Triethylamine → 5-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone

HRID 1514453Notes

Reaction equation

HRID 1514453 reaction equation
[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[N:24][C:23]1=[O:34].C(N(CC)CC)C>CN(C)C=O>[C:28]1([C:26]2[CH:25]=[N:24][C:23](=[O:34])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:27]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 592427891-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinoneHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Product 1

HCID 247506365-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (52 mg, 0.23 mmol, prepared with a similar procedure to that reported in WO 2005080382) in N,N-dimethylformamide (DMF) (3 ml) were added at room temperature 1-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinone (Prep51, 60.1 mg, 0.23 mmol, D1) and triethylamine (0.064 ml, 0.46 mmol). The reaction mixture was heated at 100° C. for 24 hours, then passed through a SCX cartridge (10 g) (eluting with methanol followed by 2N ammonia solution in methanol). The crude obtained was then purified by column chromatography on silica gel eluting with DCM/methanol 96/4. After evaporation of the solvent the compound recovered (20 mg, 0.044 mmol) was dissolved in DCM (1 ml) and treated with HCl (1.1 eq of a 1.25 M solution in methanol, 0.048 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. Evaporation of the solvent and trituration with diethyl ether (2×3 ml) gave the hydrochloride salt of the title compound. The recovered material was passed through SCX (2 g) cartridge (eluting with methanol followed by 2N ammonia solution in methanol) to recover (6 mg, 0.013 mmol) of the title compound.

Workup

  1. washpassed through a SCX cartridge (10 g) (eluting with methanol followed by 2N ammonia solution in methanol)
  2. customThe crude obtained
  3. customwas then purified by column chromatography on silica gel eluting with DCM/methanol 96/4
  4. customAfter evaporation of the solvent the compound
  5. customrecovered (20 mg, 0.044 mmol)
  6. dissolutionwas dissolved in DCM (1 ml)
  7. additiontreated with HCl (1.1 eq of a 1.25 M solution in methanol, 0.048 mmol)
  8. customEvaporation of the solvent and trituration with diethyl ether (2×3 ml)

Sources & evidence

ORD record
ord-9d77137418fd478bade573350da961ee
Source dataset
uspto-grants-2012_07
Patent number
US08222266B2

Reaction notes

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