Potassium Carbonate → cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile

HRID 386590Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 386590
Cl.[Cl:2][C:3]1[C:4]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH:34]2[CH2:36][CH2:35]2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:2][C:3]1[C:4]([O:19][C@H:20]2[CH2:25][CH2:24][N:23]([C:28]3[N:33]=[CH:32][C:31]([CH:34]4[CH2:36][CH2:35]4)=[CH:30][N:29]=3)[CH2:22][C@H:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1

Komponenten

5

Edukt 3

HCID 11430Potassium Carbonate2×HCID 468640872-Chloro-5-cyclopropylpyrimidineHCID 670726194-(5-chloro-4-(3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile hydrochloride

Produkt 1

HCID 67445202cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrileAusbeute 5,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A mixture of 4-(5-chloro-4-(3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile hydrochloride (159 mg, 0.399 mmol), 2-chloro-5-cyclopropylpyrimidine (67.9 mg, 0.439 mmol) and potassium carbonate (221 mg, 1.597 mmol) in DMSO (1.5 mL) was heated at 90-110° C. for 40 hrs and then additional potassium carbonate (110 mg, 0.788 mmol) was added. The resulting mixture was continuously heated at 100° C. overnight and then partitioned between EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (10.2 mg, 5%, top spot on TLC plate) as a light yellow solid and to yield trans-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (34.4 mg, 15%, bottom spot on TLC plate) as a light yellow solid. Cis-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.04 (s, 1H), 4.48-4.62 (m, 2H), 4.16 (td, J=8.80, 3.85 Hz, 1H), 3.19-3.29 (m, 1H), 2.98 (dd, J=13.75, 9.90 Hz, 1H), 2.18-2.30 (m, 1H), 2.01-2.12 (m, 1H), 1.63-1.77 (m, 2H), 1.08 (d, J=6.60 Hz, 3H), 0.89-0.95 (m, 2H), 0.57-0.62 (m, 2H). MS (ESI) 480 (M+H). Trans-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.43 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.03 (s, 1H), 4.58 (app br s, 1H), 4.29-4.42 (m, 2H), 3.28-3.40 (m, 2H), 2.01-2.17 (m, 2H), 1.77-1.89 (m, 1H), 1.68-1.77 (m, 1H), 0.99-1.12 (m, 3H), 0.85-0.97 (m, 2H), 0.51-0.63 (m, 2H). MS (ESI) 480 (M+H).

Aufarbeitung

  1. temperatureThe resulting mixture was continuously heated at 100° C. overnight
  2. custompartitioned between EtOAc and water
  3. extractionThe aqueous layer was extracted further with EtOAc (3×)
  4. washThe combined organic extracts were washed with water and brine
  5. dry with materialdried (Na2SO4)
  6. customevaporated under reduced pressure
  7. customThe residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane)

Quellen und Nachweise

ORD-Eintrag
ord-2b484c9a884f4aa8aa559f0458f20ca7
Quelldatensatz
uspto-grants-2013_02
Patentnummer
US08372837B2

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