Hydrochloric Acid → HCID 178492170, compound

HRID 1811966Notes

Reaction equation

HRID 1811966 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][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>ClCCl.CCO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CO>[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][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 773174-PyridinemethanamineHCID 4311764Sodium borohydrideHCID 59548351HCID 59548351, compound

Product 1

HCID 178492170HCID 178492170, compoundYield 121.4%

Reagents, catalysts & solvents 4

HCID 178460666HCID 178460666, compoundCatalystHCID 702EthanolSolventHCID 887MethanolSolvent3×HCID 6344DichloromethaneSolvent2×

Procedure

6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (102.5 mg, 0.230 mmol) was suspended in dichloromethane (1.3 mL) and EtOH (1.3 mL), and 4-(aminomethyl)pyridine (0.070 mL, 0.69 mmol) and tetraisopropoxytitanium (0.20 mL, 0.68 mmol) were added. The reaction was stirred under nitrogen at room temperature. After 50 min, sodium borohydride (30.8 mg, 0.814 mmol) and MeOH (1 mL) were added, and stirring was continued at room temperature. After 1 h, more MeOH and 5 N aqueous HCl (0.60 mL) were added, and stirring was continued at room temperature over the weekend. Then, the reaction was treated with DCM and MeOH and was filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and treated with DCM and TFA and some DMSO (about 1 mL) and concentrated. The material was dissolved in water and partially concentrated resulting in the formation of a precipitate. The suspension was filtered, and the solid was washed with MeOH. The solid was set aside. The filtrate was concentrated and filtered again. The solid was combined with the solid collected from the first filtration. The filtrate was concentrated and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 minutes with a total flow of 100 mL/min). The fractions with product were combined with the solid that had been collected, concentrated, and dried under high vacuum, first at about 50° C., and then at room temperature overnight to afford N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-4-ylmethylamino)methyl)pyridin-2-amine (126.6 mg, 96.7% purity, 97% yield) as a TFA salt. 1H NMR (D2O, 400 MHz) δ 8.83-8.77 (m, 4H), 8.43 (s, 1H), 8.21 (dd, J=8.41 Hz, 2.35 Hz, 2H), 8.08-8.03 (m, 3H), 7.82 (dd, J=9.00 Hz, 2.74 Hz, 1H), 6.95 (dd, J=9.00 Hz, 1H), 4.63 (s, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 3.91 (s, 3H), 2.69 (s, 3H). m/z (ESI, pos. ion) 454 (M+H)+.

Workup

  1. stirringstirring
  2. customwas continued at room temperature
  3. waitAfter 1 h
  4. stirringstirring
  5. customwas continued at room temperature over the weekend
  6. filtrationwas filtered through a Celite® (diatomaceous earth) pad, which
  7. washwas washed with DCM and MeOH
  8. concentrationThe filtrate was concentrated
  9. additiontreated with DCM and TFA
  10. concentrationsome DMSO (about 1 mL) and concentrated
  11. dissolutionThe material was dissolved in water
  12. concentrationpartially concentrated
  13. customresulting in the formation of a precipitate
  14. filtrationThe suspension was filtered
  15. washthe solid was washed with MeOH
  16. concentrationThe filtrate was concentrated
  17. filtrationfiltered again
  18. filtrationcollected from the first filtration
  19. concentrationThe filtrate was concentrated
  20. custompurified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 minutes with a total flow of 100 mL/min)
  21. customthat had been collected
  22. concentrationconcentrated
  23. customdried under high vacuum, first at about 50° C.

Sources & evidence

ORD record
ord-64d7828a808447f3b00d0809bdcb3c7c
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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