Sodium Carbonate → (R)-3-(4-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-hydroxypropanoic acid

HRID 595287

Reaktionsgleichung

Reaktionsgleichung von HRID 595287
C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)O1.C[O:22][C:23](=[O:27])[C@@H:24]1[O:26][CH2:25]1.Br[C:29]1[CH:30]=[C:31]([NH:36][C:37]2[N:42]=[C:41]([CH:43]3[CH2:45][CH2:44]3)[CH:40]=[CH:39][N:38]=2)[CH:32]=[C:33]([CH3:35])[CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Pd]>[CH:43]1([C:41]2[CH:40]=[CH:39][N:38]=[C:37]([NH:36][C:31]3[CH:30]=[C:29]([C:15]4[CH:19]=[N:18][N:17]([CH2:25][C@@H:24]([OH:26])[C:23]([OH:22])=[O:27])[CH:16]=4)[CH:34]=[C:33]([CH3:35])[CH:32]=3)[N:42]=2)[CH2:45][CH2:44]1

Komponenten

9

Edukt 5

HCID 10340Sodium CarbonateHCID 10796Cesium carbonateHCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 9877347Methyl (2R)-2-oxiranecarboxylateHCID 118103319N-(3-bromo-5-methylphenyl)-4-cyclopropyl-2-pyrimidinamine

Produkt 1

HCID 118208521(R)-3-(4-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-hydroxypropanoic acid

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 23938PalladiumKatalysatorHCID 178418807HCID 178418807, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

Cesium carbonate (65.2 mg, 0.20 mmol) was added along with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.40 mg, 0.100 mmol) dissolved in DMF (1000 μL) and (R)-methylglycidate (10 μL, 0.11 mmol) was added to vial. The reaction was warmed to 80° C. and stirred overnight. PdCl2(dppf)-CH2Cl2 (8.17 mg, 10.00 μmol) was added directly to the reaction mixture along with N-(3-bromo-5-methylphenyl)-4-cyclopropyl-pyrimidin-2-amine (30 mg, 0.1 mmol) and sodium carbonate (2M in water, 100 μL, 0.200 mmol). The mixture was stirred at 90° C. overnight and then stirred at 100° C. for 72 hours. Si-Dimercaptotriazole (Si-DMT) (222 mg, 0.126 mmol) was added as a means of scavenging the palladium and the vial was resealed and allowed to stir for 6 hours at room temperature. The reaction mixture was filtered through an activated CELITE cartridge (HM-N) and washed with DMSO (2×1 mL). The solution was purified by reverse phase HPLC (ACN/water with ammonium hydroxide buffer) to afford (R)-3-(4-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)-1H-pyrazol-1-yl)-2-hydroxypropanoic acid as the ammonium salt. MS ESI calcd. for C20H22N5O3 [M+H]+ 380. found 380. 1H NMR (600 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.22 (d, J=5.0, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 6.91 (s, 1H), 6.75 (d, J=5.0, 1H), 4.37 (dd, J=2.7, 13.6, 1H), 3.95 (dd, J=8.7, 13.6, 1H), 3.89 (d, J=7.4, 1H), 2.24 (s, 3H), 2.03-1.94 (m, 1H), 1.09-0.98 (m, 5H).

Aufarbeitung

  1. stirringThe mixture was stirred at 90° C. overnight
  2. stirringstirred at 100° C. for 72 hours
  3. stirringto stir for 6 hours at room temperature
  4. filtrationThe reaction mixture was filtered through an activated CELITE cartridge (HM-N)
  5. washwashed with DMSO (2×1 mL)
  6. customThe solution was purified by reverse phase HPLC (ACN/water with ammonium hydroxide buffer)

Quellen und Nachweise

ORD-Eintrag
ord-320245a8ab5843ca953f73c201e8499d
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09242984B2

Verknüpfte Notizen

Wird geladen…