1,4-Cyclohexadiene → 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

HRID 1697299

반응식

HRID 1697299 반응식
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)[CH:5]=[C:6](Br)[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.C1(N)CC1.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

참가 물질

9

반응물 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, 화합물

생성물 1

HCID 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

시약·촉매·용매 2

HCID 23938Palladium촉매2회HCID 8028Tetrahydrofuran용매3회

반응 조건

온도
100 °C

실험 절차

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-[1,2′]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide (8 mg).

후처리

  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)

출처 및 근거

ORD 기록
ord-ca4bc7f2f57b4133be36d96b9365f158
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08163905B2

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