Imidazole → HCID 73505654, compound

HRID 590874Notes

Reaction equation

HRID 590874 reaction equation
N1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][C:10]2[C:13]([NH:35][C:36](=[O:39])[O:37][CH3:38])=[N:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:9]=2[CH:8]=1.[C:40]([N:47]1[CH:51]=[CH:50]N=C1)(N1C=CN=C1)=[O:41].Cl.[Cl:53][C:54]1[CH:59]=[CH:58][C:57]([C@H](N)C)=[CH:56][C:55]=1[O:63][CH3:64].CCN(C(C)C)C(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:53][C:54]1[CH:59]=[CH:58][C:57]([C@H:51]([NH:47][C:40](=[O:41])[NH:6][C:7]2[N:12]=[CH:11][C:10]3[C:13]([NH:35][C:36](=[O:39])[O:37][CH3:38])=[N:14][NH:15][C:9]=3[CH:8]=2)[CH3:50])=[CH:56][C:55]=1[O:63][CH3:64]

Participants

8

Reactant 6

HCID 795ImidazoleHCID 12052TriethylsilaneHCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 118380935HCID 118380935, compoundHCID 118390792HCID 118390792, compound

Product 1

HCID 73505654HCID 73505654, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 8 mL vial charged with imidazole (18 mg, 0.26 mmol) and crude methyl (6-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (23.8 mg, 0.053 mmol) in DCM (2 ml) was added 1,1′-carbonyldiimidazole (26 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 5 h, leading to a clear yellow solution. (R)-1-(4-chloro-3-methoxyphenyl)ethanamine HCl (23.41 mg, 0.105 mmol) and DIEA (0.046 ml, 0.264 mmol) was added. The vial was capped and the contents stirred at room temperature for 16 h. The reaction mixture was concentrated and the resulting residue was re-dissolved in TFA (1 ml) and stirred at room temperature for 20 minutes. Triethylsilane (0.013 ml, 0.079 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-methyl (6-(3-(1-(4-chloro-3-methoxyphenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (4.4 mg, 8.26 μmol, 15.67% yield) and 1,1′-(1H-pyrazolo[4,3-c]pyridine-3,6-diyl)bis(3-((R)-1-(4-chloro-3-methoxyphenyl)ethyl)urea), TFA (5 mg, 7.28 μmol, 13.82% yield) as white solids. (Example 322) MS ESI calc'd. For C18H20ClN6O4 [M+H]+ 419. found 419. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.40 (s, 1H); 8.95 (s, 1H); 7.81 (br s, 1H); 7.43 (s, 1H); 7.35 (d, J=8.1 Hz, 1H); 7.09 (d, J=1.9 Hz, 1H); 6.90 (dd, J=8.2, 1.9 Hz, 1H); 4.84 (t, J=7.2 Hz, 1H); 3.83 (s, 3H); 3.68 (s, 3H); 1.39 (d, J=6.9 Hz, 3H). (Example 314) MS ESI calc'd. For C26H28Cl2N7O4 [M+H]+ 572. found 572. 1H NMR (600 MHz, DMSO-d6): 9.70 (s, 1H); 9.06 (s, 1H); 7.84 (br s, 2H); 7.34-7.36 (m, 3H); 7.09-7.10 (m, 2H); 6.89-6.91 (m, 2H); 4.89 (t, J=7.2 Hz, 1H); 4.82-4.86 (m, 1H); 3.82 (s, 6H); 1.40 (dd, J=6.9 Hz, 6H).

Workup

  1. customThe vial was capped
  2. stirringthe contents stirred at room temperature for 16 h
  3. concentrationThe reaction mixture was concentrated
  4. dissolutionthe resulting residue was re-dissolved in TFA (1 ml)
  5. stirringstirred at room temperature for 20 minutes
  6. stirringthe reaction mixture stirred for an additional 5 minutes
  7. concentrationThe mixture was concentrated
  8. dissolutionre-dissolved in DMSO (1.5 mL)
  9. customsubmitted for purification by mass-triggered preparative HPLC

Sources & evidence

ORD record
ord-e3c419be24974965998be8bb834919c3
Source dataset
uspto-grants-2016_01
Patent number
US09233979B2

Reaction notes

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