Toluene → (R)-1-(7-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea

HRID 571419Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 571419
Cl[C:2]1[C:3]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].F[B-](F)(F)F.[CH:35]1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.C[Zn]C.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1C(=O)CCC1.O1CCOCC1>[CH3:35][C:2]1[C:3]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10]

Komponenten

8

Edukt 4

HCID 1140TolueneHCID 11710396Tricyclohexylphosphonium TetrafluoroborateHCID 89535972(R)-1-(7-chloro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)ureaHCID 178477796HCID 178477796, Verbindung

Produkt 1

HCID 89526478(R)-1-(7-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)ureaAusbeute 71,4 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 167845palladium(II) acetateKatalysatorHCID 13387N-methyl-2-pyrrolidoneLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

An oven-dried, nitrogen cooled 5 ml microwave vial was charged with (R)-1-(7-chloro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 571, 78.7 mg, 0.193 mmol), palladium (II) acetate (8.5 mg, 0.038 mmol) and tricyclohexylphosphonium tetrafluoroborate (36 mg, 0.098 mmol), sealed under a nitrogen atmosphere and charged with Dioxane (1.0 ml) and NMP (0.25 ml) followed by dropwise addition of dimethylzinc in toluene (1.6 ml, 1.920 mmol). Heated to 100° C. for 17 hr. Quenched with TFA until gas evolution ceased, and then poured into saturated aqueous sodium bicarbonate. Extracted 3× with DCM and filtered aqueous layer to remove precipitate. Extracted precipitate with DCM/MeOH. Concentrated combined organic extracts in vacuo and purified via flash chromatography (0-20% MeOH/DCM) followed by mass-triggered reverse-phase HPLC. Obtained (R)-1-(7-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (26.9 mg, 0.070 mmol, 36.0% yield) as a white solid. MS ESI calc'd for C22H22N6O [M+H]+=387, found 387. 1H NMR (500 MHz, DMSO-d6) δ 936 (br s, 1H), 9.16 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.37 (m, 4H), 7.21 (m, 1H), 4.97 (m, 1H), 2.56 (s, 3H), 2.48 (s, 1H), 1.45 (d, J=7.1 Hz, 3H).

Aufarbeitung

  1. temperatureAn oven-dried, nitrogen cooled 5 ml microwave vial
  2. customsealed under a nitrogen atmosphere
  3. customQuenched with TFA until gas evolution
  4. additionpoured into saturated aqueous sodium bicarbonate
  5. extractionExtracted 3× with DCM
  6. filtrationfiltered aqueous layer
  7. customto remove precipitate
  8. extractionExtracted precipitate with DCM/MeOH
  9. concentrationConcentrated
  10. custompurified via flash chromatography (0-20% MeOH/DCM)

Quellen und Nachweise

ORD-Eintrag
ord-fe8f2fc9b58746e3843641cfeebc27c4
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09023865B2

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