Synthesis of enantiopure ß-blocker (S)-esmolol

Abstract

β-Blokkere er β-adrenerge antagonister som blokkerer den naturlige cellulære responsen til adrenalin i β-reseptorer. β-Blokkere er medisiner som kan bli brukt i behandling av vanlige sykdommer som hypertensjon og angina pectoris, og de fleste β-blokkere selges med en rasemisk active pharmaceutical ingredient (API) som ofte har bivirkninger. Esmolol er en β-blokker som selges med rasemisk API, men det er (S)-enantiomeren av esmolol som har de ønskede effektene. Formålet med denne oppgaven var å syntetisere (S)-esmolol ((S)-5) på en miljøvennlig og effektiv måte.

Byggesteinen til esmolol, metyl 3-(4-(3-klor-2-hydroksypropoksy)fenyl)propanoat (3), ble syntetisert i en tostegssyntese. Det første syntesesteget dannet 3-(4-(oksiran-2- ylmetoksy)fenyl)-propanoat (2) i 70% utbytte med 99% renhet (bestemt ved 1H-NMR) fra metyl 3-(4-hydroksyfenyl)propanoat (1), epiklorhydrin og base. Reaksjonen som dannet epoksid 2 dannet to biprodukter; 3,3’-(((2-hydroksypropan-1,3-diyl)bis(oksy))bis(4,1-fenylen))dipropanoat (A) og dimetyl 3,3’-(((2-(2-klor-1- hydroksyetoksy)propan-1,3-diyl)bis(oksy)bis(4,1-fenylen))dipropanoat (L). Både biprodukt A og L ble oppdaget ved LC-MS, og biprodukt A ble isolert og karakterisert ved NMR.

Det andre syntesesteget var ringåpning av epoksid 2 med litiumklorid og protonering med eddiksyre. Reaksjonen dannet klorhydrin 3 i 96% utbytte med 98% renhet.

Kinetisk oppløsning av rasemisk klorhydrin 3 ble utført med Candida antarctica Lipase B (CALB) som katalysator og vinylbutanoat som acyldonor. Enantiomert ren (R)-3 ble oppnådd i 43% utbytte med 97% renhet og 98% ee (bestemt ved HPLC). (S)-1-klor-3-(4-(3-metoksy-3- oksypropyl)fenoksy)propan-2-yl butanoat ((S)-4) ble dannet i 50% utbytte med 71% renhet og 89% ee. Det enantiomeriske forholdet (E) ble bestemt til å være 157.

(S)-esmolol ((S)-5) ble syntetisert fra (R)-3 og isopropylamin ved oppvarming. Dette ga enantiomert ren (S)-5 i 86% utbytte med 96% renhet og 89% ee.

β-blockers are β-adrenergic antagonists blocking the natural cellular response of adrenaline at β-receptors. β-Blockers are drugs which can be used in treatment of common diseases such as hypertension and angina pectoris, and most β-blockers are sold with a racemic active pharmaceutical ingredient (API) which often have side-effects. Esmolol is a β-blocker which is sold with racemic API, but it is the (S)-enantiomer of esmolol that has the desired effects. The aim of this thesis was to synthesize (S)-esmolol ((S)-5) in an environmentally friendly and efficient fashion.

The building block for esmolol (5), methyl 3-(4-(3-chloro-2-hydroxypropoxy)phenyl)propanote (3) was synthesized in a two-step synthesis. The first synthesis step formed methyl 3-(4-(oxiran-2-ylmethoxy)phenyl)propanoate (2) in 70% yield with 99% purity (determined by 1H-NMR) from methyl 3-(4-hydroxyphenyl)propanoate (1), epichlorohydrin, and base. The reaction forming epoxide 2 formed two by-products; 3,3’-(((2-hydroxypropane-1,3-diyl)bis(oxy))bis(4,1-phenylene))dipropanoate (A) and dimethyl 3,3’-(((2-(2-chloro-1-hydroxy-ethoxy)propane-1,3-diyl)-bis(oxy))bis(4,1-phenylene))dipropionate (L). Both by-product A and L was discovered by LC-MS, and by-product A were isolated and characterized by NMR.

The second synthesis step was ring-opening of epoxide 2 with lithium chloride and protonation by acetic acid. The reaction formed chlorohydrin 3 in 96% yield with 98% purity.

Kinetic resolution of racemic chlorohydrin 3 was performed with Candida antarctica Lipase B (CALB) as catalyst and vinyl butanoate as acyl donor. Enantiopure (R)-3 was obtained in 43% yield with 97% purity and 98% ee (determined by HPLC). (S)-1-chloro-3-(4-(3-methoxy-3-oxypropyl)phenoxy)propan-2-yl butanoate ((S)-4) was formed in 50% yield with 71% purity and 89% ee. The enantiomeric ratio (E) was determined to be 157.

(S)-esmolol ((S)-5) was synthesized from (R)-3 and isopropylamine upon heating. This gave enantiopure (S)-5 in 86% yield with 96% purity and 89% ee.