Midazolam → Midazolam Maleate

HRID 1042554Notes

Reaction equation

HRID 1042554 reaction equation
[CH3:1][C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([Cl:23])=[CH:11][C:12]=3[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])=[N:14][CH2:15][C:5]2=[CH:4][N:3]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[Cl:23][C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2]([CH3:1])=[N:3][CH:4]=[C:5]3[CH2:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[C:12]=2[CH:11]=1

Participants

4

Reactant 2

HCID 4192Midazolam2×HCID 444266Maleic Acid2×

Product 1

HCID 5384200Midazolam MaleateYield 94.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
30 °C

Procedure

A 4-neck RBF was charged under nitrogen flow with: 10 g of Midazolam (IV) (prepared according to example 2) and 40 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. In an other flask was prepared the following solution: 3.72 g of maleic acid are dissolved in 15 mL of Ethanol. The slurry was stirred until complete dissolution at 25/30° C. The maleic acid solution is dropped in 30/40 minutes and keeping T=25/30° C. into the solution containing Midazolam. The slurry was cooled down at −15° C. in one hour and kept at that temperature for at least 2 hours. The slurry was then filtered and the cake was washed with 40 mL of cool Ethanol. The filter was discharged and the product was dried at 40° C. under vacuum for 2 hours and then at 60° C. for 8 hours. 12.8 g of Midazolam Maleate as white solid were collected (Molar yield=94.5%). m.p.=149-152° C. (by DSC).

Workup

  1. customIn an other flask was prepared the following solution
  2. stirringThe slurry was stirred until complete dissolution at 25/30° C
  3. custom30° C.
  4. temperatureThe slurry was cooled down at −15° C. in one hour
  5. waitkept at that temperature for at least 2 hours
  6. filtrationThe slurry was then filtered
  7. washthe cake was washed with 40 mL of cool Ethanol
  8. customthe product was dried at 40° C. under vacuum for 2 hours
  9. custom12.8 g of Midazolam Maleate as white solid were collected (Molar yield=94.5%)

Sources & evidence

ORD record
ord-b6cf86e5521348bba8dcd4a86f004861
Source dataset
uspto-grants-2013_10
Patent number
US08557981B2

Reaction notes

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