1,4-Cyclohexadiene → 3-(6'-Bromo-4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3'H-[1,2']bipyrazinyl-4'-yl)-N-cyclopropyl-4-methyl-benzamide

HRID 337039

反応式

HRID 337039 の反応式
Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1.C([N:37](CC)[CH:38]([CH3:40])[CH3:39])(C)C.C1CC=CCC=1.[CH:49]1([NH2:52])[CH2:51][CH2:50]1.C([Mg]Cl)(C)C>[Pd].O1CCCC1>[CH:38]1([NH:37][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:3]3=[O:20])[CH:10]=2)[CH2:40][CH2:39]1.[Br:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:52][CH:49]2[CH2:51][CH2:50]2)=[O:13])[CH:5]=1

参加物

10

反応物 6

HCID 123431,4-CyclohexadieneHCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 27600091-Methyl-3-phenylpiperazineHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoateHCID 178418918HCID 178418918、化合物

生成物 2

HCID 666862963-(6'-Bromo-4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3'H-[1,2']bipyrazinyl-4'-yl)-N-cyclopropyl-4-methyl-benzamideHCID 66686498N-cyclopropyl-4-methyl-3-(4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3'H-[1,2']bipyrazinyl-4'-yl)-benzamide

試薬・触媒・溶媒 2

HCID 23938Palladium触媒2 回HCID 8028Tetrahydrofuran溶媒3 回

反応条件

温度
100 °C

実験手順

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 115 mg), 1-methyl-3-phenyl-piperazine (77 mg), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 30 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120° C. An additional portion of palladium on carbon (50 mg) in tetrahydrofuran (1 mL) was added and the mixture was heated for 1 h at 120° C. After cooling, cyclopropylamine (0.3 mL) was added followed by dropwise addition of a solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. and quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded N-cyclopropyl-4-methyl-3-(4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-benzamide (49 mg) and 3-(6′-Bromo-4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide (8 mg).

後処理

  1. temperaturebefore being cooled to room temperature
  2. additionwas added
  3. temperatureThe mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120° C
  4. temperaturethe mixture was heated for 1 h at 120° C
  5. temperatureAfter cooling
  6. customquenched with sat. aqueous NH4Cl
  7. extractionextracted into ethyl acetate
  8. dry with materialThe organic phase was dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

出典と根拠

ORDレコード
ord-b637e51ff7e543caaf1fe677fbb90c5c
出典データセット
uspto-grants-2014_11
特許番号
US08889692B2

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