| dc.description.abstract | Finding a more environmentally friendly method for synthesis of enantiopure drugs is important, due to the principles of green chemistry and to avoid potential side effects from racemic drugs. The aim for this thesis was to synthesize enantiopure β-blocker S-practolol using enzyme-catalyzed kinetic resolution to separate the enantiomers of the building block N-4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide, 2.
Chlorohydrin 2 was synthesized via a two-step synthesis. In synthesis step one paracetamol reacted with epichlorohydrin and base through a SN2 reaction to form chlorohydrin 2 with N-(4-(oxiran-2-ylmethoxy)phenyl)acetamide, 1, and N,N -(((2-hydroxypropane-1,3-diyl)bis(oxy))-bis(4,1-phenylene))diacetamide, 3, as undesired by-products.
The reaction conditions were optimized regarding to different bases, different equivalents of base, different equivalents of epichlorohydrin, and different temperature to obtain an efficient reaction with high purity of chlorohydrin 2. NaOH (1.0 equiv.) and epichlorohydrin (2.0 equiv.) in room temperature resulted in the most efficient reaction, with 12 % purity of chlorohydrin 2 calculated from HPLC-analysis after eight hours reaction time.
In synthesis step two epoxide 1 was converted to chlorohydrin 2 with lithium chloride (4.0 equiv.) and acetic acid (10.0 equiv.) in 68 % yield and 99 % purity calculated from HPLC-analysis. After optimization of reagents, the use of lithium chloride and acetic acid, or acetyl chloride and water obtained the most efficient epoxide opening.
The enantiomers of chlorohydrin 2 were separated through a transesterification reaction with Candida antarctica Lipase B (CALB) as catalyst with enantiomeric ratio E =55. (R)-N- 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide, (R)- 2, remained in the reaction as the slow reacting enantiomer, and was collected in 27 % yield and 97 % ee. (S)-1-(4-Acetamidophenoxy)-3-chloropropan-2-yl butyrate, (S)- 4, was formed in 16 % yield and 86 % ee.
(S)-N- 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide, (S)-2, was obtained by hydrolysis of (S)-4 with CALB in 26 % yield and ee = 81 %. Both hydrolysis of racemic ester 4 with CALB, and transesterification reaction of racemic N-(4-(2-hydroxy-3-(isopropylamino)-\propoxy)phenyl)acetamide, 5 (practolol), with CALA or CALB, resulted in non-selective reactions.
(S)-Practolol, (S)-5, was successfully synthesized from (R)- 2 by amination with isopropylamine in water resulting in 96 % ee and 16 % yield of (S)-5.
After optimization of the synthesis of the building block chlorohydrin 2, enzymatic kinetic resolution was used to obtain, after an amination in the final synthesis step, enantiopure (S)-practolol in 96 % ee in a more environmentally friendly method, compared to the use of chemical catalysts. | en |
