Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors

Abstract

A base-induced synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl) acetonitriles by reaction of disulfides, 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride and trimethylsilyl cyanide is reported. The scope of the method is demonstrated with 30 examples. The reaction mechanism research indicates that the three-component reaction would be a SN2 reaction. The products exhibit good activities towards advanced synthesis of aqueous soluble acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitors. Our work is superior as it uses less-odor disulfides as carbon sources and EtOH as solvent in a water and dioxygen insensitive reaction system, followed by a simple purification process.

Keywords: ACAT-1 inhibitors; catalyst-free reaction; green solvent; medicinal chemistry; sulfur-containing ethyl piperazine.

Figure 1

Representative bioactive sulfur-containing ethyl piperazine compounds (a) [23], (b) [6], (c) [1], and (d) [8,20].

Scheme 1

Different strategies (a) [8,19,20,21,22], (b) [23,24,25], and (c) [26,27,28,29] to synthesize sulfur-containing ethyl piperazine compounds.

Scheme 2

Different strategies (route 1 [8]; route 2 [20,30,31,32]) to synthesize the ACAT-1 inhibitor [K-604].

Figure 2

Scope of disulfides with respect to compounds 2 ^a,b; ^a Reaction conditions: 1 (0.1 mmol), CAABC (0.2 mmol), TMSCN (0.22 mmol), Cs₂CO₃ (0.6 mmol), EtOH (1 mL), air, 100 °C, 3 h, isolated yields. ^b Reactions were conducted using 2-mercaptobenzoxazole (0.2 mmol) and 2-mercapto benzimidazole (0.2 mmol) as substrates.

Scheme 3

Control experiments: (a) Study the influence of O₂ on the yield; (b) Examine the reaction using thiophene as the thiolate source; (c) Examine the reaction in the absence of TMSCN; (d) Examine the reaction by the replacement of CAABC with CYAABC; (e) Examine the reaction by the replacement of CAABC with DABCO; (f) Examine the reaction by the replacement of CAABC with EAABB; (g) Check the standard reaction without the presence of PhSSPh.

Scheme 4

Proposed reaction mechanism.

Scheme 5

Exploration of the synthesis of ACAT-1 inhibitors 5a and 5b: (a) Our method 1 to prepare [K-604]; (b) Our method 2 to prepare [K-604].

Figure 3

Crystal structures of compounds 2b (CCDC 2328305), 2ab (CCDC 2328309), 3b (CCDC 2328313), 4b (CCDC 2328311) and 5a showing thermal ellipsoids of 50% probability surfaces. The structure of 5a was solved by fast-data collection with the crystallographic data shown in Supplementary Materials.