Ammonium Chloride → N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyridine-2-carboxamide

HRID 1911322Notes

Reaction equation

HRID 1911322 reaction equation
[NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[CH:35][C:36]([C:39](OC)=[O:40])=[N:37][CH:38]=2)[CH2:29][CH2:28]1.[NH4+].[Cl-]>C1COCC1.O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([CH2:15][O:14][C:4]2[CH:3]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][N:37]=3)=[O:40])[NH:6][N:5]=2)[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=1

Participants

7

Reactant 3

HCID 25517Ammonium ChlorideHCID 57440394Methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylateHCID 66589741Tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate

Product 1

HCID 66589730N-[5-[(3,5-Dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-5-(4-methylpiperazin-1-yl)pyridine-2-carboxamideYield 67.5%

Reagents, catalysts & solvents 3

HCID 2724254Sodium bis(trimethylsilyl)amideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

NaHMDS (1M solution in THF, 0.45 ml, 0.45 μmol, 1.5 eq) was added dropwise to a stirred suspension of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (105 mg, 0.301 mmol, 1 eq) and methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (85 mg, 0.361 mmol, 1.2 eq) in dry THF (2.5 ml) under nitrogen. The solution was stirred at room temperature for 1 h. The solution was neutralised with satd. aq. NH4Cl and diluted with water (5 ml). The aqueous phase was extracted with ethyl acetate (3×8 ml) and the combined organic extracts were dried over MgSO4, filtered and evaporated. The reaction was repeated as above on a 0.338 mmol scale. The crude extracts were combined with those above and purified on by silica column chromatography, eluting with 0-6% MeOH in DCM, to afford the title compound as a pale brown solid (92 mg, 35% yield); 1H NMR (399.902 MHz, DMSO) δ 2.25 (s, 3H), 2.45-2.50 (m, 4H), 3.37-3.43 (m, 4H), 3.75 (s, 6H), 5.08 (s, 2H), 5.88 (bs, 1H), 6.45 (t, 1H), 6.60 (d, 2H), 7.45-7.49 (m, 1H), 7.94 (d, 1H), 8.35 (d, 1H), 10.89 (bs, 1H), 11.36 (bs, 1H) MS: m/z 453 (MH+)

Workup

  1. extractionThe aqueous phase was extracted with ethyl acetate (3×8 ml)
  2. dry with materialthe combined organic extracts were dried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. custompurified on by silica column chromatography
  6. washeluting with 0-6% MeOH in DCM

Sources & evidence

ORD record
ord-9730843ebd2d40a98e3385c149d84186
Source dataset
uspto-grants-2013_12
Patent number
US08604022B2

Reaction notes

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