1-(2-Aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid → 1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylic acid

HRID 1398590

Reaktionsgleichung

Reaktionsgleichung von HRID 1398590
[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]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.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:30]#[C:29][C@@:27]([OH:31])([C:24]4[N:23]=[C:22]([CH3:21])[O:26][N:25]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Komponenten

6

Edukt 2

HCID 681816001-(2-Aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acidHCID 86669593(R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Produkt 1

HCID 681818361-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylic acid

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 8082PiperidineLösungsmittel

Reaktionsbedingungen

Temperatur
35 °C

Versuchsvorschrift

To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (150 mg, 0.39 mmol) in piperidine (1.5 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (45.5 mg, 0.04 mmol), copper(I) iodide (7.4 mg, 0.04 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). The partially purified product was suspended in 2M aqueous citric acid (3 mL) and extracted with 3:1 chloroform/isopropanol (5×5 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound as a yellow-brown solid: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 2.64 (3H, s), 6.81 (1H, s), 7.27 (1H, d, J=5.9 Hz), 7.54 (1H, dd, J=8.4, 1.2 Hz), 7.80 (2H, s), 8.22 (1H, d, J=8.3 Hz), 8.42 (1H, d, J=6.0 Hz), 8.97 (1H, s), 13.92 (1H, s); LC-MS: m/z=+406.00 (M+H)+.

Aufarbeitung

  1. temperatureAfter cooling to RT
  2. concentrationthe reaction mixture was concentrated in vacuo
  3. customthe residue purified by silica gel flash column chromatography (eluent
  4. extractionextracted with 3:1 chloroform/isopropanol (5×5 mL)
  5. dry with materialThe combined extracts were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-af1f0bec2ec1439ca106d2a81ab42efc
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08901313B2

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