The Synthesis Of Tamsulosin From L-tyrosine

(R)-5-[2-[[2-ethoxyphenoxyl]ethyl]amino]propyl]-2-methoxy-benzenesulfonami-de hydrochloride (denoted as tamsulosin), is used in treatment of benign prostatichyperplasia, a condition characterized by enlargement of prostatic tissue, whichresults in obstruction of proximal urethra. A novel process for synthesizing tamsulsionfrom a chiral molecule L-tyrosine was reported in this paper.Considering the structural similarity between commercially available L-tyrosineand tamsulosin, this molecular can be divided to compound A and compound B, inviews of the retrosyntheic analysis.Esterification of L-tyrosine with EtOH in the presence of SOCl2 followed byN-protection with Boc2O and O-methylation of the phenolic hydroxy group(CH3I/K2CO3 in DMSO)afforded ethylα-N-Boc-amino-4-methoxybenzenepropionatein 69% yield. Reduction of the ester group with NaBH4 in ethanol gave thecorresponding alcohol in 93.1% yield. Mesylation of the formed alcohol waseffectively performed in CH2Cl2/TEA to give the corresponding mesylate in 96.5%yield. Treatment of the obtained mesylate with NaI in DMSO at 60℃afforded thecorresponding iodides in 82% yield. NaBH4 reduction of the iodides in DMSOfollowed by deprotection of Boc gave theα-methylamine in 61.5% yield. The resultedα-methylamine was protected by acetyl chloride, and then was chlorosulfonated bychlorosulforic acid at -5℃-0℃followed by treatment with aqueous ammonia givingcompound A in 52.3% yield.In order to prepare compound B, O-ethoxyphenol was firstly prepared by thereaction of catechol with broethane. Afterward, O-ethoxyphenol reacted with1,2-dichloroethane using tetramethyl ammonium bromide as a phase transfer catalyst,giving compound B. The total yield was 39%.Finally, coupling reactions of compound A with compound B were preformed inacetonitrile using KI as a catalyst, affording tamsulosin in 49% yield. The overallyield was up to 8% (based on L-tyrosine).Additionally, aiternative synthesis using acetyl as L-tyrosine protecting groupwas also studied. However, the overall yield was only 2% yield. It seems that furtherinvestigation is needed in the future.