Sodium Bicarbonate → N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamide

HRID 1485563Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1485563
[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:29]1[CH:30]=[CH:31][C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:37]=2[N:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][C:5]([C:29]2[CH:30]=[CH:31][C:32]3[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:37]=3[N:38]=2)=[CH:4][N:3]=1

Komponenten

6

Edukt 3

HCID 516892Sodium BicarbonateHCID 866710656-chloro-4-[(tetrahydro-2H-pyran-4-yl)oxy]-Pyrido[3,2-d]pyrimidine2×HCID 86671081HCID 86671081, Verbindung2×

Produkt 1

HCID 66558299N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamideAusbeute 16 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide (Intermediate 14) (0.100 g, 0.253 mmol), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.074 g, 0.279 mmol), 1N aq. sodium bicarbonate (0.043 g, 0.507 mmol) and PdCl2(dppf)-CH2Cl2 (0.021 g, 0.025 mmol) in dioxane (1.26 ml) was subjected to microwave irradiation for 1 hour at 110° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with DCM. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamide (0.020 g, 16%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.05-2.13 (2H, m), 2.23-2.27 (2H, m), 3.70-3.76 (2H, m), 4.11-4.18 (2H, m), 5.65-5.71 (1H, m), 7.00-7.05 (1H, m), 7.10-7.15 (1H, m), 8.25-8.38 (3H, m), 8.84 (1H, s), 8.03 (1H, d, J=2.4 Hz), 9.19-9.24 (1H, m), 9.71 (1H, d, J=2.4 Hz). m/z=498.0 [M+1]+.

Aufarbeitung

  1. customirradiation for 1 hour at 110° C.
  2. filtrationThe reaction mixture was filtered through a Celite pad
  3. washwashed with DCM
  4. washThe combined organic layers were washed brine
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1)

Quellen und Nachweise

ORD-Eintrag
ord-66d36d45674a4b7d858a502adc018ed8
Quelldatensatz
uspto-grants-2016_08
Patentnummer
US09422298B2

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