Benzophenone imine → 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-alpha]pyridin-5-amine

HRID 723988Notes

Reaction equation

HRID 723988 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.[C:30](=[NH:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:8][N:5]4[CH:6]=[CH:7][C:2]([N:43]=[C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1

Participants

9

Reactant 5

HCID 136809Benzophenone imineHCID 516892Sodium BicarbonateHCID 634876Binap, (A+-)-HCID 102231334-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamineHCID 23676156Sodium t-butoxide

Product 1

HCID 1317261053-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-alpha]pyridin-5-amine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.1 g, 0.25 mmol) in toluene (5 mL) was added benzophenone imine (0.13 g, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.03 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.09 mmol) and sodium tert-butoxide (0.07 g, 0.75 mmol). The reaction was heated at 100° C. for 3 hours, then allowed to cool to room temperature. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The phases were separated and the organic phase was washed with brine and dried (magnesium sulfate). Filtration and concentration, followed by purification by flash chromatography (1:4 ethyl acetate-hexanes to 1:1 ethyl acetate-hexanes) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine as a solid. This solid was dissolved in tetrahydrofuran (10 mL). To this solution at 0° C. was added 4N hydrochloric acid (2 mL) dropwise. Subsequently, the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate, then saturated aquous bicarbonate was added slowly until the ethyl acetate layer turned clear. The resulting mixture was stirred for 30 minutes. The organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration, followed by flash chromatography (ethyl acetate) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine (54 mg, 57%) as a yellow foam. 1H-NMR (CDCl3): δ 8.22 (d, 1H), 7.97 (d, 1H), 7.58 (q, 2H), 7.11 (t, 2H), 6.34 (dd, 1H), 6.20 (d, 1H), 5.14 (d, 1H), 4.31 (m, 1H), 4.10 (m, 3H), 1.5–2.2 (m, 8H); 19F-NMR (CDCl3): δ −113.4; MS m/z 389 (M+1).

Workup

  1. temperatureto cool to room temperature
  2. customThe phases were separated
  3. washthe organic phase was washed with brine
  4. dry with materialdried (magnesium sulfate)
  5. filtrationFiltration and concentration
  6. customfollowed by purification by flash chromatography (1:4 ethyl acetate-hexanes to 1:1 ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-424145c3124c40aba3d906badc78f2c0
Source dataset
uspto-grants-2006_11
Patent number
US07141569B2

Reaction notes

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