Cesium carbonate → HCID 66801376, compound

HRID 2366326Notes

Reaction equation

HRID 2366326 reaction equation
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=3[C:13]#[N:14])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([CH2:28][OH:29])[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]>[ClH:19].[Cl:19][C:18]1[C:11]([C:9]2[S:8][C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([CH2:28][OH:29])[N:25]=[CH:26][N:27]=4)=[N:3][CH:4]=[CH:5][C:6]=3[N:10]=2)=[C:12]([CH:15]=[C:16]([F:20])[CH:17]=1)[C:13]#[N:14]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 21934615(6-Aminopyrimidin-4-yl)methanolHCID 86669033HCID 86669033, compound

Product 1

HCID 66801376HCID 66801376, compoundYield 70.2%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile (98 mg, 0.26 mmol), (6-aminopyrimidin-4-yl)-methanol (33 mg, 0.26 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), XantPhos (15 mg, 0.026 mmol) and cesium carbonate (219 mg, 0.67 mmol) in 1,4-dioxane (2 mL) was heated under argon at 80° C. for 16 hours. The cooled reaction mixture was diluted with water and extracted five times with ethyl acetate, then three times with 10% methanol in DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica (20-100% ethyl acetate in cyclohexane) to yield the free base of the title compound (41 mg, 38%). This material was suspended in DCM (2 mL) and 2-propanol (0.5 mL), and a solution of hydrogen chloride in 2-propanol (1.25 N, 1 mL) was added and the resultant mixture was stirred for 10 minutes. The solvent was removed under reduced pressure and the resultant residue was triturated three times with diethylether and dried (50° C. under vacuum) to give the title compound as an off-white solid (44 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.28-8.23 (m, 2H), 8.05 (d, J=5.6 Hz, 1H), 7.87 (br s, 1H), 4.64 (s, 2H). LCMS (Method C): RT=3.14, m/z: 413 [M+H+].

Workup

  1. customThe cooled reaction mixture
  2. extractionextracted five times with ethyl acetate
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by chromatography on silica (20-100% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-8c582534f4894022ad0db29c0eb9ed7a
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

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