Novel Process for Preparation of Tetrabenazine and Deutetrabenazine

Ray, Purna Chandra; Pawar, Yogesh Dadaji; Singare, Dnyaneshwar Tukaram; Deshpande, Tushar Nandkumar; Singh, Girij Pal

doi:10.1021/acs.oprd.8b00011

Cited by 27 publications

(16 citation statements)

References 14 publications

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“…A similar approach from the adduct 2.8.b was developed by Ray and co-workers. [106] Notably, the synthesis of the drug substance 2.8 was performed on a large scale with a total yield of 66 % (Scheme 22(b)).…”

Section: Tetrabenazinementioning

confidence: 99%

Reductive Aldol‐type Reactions in the Synthesis of Pharmaceuticals

Runikhina

Eremin

Chusov

2021

Chemistry A European J

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The efficient chemo-, regio-and stereoselective formation of saturated carbon-carbon fragment is the critical challenge of organic synthesis; therefore, developing new methods for formation of these bonds is paramount. The rising interest for reductive aldol-type reactions is conditioned by its versatile applications, allowing the efficient formation of carbon-carbon bonds. The review aims to highlight the advantages and disadvantage of reductive aldol-type reactions to total synthesis of pharmaceutical substances in order to summarize knowledge and encourage further investigation of the field.

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Section: Tetrabenazinementioning

confidence: 99%

Reductive Aldol‐type Reactions in the Synthesis of Pharmaceuticals

Runikhina

Eremin

Chusov

2021

Chemistry A European J

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“…Finally, a Mitzunobu-type reaction between CD 3 OD and intermediate 68 was carried out in the presence of PPh 3 and diisopropyl azodicarboxylate (DIAD). This two-step procedure provided deutetrabenazine 4 on a kilogram scale [73]. Scheme 15 summarizes the synthesis of deutetrabenazine, a deuterium-incorporated TBZ derivative, which was the first deuterium-containing drug approved by the US FDA in 2017.…”

Section: Preparation Of a Tbz Prodrugmentioning

confidence: 99%

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confidence: 99%

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

Paek

2020

Molecules

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Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington’s disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson’s disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.

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“…The incorporation of deuterium is a very efficient strategy not only to measure the kinetic isotope effect and track the reaction path in synthetic chemistry but also to change the absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates in pharmaceutical chemistry (Atzrodt et al, 2007 ; Meanwell, 2011 ; Guengerich, 2012 ; Katsnelson, 2013 ; Gant, 2014 ). Since the first deuterated drug, deutetrabenazine, for the treatment of chorea associated with Huntington's disease was approved by the Food and Drug Administration in 2017 (Schmidt, 2017 ), which clearly proved a route for the development of deuterated drugs in clinical medicine ( Scheme 1A ) (Junk and Catallo, 1997 ; Gowrisankar et al, 2012 ; Tolnai et al, 2014 ; Ray et al, 2018 ), considerable interests have been devoted to developing novel and efficient methods for the synthesis of such compounds (Yu et al, 2016 ; Kerr et al, 2017 ; Liang et al, 2017 ; Li et al, 2017 ; Liu et al, 2018 ; Yang et al, 2018 ; Han et al, 2019 ; Shen et al, 2019 ; Xu et al, 2019 ; Zhao et al, 2019 ; Chang et al, 2020 ; Dong et al, 2020 ). For instances, in 2016, Chirik and coworkers reported an iron-catalyzed transformation for the deuteration and tritiation of pharmaceuticals (Yu et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%