Hydrochloric Acid → HCID 178492169, compound

HRID 1811967Notes

Reaction equation

HRID 1811967 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:37]=[N:38][CH:39]=[CH:40][CH:41]=1.[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>ClCCl.C(O)C.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[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:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1

Participants

10

Reactant 5

HCID 313Hydrochloric Acid2×HCID 6422Trifluoroacetic acidHCID 310183-PyridinemethanamineHCID 4311764Sodium borohydrideHCID 59548351HCID 59548351, compound

Product 1

HCID 178492169HCID 178492169, compoundYield 101.3%

Reagents, catalysts & solvents 4

HCID 178460666HCID 178460666, compoundCatalystHCID 702EthanolSolventHCID 887MethanolSolvent4×HCID 6344DichloromethaneSolvent2×

Procedure

6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (113.7 mg, 0.255 mmol) was suspended in dichloromethane (1.3 mL) and ethanol (1.3 mL), and 3-(aminomethyl)pyridine (0.080 mL, 0.79 mmol) and tetraisopropoxytitanium (0.23 mL, 0.78 mmol) were added. The reaction was stirred under nitrogen at room temperature. After 85 min, sodium borohydride (33.8 mg, 0.893 mmol) and MeOH (1 mL) were added, and stirring was continued at room temperature. After another 70 min, 5 N HCl (0.50 mL) was added, along with MeOH, and stirring was continued at room temperature for 3 days. More 5 N HCl (0.20 mL) and MeOH were added, and stirring was continued at room temperature overnight. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM, MeOH, TFA, and concentrated again. The material was dissolved with water and MeOH and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min). The HPLC fractions with product were collected, concentrated, and dried under high vacuum, first in a water bath at 50° C., and then at room temperature overnight to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-3-ylmethylamino)methyl)pyridin-2-amine (117.1 mg, 81% yield) as a TFA salt. 1H NMR (D2O, 400 MHz) δ 8.94 (s, 1H), 8.92-8.87 (m, 1H), 8.83 (d, J=5.87 Hz, 1H), 8.69 (d, J=8.22 Hz, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 8.26 (d, J=2.15 Hz, 1H), 8.13-8.06 (m, 1H), 7.98 (dd, J=9.19 Hz, 2.54 Hz, 1H), 7.11 (d, J=9.19 Hz, 1H), 4.61 (s, 2H), 4.44 (s, 2H), 3.99 (s, 3H), 2.73 (s, 3H). m/z (ESI, +ve ion) 454 (M+H)+.

Workup

  1. stirringstirring
  2. customwas continued at room temperature
  3. waitAfter another 70 min
  4. stirringstirring
  5. waitwas continued at room temperature for 3 days
  6. stirringstirring
  7. waitwas continued at room temperature overnight
  8. filtrationfiltered through a Celite® (diatomaceous earth) pad, which
  9. washwas washed with DCM and MeOH
  10. concentrationThe filtrate was concentrated
  11. additiontreated with DCM, MeOH, TFA
  12. concentrationconcentrated again
  13. dissolutionThe material was dissolved with water and MeOH
  14. custompurified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min)
  15. customThe HPLC fractions with product were collected
  16. concentrationconcentrated
  17. customdried under high vacuum, first in a water bath at 50° C.

Sources & evidence

ORD record
ord-e6003a9c4f6d4ddaaa8a3fd6dc565cff
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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