Potassium Phosphate, Tribasic → N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide

HRID 68927ノート

反応式

HRID 68927 の反応式
I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:51]1[CH:52]=[N:53][CH:54]=[C:55]([CH:63]=1)[C:56]([NH:58][CH2:59][CH:60]1[CH2:62][CH2:61]1)=[O:57]>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].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[CH:60]1([CH2:59][NH:58][C:56](=[O:57])[C:55]2[CH:63]=[C:51]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=[C:5]4[CH:17]=[O:18])[CH:52]=[N:53][CH:54]=2)[CH2:62][CH2:61]1

参加物

10

反応物 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 205807365-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehydeHCID 401425785-bromo-N-(cyclopropylmethyl)nicotinamide

生成物 1

HCID 58138439N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide収率 90%

試薬・触媒・溶媒 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 178418397HCID 178418397、化合物触媒HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
80 °C

実験手順

A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) (1.068 g, 3.0 mmol), bis(pinacolato)diboron (0.914 g, 3.6 mmol), KOAc (0.883 g, 9.0 mmol) and dry DMF (20 mL) was purged with nitrogen. PdCl2(dppf)2 was added to the reaction and purged again with nitrogen. The solution was heated at 80° C. for 2 h. Once TLC showed the disappearance of (I), the solution was cooled to r.t. To this solution was added K3PO4 (0.955 g, 4.5 mmol), 5-bromo-N-(cyclopropylmethyl) nicotinamide (XVII) (0.765 g, 3.0 mmol), Pd(PPh3)4 (104 mg, 0.09 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90° C. for 3 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and then evaporated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXI) as a yellow solid (1.09 g, 2.7 mmol, 90% yield), 1H NMR (DMSO-d6) δ ppm 0.20-0.31 (m, 2H), 0.35-0.57 (m, 2H), 1.65 (m, 2H), 1.74-1.87 (m, 1H), 2.10 (d, J=12.06 Hz, 2H), 2.35-2.44 (m, 1H), 3.10-3.27 (m, 3H), 3.78-3.99 (m, 2H), 6.14 (d, J=7.35 Hz, 1H), 7.90-8.14 (m, 2H), 8.50 (d, J=12.5, 2H), 9.05 (dd, J=14.60, 1.98 Hz, 2H), 10.25 (s, 1H); ESIMS found C23H24N4O3 m/z 405 (M+H).

後処理

  1. custompurged again with nitrogen
  2. temperaturethe solution was cooled to r.t
  3. customThe solution was purged with nitrogen
  4. temperatureheated at 90° C. for 3 h
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in DCM
  7. washwashed with water and brine
  8. dry with materialdried over MgSO4
  9. customevaporated under vacuum
  10. customThe crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM)

出典と根拠

ORDレコード
ord-378f551a5859407585744aa355401644
出典データセット
uspto-grants-2014_09
特許番号
US08822478B2

反応ノート

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