Water → HCID 67314518, compound

HRID 2179613Notes

Reaction equation

HRID 2179613 reaction equation
[ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29](OC)(=O)[CH3:30].O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:29]([CH3:30])[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2

Participants

7

Reactant 4

HCID 962WaterHCID 6584Methyl Acetate2×HCID 24758Sodium hydride2×HCID 145784130HCID 145784130, compound

Product 1

HCID 67314518HCID 67314518, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

154 mg (0.37 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissoved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added, and the mixture is stirred at room temperature for 30 min. Addition of 44.4 mg (1.11 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 90 μl (1.11 mmol) of methyl acetate in 1 ml of THF is then added to the reaction mixture, after which it is heated at 80° C. for 14 h. Addition of a further 29.6 mg (0.74 mmol) of sodium hydride (60% suspension in mineral oil) and 0.88 ml (11.1 mmol) of methyl acetate in 1 ml of THF is followed by heating at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacum results in 41.9 mg (23.6% of theory) of the title compound.

Workup

  1. addition250 mg of 4 Å molecular sieves are added
  2. temperatureby heating at 60° C. for 20 min
  3. temperaturecooling to room temperature
  4. temperatureafter which it is heated at 80° C. for 14 h
  5. temperatureby heating at 70° C. for a further 24 h
  6. customPurification
  7. concentrationThe product fractions are concentrated
  8. additionafter addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane
  9. concentrationagain concentrated
  10. customDrying under high vacum

Sources & evidence

ORD record
ord-6c53b9d6f78648409fc8a1d6887f2bd9
Source dataset
uspto-grants-2015_06
Patent number
US09067931B2

Reaction notes

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