Process Development of a GCS Inhibitor Including Demonstration of Lossen Rearrangement on Kilogram Scale

Zhao, Jin Ku; Gimi, Rayomand; Katti, Sanjeev; Reardon, Michael B.; Nivorozhkin, Vitaly; Konowicz, Paul A.; Lee, Edward; Sole, Lynne; Green, Jerome; Siegel, Craig

doi:10.1021/op500379a

Cited by 15 publications

(16 citation statements)

References 20 publications

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“…9 To gain detailed information, we conducted differential scanning calorimeter (DSC) measurements of benzoyl azide (7) and 3-phenyl-1,4,2-dioxazol-5-one (8). In the temperature range of -20 ~ 100 o C, crystallization temperature (T c ) and melting temperature (T m ) were observed during the first and second cycle of benzoyl azide treatment (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Study of Sustainability and Scalability in the Cp*Rh(III)-Catalyzed Direct C–H Amidation with 1,4,2-Dioxazol-5-ones

Park

Jee

Kim

et al. 2015

Org. Process Res. Dev.

126

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The practical aspects of Cp*Rh(III)-catalyzed direct C−H amidation with 1,4,2-dioxazol-5-ones were investigated on the operational safety, use of green solvent, and scalability. Differential scanning calorimeter (DSC) measurement showed that 3-phenyl-1,4,2-dioxazol-5-one is thermally stable while benzoyl azide, a conventionally employed precursor of acyl nitrene, rapidly decomposes to isocyanate. It was confirmed that the replacement of acyl azide with 1,4,2-dioxazol-5-one brings not only high reactivity but also improvement in safety. In respect to a green process development, functional group tolerant Cp*Rh(III) catalyst exhibited high reactivity in ethyl acetate, successfully replacing 1,2-dichloroethane solvent used in the original report. Upon the validation on safety and environmental concerns, scalability was also tested.Two different types of arenes bearing pyridyl and oxime directing groups showed excellent conversions on tens of gram scale reactions, and single recrystallization gave desired products with high yields and purity.

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Section: Resultsmentioning

confidence: 99%

Study of Sustainability and Scalability in the Cp*Rh(III)-Catalyzed Direct C–H Amidation with 1,4,2-Dioxazol-5-ones

Park

Jee

Kim

et al. 2015

Org. Process Res. Dev.

126

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“…Many factors affecting the yield and purity of Curtius rearrangement products have been reported, including reaction kinetics, − solvents, ,,,, temperature, ,,− calorimetry, , energy release, residence time, , and analytics . We found that the use of toluene provided optimal rearrangement conditions at 85 °C. ,, Because of the potentially explosive and hazardous nature of acyl azide intermediates formed in situ, appropriate concentration of acyl hydrazide, reactor volume and flow, and residence time should be carefully considered to control the energy release.…”

mentioning

confidence: 87%

“…Heat release can be attributed to the decomposition of the acyl azide to form the isocyanate and nitrogen, which is dependent on the concentration of the intermediate and temperature . Differential scanning calorimetry (DSC) indicated that 0.5 M acyl azide releases a heat energy of 187 J/g, while 1 M acyl azide liberates an energy of 364 J/g, which exceeds safety criteria. ,, On the basis of calorimetric data from previous reports, ,− we chose a hydrazide concentration of 0.1 M, a reactor volume for the Curtius rearrangement of 1.6 mL, and a residence time of 97s, which kept the energy release at a minimum for improved safety. In a flow system, the thermal stability of acyl azides generated in situ is increased through solvent dilution during the flow reaction.…”

mentioning

confidence: 99%

“…We used this setup to prepare 100 g of heptamethylene diisocyanate from algae-sourced azelaic acid, a nine-carbon diacid derived from palmitoleic acid via ozonolysis. 14 Many factors affecting the yield and purity of Curtius rearrangement products have been reported, including reaction kinetics, 41−43 solvents, 9,11,38,44,45 temperature, 11,38,46−48 calorimetry, 49,50 energy release, 13 residence time, 13,37 and analytics. 13 We found that the use of toluene provided optimal rearrangement conditions at 85 °C.…”

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confidence: 99%

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Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Hai

Backer

Cosford

et al. 2020

Org. Process Res. Dev.

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Diisocyanates used in polyurethanes are commonly prepared by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodology for the production of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chemistry to prepare and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepared from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prepare isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufacturing processes.

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“…Eliglustat tartrate used in these studies was obtained from Genzyme Corporation. Genz-682452 ( 3 , venglustat) was prepared by the method described by Zhao et al…”

Section: Methodsmentioning

confidence: 99%

Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3

Wilson

Shu

Hinkovska‐Galcheva

et al. 2020

ACS Chem. Neurosci.

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There remain no approved therapies for rare but devastating neuronopathic glyocosphingolipid storage diseases, such as Sandhoff, Tay-Sachs, and Gaucher disease type 3. We previously reported initial optimization of the scaffold of eliglustat, an approved therapy for the peripheral symptoms of Gaucher disease type 1, to afford 2, which effected modest reductions in brain glucosylceramide (GlcCer) in normal mice at 60 mg/kg. The relatively poor pharmacokinetic properties and high Pgp-mediated efflux of 2 prompted further optimization of the scaffold. With a general objective of reducing topological polar surface area, and guided by multiple metabolite identification studies, we were successful at identifying 17 (CCG-222628), which achieves remarkably greater brain exposure in mice than 2. After demonstrating an over 60-fold improvement in potency over 2 at reducing brain GlcCer in normal mice, we compared 17 with Sanofi clinical candidate venglustat (Genz-682452) in the CBE mouse model of Gaucher disease type 3. At doses of 10 mg/kg, 17 and venglustat effected comparable reductions in both brain GlcCer and glucosylsphingosine. Importantly, 17 achieved these equivalent pharmacodynamic effects at significantly lower brain exposure than venglustat.

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Process Development of a GCS Inhibitor Including Demonstration of Lossen Rearrangement on Kilogram Scale

Cited by 15 publications

References 20 publications

Study of Sustainability and Scalability in the Cp*Rh(III)-Catalyzed Direct C–H Amidation with 1,4,2-Dioxazol-5-ones

Study of Sustainability and Scalability in the Cp*Rh(III)-Catalyzed Direct C–H Amidation with 1,4,2-Dioxazol-5-ones

Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3

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