Hydrochloric Acid → 9-Cyclopentyl-N-(5-(3,5-dimethyl-1-piperazinyl)-2-pyridinyl)-8-fluoro-9H-pyrido-[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine

HRID 876003Notes

Reaction equation

HRID 876003 reaction equation
[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH:32]([CH3:34])[NH:31][CH:30]([CH3:35])[CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>CO.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)C.O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH:32]([CH3:34])[NH:31][CH:30]([CH3:35])[CH2:29]5)=[CH:26][N:27]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 582995991-(6-Chloropyridin-3-yl)-3,5-dimethylpiperazineHCID 582996889-Cyclopentyl-8-fluoro-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amine

Product 1

HCID 582998469-Cyclopentyl-N-(5-(3,5-dimethyl-1-piperazinyl)-2-pyridinyl)-8-fluoro-9H-pyrido-[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amineYield 67%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A 10 mL reaction vessel was charged with compound 245 (80.0 mg, 295 μmol), 1-(6-chloropyridin-3-yl)-3,5-dimethylpiperazine (66.6 mg, 295 μmol), tris(dibenzylideneacetone)dipalladium (0) (20.3 mg, 22.1 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (25.6 mg, 44.2 μmol), sodium t-butoxide (56.7 mg, 590 μmol), and dioxane (2.5 mL). The reaction was purged with argon and heated with microwave energy (300 W) for 3.5 hours at 120° C. The reaction was taken up in ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-100% ethyl acetate+2.5% TEA, then ethyl acetate+2.5% TEA, 0-8% methanol) afforded a yellow solid. This residue was taken up in 2 mL methanol (2 mL) and 1M ethanolic HCl (1 mL) was added, followed by the addition of diethyl ether (20 mL). The resulting precipitate was collected and dried in vacuo to give compound 289 as a yellow solid (91 mg, 67%) 1H NMR (500 MHz, DMSO-d6) δ 9.54-9.67 (m, 2 H) 9.47-9.54 (m, 1 H) 9.05-9.23 (m, 1 H) 8.19-8.30 (m, 1 H) 8.06-8.17 (m, 3 H) 7.94-8.04 (m, 1 H) 7.81-7.94 (m, 1 H) 5.45-5.58 (m, 1 H) 3.81-3.94 (m, 2 H) 3.34-3.48 (m, 2 H) 2.75-2.91 (m, 2 H) 2.23-2.35 (m, 2 H) 2.10-2.20 (m, 2 H) 2.05 (none, 2 H) 1.68-1.86 (m, 2 H) 1.34 (d, J=6.60 Hz, 7 H) ppm.

Workup

  1. customA 10 mL reaction vessel
  2. customThe reaction was purged with argon
  3. washwashed with water (30 mL) and brine (30 mL)
  4. dry with materialThe organic phase was dried (MgSO4)
  5. customevaporated
  6. customto give an orange oil
  7. washSilica gel chromatography (gradient elution hexanes+2.5% TEA/0-100% ethyl acetate+2.5% TEA
  8. customethyl acetate+2.5% TEA, 0-8% methanol) afforded a yellow solid
  9. customThe resulting precipitate was collected
  10. customdried in vacuo

Sources & evidence

ORD record
ord-eebaf9660a2344d999081c99ae2f6040
Source dataset
uspto-grants-2015_03
Patent number
US08980903B2

Reaction notes

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