Synthesis of (+)- and (−)-Tetrabenazine from the Resolution of α-Dihydrotetrabenazine

Boldt, Karl G.; Biggers, Michael S.; Phifer, Sharnelle S.; Brine, George A.; Rehder, Ken S.

doi:10.1080/00397910902788125

Cited by 14 publications

(18 citation statements)

References 8 publications

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“…In contrast, in the previous study [17], (−)-TBZ proved only 3-fold less potent than (+)-TBZ. In this prior study, the VMAT2 affinity of (−)-TBZ and (+)-TBZ was assessed in the form of their camphorsulfonate salts rather than their corresponding free bases, and although X-ray crystallographic analysis and optical rotation were provided and matched the literature [16], their optical purity was not reported.…”

Section: Resultsmentioning

confidence: 99%

“…However, this method suffers from several practical limitations, such as the use of an expensive chiral catalyst, long reaction sequences, and a low total yield, and thus is not suitable for industrial production. Recently, Boldt et al developed a synthesis of (+)- 1 from the resolution of a-DHTBZ, followed by Swern oxidation of the resulting (+)-α-DHTBZ [16]. This indirect methodology suffers from a low atom-economy due to additional reduction/oxidation steps.…”

Section: Introductionmentioning

confidence: 99%

“…Another access to optically pure TBZ employs the resolution of (±)- 1 with preparative chiral HPLC that, similarly, is not suitable for large-scale preparation [13]. Surprisingly, since the initial launch of (±)- 1 in 1971, direct chemical resolution of (±)-TBZ has seen little success [16]. Recently, Yu et al [17] reported the preparation of (+)- 1 and (−)- 1 by a chemical resolution procedure that is similar to ours [18].…”

Section: Introductionmentioning

confidence: 99%

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Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Yao

Xue-ying

et al. 2011

European Journal of Medicinal Chemistry

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Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki = 4.47 nM) was 8000-fold more potent than (−)-1 (Ki = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki = 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington’s disease and other hyperkinetic disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Yao

Xue-ying

et al. 2011

European Journal of Medicinal Chemistry

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“…To our knowledge, this was the first report to synthesize chiral N ‐dichloroacetyl‐4‐ethyl‐1,3‐oxazolidine derivatives. When compared with the reported strategy [14–18], the described procedure offered the advantages of operational simplicity and use of cheap and readily available solvents.…”

Section: Resultsmentioning

confidence: 99%

“…Boldt et al . reported a highly enantioselective resolution of α‐dihydrotetrabenazine using di‐ p ‐toluoyl‐ L ‐tartrate and di‐ p ‐toluoyl‐ D ‐tartrate in low yields . A wide variety of N ‐protected chiral amino alcohol was prepared in high yields by asymmetric reduction of N ‐carboxyanhydride (UNCAs) amino acid derivatives .…”

Section: Introductionmentioning

confidence: 99%

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Zhao

et al. 2012

Journal of Heterocyclic Chem

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Chiral 2‐amino‐butanols (4 and 5) were obtained via the isolation of diastereomeric salt. Then, chiral compounds (6–9) were synthesized by a sequential procedure involving condensation of chiral 2‐amino‐butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, 1H NMR, 13C NMR, and element analysis. The absolute configurations of (S)‐8 was determined by X‐ray crystallography.

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Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition^†

Peng,

Lin,

Zhu

et al. 2024

Chin. J. Chem.

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Comprehensive SummaryValbenazine (Ingrezza), a potent and highly selective inhibitor of vesicular monoamine transporter type 2 (VMAT2) through the active metabolite hydrotetrabenazine (HTBZ), has been approved for the treatment of tardive dyskinesia and, very recently, for chorea, which is associated with Huntington's disease. Despite numerous synthetic efforts dedicated to the synthesis of HTBZ, the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction. Herein, we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3‐dipolar cycloaddition and enzymatic kinetic resolution. The cascade process includes cycloaddition, N˗O bond cleavage, and lactamization, which proved to be operationally simple. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline (THIQ)‐fused piperidine to access key frameworks in the production of medically significant compounds, such as yohimbine and reserpine.This article is protected by copyright. All rights reserved.

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Synthesis of (+)- and (−)-Tetrabenazine from the Resolution of α-Dihydrotetrabenazine

Cited by 14 publications

References 8 publications

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition^†

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Synthesis of (+)- and (−)-Tetrabenazine from the Resolution of α-Dihydrotetrabenazine

Cited by 14 publications

References 8 publications

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

A Mild and Highly Efficient Synthesis of Chiral N‐Dichloroacetyl‐4‐ethyl‐1,3‐oxazolidines

Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition†

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Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition^†