Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780

McLaws, Mark D.; Keefe, Daniel K.; Haney, Brian P.; Zha, Congxiang; Guzzo, Peter R.; Liu, Shuang

doi:10.1021/op3000064

Cited by 20 publications

(8 citation statements)

References 20 publications

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“…Yang and co‐workers68 studied the synthesis of α‐arylated THIQs (tetrahydroisoquinolines) by α‐arylation of 63 . A catalyst generated from Pd(OAc) 2 and BINAP as the ligand in dioxane gave 65 in 98.8 % isolated yield.…”

Section: Syntheses Involving α‐Arylation Of Carboxyamides and Lactamsmentioning

confidence: 99%

Palladium‐Catalyzed α‐Arylation Reactions in Total Synthesis

et al. 2014

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The development of palladium‐catalyzed α‐arylation of carbonyl compounds has emerged as a new avenue in the design of new routes for the synthesis of natural products and active pharmaceutical ingredients (APIs). In many cases, syntheses based on α‐arylation strategies provide elegant routes in terms of increasing the overall yields, improving the synthesis scope, and decreasing the number of steps. This microreview aims to highlight the importance of palladium‐catalyzed α‐arylation methodologies, covering a range of notable reported examples of the total syntheses of structurally important compounds, thereby highlighting the importance of this powerful methodology for key steps in organic synthesis.

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Section: Syntheses Involving α‐Arylation Of Carboxyamides and Lactamsmentioning

confidence: 99%

Palladium‐Catalyzed α‐Arylation Reactions in Total Synthesis

et al. 2014

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“…On the basis of its most potent and balanced triple inhibition profile and weak CYP2D6 inhibition profile, compound 10i was advanced for profiling in a number of in vitro and in vivo assays. An ex vivo binding assay was used to measure the transporter occupancy levels in rodent brain .…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

Liu

Zha

Nacro

et al. 2014

ACS Med. Chem. Lett.

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A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure−activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forcedswim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/ kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

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“…ALB109780 (353) is a triple-reuptake inhibitor that could lead to improved treatment for depression, 205 for which Yang et al at AMRI reported a robust synthetic route (Scheme 72). 206 The discovery route was successfully used to prepare ∼150 g of drug substance ALB109780 (353). However, this route was deemed not suitable for larger scale production, mainly because of the formation of two des-bromo impurities 356 and 357 during the two Pd-catalyzed cross-coupling reactions that required extensive column chromatographic purifications to remove.…”

Section: Applications In Route Design Process Development and Scale-u...mentioning

confidence: 99%

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

Yang

Zhao

2022

Org. Process Res. Dev.

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154

100

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Cu-mediated Ullmann-type cross-coupling has experienced significant advances over the last century since the seminal publication by Ullmann in 1901. These advances have significantly expanded the scope of the original classical Ullmann coupling of aryl halides for formation of diaryl compounds to include the formation of carbon−heteroatom and other carbon− carbon bonds. The introduction of bidentate ligands drastically improved the performance of this class of transformations to enable milder reaction conditions that can tolerate a wide range of sensitive functional groups. Recent development of more powerful second-generation bidentate ligands has further allowed the coupling of less reactive aryl chlorides to proceed smoothly and realized low catalyst and ligand loadings for a broad scope of Ullmann-type cross-coupling reactions. As a result of these breakthrough advances in the past decades, Cu-mediated Ullmann-type cross-coupling reactions have been frequently implemented in academic research and have found ubiquitous industrial applications including the preparation of pharmaceutical and agrochemical products. This review provides an overview of selected general Cu-mediated Ullmann-type transformations for the formation of carbon− carbon and carbon−heteroatom (C−N, C−O, C−S, and C−P) bonds and their applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes.

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Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780

Cited by 20 publications

References 20 publications

Palladium‐Catalyzed α‐Arylation Reactions in Total Synthesis

Palladium‐Catalyzed α‐Arylation Reactions in Total Synthesis

Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

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