Cesium carbonate → Cyclopropanecarboxylic acid {6-[2-(2,6-dichloro-4-cyanophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-amide

HRID 626698Notes

Reaction equation

HRID 626698 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1)[C:5]#[N:6].[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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].C(#N)C>[OH-:30].[NH4+:6].[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([Cl:20])[C:9]=1[N:10]1[CH:19]=[C:13]2[C:14]([NH:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH:23]=3)=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1

Participants

10

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86346445N-(6-Aminopyrimidin-4-yl)cyclopropanecarboxamideHCID 866970463,5-Dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile

Product 2

HCID 14923Ammonium HydroxideYield 0.1%HCID 86697047Cyclopropanecarboxylic acid {6-[2-(2,6-dichloro-4-cyanophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-amideYield 51.4%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Procedure

A suspension of 3,5-dichloro-4-(4-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile (132 mg, 0.41 mmol), cyclopropanecarboxylic acid (6-amino-pyrimidin-4-yl)-amide (80 mg, 0.45 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate (266 mg, 0.82 mmol) in dioxane (2 mL) was sealed in a microwave vial after degassing with nitrogen. The mixture was irradiated at 150° C. for 30 minutes in the microwave and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane), then by HPLC (gradient: 5 to 98% acetonitrile in water with 0.1% ammonium hydroxide), to afford the title compound as an off-white solid (49 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6+d-TFA): δ 9.47 (s, 1H), 8.79 (d, 1H), 8.47 (s, 2H), 8.09 (d, J=0.9 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.55 (dd, J=7.6, 0.9 Hz, 1H), 2.10-2.02 (m, 1H), 0.93-0.90 (m, 4H). LCMS (Method B): RT=3.17 min, m/z: 465 [M+H+].

Workup

  1. customwas sealed in a microwave vial
  2. customafter degassing with nitrogen
  3. customThe mixture was irradiated at 150° C. for 30 minutes in the microwave
  4. customThe reaction mixture was partitioned between ethyl acetate and water
  5. customThe organic layer was separated
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-f48df1ce121140d2a6dd052cd883b9e5
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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