Lithium Hydroxide → n-[(1,3-Benzodioxol-5-yl)methyl]-1-[2-(1h-imidazol-1-yl)pyrimidin-4-yl]indole-6-carboxamide

HRID 1761210

Reaction equation

HRID 1761210 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][CH:2]=1.[Li+].[OH-].CN(C(ON1N=[N:24][C:19]2C=C[CH:22]=[N:23][C:18]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:35]([CH:39]([CH3:41])C)[CH:36]([CH3:38])[CH3:37].[CH2:42]([NH2:52])[C:43]1[CH:51]=[CH:50][C:49]2[O:48][CH2:47][O:46][C:45]=2[CH:44]=1.[CH2:53]1[CH2:57][O:56][CH2:55][CH2:54]1.O>>[O:48]1[C:49]2[CH:50]=[CH:51][C:43]([CH2:42][NH:52][C:55]([C:54]3[CH:37]=[C:36]4[C:38]([CH:41]=[CH:39][N:35]4[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:23]5[CH:18]=[CH:19][N:24]=[CH:22]5)[N:1]=4)=[CH:57][CH:53]=3)=[O:56])=[CH:44][C:45]=2[O:46][CH2:47]1

Participants

7

Reactant 6

HCID 3939Lithium HydroxideHCID 9260PyrimidineHCID 75799Benzo-1,3-dioxole-5-methylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21881883Oxolane--water (1/1)

Product 1

HCID 22487625n-[(1,3-Benzodioxol-5-yl)methyl]-1-[2-(1h-imidazol-1-yl)pyrimidin-4-yl]indole-6-carboxamideYield 4%

Conditions

Temperature
60 °C

Procedure

To a solution of indole-5-carboxylic acid (0.50 g, 3.1 mmol) in MeOH (25 mL) was added trimethylsilyldiazomethane until no gas evolution was observed. The solution was concentrated, dissolved in CH2Cl2, and washed with saturated NaHCO3 and brine. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give 0.54 g of the ester (1H NMR (CDCl3) δ 3.95 (s, 3), 6.63 (s, 1), 7.25 (m, 1), 7.40 (d, 1), 7.95 (d, 1), 8.25-8.4 (br s, 1), 8.45 (s, 1)). The ester (100 mg, 0.58 mmol) was dissolved in DMF (10 mL) and 4-chloro-2-imidazol-1-ylpyrimidine (113 mg, 0.63 mmol) was added. After heating at 60° C. for 18 hours, the solvent was removed in vacuo, the residue was dissolved in CH2Cl2, and washed with saturated NaHCO3 and brine. The organic layer was dried (MgSO4), the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 68 mg (37%) of the pyrimidine (1H NMR (CDCl3) δ 3.95 (s, 3), 6.90 (s, 1), 7.25 (m, 2), 7.80 (m, 1), 7.95 (s, 1), 8.10 (d, 1), 8.4 (s, 1), 8.50 (d, 1), 8.70 (m, 2)). The pyrimidine was dissolved in THF/water (1/1) and LiOH (6 mg, 0.21 mmol) was added. After heating at 60° C. for 3 hours, the solvent was removed in vacuo and acidified with methanolic HCl. The solvent was removed in vacuo, dissolved in DMF and treated with HATU (42 mg, 0.11 mmol), DIEA (37 mg, 0.21 mmol), and piperonylamine (26 mL, 0.21 mmol). After stirring for 18 hours, the solvent was removed in vacuo, the residue was dissolved in CH2Cl2, and washed with saturated NaHCO3 and brine. The organic layer was dried (MgSO4), the solvent was removed in vacuo, and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 2 mg (4%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]indole-6-carboxamide; 1H NMR (CDCl3) δ 3.75 (s, 2), 5.95 (s, 2), 6.80-6.90 (m, 2), 7.05-7.15 (m, 2), 7.25 (m, 2), 7.75-7.85 (m, 2), 8.00 (s, 2), 8.50-8.60 (m, 2), 8.70-8.80 (m, 1); MS: (439.2 M+H)+.

Workup

  1. customthe solvent was removed in vacuo
  2. customThe solvent was removed in vacuo
  3. dissolutiondissolved in DMF
  4. customthe solvent was removed in vacuo
  5. dissolutionthe residue was dissolved in CH2Cl2
  6. washwashed with saturated NaHCO3 and brine
  7. dry with materialThe organic layer was dried (MgSO4)
  8. customthe solvent was removed in vacuo
  9. customthe residue was chromatographed (CH2Cl2/MeOH, 19/1)

Sources & evidence

ORD record
ord-18652e88a7794a38bfd03d0a9f5f81b0
Source dataset
uspto-grants-2005_01
Patent number
US06846829B2

Linked notes

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