Cesium carbonate → 1-(4-(6-((9-Cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-pyridinyl)-1-piperazinyl)-2-methyl-2-propanol

HRID 79156Notes

Reaction equation

HRID 79156 reaction equation
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+].Cl[C:50]1[N:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][N:59]([CH2:62][C:63]([CH3:66])([OH:65])[CH3:64])[CH2:58][CH2:57]2)=[CH:52][CH:51]=1.[CH:67]1([N:72]2[C:76]3[N:77]=[C:78]([NH2:81])[N:79]=[CH:80][C:75]=3[C:74]3[CH:82]=[CH:83][N:84]=[C:85]([F:86])[C:73]2=3)[CH2:71][CH2:70][CH2:69][CH2:68]1>C(Cl)Cl.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]>[NH3:55].[CH:67]1([N:72]2[C:76]3[N:77]=[C:78]([NH:81][C:50]4[N:55]=[CH:54][C:53]([N:56]5[CH2:61][CH2:60][N:59]([CH2:62][C:63]([CH3:66])([OH:65])[CH3:64])[CH2:58][CH2:57]5)=[CH:52][CH:51]=4)[N:79]=[CH:80][C:75]=3[C:74]3[CH:82]=[CH:83][N:84]=[C:85]([F:86])[C:73]2=3)[CH2:68][CH2:69][CH2:70][CH2:71]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 582996541-(4-(6-Chloro-3-pyridinyl)-1-piperazinyl)-2-methyl-2-propanolHCID 582996889-Cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine

Product 2

HCID 222AmmoniaYield 1%HCID 583002151-(4-(6-((9-Cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-pyridinyl)-1-piperazinyl)-2-methyl-2-propanolYield 193.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
105 °C

Procedure

To tris(dibenzylideneacetone)dipalladium (0) (0.0190 g, 0.0207 mmol), Xantphos (0.0240 g, 0.0415 mmol), cesium carbonate (0.126 g, 0.387 mmol), 1-(4-(6-chloropyridin-3-yl)piperazin-1-yl)-2-methylpropan-2-ol (251) (0.0746 g, 0.276 mmol), and compound 245 (0.0750 g, 0.276 mmol) was added degassed dioxane (1.1 mL). The reaction was stirred at 105° C. overnight. After 16 h, the reaction was cooled to room temperature and partitioned between dichloromethane (30 mL) and water. The aqueous was brought to pH 12 w/5 N NaOH and extracted further with dichloromethane (15 mL) and 10% methanol in dichloromethane (10 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (1% to 5% 2M methanolic NH3 in DCM) afforded compound 250 (0.135 g, 96.8% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.13 (s, 6 H) 1.67-1.81 (m, 2 H) 1.96-2.06 (m, 2 H) 2.07-2.16 (m, 2 H) 2.27 (s, 2 H) 2.33 (d, J=8.56 Hz, 2 H) 2.65-2.74 (m, 4 H) 3.10-3.17 (m, 4 H) 4.14 (s, 1 H) 5.46 (quin, J=9.05 Hz, 1 H) 7.47 (dd, J=9.17, 2.81 Hz, 0 H) 7.97-8.07 (m, 3 H) 8.12 (d, J=9.05 Hz, 0 H) 9.33 (s, 1 H) 9.90 (s, 1 H) ppm.

Workup

  1. customdegassed dioxane (1.1 mL)
  2. waitAfter 16 h
  3. temperaturethe reaction was cooled to room temperature
  4. custompartitioned between dichloromethane (30 mL) and water
  5. extractionextracted further with dichloromethane (15 mL) and 10% methanol in dichloromethane (10 mL)
  6. dry with materialThe combined organics were dried with sodium sulfate
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b5aeb59cfbaf45c0a9700175e917eb9b
Source dataset
uspto-grants-2014_09
Patent number
US08841312B2

Reaction notes

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