Piperidine → 1-{[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

HRID 1398588

Reaktionsgleichung

Reaktionsgleichung von HRID 1398588
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[NH:25]1CCCC[CH2:26]1.O1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:39]#[C:38][C@@:36]([OH:40])([C:32]4[N:25]=[CH:26][CH:35]=[CH:34][N:33]=4)[CH3:37])[CH:15]=3)[C:10]([C:18]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Komponenten

6

Edukt 3

HCID 8082PiperidineHCID 681818701-{[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]carbonyl}azetidin-3-olHCID 866695942-(1,3-Oxazol-2-yl)but-3-yn-2-ol

Produkt 1

HCID 681818471-{[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysator

Reaktionsbedingungen

Temperatur
35 °C

Versuchsvorschrift

To a pressure tube was added 1-{[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]carbonyl}azetidin-3-ol (150 mg, 0.34 mmol) followed by piperidine (2.0 mL), Pd(PPh3)4 (39.74 mg, 0.03 mmol), copper(I) iodide (6.5 mg, 0.03 mmol) and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol (70.74 mg, 0.5 mmol). The reaction vessel was capped and stirred at 35° C. for 2.5 hr. The reaction mixture was concentrated in vacuo. DCM (5 mL×2) added and the mixture was concentration in vacuo. The crude material purified by column chromatography (elution with 1-10% MeOH in DCM) and was then triturated from a MeCN/Ether mixture (3:1) to give the title compound: 1H NMR (DMSO-d6, 500 MHz) delta 1.94 (3H, s), 3.87 (1H, dd, J=10.4, 3.9 Hz), 4.31-4.44 (2H, m), 4.51-4.64 (1H, m), 4.88 (1H, dd, J=9.9, 6.9 Hz), 5.83 (1H, d, J=6.5 Hz), 6.81 (1H, s), 7.12 (1H, d, J=5.5 Hz), 7.18 (2H, s), 7.24 (1H, s), 7.46 (1H, d, J=8.4 Hz), 8.16 (1H, s), 8.27 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=5.5 Hz), 8.96 (1H, s). LC-MS: m/z+388.05 (M+H)+.

Aufarbeitung

  1. customThe reaction vessel was capped
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. additionDCM (5 mL×2) added
  4. concentrationconcentration in vacuo
  5. customThe crude material purified by column chromatography (elution with 1-10% MeOH in DCM)
  6. customwas then triturated from a MeCN/Ether mixture (3:1)

Quellen und Nachweise

ORD-Eintrag
ord-052bd57324f647e9a29a1ed575e71bf7
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08901313B2

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