Cesium carbonate → 4-(5-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

HRID 1923179

Reaktionsgleichung

Reaktionsgleichung von HRID 1923179
Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]1([C:31]2[NH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:30][CH2:29]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]1([C:31]2[N:32]([C:2]3[N:3]=[C:4]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:5]4[N:10]=[C:9]([CH2:11][N:12]5[CH2:13][CH:14]([CH:16]6[CH2:21][CH2:20][O:19][CH2:18][CH2:17]6)[CH2:15]5)[S:8][C:6]=4[N:7]=3)[C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:30][CH2:29]1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 10844192-cyclopropyl-1H-1,3-benzodiazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596060255-Chloro-7-morpholin-4-yl-2-[3-(tetrahydro-pyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine

Produkt 1

HCID 596059934-(5-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-2-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
145 °C

Versuchsvorschrift

A mixture of 5-chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine (90 mg, 0.22 mmol), 2-cyclopropylbenzimidazole (42 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), Xphos (21 mg, 0.04 mmol) and Cs2CO3 (143 mg, 0.44 mmol) in dioxane (2.5 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 484 as an orange solid (83 mg, 71%). LCMS (Method I): RT 2.89 min, [M+H]+ 532.2. 1H NMR (CDCl3, 400 MHz): δ 7.94-7.89 (m, 1 H); 7.69-7.65 (m, 1 H); 7.26-7.20 (m, 2 H); 4.43 (m, 4 H); 3.99 (m, 4 H); 3.87 (m, 4 H); 3.61 (m, 2 H); 3.38 (m, 2 H); 3.10 (m, 2 H); 2.89-2.82 (m, 1 H); 2.36 (m, 1 H); 1.71 (m, 1 H); 1.56 (m, 2 H); 1.37-1.31 (m, 2 H); 1.30-1.18 (m, 2 H) and 1.10-1.04 (m, 2 H)

Aufarbeitung

  1. customwas purged with argon
  2. filtrationThe reaction mixture was filtered through a pad of celite
  3. washwashing with EtOAc
  4. concentrationThe filtrate was concentrated in vacuo
  5. custompurified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%)
  6. washwas washed with MeOH/DCM
  7. washthe product eluted with 2M NH3/MeOH affording 484 as an orange solid (83 mg, 71%)
  8. customRT 2.89 min, [M+H]+ 532.2

Quellen und Nachweise

ORD-Eintrag
ord-b8513d7ca7f3475b881e275e55844cc8
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08173650B2

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