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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 1430903
ノート
印刷プレビュー

反応式

HRID 1430903 の反応式
[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
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

6

反応物 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 回HCID 86708595Tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)azetidine-1-carboxylate

生成物 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-carboxylate
収率 67.4%

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)触媒

反応条件

温度
100 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-8320432d760e41fc8bcadd5b881dc5f4
出典データセット
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08940736B2

反応ノート

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