Cesium carbonate → 2-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide

HRID 2381534Notes

Reaction equation

HRID 2381534 reaction equation
[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](ON4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:45]1[C:53]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:54])[C:48]=2[CH:47]=[CH:46]1>CN(C)C=O>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([N:45]4[C:53]5[C:48](=[C:49]([OH:54])[CH:50]=[CH:51][CH:52]=5)[CH:47]=[CH:46]4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 754211H-indol-4-olHCID 669004582-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide

Product 1

HCID 668932372-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amideYield 13.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.50 g, 0.95 mmol) in N,N-dimethylformamide (4 mL, 0.24M) was treated with cesium carbonate (0.62 g, 1.90 mmol) and 1H-indol-4-ol (0.15 g, 1.13 mmol). The resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), and acidified with a 1N aqueous hydrochloric acid solution. Ethyl acetate (75 mL) was added, and the mixture was filtered through filter paper, rinsing with water and ethyl acetate. The layers were separated, and the aqueous layer was back extracted with ethyl acetate (75 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 1-10% methanol/methylene chloride) followed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run) afforded impure 2-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (66 mg).

Workup

  1. customThe resulting reaction mixture
  2. concentrationThe reaction mixture was then concentrated in vacuo
  3. additiondiluted with water (100 mL)
  4. additionEthyl acetate (75 mL) was added
  5. filtrationthe mixture was filtered
  6. filtrationthrough filter paper
  7. washrinsing with water and ethyl acetate
  8. customThe layers were separated
  9. extractionthe aqueous layer was back extracted with ethyl acetate (75 mL)
  10. washThe combined organics were washed with a saturated aqueous sodium chloride solution (100 mL)
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. washrinsed
  14. concentrationconcentrated in vacuo
  15. customfollowed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run)

Sources & evidence

ORD record
ord-9bc8110c0535443ab36dc06eaf7ed317
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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