Cesium carbonate → HCID 66801371, compound

HRID 2366313Notes

Reaction equation

HRID 2366313 reaction equation
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[N:10][C:6]=2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([CH2:29][OH: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]>[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]([CH2:29][OH:30])[N:25]=[C:26]([CH3:28])[N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]=3[N:10]=2)=[C:12]([CH:15]=[CH:16][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 66801733HCID 66801733, compoundHCID 86669020HCID 86669020, compound

Product 1

HCID 66801371HCID 66801371, compoundYield 81.1%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

To a mixture of 2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile (150 mg, 0.41 mmol), (6-amino-2-methylpyrimidin-4-yl)-methanol (56 mg, 0.41 mmol), XantPhos (24 mg, 0.042 mmol) and Cs2CO3 (345 mg, 1.05 mmol) in 1,4-dioxane (2.5 mL) was added Pd2(dba)3 (20 mg, 0.022 mmol), and the reaction mixture was heated under argon at 80° C. for 24 hours. The resultant mixture was allowed to cool, diluted with water and extracted with ethyl acetate, then further extracted with 10% methanol in DCM (×5). The resultant insoluble material was filtered off, triturated twice with methanol and dried (50° C. under vacuum) to give the free base of the title compound as a solid (77 mg). The previously combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by chromatography on silica (0-100% ethyl acetate in cyclohexane) to give a further crop of the free base of the title compound [(30 mg), total yield 107 mg, 61%]. The combined batches of free base were suspended in 2-propanol (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 N, 2 mL) was added. The mixture was stirred for 1 hour, then the solvent was removed under reduced pressure, and the resultant residue was triturated with diethylether and dried (50° C. under vacuum) to give the title compound as an off-white solid (104 mg, 55%). 1H NMR (400 MHz, DMSO-d6): δ 11.76 (br s, 1H), 8.63 (s, 1H), 8.17-8.09 (m, 2H), 7.88 (t, J=8.1 Hz, 1H), 7.44 (br s, 1H), 4.58 (s, 2H), 2.57 (s, 3H). LCMS (Method C): RT=3.07, m/z: 427 [M+H+].

Workup

  1. temperatureto cool
  2. extractionextracted with ethyl acetate
  3. extractionfurther extracted with 10% methanol in DCM (×5)
  4. filtrationThe resultant insoluble material was filtered off
  5. customtriturated twice with methanol
  6. customdried (50° C. under vacuum)

Sources & evidence

ORD record
ord-aa2e4d894ad24d0fbe444de6d9a322c5
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

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