Large Scale Deprotection of a <i>tert</i>-Butoxycarbonyl (Boc) Group Using Aqueous HCl and Acetone

Coffey, Donald S.; Hawk, Mai Khanh; Pedersen, Steven W.; Ghera, Steven J.; Marler, Paul G.; Dodson, Paul N.; Lytle, Michelle L.

doi:10.1021/op049842z

Cited by 19 publications

(9 citation statements)

References 2 publications

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“…14 Other strategies reported for the deprotection of N-Boc include the use of metal catalysts, 15,16 as well as acetylchloride in methanol, 17 N-Boc removal with HCl in organic solvents: ethylacetate, 18 dioxane, 19 in acetone. 20 Other N-Boc deprotection methodologies include aqueous phosphoric acid, 21,22 conc. sulfuric acid in tert butylacetate, 3 boiling water; 23 silica gel has also been reported to effect the deprotection of N-Boc from thermally-sensitive heterocycles including heterocondensed pyrroles.…”

Section: Introductionmentioning

confidence: 99%

Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride

et al. 2020

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“…In our case, best results were obtained using aqueous hydrochloric acid for removal of the protecting group. The same strategy has also been reported for achieving Boc-removal on a large scale for the synthesis of APIs in batch [55] as well as in continuous flow [24].…”

Section: Optimization Of the Individual Steps In Continuous Flowmentioning

confidence: 84%

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

et al. 2019

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The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical "Design of Experiments" (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield. Keywords Continuous flow chemistry. Heterogeneous catalysis. Multistep reaction cascade. Palladium. Sacubitril Highlights • Development of a multistep setup for the integrated synthesis of a latestage sacubitril precursor in continuous flow. • Intensification of Suzuki coupling in continuous flow employing a heterogeneous palladium catalyst implemented in a packed-bed reactor. • Optimization of Boc-deprotection as well as N-amidation using the "Design of Experiments" approach.

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“…The formation of alkyl chlorides was avoided by using acetone as organic solvent: 13 was suspended in a water/acetone mixture, and concentrated aqueous hydrochloric acid (3.5 equiv) was added at ∼50 °C (Scheme ). Gas evolution (isobutene and carbon dioxide) did not start until after dosing of the first equivalent of acid.…”

Section: Resultsmentioning

confidence: 99%

An Efficient Process for the Manufacture of Carmegliptin

Abrecht

Adam

Bromberger

et al. 2011

Org. Process Res. Dev.

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A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.

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Large Scale Deprotection of a tert-Butoxycarbonyl (Boc) Group Using Aqueous HCl and Acetone

Abstract: A procedure for tert-butoxycarbonyl (Boc) group removal using concentrated HCl and acetone was developed and utilized on multi-kilogram scale in the synthesis of LY544344·HCl (1). The details surrounding this procedure and the advantages offered by it are described herein.

Cited by 19 publications

References 2 publications

Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride

Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

An Efficient Process for the Manufacture of Carmegliptin

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