Practical Synthesis of Low-Density Lipoprotein Receptor Upregulator, N-[1-(3-Phenylpropane-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4- carboxamide

Abstract

A shorter and more practical method for the preparation of N-[1-(3-phenylpropane-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (4) as an upregulator of the LDL receptor has been developed. 1-(3-Phenylpropyl)piperidin-4-amine (7) was synthesized with 71% yield by the alkylation of 4-aminopyridine (5) with 3-phenylpropylbromide followed by reduction with NaBH 4 in the presence of base in a mixture of 2-propanol and methanol. The addition of base (1 equiv), for example, KOH and NaOMe, in the above reduction afforded a decrease of 1-(3-phenylpropyl)-N-[1-(3-phenylpropyl)piperidin-4-yl]piperidin-4-amine (8) to increase the yield of 7. The amidation of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1) with the primary amine (7) using EDCI in the presence of HOBt (0.2 equiv) provided 4 in 94% yield.

Toward Intelligent CO2 Capture Solvent Design through Experimental Solvent Development and Amine Synthesis

“…Designer amines of Subgroups (3), ( 4), ( 6) and (7) were synthesised using reductive amination followed by Boc-deprotection (Figure S2). tert-Butyl 4-oxopiperide-carboxylate (8) reacted with primary or secondary amines followed by the reduction using sodium triacetoxylborohydride (Na(OAc) 3 BH) 1 or catalytic hydrogenation 2 in the same reaction pot gave the corresponding Boc-protected precursors, (9) and (10).…”

“…These synthetic methods (Steps i and ii in Figure S2) are presented in the experimental section (Methods I to IV). To obtain the target amines (3), ( 4), ( 6) and (7) in Figure S2, the Boc protecting group of Compounds (9), (10), (12) and (13) were removed using Amberlyst 15 ion-exchange resins. Modification was made to this method in the de-Boc process of amino-acid precursors by using trimethylamine and water as eluent rather than dimethylamine and methanol to prevent unwanted reactions between the eluent and amino acids.…”

“…Modification was made to this method in the de-Boc process of amino-acid precursors by using trimethylamine and water as eluent rather than dimethylamine and methanol to prevent unwanted reactions between the eluent and amino acids. 3), ( 4), ( 6) and (7)…”

Efficient Electrochemical N-Alkylation of N-Boc-Protected 4-Aminopyridines: Towards New Biologically Active Compounds

“…The two different nitrogen atoms compete in the alkylation reaction and usually the more nucleophilic pyridine nitrogen atom reacts faster, leading to the corresponding pyridinium salt (Scheme 1) [14, 15]. …”

“…The most straightforward method, however, is the direct alkylation of 4AP with alkyl halides, although it suffers from some drawbacks. The two different nitrogen atoms compete in the alkylation reaction and usually the more nucleophilic pyridine nitrogen atom reacts faster, leading to the corresponding pyridinium salt ( Scheme 1 ) [ 14 , 15 ].…”