Methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate → Levalbuterol

HRID 1455720

Reaction equation

HRID 1455720 reaction equation
B.CSC.[CH3:5][C:6]([NH:9][CH2:10][CH:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18](OC)=[O:19])[OH:12])([CH3:8])[CH3:7].C1(C)C(C([C@@](C(O)=O)(O)[C@@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1.C1(C)C(C([C@](C(O)=O)(O)[C@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1>CO>[CH3:8][C:6]([NH:9][CH2:10][C@H:11]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH2:18][OH:19])[CH:22]=1)([CH3:5])[CH3:7]

Participants

6

Reactant 4

HCID 11086725Methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoateHCID 12423031(Dimethyl sulfide)trihydroboronHCID 129746773Ditoluoyl-l-tartaric acidHCID 129858806(+)-di-toluoyl-D-tartaric acid

Product 1

HCID 123600Levalbuterol

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Several patents report synthetic routes using enantiomeric separation, however, the synthetic routes result in low yields of the enantiomerically pure product. Optically pure levalbuterol was synthesized by the borane-methylsulfide reduction of the enantiomerically pure precursor (Formula 2) as described in U.S. Pat. No. 5,399,765. The reaction dissolved a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from (−)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol, upon cooling one stereoisomer crystallized, which was separated, and recrystallized as a diastereomer from methanol, the diastereomer was separated, treated with base, and upon reduction formed optically active levalbuterol.

Workup

  1. customseparation
  2. customhowever, the synthetic routes result
  3. customin low yields of the enantiomerically pure product
  4. dissolutionThe reaction dissolved
  5. temperatureupon cooling one stereoisomer crystallized, which
  6. customwas separated
  7. customrecrystallized as a diastereomer from methanol
  8. customthe diastereomer was separated
  9. additiontreated with base

Sources & evidence

ORD record
ord-c07eb2839d6b4c14a590a0ea09564163
Source dataset
uspto-grants-2009_01
Patent number
US07482489B2

Linked notes

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