2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → HCID 178501166, compound

HRID 1482888Notes

Reaction equation

HRID 1482888 reaction equation
Cl[C:2]1[CH:3]=[N:4][C:5]([CH:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:24][CH:25]([F:49])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[C:35]([CH3:48])[CH:34]=2)[N:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.[Cl-].[Na+].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]>[F:49][CH:25]([F:24])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]2[CH:38]=[C:37]([C:2]3[CH:3]=[N:4][C:5]([CH:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[C@H:9]4[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]4)=[N:6][CH:7]=3)[CH:36]=[C:35]([CH3:48])[CH:34]=2)[N:27]=1

Participants

7

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 584561714-(difluoromethyl)-N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineHCID 178501167HCID 178501167, compound

Product 1

HCID 178501166HCID 178501166, compound

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 218864351,4-Dioxane--water (1/1)SolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of methyl trans-4-{(5-chloropyrimidin-2-yl)[(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate (48 mg, 0.13 mmol), 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (48 mg, 0.13 mmol), tris(dibenzylideneacetone)-dipalladium(0) (6.1 mg, 0.006 mmol), XPhos (6.2 mg, 0.012 mmol), and potassium phosphate tribasic trihydrate (0.11 g, 0.4 mmol) in 1,4-dioxane/water (2 mL/0.5 mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours. After cooling to 20° C., the mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl][(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate. MS ESI calc'd. for C26H30F2N5O5S[M+H]+ 562. found 562. 1H NMR: (400 MHz, CD3OD) δ 9.12 (s, 2H), 8.66 (d, J=4.8 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.26 (s, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.61 (t, J=54.4 Hz, 1H), 5.47 (d, J=7.0 Hz, 1H), 3.66 (s, 3H), 3.08 (s, 3H), 2.46 (s, 3H), 2.34 (s, 1H), 2.10-2.00 (m, 4H), 1.52-1.31 (m, 5H).

Workup

  1. temperatureAfter cooling to 20° C.
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic layers were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-6c1963c75a1342629c7a08cddbf0f586
Source dataset
uspto-grants-2016_08
Patent number
US09416111B2

Reaction notes

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