f.s. moosavi et al- industrial preparation of dextromethorphan.hbr
TRANSCRIPT
First Seminar of Medicinal & Natural
Products Chemistry Shiraz, Iran. May 10-11, 2005
M11
Industrial Preparation of Dextromethorphan.HBR
F.S. Moosavi1, M. Farzaneh1, L. Bahrami1, N. Sakhaie1, H.A. Motahari1,
M.S. Abaee2, M.M. Mojtahedi2 and M.M. Heravi3
1. TEMAD (Active Pharmaceutical Ingredients) Company, Karaj Special road, Tehran Iran
2. Chemistry and Chemical Engineering Research Center of Iran, P.O.Box 14335-186 Tehran Iran
3. Chemistry Department, Al-Zahra University, Tehran Iran Dextromethorphan hydrobromide is an anti tussive morphinane compound which is prepared in a four-step synthetic pathway from (-)-octa base, a commercial name for (-)-(4-methoxybenzyl)-octahydroisoquinoline. The Temad company decided to attempt for the preparation of octa base in conjunction with the "Industrial Production of Dextromethorphan hydrobromide" project. Preparation of octa base is consisted of four steps, involving a condensation reaction followed by a cyclization process. A hexahydroisoquinoline moiety is produced which in turn is converted to a racemic mixture containing both enantiomers of octa base. Stereoselective separation of isomers is carried out by means of a chiral reagent to obtain the desired compound.
N
OMe
NH
OMe
racemic octa base
(-)-octa base
The (-)-octa base product itself is transformed into dextromethorphan hydrobromide via another four-step-pathway. The first step involves synthesis of (+)-N-formyl octa base followed by preparation of (+)-N-formylmorphinane. The product of the previous step is them reduced to dextromethorphan. The final step is the synthesis of dextromethorphan hydrobromide (DM.HBr). The product meets the international pharmacopias criteria after recrystalization.The key step of this multi-step synthesis is the reduction of the N-formylmorphinane into dextromethorphane. This step was attempted by use of various reagents and the most efficient conditions were chosen. Other steps were optimized as well in our
First Seminar of Medicinal & Natural
Products Chemistry Shiraz, Iran. May 10-11, 2005
laboratories. M eO
N CHO
N -fo rm y l m o rp h in a n e
M eO
N CH 3
D e xtro m e th o rp h a n
The production of both octa base and DM.HBr is now running at several-kilogram-pilot scales and the results will be extended to industrial productions at due time.