High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences

Bogdan, Andrew R.; Charaschanya, Manwika; Dombrowski, Amanda W.; Wang, Ying; Djurić, Stevan W.

doi:10.1021/acs.orglett.6b00378

Cited by 45 publications

(24 citation statements)

References 28 publications

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“…N-methylaniline 3a could then be formed by an in situ thermal decarboxylation of 4, analogous to a solvent-free thermal tert-butyloxycarbonyl (Boc) deprotection. 14 Based on these observations, we propose that the reaction sequence begins by reaction of aniline 1a with DMC to form carbamate 6, followed by methylation of the carbamate via reaction with a second equivalent of DMC in the presence of DBU to form 4. Carbamate 4 then undergoes a thermal decarboxylation to provide N-methylaniline 3a.…”

Section: Resultsmentioning

confidence: 95%

Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

et al. 2018

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N-alkylanilines are ubiquitous motifs in the pharmaceutical and agrochemical industries. 1 In particular, N-methylanilines are found in a range of biologically active compounds such as diazepam, flobetapir, triafamone, and broflanilide (Figure 1). 2 Nalkylation reactions are common and essential transformations for the synthesis of pharmaceuticals and fine chemicals. 3 However, selective mono-N-alkylation of primary alkyl and aryl amines remains a challenging transformation due to the greater nucleophilicity of secondary amines compared to primary amines. 4 The synthesis of N-methylanilines is particularly challenging and the use of classical approaches for N-alkylation via reaction with alkyl halides or by reductive amination often results in the formation of mixtures of secondary and tertiary anilines. 4,5 Often, lab-scale syntheses of N-methylanilines require multistep sequences involving the incorporation and removal of protecting groups or the installation and exhaustive reduction of a carbamate. 6 The difficulty associated with the selective N-monomethylation of primary anilines is often reflected in the price of N-methylanilines versus their primary aniline analogs. A 50-to 100-fold increase in the price per gram is not unusual for this seemingly simple functionalization.The development of robust and selective methods for the selective N-monomethylation of primary anilines would greatly simplify the synthesis of N-methylanilines and several approaches have been reported. On the industrial scale, Nmonomethylation of primary anilines is accomplished via reaction with methanol in the vapor phase using heterogeneous

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Section: Resultsmentioning

confidence: 95%

Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

et al. 2018

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“…We selected not to modify an acid free Boc deprotection flow protocol at high temperature (300°C) and high pressure (100 bar), which was reported by Djuric and co-workers, due to concern over decomposition. 29 Each N-Boc-protected dipeptide 5a-5e was treated with a solution of 4 M HCl in dioxane based on a literature batch protocol (Scheme 4). 30 The Boc-group was successfully cleaved at room temperature within 1 h reaction time.…”

Section: Reaction Chemistry and Engineering Communicationmentioning

confidence: 99%

Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

et al. 2020

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“…48 On a similar note, acidic conditions could be avoided in high temperature tert-butyloxycarbonyl (Boc) deprotections. 63 Highly corrosive reagents may not be suitable for a standard flow chemistry equipment and require special handling techniques and construction materials, such as a specialized dry zone for handling anhydrous HCl gas. 39,64 In course of the flow syntheses of Ibuprofen (Fig.…”

Section: Ensuring Stability For Continuous Productionmentioning

confidence: 99%

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

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Örkényi

Lövei

et al. 2017

Bioorganic & Medicinal Chemistry

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a b s t r a c tRecent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.

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High-Temperature Boc Deprotection in Flow and Its Application in Multistep Reaction Sequences

Cited by 45 publications

References 28 publications

Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

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