Potassium Carbonate → (S)-1-isopropyl-4-(piperidine4-carbonyl)-2-methyl piperazine

HRID 734353Notes

Reaction equation

HRID 734353 reaction equation
Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH2:8][C@@H:7]1[CH3:20])([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+]>O>[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:13])[CH2:8][C@@H:7]1[CH3:20])([CH3:5])[CH3:4]

Participants

4

Reactant 2

HCID 11430Potassium CarbonateHCID 68817427(S)-1-isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride

Product 1

HCID 68815891(S)-1-isopropyl-4-(piperidine4-carbonyl)-2-methyl piperazine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

(S)-1-Isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride (D29) (1.5 g) in water 5 ml was treated with solid K2CO3. The resulting oil was extracted with EtOAc (25 ml), dried (MgSO4) and evaporated to give (S)-1-isopropyl-4-(piperidine4-carbonyl)-2-methyl piperazine as the free base (1 g). 5-Bromo-2-trifluoromethylpyridine (F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327-330)(0.13 g) in degassed dry dioxan (3 ml) was charged with tris(dibenzylideneacetone) dipalladium(0)(30mg) and 2-dicyclohexylphosphino-2′-(N,N-dimrethylamino)biphenyl (60 mg). The dark suspension was stirred at rt for 20 min under a blanket of argon. To this reaction a solution of (S)-1-isopropyl-4-(piperidine-4-carbonyl)-2-methyl piperazine (0.15 g) in degassed dioxan (2 ml) was added followed by sodium tert-butoxide (0.11 g). The reaction mixture was stirred at 90° C. for 2 h. After allowing the reaction to cool to rt MeOH (20 ml) was added and the crude reaction mixture was poured onto a 10 g isolute SCX column which was washed with MeOH (50 ml) and then eluted with 10% ammonia in MeOH (50 ml). The product was further purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base which was dissolved in DCM (10 ml) and treated with 1N HCl in diethyl ether to give the title compound (E79) as a solid (150 mg). LCMS electrospray (+ve) 399 (MH+). 1H NMR [DMSO-d6]δ: 1.09 (3H, d, J=6.4 Hz), 1.33-1.35 (6H, m), 1.54-1.74 (4H, m), 2.98-3.16 (5H, m), 3.23-3.68 (3H, m), 3.83-4.45 (5H, m) 7.44 (1H, dd, J=8.8 Hz), 7.63 (1H, d, J=8.8 Hz), 8.4 (1H, d, J=2.8 Hz), 10.55 (1H, bs).

Workup

  1. extractionThe resulting oil was extracted with EtOAc (25 ml)
  2. dry with materialdried (MgSO4)
  3. customevaporated

Sources & evidence

ORD record
ord-73fbdce2cf004fb08f09bdc6f9f8bf98
Source dataset
uspto-grants-2009_09
Patent number
US07592347B2

Reaction notes

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