Potassium Phosphate, Tribasic → (R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile

HRID 1514390ノート

反応式

HRID 1514390 の反応式
Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)=[O:15])[CH2:10][C@H:9]2[CH3:24])=[C:4]2[CH:25]=[N:26][CH:27]=[CH:28][C:3]=12.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C1(P(C2CCCCC2)C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:22][C:19]1([F:23])[CH2:20][CH2:21][CH:16]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=4)=[C:3]4[CH:28]=[CH:27][N:26]=[CH:25][C:4]=34)[C@H:9]([CH3:24])[CH2:10]2)=[O:15])[CH2:17][CH2:18]1

参加物

6

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 27343264-Cyanophenylboronic acidHCID 57474835Dicyclohexyl(2,6-dimethoxyphenyl)phosphineHCID 57657597(R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone

生成物 1

HCID 25227316(R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile

試薬・触媒・溶媒 1

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium触媒

反応条件

温度
100 °C

実験手順

A 15 ml Schlenk tube was charged with (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 (123 mg, 300 μmol), 4-cyanophenylboronic acid (66 mg, 450 μmol), tris(dibenzylideneacetone)-dipalladium (o) (5.5 mg, 6.0 μmol), dicyclohexyl(2,6-dimethoxyphenyl)phosphine (4.0 mg, 12 μmol), and potassium phosphate tribasic (127 mg, 600 μmol). The tube was evacuated and backfilled with argon 5 times and previously degassed n-butanol (1 ml) was added. The reaction was heated at 100° C. for 21 hours, then cooled and added to 30 ml aqueous K2CO3. This was extracted three times with dichloromethane (30 ml) and the combined extracts were dried (MgSO4) and evaporated to give an orange oil. The residue was chromatographed over silica with a gradient of hexane with 2.5% triethylamine and 0-100% ethyl acetate with 2.5% triethylamine to give (R)-4-(4-(4-(4,4-difluorocyclohexanecarbonyl)-2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)benzonitrile 65 as a yellow solid. LC/MS m/z=477 (M+H+).

後処理

  1. customThe tube was evacuated
  2. additionwas added
  3. temperaturecooled
  4. additionadded to 30 ml aqueous K2CO3
  5. extractionThis was extracted three times with dichloromethane (30 ml)
  6. dry with materialthe combined extracts were dried (MgSO4)
  7. customevaporated
  8. customto give an orange oil
  9. customThe residue was chromatographed over silica with a gradient of hexane with 2.5% triethylamine and 0-100% ethyl acetate with 2.5% triethylamine

出典と根拠

ORDレコード
ord-aa955ed2e82e45f3b3bdc209e099b6a3
出典データセット
uspto-grants-2012_07
特許番号
US08222251B2

反応ノート

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