Dichloromethane → Tert-butyl 4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

HRID 1487766

反応式

HRID 1487766 の反応式
ClCCl.Cl[C:5]1[C:6]([F:34])=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:9].C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].O>[F:34][C:6]1[CH:5]=[CH:33][CH:32]=[CH:31][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:9]

参加物

10

反応物 5

HCID 6344DichloromethaneHCID 10340Sodium Carbonate3 回HCID 61668Boronic Acid2 回HCID 66827Phenylboronic AcidHCID 59671574Tert-butyl 4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

生成物 1

HCID 66796871Tert-butyl 4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate収率 28.5%

試薬・触媒・溶媒 4

HCID 23938Palladium触媒2 回HCID 962Water溶媒HCID 1140Toluene溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
110 °C

実験手順

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (18 mg, 0.022 mmol) was added to a mixture of tert-butyl 4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (100 mg, 0.222 mmol), benzeneboronic acid (81 mg, 0.67 mmol) and sodium carbonate (71 mg, 0.67 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 110° C. overnight. Additional portions of the palladium catalyst, boronic acid and sodium carbonate were added and heating continued at 110° C. After stirring overnight, additional portions of the palladium catalyst, boronic acid and sodium carbonate were again added and heating continued at 110° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 115 mg (86%) of the title compound as the TFA salt that was −80% pure by LC-MS. LC-MS: RT=9.06 min, [M+H]+=492.9. 26.3 mg (22%) of tert-butyl 4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate were also isolated as the TFA salt. LC-MS: RT=7.53 min, [M+H]+=416.7.

後処理

  1. temperatureheating
  2. customcontinued at 110° C
  3. temperatureheating
  4. waitcontinued at 110° C. overnight
  5. temperatureUpon cooling to room temperature
  6. filtrationthe reaction mixture was filtered through Celite®
  7. concentrationconcentrated under reduced pressure
  8. custompurified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient)

出典と根拠

ORDレコード
ord-268cb510602e4737b317ab82b17bba7e
出典データセット
uspto-grants-2016_08
特許番号
US09428522B2

関連ノート

読み込み中…