Trifluoromethanesulfonic acid → 2-(4-(3-Methyl-5-phenylpyrazin-2-yl)piperazin-1-yl)pyrimidine

HRID 1479212Notes

Reaction equation

HRID 1479212 reaction equation
OS(C(F)(F)F)(=O)=O.N1C=CN=CC=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[CH3:27][C:28]1[C:29](=O)[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1.FC(F)(F)S(O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:27][C:28]1[C:29]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[CH2:22][CH2:23]2)=[N:30][CH:31]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:33]=1

Participants

10

Reactant 5

HCID 62406Trifluoromethanesulfonic acidHCID 887471-(2-Pyrimidinyl)piperazine2×HCID 2758875TrifluoromethanesulfonateHCID 113674363-methyl-5-phenylpyrazin-2(1H)-oneHCID 86637578Pyrazine triflate

Product 1

HCID 598675562-(4-(3-Methyl-5-phenylpyrazin-2-yl)piperazin-1-yl)pyrimidineYield 63%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1049PyridineSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

This compound was prepared via the pyrazine triflate with 1-(2-pyrimidyl)piperazine as the amine following the procedure of Adams et al (Synlett 2004, 11, 2031-2033). Pyridine was used as an anhydrous reagent kept under argon in a sure-seal bottle (Aldrich). The compound 24 (100 mg, 0.52 nmol) and DMAP (65.7, 0.52 mmol) were dissolved in pyridine and methylene chloride (0.5:4 ml v/v), and cooled to 0° C. The trifluoromethane sulfonic acid (0.8 mmol, 135.5 μL) was added dropwise and stirred for 15 min at 0° C. and then 3 h at RT. The triflate was confirmed by ESI (363.7 (MH+)) and HPLC (tR=25.33 min). The reaction mixture was diluted with dichloromethane and washed one time each with 20 ml of water, sodium bicarbonate and brine. The dichloromethane was removed under reduced pressure, and the remaining residue was dissolved directly in DMSO. 1-(2-pyrimidyl)piperazine (5.3 mmol, 750 μL) was added and the reaction heated to 60° C. and stirred for 2 h. When complete, the reaction was diluted with ethyl acetate and washed with 1N HCl, after washes with brine and water to remove remaining pyridine. The organics were then dried and evaporated in vacuo to give 25 as a yellow solid (63% yield). HPLC (tr/purity): 24.74 min, >98%. ESI m/z (CH2Cl2) 333.29 (MH+). 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H); 8.36 (d, J=4 Hz, 2H); 8.01 (d, J=7.5 Hz, 2H); 7.48-7.40 (m, 3H); 6.54 (bs, 1H); 4.03 (bs, 4H), 3.42 (bs, 4H); 2.62 (s, 6H). HRMS calculated GIVEN Apr. 21, 2006

Workup

  1. custom3 h
  2. customat RT
  3. washwashed one time each with 20 ml of water, sodium bicarbonate and brine
  4. customThe dichloromethane was removed under reduced pressure
  5. dissolutionthe remaining residue was dissolved directly in DMSO
  6. temperaturethe reaction heated to 60° C.
  7. stirringstirred for 2 h
  8. washwashed with 1N HCl
  9. customafter washes with brine and water to remove
  10. customThe organics were then dried
  11. customevaporated in vacuo

Sources & evidence

ORD record
ord-5da15bc27b6943528ded9f2de118c959
Source dataset
uspto-grants-2016_08
Patent number
US09408845B2

Reaction notes

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