1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → Tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)-imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)azetidine-1-carboxylate

HRID 1430903Notes

Reaction equation

HRID 1430903 reaction equation
[NH2:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([N:29]([CH2:39][CH3:40])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:26]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]2[N:24]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:21][C:3]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([N:29]([CH2:39][CH3:40])[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:13]1

Participants

6

Reactant 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867084732-Chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile2×HCID 86708595Tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate

Product 1

HCID 86708605Tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)-imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)azetidine-1-carboxylateYield 67.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
100 °C

Procedure

A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate (Example 357D) (154 mg, 0.500 mmol), 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10) (172 mg, 0.500 mmol), Cs2COs (326 mg, 1.00 mmol), DPPF (27.7 mg, 0.050 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (29 mg, 0.050 mmol), and Pd(OAc)2 (34 mg, 0.150 mmol) in a microwave vial was flushed with nitrogen. Dioxane (5 mL) was added and vial was sealed and heated at 100° C. for 3 hr. After cooling to RT, the reaction was partitioned between EtOAc and water and then filtered through celite. The solvent was removed and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)-imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)azetidine-1-carboxylate (207 mg, 67% yield) as a foam. It was dissolved in DCM (0.6 mL) and anisole (30 uL, 0.272 mmol) and TFA (0.4 mL) were added. After 2 hr, the solvent was removed and the residue was applied onto an SCX cartridge using a 1:1 mixture of DCM and MeOH. This was washed with MeOH and eluted with a 1:1 mixture of 1N NH3 in MeOH and DCM to give crude 2-((3-(azetidin-3-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (70 mg). A sample was purified by preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound. This was converted to the momo HCl salt.

Workup

  1. customwas flushed with nitrogen
  2. additionDioxane (5 mL) was added
  3. customvial was sealed
  4. temperatureAfter cooling to RT
  5. customthe reaction was partitioned between EtOAc and water
  6. filtrationfiltered through celite
  7. customThe solvent was removed
  8. washradial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc

Sources & evidence

ORD record
ord-8320432d760e41fc8bcadd5b881dc5f4
Source dataset
uspto-grants-2015_01
Patent number
US08940736B2

Reaction notes

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