Hydrochloric Acid → HCID 178492167, compound

HRID 1621460Notes

Reaction equation

HRID 1621460 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[N:35]=1.[BH4-].[Na+].Cl>C(O)C.C(Cl)Cl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH2:14][NH:40][C:36]3[N:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)=[CH:5][CH:4]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 230373Aminopyridazine3×HCID 4311764Sodium borohydrideHCID 59548351HCID 59548351, compound

Product 1

HCID 178492167HCID 178492167, compoundYield 17%

Reagents, catalysts & solvents 4

HCID 178460666HCID 178460666, compoundCatalyst3×HCID 702EthanolSolventHCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent5×

Procedure

6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (106.1 mg, 0.2382 mmol) was suspended in ethanol (1.5 mL) and dichloromethane (1.5 mL) and pyridazin-3-amine (39.2 mg, 0.412 mmol) and tetraisopropoxytitanium (0.11 mL, 0.37 mmol) were added. The reaction was stirred overnight at room temperature, and then more DCM (1 mL), 3-aminopyridazine (40.4 mg, 0.425 mmol), and Ti(OiPr)4 (0.12 mL, 0.41 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (50° C.) and stirred for 5 hours. Then, the temperature was raised to 70° C., and stirring was continued overnight. More DCM was added, along with more 3-aminopyridazine (35.2 mg, 0.370 mmol) and Ti(OiPr)4 (0.10 mL, 0.34 mmol) and stirring was continued at 65° C. for 6 hours. Then, the oil bath temperature was raised to 70° C., and stirring was continued. More DCM was added 45 minutes later, and stirring was continued at 70° C. overnight. Then, the reaction was cooled to room temperature, and MeOH (1 mL) was added, followed by sodium borohydride (25.8 mg, 0.682 mmol). The reaction was stirred at room temperature for 75 minutes, and then 5N HCl (0.50 mL) was added dropwise via syringe and the flask, with a reflux condenser attached, was put in a preheated oil bath (50° C.) and the reaction was stirred for 4.5 hours. The reaction was then cooled to room temperature, diluted with DCM and MeOH, and filtered through a Celite® (diatomaceous earth) pad. The Celite® (diatomaceous earth) pad was washed with DCM, MeOH, and a 1:1 mixture of DCM and MeOH. The filtrate was concentrated and again filtered (no Celite® (diatomaceous earth) pad this time). This filtrate was concentrated and again filtered through Celite® (diatomaceous earth). The filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)methyl)pyridazin-3-amine (17.4 mg, 17% yield). MS (ESI pos. ion) m/z 441 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.65 (br s, 1H), 12.63 (br s, 1H), 9.60 (br s, 1H), 9.16 (br s, 1H), 8.61 (d, J=3.33 Hz, 1H), 8.57 (s, 1H), 8.55 (d, J=2.74 Hz, 1H), 8.38 (d, J=2.35 Hz, 1H), 8.16 (dd, J=8.90 Hz, 2.84 Hz, 1H), 7.78 (dd, J=9.39 Hz, 4.30 Hz, 1H), 7.51 (d, J=9.19 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.62 (d, J=5.09 Hz, 2H), 3.85 (s, 3H), 2.85 (s, 3H).

Workup

  1. customThe flask was fitted with a reflux condenser
  2. customplaced in a preheated oil bath
  3. stirring(50° C.) and stirred for 5 hours
  4. temperatureThen, the temperature was raised to 70° C.
  5. stirringstirring
  6. waitwas continued overnight
  7. stirringstirring
  8. waitwas continued at 65° C. for 6 hours
  9. temperatureThen, the oil bath temperature was raised to 70° C.
  10. stirringstirring
  11. stirringstirring
  12. waitwas continued at 70° C. overnight
  13. temperatureThen, the reaction was cooled to room temperature
  14. stirringThe reaction was stirred at room temperature for 75 minutes
  15. customthe flask, with a reflux condenser attached
  16. customwas put in a preheated oil bath
  17. stirring(50° C.) and the reaction was stirred for 4.5 hours
  18. temperatureThe reaction was then cooled to room temperature
  19. filtrationfiltered through a Celite® (diatomaceous earth) pad
  20. washThe Celite® (diatomaceous earth) pad was washed with DCM, MeOH
  21. additiona 1:1 mixture of DCM and MeOH
  22. concentrationThe filtrate was concentrated
  23. filtrationagain filtered (no Celite® (diatomaceous earth) pad this time)
  24. concentrationThis filtrate was concentrated
  25. filtrationagain filtered through Celite® (diatomaceous earth)
  26. customThe filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min)

Sources & evidence

ORD record
ord-fddd15a0a5644b1da5b0a7fe2791f042
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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