Hydrochloric Acid → HCID 178492165, compound

HRID 1811873Notes

Reaction equation

HRID 1811873 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.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.[BH4-].[Na+].Cl>ClCCl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(O)C>[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][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 104392-Aminopyridine2×HCID 4311764Sodium borohydrideHCID 59548351HCID 59548351, compound

Product 1

HCID 178492165HCID 178492165, compoundYield 52.2%

Reagents, catalysts & solvents 4

HCID 178460666HCID 178460666, compoundCatalyst2×HCID 702EthanolSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent4×

Conditions

Temperature
70 °C

Procedure

6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (121.8 mg, 0.2734 mmol) and 2-aminopyridine (72.0 mg, 0.765 mmol) were suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL) and tetraisopropoxytitanium (0.16 mL, 0.54 mmol) was added. The flask was fit with a reflux condenser and put in a preheated oil bath (70° C.) and stirred under nitrogen. After 5 hours, the reaction was diluted with DCM, and stirring was continued overnight. Then, more 2-aminopyridine (63.6 mg, 0.676 mmol) and Ti(OiPr)4 (0.18 mL, 0.61 mmol), and DCM were added, and stirring was continued at 70° C. for about 6 hours. Then, the reaction was cooled to room temperature, and sodium borohydride (38.9 mg, 1.028 mmol) was added. The reaction was stirred at room temperature for 25 minutes, and then aqueous 5 N HCl (0.55 mL) was added. The flask was put in a preheated oil bath (50° C.) and stirring was continued overnight. Then, the reaction was cooled to room temperature, diluted with DCM and MeOH, and filtered through a Celite® (diatomaceous earth) pad, which was washed with a 1:1 mixture of DCM and MeOH. The filtrate was concentrated, treated with water, and filtered. The solid was washed with water, collected, treated with DMSO (about 1 mL), diluted with DCM, and filtered. The solid was washed with DCM, collected, and 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-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-2-ylamino)methyl)pyridin-2-amine (62.7 mg, 52% yield). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.60 (br s, 1H), 12.63 (s, 1H), 9.80 (s, 1H), 9.01 (br s, 1H), 8.56 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.15 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.98 (d, J=6.26 Hz, 1H), 7.92 (t, J=7.43 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.90 (t, J=6.46 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).

Workup

  1. customThe flask was fit with a reflux condenser
  2. customput in a preheated oil bath
  3. stirringstirring
  4. waitwas continued overnight
  5. stirringstirring
  6. waitwas continued at 70° C. for about 6 hours
  7. temperatureThen, the reaction was cooled to room temperature
  8. stirringThe reaction was stirred at room temperature for 25 minutes
  9. customThe flask was put in a preheated oil bath
  10. stirring(50° C.) and stirring
  11. waitwas continued overnight
  12. temperatureThen, the reaction was cooled to room temperature
  13. filtrationfiltered through a Celite® (diatomaceous earth) pad, which
  14. washwas washed with a 1:1 mixture of DCM and MeOH
  15. concentrationThe filtrate was concentrated
  16. additiontreated with water
  17. filtrationfiltered
  18. washThe solid was washed with water
  19. customcollected
  20. additiontreated with DMSO (about 1 mL)
  21. additiondiluted with DCM
  22. filtrationfiltered
  23. washThe solid was washed with DCM
  24. customcollected
  25. custompurified 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-81b48c4e448a42c98b3ecf238be50e65
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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