Figure 2 Fentanyl analogs and their potencies

Figure 2 fentanyl analogs and their potencies

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doi:10.1371/journal.pone.0108250.g001Figure 2.Fentanylanalogs and theirpotencies relative tomorphine.doi:10.1371/journal.pone.0108250.g002Optimized Synthesis of FentanylsPLOS ONE |2September 2014 |Volume 9 | Issue 9 | e108250
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quantitativeyields(Fig.3). The synthesisof the thiofentanylanalogs was accomplished in a similar fashion as shown in Fig.5.Thus,4-piperidone monohydrate hydrochloride 12 was alkylatedwith 2-(thiophen-2-yl)ethylmethanesulfonate(19)[32] in thepresenceofcesium carbonateto giveN-[2-(2-thienyl)ethyl]-4-piperidinone (20)in 90% yield. Reductive amination with anilineof 20 with sodium triacetoxyborohydride and acetic acid yieldedthe4-piperidineamineprecursor21in87% yield.Lastly,piperidineamine21 was acylated using propionylchloridetoprovide thiofentanyl(10)in 97% yield. Likewise, piperidineamine21 was treated with acetic anhydride in the presence ofHunig’sbase to provide acetylthiofentanyl(11)in 94% yield.As before,conversion of10 and 11 to their respective hydrochloride andcitric acid salts was accomplished smoothly in nearly quantitativeyields (Fig.3).Due to the low-yielding characteristics of our initial attempts, wedecided to explore optimization studies for the synthesis of fentanyl(4)and then apply these to the syntheses ofthe analogs.Severalconditionsforeach oneofthe stepscomposingthe overallsequence were considered and evaluated (Table 1).We deducedthat optimalconditions discovered for the synthesis of 4 could bedirectly translated to the syntheses offentanyls 9–11 as they allshare a common synthetic pathway.Thus,it was found that theuse ofacetonitrile instead ofdimethylformamide increased theyields of the first alkylation step from 72 to 88% (Table 1, entries 1and 2). Thiswasalso observed duringthe synthesisof thethiofentanylprecursor (20)that made use ofthe mesylate (19)asthe alkylating species where the yield markedly increased from 62to 83% (Table 1,entries 3 and 4).For the reductive amination(RA) step,the need for an equimolar amountof acetic acid wasnoted as this resulted in the efficient conversion of ketone 13 intothe piperidineamineprecursor14 in thepresenceof sodiumtriacetoxyborohydride (Table 1, entry 5) [33,34]. Carrying out thereductive amination under the same conditions but switching thehydride source to eithersodium cyanoborohydride orsodiumborohydrideresultedinsignificantloss of yield at roomtemperature (Table 1, entries 6 and 7). However, use of the latterhydride reagents under refluxing conditions (80uC) increased theiyieldssignificantly (Table 1,entries8 and 9). Lastly,for theacylation step of the sequence, the use of either propanoyl chloridFigure 3. Fentanyl analogs synthesized in this work.doi:10.1371/journal.pone.0108250.g003Figure 4. Synthesis of fentanyl and acetylthiofentanyl. Yields reflect the isolated materials by column chromatography after each step andusing the optimized conditions (cf.Table 1).Citrate and hydrochloride salts for each analog were obtained in nearly quantitative yields by treatingthe free bases at the end of these routes with the corresponding acids.
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