Hydrochloric Acid → (S)-1-Isopropyl-4-[1-(6-cyanopyridin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine hydrochloride

HRID 734352Notes

Reaction equation

HRID 734352 reaction equation
[ClH:1].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:21]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C(Cl)Cl.C(OCC)C>[ClH:1].[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]2[CH2:15][CH2:16][N:17]([C:26]3[CH:25]=[N:24][C:23]([C:21]#[N:22])=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:8][C@@H:7]1[CH3:20])([CH3:5])[CH3:4]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 8171545-Bromopyridine-2-carbonitrileHCID 68817427(S)-1-isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride

Product 1

HCID 68819699(S)-1-Isopropyl-4-[1-(6-cyanopyridin-3-yl)-piperidine-4-carbonyl]-2-methyl piperazine hydrochlorideYield 12.5%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

(S)-1-Isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride (D29) (0.2 g), 2-cyano-5-bromopyridine (0.14 g) and potassium carbonate (0.22 g) were stirred in DMSO (4 ml) at 120° C. for 2 h. After cooling, the potassium carbonate was filtered off and the DMSO filtrate was diluted with MeOH (20 ml). The crude mixture was poured onto a 10 g isolute SCX column which was washed first 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 (E78) as a light yellow solid (30 mg). LCMS electrospray (+ve) 356.(MH+). 1H NMR [DMSO-d6]δ: 1.09 (3H, d, J=6.4 Hz), 1.33-1.35 (6H, d, J=6.5 Hz), 1.54-1.74 (4H, m), 2.98-3.16 (5H, m), 3.23-3.68 (3H, m), 3.83-4.45 (5H, m), 7.37 (1H, dd, J=8.8 Hz), 7.72 (1H, d, J=8.8 Hz), 8.4(1H, d, J=2.8 Hz), 10.9 (1H, bs)

Workup

  1. temperatureAfter cooling
  2. filtrationthe potassium carbonate was filtered off
  3. additionthe DMSO filtrate was diluted with MeOH (20 ml)
  4. additionThe crude mixture was poured onto a 10 g isolute SCX column which
  5. washwas washed first with MeOH (50 ml)
  6. washeluted with 10% ammonia in MeOH (50 ml)
  7. customThe product was further purified by column chromatography (silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]
  8. additionFractions containing the required product
  9. customwere evaporated
  10. customto give the free base which

Sources & evidence

ORD record
ord-94cfba69c93640cb85bb5c010bdaaa5f
Source dataset
uspto-grants-2009_09
Patent number
US07592347B2

Reaction notes

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