(3S)-1-(5-bromopyrimidin-2-yl)-N-[(2,4-dichlorophenyl)methyl]pyrrolidin-3-amine → (S)-(2,4-Dichlorobenzyl)-[1-(5-methylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine

HRID 252123Notes

Reaction equation

HRID 252123 reaction equation
[CH3:1][Al](C)C.Br[C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:13]2)=[N:10][CH:11]=1>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]>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:9]2[N:8]=[CH:7][C:6]([CH3:1])=[CH:11][N:10]=2)[CH2:13]1

Participants

5

Reactant 2

HCID 11503055(3S)-1-(5-bromopyrimidin-2-yl)-N-[(2,4-dichlorophenyl)methyl]pyrrolidin-3-amineHCID 16682925Trimethylaluminum2×

Product 1

HCID 59860363(S)-(2,4-Dichlorobenzyl)-[1-(5-methylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

Add trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) to (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine in dry THF (1.5 mL) and heat at 65° C. for 2 h, then add extra trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) and heat at 65° C. for 30 min and 48 h at room temperature. Add water and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and dissolve the residue in methanol (2 mL) and deposit onto an SCX-2 cartridge; eluting with methanol, then with 2 N ammonia in methanol. Concentrate the ammonia washing and chromatograph the residue by preparative mass guided chromatography to give the title compound as a residue. Treatment of the residue essentially as described in Example 1 gives the title compound as its hydrochloride. 1H NMR (300 MHz, CDCl3) δ 8.16 (2H, s), 7.37 (2H, dd, J=5.09, 3.01 Hz), 7.21 (1H, dd, J=8.29, 2.07 Hz), 3.90 (2H, d, J=4.90 Hz), 3.68-3.83 (2H, m), 3.58 (1H, m), 3.39-3.51 (2H, m), 2.14-2.25 (1H, m), 2.12 (3H, s), 1.84-1.96 (1H, m), MS (ES): m/z=337 [M+].

Workup

  1. temperatureheat at 65° C. for 30 min and 48 h at room temperature
  2. extractionAdd water and extract with chloroform
  3. washwash with saturated aqueous sodium chloride
  4. dry with materialdry (magnesium sulfate)
  5. concentrationconcentrate
  6. dissolutiondissolve the residue in methanol (2 mL)
  7. washeluting with methanol
  8. concentrationConcentrate the ammonia washing and chromatograph the residue by preparative mass

Sources & evidence

ORD record
ord-81f0f935cd304437802f8857533d7a82
Source dataset
uspto-grants-2011_01
Patent number
US07868014B2

Reaction notes

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