1-Methylpiperazine → 4-[5-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

HRID 1878600Notes

Reaction equation

HRID 1878600 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.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]>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]([C:8]3[C:9]4[CH:23]=[CH:22][NH:21][C:10]=4[N:11]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=4)[N:13]=3)[CH:5]=[N:6][CH:7]=2)[CH2:27][CH2:26]1

Participants

7

Reactant 4

HCID 531671-MethylpiperazineHCID 2733832Lithium HexamethyldisilazideHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 441944484-(5-Bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Product 1

HCID 687361094-[5-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.81 mmol, 300 mg) in THF (5 ml), 1-methylpiperazine (Sigma-Aldrich, St. Louis, USA) (1.25 eq, 1.01 mmol, 0.114 ml), Pd2(dba)3 (0.04 eq, 0.032 mmol, 29.7 mg), and 2-(dicyclohexylphosphino)biphenyl (0.08 eq, 0.065 mmol, 25.5 mg) are added. After addition of LHMDS (1 M in THF, 2.2 eq, 1.8 mmol, 1.8 ml) the mixture is refluxed for 5 h, cooled down and quenched by addition of aqueous HCl solution (2M, 5 ml). The mixture is adjusted to pH 6 using aqueous NaOH solution and washed with ethyl acetate. The aqueous layer is adjusted to pH 12 and extracted with EtOAc. The organic layer is washed with brine, dried with MgSO4, filtered, and concentrated. Purification by reversed phase HPLC is giving the title compound, [M+H]+=422; 1H-NMR (400 MHz, CD3OD): δ 9.20 (s, 1H), 9.06-9.03 (m, 2H), 8.74 (d, 1H), 8.67 (t, 1H), 8.04 (d, 1H), 7.99 (d, 1H), 7.23 (d, 1H), 4.41 (m, 2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.43 (m, 2H), 3.04 (s, 3H), 3.03 (s, 3H).

Workup

  1. temperatureis refluxed for 5 h
  2. temperaturecooled down
  3. customquenched by addition of aqueous HCl solution (2M, 5 ml)
  4. washwashed with ethyl acetate
  5. extractionextracted with EtOAc
  6. washThe organic layer is washed with brine
  7. dry with materialdried with MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by reversed phase HPLC

Sources & evidence

ORD record
ord-912c0190f0cf43138cd26bfce24ed7fc
Source dataset
uspto-grants-2012_11
Patent number
US08314112B2

Reaction notes

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