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

HRID 1842753Notes

Reaction equation

HRID 1842753 reaction equation
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

Participants

9

Reactant 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-diamine2×HCID 178514179HCID 178514179, compound

Product 1

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

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
95 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-2702bcbae7674cc392f23df5726a1b65
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

Loading…