Synthesis of Deuterio-l-amphetamine, d1 Sulfate

Foreman, Ronald; Siegel, Frederick P.; Mrtek, Robert G.

doi:10.1002/jps.2600580209

Cited by 26 publications

(12 citation statements)

References 15 publications

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“…Synthesis of Levobupivacaine According to Ramachandran126 (5 equiv) in acetic acid as a reducing agent in the reaction of ammonium acetate with 2.26.a to reach a 41% yield of evekeo 134. Foreman et al utilized 1.1. equiv LiAlD 4 to obtain deuterium-labeled racemic evekeo from oxime 2.26.b in 46% yield (4.6 g, 32% RME) 135. The recrystallization of evekeo bitartrate completed the process of obtaining pure enantiomers.…”

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confidence: 99%

Reductive Amination in the Synthesis of Pharmaceuticals

et al. 2019

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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.

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confidence: 99%

Reductive Amination in the Synthesis of Pharmaceuticals

et al. 2019

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“…The secondary amine, racemic 4, was prepared by carbamoylation of 3 to give the methyl carbamate 7 followed by reduction (Scheme 1). Attempted resolution of 2 0 ,6 0 -dichloroamphetamine (3) using (1)-tartaric acid, based on reported methodology for amphetamine (1), 12 was not successful. Use of camphoric acid or dibenzoyltartaric acid also failed to resolve 3.…”

Section: In Order To Provide (S)-amphetamine [(S)-1] and Methamphetammentioning

confidence: 99%

High specific activity (+)‐amphetamine and (+)‐methamphetamine

Lamb

McElhinny

Sninski

et al. 2009

Labelled Comp Radiopharmac

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High specific activity (1)-amphetamine and (1)-methamphetamine were prepared by reductive dechlorination of (S)-(3 0 ,5 0 -dichlorophenyl)-2-propylazide and (S)-2 0 6 0 -dichloromethamphetamine, respectively. While the latter was readily obtained by resolution of racemic 2 0 6 0 -dichloromethamphetamine using (1)-dibenzoyltartaric acid, the analogous amphetamine resisted all efforts to resolve it. Hence, the required chiral precursor was prepared by stereospecific total synthesis following methodology that had been previously developed in our Laboratories. The tritium labeled compounds had specific activity 30.1 Ci/mmol and 38.3 Ci/mmol, respectively.

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“…Since the C–D bond is stronger than the C–H bond, the metabolic stability of amines is improved by the selective α-deuteration of the amine moiety. For example, d –amphetamine (Figure A) is significantly more stable in vitro compared to its unlabeled parent drug, while the half-life of d -bupropion, an important antidepressant (Figure A), was extended more than 30-fold compared with that of bupropion . Amine drugs with hydrogen-containing chiral centers suffer from rapid stereoisomerization (Figure B). , In this respect, deuterium incorporation is a very effective way to improve the stability of chemically unstable chiral drugs, which is known as “deuterium-enabled chiral switching” …”

Section: Introductionmentioning

confidence: 99%

“…Despite the widespread use of amines and the enormous potential of α-deuterated primary amine drugs and pesticides for academic and industrial use, their development is at present restricted by the limited synthetic methods to access this key building block. In general, there are two synthetic strategies for the synthesis of α-deuterated primary amines, namely, direct hydrogen isotope exchange (Scheme A) and reductive deuteration (Scheme B). , The traditional pH-dependent H/D exchange strategy suffers from a limited scope, harsh reaction conditions, and low deuterium incorporations. , Recent advances in the field of C(sp 3 )–H activation have led to the emergence of Ru-catalyzed H/D exchange methods via reversible dehydrogenation/hydrogenation pathways, which has enabled the synthesis of an increasing number of α-deuterated amines. − However, reactions facilitated by the Ru-dehydrogenation catalysis often result in the formation of side products and generally suffer from dehydrogenative conditions. Moreover, unsatisfactory regioselectivities and low levels of deuterium incorporation remain as major limitations for most H/D exchange methods .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D₂O as a Deuterium Source

Lei

Lai

et al. 2021

J. Org. Chem.

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Selective introduction of the deuterium atom into the α-position of amines is important for the development of all types of novel deuterated drugs and agrochemicals due to the pervasive presence of amines. In this study, we report the first general single-electron-transfer reductive deuteration of both ketoximes and aldoximes using SmI2 as an electron donor and D2O as a deuterium source for the synthesis of α-deuterated primary amines with excellent levels of deuterium incorporations (>95% [D]). This protocol exhibits excellent chemoselectivity and tolerates a variety of functional groups. The potential application of this new method was showcased in the synthesis of deuterated drugs, such as rimantadine-d 4, the tebufenpyrad analogue, derivatives of nabumetone and pregnenolone, and a series of building blocks for the rapid and general assembly of deuterated drugs and pesticides.

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Synthesis of Deuterio-l-amphetamine, d1 Sulfate

Cited by 26 publications

References 15 publications

Reductive Amination in the Synthesis of Pharmaceuticals

Reductive Amination in the Synthesis of Pharmaceuticals

High specific activity (+)‐amphetamine and (+)‐methamphetamine

Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D₂O as a Deuterium Source

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Synthesis of Deuterio-l-amphetamine, d1 Sulfate

Cited by 26 publications

References 15 publications

Reductive Amination in the Synthesis of Pharmaceuticals

Reductive Amination in the Synthesis of Pharmaceuticals

High specific activity (+)‐amphetamine and (+)‐methamphetamine

Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D2O as a Deuterium Source

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Product

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Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D₂O as a Deuterium Source