5/2/2023 0 Comments Photoflow download![]() ![]() Unfortunately, greater amounts of AscH 2 were not supported by the solvent due to its low solubility. ![]() (25−27) Initially, the product yield was increased by 30% after raising the amount of AscH 2 from 0.2 to 1.5 equiv (entries 1 and 2, Table 1). This seems to be an important parameter to evaluate, considering that ascorbate reacts with the thiol radical formed in the reversible and faster polarity-matched HAT between MPA and the α-amino alkyl radical intermediate, recovering the hydrogen of the thiol and shifting the equilibrium toward the amine product. We then decided to investigate analogous conditions with a high throughput batch photoreactor (5 W blue LEDs, 12 positions, Figure S3, Supporting Information), this time varying the amount of AscH 2 ( Table 1). One tendency that could be observed comparing all the screened conditions ( Table S1, Supporting Information) is that the use of higher loads of ascorbic acid (AscH 2) and more dilute conditions improve the results in batch. Additional reaction conditions were tested such as an excess of aldehyde 6, different photocatalysts, (23,24) and different solvents, but unsuccessfully ( Table S1). Then, we tested both dry and wet conditions, confirming that the absence of water is preferential to give 7 in 44% yield. Initially, the reaction provided product 7 in 21% yield after 24 h of irradiation ( Table S1, Supporting Information). (12) As our group is working with photoredox catalysis and flow chemistry, (13−15) we evaluated the application of this state-of-the-art reductive amination methodology for the synthesis of the first two intermediates of fentanyl, as proposed in Scheme 2. The reductive amination of aldehydes and ketones promoted by photoredox catalysis and polarity-matched hydrogen atom transfer (HAT) was recently described by Guo and Wenger (2018). Therefore, we planned a synthetic route that takes advantage of both photochemistry and continuous flow technologies and applied them to the synthesis of this highly in demand active pharmaceutical ingredient (API) in a fast, economical, safe, and scalable procedure ( Scheme 1d). The reported literature on the syntheses of fentanyl ( 4) shows that procedures are energy demanding, with long reaction times and multiple steps, also requiring expensive reducing agents, protecting groups, and the use of halogenated solvents (9−11) ( Scheme 1a–c). Figure 1Ĭrediting the pharmacophoric nature of the molecules to the piperidine ring, the Janssen group synthesized several lipophilic molecules maintaining the piperidine ring untouched but seeking a better penetration through the blood–brain barrier in the central nervous system.Īfter the development of phenoperidine ( 3) ( Figure 1) in 1957, and its successful introduction into the European pharmaceutical market, (8) Janssen’s group continued efforts led to the synthesis of fentanyl ( 4) in 1960 (6) ( Figure 1). The fentanyl crisis is almost overshadowing its highly positive applications as an opioid analgesic and pain reliever, specifically due to the much higher activity than that of morphine.įentanyl was first synthesized by Janssen and co-workers (6,7) to produce molecules capable of delivering better onset analgesics than the prevailing morphine ( 1) and pethidine ( 2) ( Figure 1). (1−5) Since the beginning of this century, fentanyl has also become of very high concern, especially in the United States, due to its use as a recreational drug and contaminant in other illegal drugs. It can also be offered for oral and epidural administration in a variety of formulated medicines. ![]() Fentanyl is an FDA-approved drug also indicated for chronic pain that requires continuous, around-the-clock opioid administration for an extended period that cannot be managed by other means such as nonsteroidal analgesics, opioid combination products, or immediate-release opioids. ![]() In some countries, transdermal application forms of fentanyl are also used to treat the chronic pain of many forms of cancers, as well as persistent intense pain from many noncancerous maladies. Note Made available for a limited time for personal research and study only License.įentanyl is one of the most frequently and worldwide administered opioids for intraoperative analgesia. ![]()
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