Hydrochloric Acid → HCID 178492164, compound

HRID 1621462Notes

Reaction equation

HRID 1621462 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][CH:36]=1.[BH4-].[Na+].Cl>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][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 6115AnilineHCID 4311764Sodium borohydrideHCID 59548351HCID 59548351, compound

Product 1

HCID 178492164HCID 178492164, compoundYield 77%

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 (122 mg, 0.274 mmol) was suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL), and aniline (0.080 mL, 0.88 mmol) and tetraisopropoxytitanium (0.25 mL, 0.84 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (70° C.-74° C.) and stirred under nitrogen for 45 minutes. Then, the reaction was cooled to room temperature and treated with sodium borohydride (39.8 mg, 1.05 mmol), along with MeOH (about 1 mL). The reaction was stirred at room temperature for 45 minutes, and then MeOH (about 1 mL) and aqueous 5N HCl (0.55 mL) were added. The reaction flask was put in a preheated oil bath (50° C.-61° C.), stirred for 3.5 hours, and then cooled to room temperature. The resulting suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM, MeOH, and a 1:1 mixture of these 2 solvents. The filtrate was concentrated, treated with water, and filtered, and the solid was washed with water, collected, and washed with DCM. The solid was then 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-((phenylamino)methyl)pyridin-2-amine (92.0 mg, 77% yield). MS (ESI pos. ion) m/z 439 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.56 (br s, 1H), 9.77 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.54 Hz, 1H), 8.29 (d, J=1.56 Hz, 1H), 8.15 (dd, J=8.90 Hz, 2.64 Hz, 1H), 7.10 (t, J=7.82 Hz, 2H), 6.85 (d, J=9.00 Hz, 1H), 6.71 (d, J=7.63 Hz, 2H), 6.60 (t, J=6.85 Hz, 1H), 4.29 (s, 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. stirringThe reaction was stirred at room temperature for 45 minutes
  4. customThe reaction flask was put in a preheated oil bath
  5. stirring(50° C.-61° C.), stirred for 3.5 hours
  6. temperaturecooled to room temperature
  7. filtrationfiltered through a Celite® (diatomaceous earth) pad, which
  8. washwas washed with DCM, MeOH
  9. additiona 1:1 mixture of these 2 solvents
  10. concentrationThe filtrate was concentrated
  11. additiontreated with water
  12. filtrationfiltered
  13. washthe solid was washed with water
  14. customcollected
  15. washwashed with DCM
  16. customThe solid was then 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-c5a3d35e389a418eb47546a6015395fd
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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