1,4-Dioxane → (3S,6R)-1-[6-(4-Cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide

HRID 2367302ノート

反応式

HRID 2367302 の反応式
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:38])#[N:28]

参加物

8

反応物 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 58504823(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide

生成物 1

HCID 58504663(3S,6R)-1-[6-(4-Cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide収率 173.4%

試薬・触媒・溶媒 3

HCID 75806Tricyclohexylphosphine触媒HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒

反応条件

温度
100 °C

実験手順

(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (300 mg, 0.80 mmol), (4-cyano-3-fluorophenyl)boronic acid (176 mg, 1.07 mmol, 1.3 equiv), Pd2(dba)3 (56 mg, 0.061 mmol, 0.075 equiv), tricyclohexylphosphine (34.5 mg, 0.123 mmol, 0.15 equiv), and K3PO4 (296 mg, 1.39 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. A duplicate run was performed. The crude mixture of both runs were combined and filtered through celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered and conc in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (636 mg) as a foam. LC-MS (ES) m/z=459 [M+H]+.

後処理

  1. customThe mixture was bubbled with argon for 10 minutes
  2. additionThe crude mixture of both runs
  3. filtrationfiltered through celite
  4. concentrationthe filtrate was concentrated in vacuo
  5. customThe residue was partitioned between EtOAc (50 mL) and brine (15 mL)
  6. dry with materialThe organic was dried over Na2SO4
  7. filtrationfiltered and conc in vacuo
  8. customPurification by silica gel column chromatography
  9. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

出典と根拠

ORDレコード
ord-7d23c934fd2f40398399c33e9b6bd58b
出典データセット
uspto-grants-2014_04
特許番号
US08697685B2

反応ノート

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