Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?

Verzijl, Gerard K. M.; Vries, André H.M. de; Vries, Johannes G. de; Kapitán, Peter; Dax, Thomas G.; Helms, Matthias; Nazir, Zarghun; Skranc, Wolfgang; Imboden, Christoph; Stichler, Juergen; Ward, Richard A.; Abele, Stefan; Lefort, Laurent

doi:10.1021/op400268f

Cited by 27 publications

(24 citation statements)

References 43 publications

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“…Although the great majority of research work on ATH catalysts as tethered catalysts has focused on ketones, there have been some limited studies on C=N reduction 67. However, this field is significantly less developed and the catalyst versatility is not as extensive, even with untethered catalysts, although there are some very impressive examples, particularly of cyclic imine reductions 14,15,68–70. One very impressive recent example of C=N reductions using a tethered catalyst was reported by scientists at Merck, who found that catalyst 8 was particularly beneficial, and indeed superior to other catalysts tested, in the reduction of an imine substrate to a primary amine during the synthesis of a target drug molecule (Figure ) 71…”

Section: Ath Of Substrates Of Industrial Interestmentioning

confidence: 99%

The Development of Phosphine‐Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines

Nedden

Zanotti‐Gerosa

Wills

2016

The Chemical Record

114

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In this account, we describe the design, synthesis and applications of tethered versions of the Ru(II)/N-tosyl-1,2-diphenylethylene-1,2-diamine (TsDPEN) class of catalyst that are commonly used for asymmetric transfer hydrogenation and asymmetric hydrogenation of ketones and imines. The review covers key aspects of the reaction mechanisms and examples of applications, including industrial applications to pharmaceutically important target molecules. In addition, closely related catalysts based on Rh(III) and Ir(III) are also described.

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Section: Ath Of Substrates Of Industrial Interestmentioning

confidence: 99%

The Development of Phosphine‐Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines

Nedden

Zanotti‐Gerosa

Wills

2016

The Chemical Record

114

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“…The significance of asymmetric imine hydrogenation in the context of pharmaceutical and agricultural industries has been reviewed extensively. [1][2][3][4][5][6][7][8] To date, large scale AH processes have been predominantly developed with precious metal catalysts based primarily on iridium, [9][10][11][12] and rhodium 13 while ruthenium complexes are often used in asymmetric transfer hydrogenation (ATH) processes. 10,14,15 Imines are generally challenging substrates to reduce in a stereoselective manner.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P′ Complex

et al. 2019

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Reports of the use of first row transition metal complexes for the catalytic AH of imine are limited. In 2011 Beller and coworkers reported that a range of N-aryl substituted imines were hydrogenated to amines with ee ranging from 88 to 98% using Knölker's iron complex FeH(CO)2(Cp'OH) (5 mol%) in combination with the homochiral phosphoric acid (S)-TRIP (1 mol%) at 50 bar H2 and 65 °C. 23 In 2014 our group reported that an iron complex [FeBr(CO)2(L 1)]BF4 with the asymmetric ligand (S,S)-PPh2CHPhCHMeNHCH2CH2P i Pr2 (L 1) when activated with LiAlH4/iso-amylalcohol was active in the presence of 10 mol% KO t Bu for the AH of the N-diphenylphosphinoyl imine derived from 1-propiophenone to the amine (90% ee) at 20 atm H2 and 50 °C. 24 Bai et al have described the use of homochiral cyclopentadienone)iron complex for the AH of activated imines but the enantioselectivity was poor (ee of the amine up to 40%). 25 Otherwise there have been several reports of the ATH of activated imines by catalysts based on iron, 26-29 cobalt 30,31 and nickel. 32

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“…1), almorexant, suvorexant, and their corresponding salts were synthesized by the medicinal chemistry department of Actelion Pharmaceuticals Ltd (Allschwil, Switzerland) as described in Supplemental Fig. S1, or according to published methods (Baxter et al, 2011;Mangion et al, 2012;Boss et al, 2013;Verzijl et al, 2013;Boss et al, 2015a,b). Chemical purity of all compounds was in excess of 97%.…”

Section: Introductionmentioning

confidence: 99%

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468

Treiber

Kanter

Roch

et al. 2017

J Pharmacol Exp Ther

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The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX and OX) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.

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Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?

Cited by 27 publications

References 43 publications

The Development of Phosphine‐Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines

The Development of Phosphine‐Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines

Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P′ Complex

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468

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