Asymmetric Synthesis of (S) - Metoprolol Dr. A. G. Nikalje

Structure of (S)- Metoprolol 6’ 1’ 2 5’ 3 1 2” 4’ 2’ 1” 3’ (S)-1-(isopropylamino)-3-(4’-(2”-methoxyethyl)phenoxy)propan-2-ol

Introduction 1. metoprolol is used widely for the treatment of angina, hypertension and open angle glaucoma. 2. They are also known to exhibit lower blood pressure, by slowing down the heart rate and increase life expectancy after the heart attack. 3. The (S)-isomers of metoprolol associated with β-blocking activity (β1-selective adrenergic receptor blocking activity), while the (R)-isomers are responsible for adverse side effects. 4. In the market metoprolol is sold under trade names as “Lopressor”.

Asymmetric Synthesis of (S)-Metoprolol 1. synthesis of (S)-Metoprolol started with commercially available phenolic ester , which was protected as its benzyl ether by treating it with benzyl bromide.

2. Then reduction on ester in presence of LiAlH4, we get corresponding alcohol. 3. This, 2-(4-(benzyloxy)phenyl)ethanol on methylation in presence of Methyl iodide, it gives methyl ether e.g 1-(benzyloxy)-4-(2 methoxyethyl)benzene.

4. Then debenzylation under hydrogenation conditions [10% Pd/C, H2 (20psi)] was achieved to obtain phenol . 5.Then this phenol is subjected to phenolytic kinetic resolution with (±)-epichlorohydrin in the presence of (R,R)-Co(III)-salen as the chiral catalyst in tert.-butyl methyl ether at 0-250C led to the isolation of (R)- chloroalcohol to afford optically active (S)-chloroalcohol in 71% yield.

6. The choroalcohol was then converted to the corresponding epoxide (KOBut ) in 90% yield. 8. The regiospecific ring opening of epoxide with isopropyl amine in the presence of water at 500C resulted in the formation of (S)-metoprolol in 99% yield.

Muthukrishnan’s approach for synthesis of (S)-metoprolol Muthukrishnan et al also have described the synthesis of (S)- Metoprolol by employing hydrolytic kinetic resolution as the key step. 1. Epoxide was subjected to Jacobsen’s HKR using (R,R)-salen-Co(OAc) as catalyst to give (S)-epoxide in 98% yield. (±)-

Muthukrishnan’s approach for synthesis of (S)-metoprolol 2. Epoxide was alkylated (MeI, KOBut) to produce iodo alcohol, which on treatment with isopropyl amine produced (S) metoprolol in 97% yield. isopropylamine, H2O, 50 °C. Scheme –(2)

Liu’s approach for synthesis of (S)- metoprolol Liu et al have described the synthesis of (S)-metoprolol by using non-enzymatic kinetic resolution (NKR) as the key step. The β-amino alcohol was subjected to kinetic resolution using a chiral reagent (derived from sugar) in the presence of p-toluenesulphonic acid to give (S) isomer of β-amino alcohol (47% yield and 99%). (±)-

Liu’s approach for synthesis of (S)-metoprolol

Liu’s approach for synthesis of (S)-metoprolol Then alkylation with isopropyl bromide in presence of K2CO3 afforded (S)-metoprolol .

References: A thesis of “Tanveer mahamadali shaikh”, “Enantioselective Synthesis of Bioactive Molecules via Asymmetric Hydroxylations, Aminoallylation and Synthetic Methodologies Involving Activation of C-H Bonds”, November 2009. Chem draw.

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