Hydrochloric Acid → HCID 178492158, compound

HRID 1621558Notes

Reaction equation

HRID 1621558 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16](O)[CH3:17])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3C2CCCCO2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49].[OH-].[Na+].Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:19]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)=[CH:12][C:13]([CH:16]([N:54]3[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]3)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 31297Methanesulfonyl chlorideHCID 7091611-(Methylsulfonyl)piperazineHCID 66600184HCID 66600184, compound

Product 1

HCID 178492158HCID 178492158, compoundYield 30.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Separately, 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (231 mg, 0.501 mmol) was dissolved in DCM (10 mL) and triethylamine (Aldrich 99.5%, 0.28 ml, 2.0 mmol) was added. The reaction was cooled in an ice water bath, and methanesulfonyl chloride (0.15 mL, 1.9 mmol) was added. The reaction was stirred at 0° C. for 15 min, and then 1-methanesulfonylpiperazine (474.4 mg, 2.89 mmol) was added, causing precipitation. The reaction was warmed to room temperature and stirring was continued. After 2 h, the reaction was diluted with MeOH (10 mL) and 5N HCl (2.0 mL) was added. Stirring was continued at room temperature. After another hour, this reaction was combined with the other reaction, treated with 5N NaOH and 5N HCl to adjust the pH to around 6, and allowed to stand at room temperature over the weekend. The resultant suspension was filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was washed with water. The filtrate was discarded. The solid was collected and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min.) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (81.0 mg, 24% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.61 (br s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.54 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.16 (dd, J=9.0 Hz, 2.74 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 4.69 (br, s, 1H), 3.85 (s, 3H), 3.45-3.00 (m, 6H), 2.98 (s, 3H), 2.86 (s, 3H), 1.76 (d, J=7.04 Hz, 3H). m/z (ESI, pos. ion) 524 (M+H)+.

Workup

  1. temperatureThe reaction was cooled in an ice water bath
  2. customprecipitation
  3. temperatureThe reaction was warmed to room temperature
  4. stirringstirring
  5. waitAfter 2 h
  6. additionthe reaction was diluted with MeOH (10 mL) and 5N HCl (2.0 mL)
  7. additionwas added
  8. stirringStirring
  9. customwas continued at room temperature
  10. waitAfter another hour
  11. customthis reaction was combined with the other reaction
  12. customto stand at room temperature over the weekend
  13. filtrationThe resultant suspension was filtered
  14. washthe solid was washed with DCM and MeOH
  15. concentrationThe filtrate was concentrated
  16. additiontreated with water
  17. filtrationfiltered
  18. washThe solid was washed with water
  19. customThe solid was collected
  20. custompurified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min

Sources & evidence

ORD record
ord-29255bf21caf4c7fae4ed61ee0d5f971
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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