Cesium carbonate → 1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one

HRID 2175394Notes

Reaction equation

HRID 2175394 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[C@@H:19]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12][CH2:11]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:35][CH:36]2[CH2:39][O:38][CH2:37]2)=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[NH3:3].[CH3:32][OH:33].[C@H:10]1([CH2:9][NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:35][CH:36]4[CH2:39][O:38][CH2:37]4)=[C:26]([N:28]4[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]4)[CH:27]=3)[N:7]=2)[C@@H:19]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 582872321-(5-amino-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneHCID 867213272-chloro-5-fluoro-N-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidin-4-amine

Product 2

HCID 21705897Ammonia methanolYield 1%HCID 867213261-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-oneYield 76%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a microwave vial, was added 2-chloro-5-fluoro-N-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methyl)pyrimidin-4-amine (prepared according to Example 1; 400 mg, 1.34 mmol, 1 equiv), 1-(5-amino-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (prepared as described in WO2011/068898, the disclosure of which is incorporated herein by reference; 493 mg, 1.87 mmol, 1.4 equiv), rac-BINAP (181 mg, 0.291 mmol, 0.217 equiv), Cs2CO3 (1.31 g, 4.02 mmol, 3 equiv), Pd(OAc)2 (26 mg, 0.116 mmol, 0.0870 equiv), and dioxane (10 mL). The microwave vial was capped and sonicated under vacuum for 5 min. The reaction mixture was heated in the microwave at 120° C. for 2 h. The cooled reaction mixture was filtered using a pad of celite and rinsed with dioxane, and the filtrate was concentrated. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 94:4 using 1% 2M NH3/MeOH increments to provide the desired product Compound 14 1-(5-(4-(((1S,9aR)-octahydro-1H-quinolizin-1-yl)methylamino)-5-fluoropyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (535 mg, 76%) as a solid.

Workup

  1. customprepared
  2. customThe microwave vial was capped
  3. customsonicated under vacuum for 5 min
  4. customThe cooled reaction mixture
  5. filtrationwas filtered
  6. washrinsed with dioxane
  7. concentrationthe filtrate was concentrated
  8. customThe crude product was purified by flash chromatography
  9. washeluted with DCM

Sources & evidence

ORD record
ord-386b895c4bc2439fa028d271ad8c07dd
Source dataset
uspto-grants-2015_06
Patent number
US09062068B2

Reaction notes

Loading…