Midazolam → Midazolam Maleate

HRID 502498Notes

Reaction equation

HRID 502498 reaction equation
[CH3:1][C:2]1[N:6]2[C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[C:14]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH2:16][C:5]2=[CH:4][N:3]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>O.C1COCC1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[N:15][CH2:16][C:5]2=[CH:4][N:3]=1.[CH:25](/[C:24]([OH:31])=[O:30])=[CH:26]/[C:27]([OH:29])=[O:28]

Participants

5

Reactant 2

HCID 4192MidazolamHCID 444266Maleic Acid

Product 1

HCID 5384200Midazolam MaleateYield 85.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

2 g of the crystallized midazolam base, containing 0.039% of compound VIII and 0.464% of compound IX (according to HPLC), was dissolved in a mixture of 0.4 ml of water and 6.0 ml of THF and heated with stirring to 50° C. A solution of maleic acid in 4 ml of THF was added to the reaction mixture and the mixture was stirred for 30 minutes. After cooling to room temperature and agitating for 2 hours the thus formed solid was filtered, washed with 2×5 ml of cold THF and dried under reduced pressure at 50° C. to afford midazolam maleate in 85.6% yield having purity of 99.87%, containing 0.033% of compound VIII and 0.072% of compound IX (according to HPLC).

Workup

  1. temperatureheated
  2. stirringthe mixture was stirred for 30 minutes
  3. temperatureAfter cooling to room temperature
  4. stirringagitating for 2 hours the thus formed solid
  5. filtrationwas filtered
  6. washwashed with 2×5 ml of cold THF
  7. customdried under reduced pressure at 50° C.

Sources & evidence

ORD record
ord-7b16b64ea4f7420fab2fa4e65196db77
Source dataset
uspto-grants-2010_08
Patent number
US07776852B2

Reaction notes

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