Asymmetric Synthesis of (S ) - Metoprolol

1. Asymmetric Synthesis of(S) - Metoprolol

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

3. 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 agent), while the (R)-isomers are responsible for adverse side effects. 4. In the market metoprolol is sold under trade names as “Lopressor”.

4. Asymmetric Synthesis of (S)-Metoprolol • synthesis of metoprololstarted from alcohol , which on methylation (CH3I,NaH) gave the methyl ether, in 89% yield. (Scheme 1). Then debenzylation of under hydrogenation conditions [10% Pd/C, H2 (20 psi)] was achieved to obtain phenol , which was then subjected to phenolytic kinetic resolution with (±)-epichlorohydrin (2.5 equiv.) in the presence of (R,R)-Co(III)-salenas the chiralcatalyst to afford optically active chloroalcoholin 71% yield. The choroalcoholwas then converted to the corresponding epoxide (KOBut) in 90% yield. The regiospecific ring opening of epoxide with isopropyl amine in the presence of water at 500C resulted in the formation of (S)- metoprololin 99% yield.

6. (Scheme – 1)

7. Muthukrishnan’s approach for synthesis of (S)-metoprolol Muthukrishnanet al also have described the synthesis of (S)- Metoprolol by employing hydrolytic kinetic resolution as the key step. Epoxide was subjected to Jacobsen’s HKR using (R,R)-salen-Co(OAc) as catalyst to give (S)-epoxide in 98% yield. Epoxide was alkylated (MeI, KOBut) to produce iodo alcohol, which on treatment with isopropyl amine produced (S) metoprolol in 97% yield.

8. Muthukrishnan’s approach for synthesis of (S)-metoprolol (±)-

9. isopropylamine, H2O, 50 °C. (Scheme – 2)

10. 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%). Then alkylation with isopropyl bromide in presence of K2CO3 afforded (S)-metoprolol .

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

13. (Scheme – 3)

14. References: A thesis of “Tanveermahamadalishaikh”, “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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