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3-Amino-2-phenylthietanes as potential MAO inhibitors

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Title: 3-Amino-2-phenylthietanes as potential MAO inhibitors
Author: Kang, Gun-Il
Degree Master of Science - MSc
Program Pharmaceutical Sciences
Copyright Date: 1977
Abstract: 3-Amino-2-phenylthietane derivatives were considered as a useful tool to elucidate the mechanism of inhibition of MAO by tranylcypromine-type inhibitors. The synthesis of 3-amino-2-phenylthietanes appeared worthwhile from the synthetic point of view since no successful preparation has been reported for this type of compound. It was considered that the reaction between suitable 1,3-dihalogeno alkanes with alkali sulfide would be the most effective for the synthesis of 3-amino-2-phenylthietane derivatives. Phenylserinol was prepared by reducing phenyl-serine ethylester using NaBH₄. Treatment of phenylserinol with thionyl chloride gave 1-phenyl-1-chloro-2-aminopropane-3-ol. Further chlorination of the 3-hydroxyl group was not successful. Attempts were performed to synthesize 3-amino-2-phenylthietane via 1-phenyl-1-thiocyanato-2-aminopropane-3-ol intermediate. 1-phenyl-1-thiosulfuryl-2-aminopropane-3-ol was obtained by treating 1-phenyl-1-chloro-2-aminopropane-3-ol with thiosulfate. 1-Phenyl-1-thiocyahato-2-aminopropane-3-ol was not obtained from the reaction of 1-phenyl-1-thiosulfuryl-2-aminopropane-3-ol with sodium cyanide, but 2-amino-4-hydroxylmethyl-5-phenyl-2-thiazoline was isolated. Hydrolysis of 1-phenyl-1-thiosulfuryl-2-aminopropane-3-ol gave 1-phenyl-1-mercapto-2-aminopropane-3-ol. The unsuccessful attempt to prepare 1-phenyl-1,3-dichloro-2-aminopropane appeared due to the electronic character of the primary amino group. Supporting this assumption, 1-phenyl-1,3-dichloro-2-benzoylaminopropane was synthesized from N-benzoylphenylserinol. When an ethanol solution of 1-phenyl-1,3-dichlorp-2-benzoylaminopropane was treated with sodium sulfide, 2-phenyl-4-benzylidene-2-oxazoline was isolated instead of 3-N-benzoylamino-2-phenylthietane, indicating the ease of the elimination reaction compared to ring formation. The same result was observed when 1-phenyl-1,3-dibromo-2-benzoylaminopropane synthesized from cinnamyl alcohol was used. The reduction of the amide group of 1-phenyl-1,3-dibromo-2-benzoylaminopropane using diborane was not successful. N,N-Dimethylphenylserinol was prepared for the purpose of synthesizing 3-N,N-dimethylamino-2-phenylthietane via the intermediate of 1-phenyl-1-thiocyanato-2-N,N-dimethylamino-propane-3-ol. Synthesis of 1-phenyl-1-chloro-2-N,N-dime-thylaminopropane-3-ol was not successful. 1-p-Nitrophenyl-1, 3-dichloro-2-N,N-dimethylaminopropane prepared from p-nitrophenylserinol was treated with sodium sulfide. Isolation of the product as a hydrochloride salt indicated the formation of bis (1-p-nitrophenyl-2-N,N-dimethylamino-3-chloropropane) sulfide hydrochloride. 3-Hydroxy-2-phenylthietane prepared from 3-chloro-propenyl benzene was reacted with benzylsulfonylchloride or benzylsulfonylchloride and sodium azide. All attempts using column chromatography to isolate products resulted in the identification of starting materials, revealing that the sulfonate or the azide might not be formed by the reaction probably because of the resistance of the hydroxyl group of 3-hydroxy-2-phenylthietane to the alkylation. Discussions on the determination of the synthesized compounds using ir, nmr, uv, and gc-mass spectrometry are included. Recent concepts of the active sites of MAO and mechanisms of inhibition of MAO are reviewed.
URI: http://hdl.handle.net/2429/20317
Series/Report no. UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/]

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