Dimethylacetamide → 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile

HRID 1842753노트

반응식

HRID 1842753 반응식
Cl[C:2]1[C:3]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:68]([Zn]C#N)#[N:69].CC(N(C)C)=O>CCOC(C)=O.[Zn].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.CO>[NH2:24][C:11]1[C:12]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[C:2]([C:68]#[N:69])=[CH:7][N:6]=2)[CH:10]=1

참가 물질

9

반응물 4

HCID 31374DimethylacetamideHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 73292722N'-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine2회HCID 178514179HCID 178514179, 화합물

생성물 1

HCID 866772682-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile수율 30.2%

시약·촉매·용매 4

HCID 23994Zinc촉매HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 8857Ethyl Acetate용매HCID 21226129Dichloromethane methanol용매

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온도
95 °C

실험 절차

N′-[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 268 mg, 0.58 mmol), zinc powder (3.78 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (52.9 mg, 0.06 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 55.1 mg, 0.12 mmol), and dicyanozinc (40.7 mg, 0.35 mmol) were placed in a flask under N2 and then degassed DMA (3 mL) was added. The resulting suspension was stirred for 3 h at 95° C. The mixture was then diluted with EtOAc and washed 5 times with water and then brine. The solution was then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated with diethyl ether and the resulting solid was collected by filtration and washed with diethyl ether to give crude product. This crude material was dissolved into CH2Cl2/CH3OH and concentrated in vacuo onto silica. Purification by FCC, eluting with 1.5-8% 7N methanolic ammonia in CH2Cl2 provided a solid which was washed with CH3OH (0.2 mL) to give the title compound (48 mg, 18%) as a beige crystalline solid; 1H NMR: 2.26 (3H, s), 2.53 (4H, m), 2.91 (4H, s), 3.65 (3H, s), 4.38 (2H, d), 6.74 (1H, s), 6.85 (1H, s), 6.99 (1H, s), 7.19 (1H, s), 7.48 (1H, d), 8.01 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 9.21 (1H, s), 11.97 (1H, s); m/z: ES+ MH+ 455.

후처리

  1. washwashed 5 times with water
  2. dry with materialThe solution was then dried (MgSO4)
  3. concentrationconcentrated in vacuo
  4. customThe resulting residue was triturated with diethyl ether
  5. filtrationthe resulting solid was collected by filtration
  6. washwashed with diethyl ether
  7. customto give crude product
  8. concentrationconcentrated in vacuo onto silica
  9. customPurification by FCC
  10. washeluting with 1.5-8% 7N methanolic ammonia in CH2Cl2
  11. customprovided a solid which
  12. washwas washed with CH3OH (0.2 mL)

출처 및 근거

ORD 기록
ord-2702bcbae7674cc392f23df5726a1b65
출처 데이터셋
uspto-grants-2015_02
특허 번호
US08946235B2

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