Ammonia → 4-{4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

HRID 1773901ノート

反応式

HRID 1773901 の反応式
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].N>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2].O>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH:46]=[C:47]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:17]=[C:16]4[N:10]([CH2:11][CH2:12][C:13]5[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=5[CH:15]4[O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[C:9]=3[CH3:30])=[CH:6][CH:7]=2)[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]

参加物

8

反応物 4

HCID 222AmmoniaHCID 11430Potassium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 726953822-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

生成物 1

HCID 867039774-{4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 962Water溶媒2 回HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To a solution of compound 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (100 mg, 0.214 mmoles) in 1,4-dioxane (1 mL) in a screw-capped vial under argon are added K2CO3 (89 mg, 0.642 mmole), PdCl2(dppf)2 (6 mg, 10.7 μmole), water (0.2 mL) and 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (99 mg, 0.321 mmole). The reaction mixture is heated at 100° C. overnight. Water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (98:2:0.2) to (96.5:3.5:0.35). The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1) to afford 4-{4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester melting at 171° C.

後処理

  1. extractionThe aqueous phase is extracted three times with CH2Cl2
  2. dry with materialThe organic phase is dried over magnesium sulphate
  3. filtrationfiltered
  4. customthe solvent is removed under reduced pressure
  5. customThe residue is pre-purified by silica gel chromatography
  6. customThe residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1)

出典と根拠

ORDレコード
ord-afb4d312a976452da37ed3d0fdb0dbbf
出典データセット
uspto-grants-2016_02
特許番号
US09255101B2

反応ノート

読み込み中…