611HCID 69284611, compoundHCID 86685625((1S,2R)-2-((6-chloro-5-cyanopyrazin-2-yl)amino)cyclohexyl)carbamate

Product 1

HCID 86685630HCID 86685630, compoundYield 30.8%

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 (100 mg, 0.28 mmol), 5-(pyrimidin-2-yl)pyridin-3-amine (100 mg, 0.58 mmol), powder cesium carbonate (380 mg, 1.16 mmol), BINAP (37 mg, 0.06 mmol), Pd(OAc)2 (14 mg, 0.06 mmol) in 15 mL dioxane was degassed with argon stream. It was stirred in argon atmosphere at 110° C. for overnight. 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 20-100% EtOAc in DCM 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 (35 mg). MS found for C20H23N90 as (M+H)+ 406.5. UV: λ=259, 306 nm. 1H NMR: (CD3OD) δ 9.63 (1H, s), 9.24 (1H, s), 9.02 91H, s), 8.98 (2H, d, J=4.4 Hz), 7.70 (1H, s), 7.53 (1H, t, J=4.8 Hz), 4.74 (1H, m), 3.69 (1H, m), 1.92-1.56 (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-40c124915e894518be0b0e99932a6417
Source dataset
uspto-grants-2014_11
Patent number
US08877760B2

Reaction notes

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