Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Lall, Manjinder S.; Tao, Yong; Arcari, Joel T.; Boyles, David C.; Brown, Matthew F.; Damon, David B.; Lilley, Susan C.; Mitton‐Fry, Mark J.; Starr, Jeremy T.; Stewart, A. Morgan; Sun, Jianmin

doi:10.1021/acs.oprd.7b00359

Cited by 16 publications

(14 citation statements)

References 29 publications

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“…Finally, another convenient method was used to synthesize the ß-lactam ring from t -butylcarbamate or benzylcarbamate-protected α-amino acids by Staudinger reaction. [ 36 ] Cycloaddition was carried out with the ketenes derived from the mixed anhydride at −70 °C in dry tetrahydrofuran ( 35 – 37 , Scheme 4 ). Again, the cis isomer was a major product but with lower yields, which could not be improved by changing the addition order of the reactants.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Grabrijan

Strašek

Gobec

2021

IJMS

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Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also an important determinant of their biological activity. We present the optimized synthesis of orthogonally protected 3-amino-4-substituted monocyclic ß-lactams. Among several possible synthetic approaches, Staudinger cycloaddition proved to be the most promising method for initial ring formation, yielding monocyclic ß-lactams with different substituents at the C-4 position, a phthalimido-protected 3-amino group, and a (dimethoxy)benzyl protected ring nitrogen. Challenging deprotection methods were then investigated. Oxidative cleavage with cerium ammonium nitrate and ammonia-free Birch reduction was found to be most effective for selective removal of ring nitrogen protection. Hydrazine hydrate was used for deprotection of the phthalimido group, and the procedure had to be modified by the addition of HCl in the case of aromatic substituents at the C-4 position. The presented methods and the synthesized 3-amino-4-substituted monocyclic ß-lactam derivatives are an important step toward new ß-lactams with potential pharmacological activities.

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Section: Resultsmentioning

confidence: 99%

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Grabrijan

Strašek

Gobec

2021

IJMS

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“…With large amounts of racemic piperidine 6 in hand, we investigated a resolution using various chiral acids (Table ) . Initially, we tested six different chiral acids (0.5 equiv) with 30 mL g −1 concentration in i PrOH as the solvent (see supporting information for details).…”

Section: Figurementioning

confidence: 99%

Total Synthesis of (−)‐Himeradine A

Burtea

DeForest

et al. 2019

Angew Chem Int Ed

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(−)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2,4,6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (−)‐Himeradine A was prepared in 17 steps in the longest linear sequence.

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“…To fast-track this candidate for early development, we were initially requested to prepare 500 g of 1 for exploratory toxicity studies, followed by additional multikilograms of the active pharmaceutical ingredient (API) for regulatory toxicity studies and Phase I clinical trials. As described in the previous papers, , the original synthesis was unable to meet bulk API demands due to high step count and extremely poor throughput (∼0.2% overall yield). Therefore, a more concise and efficient synthesis to 1 was needed.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, a more concise and efficient synthesis to 1 was needed. Previously, we reported a process to prepare kilogram quantities of monocyclic β-lactam core ( 2 ) . Herein, we describe the process development to synthesize 1 from 2 , 3 (the “left-hand” thiazole piece, LHP), and 4 (the “right-hand” pyridone piece, RHP) …”

Section: Introductionmentioning

confidence: 99%

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Enabled Process To Synthesize Monobactam 1 for Early Development

Tao

Lall

Boyles

et al. 2019

Org. Process Res. Dev.

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An efficient process to synthesize Monobactam 1 from intermediates 2, 3, and 4 was developed. The process was initially enabled to deliver 500 g of 1 for exploratory toxicity studies and further improved to facilitate kilogram-scale production of the active pharmaceutical ingredient with enhanced quality and throughput. Highlights of the process encompass utilizing 1,1′-carbonyldiimidazole to construct a urea linker with good selectivity, oxidative cleavage to remove a 2,4-dimethoxybenzyl protecting group, two activation methods to form an amide bond, a high yielding reaction to introduce N-sulfonic moiety, and a global deprotection to remove all protecting groups. Practical procedures were developed to isolate intermediates en route by adding a concentrated substrate to antisolvents to obtain filterable amorphous solids with partial purification. Amberchrom CG161M resin was applied not only as a "resin-capture−release" tool to remove the bulk amount of water but also as an effective method to purify 1. Finally, a process isolating 1 pentahydrate (1•5H 2 O) as a crystalline solid from the acidic aqueous solution was developed based on zwitterionic crystallization methodology.

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Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Cited by 16 publications

References 29 publications

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams—Important Structural Motifs in Medicinal Chemistry

Total Synthesis of (−)‐Himeradine A

Enabled Process To Synthesize Monobactam 1 for Early Development

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