Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

Reductive Amination in the Synthesis of Pharmaceuticals.

Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.

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Prescribed drugs containing nitrogen heterocycles: an overview

1,2-Carbon atom rearrangement has been broadly applied as a guiding strategy in complex molecule assembly. As it entails the carbon–carbon or carbon–heteroatom bond migration between two vicinal atoms, this type of reaction is capable of generating structural complexity through a molecular skeletal reorganization. This review will focus on recent employment of this strategy in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors.

Recent applications of the 1,2-carbon atom migration strategy in complex natural product total synthesis

Oxycodone is one of the most widely prescribed painkillers in the USA. However, its use is complicated by high abuse potential. As sex differences have been described in drug addiction, the present study tested for sex differences in intravenous oxycodone self-administration in rats. Male and female Sprague-Dawley rats were implanted with jugular vein catheters and trained to self-administer oxycodone (0.03 mg/kg/infusion) under fixed ratio 1 (FR1), FR2, and FR5 schedules of reinforcement followed by a dose-response study to assess sensitivity to the reinforcing effects of oxycodone. In separate rats, sucrose pellet self-administration was assessed under an FR1 schedule to determine whether sex differences in oxycodone self-administration could be generalized across reinforcers. In separate rats, oxycodone distribution to plasma and brain was measured after intravenous drug delivery. In the first 3 trials under an FR1 schedule of reinforcement, male rats self-administered more oxycodone than females. In contrast, females self-administered more sucrose pellets. Under FR2 and FR5 schedules, no significant sex differences in oxycodone intake were observed, although female rats had significantly more inactive lever presses. Male and female rats showed similar inverted U-shaped dose-effect functions, with females tending to self-administer more oxycodone than males at higher doses. No significant sex differences were observed in plasma or brain oxycodone levels, suggesting that sex differences in oxycodone self-administration behavior were not due to pharmacokinetics. Our results suggest subtle sex differences in oxycodone self-administration, which may influence the abuse liability of oxycodone and have ramifications for prescription opioid addiction treatment.

Oxycodone self-administration in male and female rats

We previously developed a reliable method for multiparametric scaling of Fermi contacts to achieve fast and accurate prediction of proton–proton spin–spin coupling constants (SSCC) in 1H NMR. We now report that utilization of NBO hybridization coefficients for carbon atoms in the involved C–H bonds allows for a significant simplification of this parametric scheme, requiring only four general types of SSCCs: geminal, vicinal, 1,3-, and long-range constants. The method is optimized for inexpensive B3LYP/6-31G(d) molecular geometries. A new DU8 basis set, based on a training set of 475 experimental spin–spin coupling constants, is developed for hydrogen and common non-hydrogen atoms (Li, B, C, N, O, F, Si, P, S, Cl, Se, Br, I) to calculate Fermi contacts. On a test set of 919 SSCCs from a diverse collection of natural products and complex synthetic molecules the method gave excellent accuracy of 0.29 Hz (rmsd) with the maximum unsigned error not exceeding 1 Hz.

Yokoshima

Papers

Synthesis of (â)-Oxycodone