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 876003노트

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HRID 876003 반응식
[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

참가 물질

10

반응물 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

생성물 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-amine수율 67%

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 887Methanol용매HCID 3283Diethyl Ether용매HCID 312751,4-Dioxane용매

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온도
120 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-eebaf9660a2344d999081c99ae2f6040
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08980903B2

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