Cesium carbonate → Altiratinib

HRID 476372Notes

Reaction equation

HRID 476372 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:33]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.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].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>[CH:33]1([C:36]([NH:38][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4([C:22]([NH:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:23])[CH2:21][CH2:20]4)=[O:18])=[C:11]([F:32])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:37])[CH2:35][CH2:34]1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 80376CyclopropanecarboxamideHCID 86662871N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576299AltiratinibYield 86.2%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.25 g, 0.541 mmol) (as prepared in Example 1), cyclopropanecarboxamide (0.092 g, 1.083 mmol), xantphos (0.014 g, 0.024 mmol), and cesium carbonate (0.265 g, 0.812 mmol) were dissolved in dry dioxane (5.41 mL) and argon was bubbled through the mixture for 5 minutes. Pd2(dba)3 (7.44 mg, 0.00812 mmol) was added and additional argon was bubbled through the system. It was then fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature and then partitioned between water (40 mL) and ethyl acetate (70 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, and evaporated to yield a peach-colored solid. It was stirred in dichloromethane (10 mL) and a cream-colored solid was collected by suction filtration and washed with additional dichloromethane to yield N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.238 g, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.89 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.07 (dd, 1H), 7.63 (d, 1H), 7.56 (m, 3H), 7.16 (m, 2H), 6.74 (dd, 1H), 1.95 (quintet, 1H), 1.62 (m, 2H), 1.56 (m, 2H), 0.75 (m, 4H); MS (ESI) m/z: 511.1 (m+H+).

Workup

  1. customargon was bubbled through the mixture for 5 minutes
  2. customadditional argon was bubbled through the system
  3. customIt was then fitted with a reflux condenser
  4. temperatureThe reaction mixture was cooled to room temperature
  5. custompartitioned between water (40 mL) and ethyl acetate (70 mL)
  6. customThe layers were separated
  7. washthe organic layer was washed with brine (50 mL)
  8. dry with materialdried over magnesium sulfate
  9. customevaporated
  10. customto yield a peach-colored solid
  11. filtrationa cream-colored solid was collected by suction filtration
  12. washwashed with additional dichloromethane

Sources & evidence

ORD record
ord-94e6bec2f65b46f1b6d5ad1ca3230e5a
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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