Development of a Practical Route for the Manufacture of <i>N</i>-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide

Hirt, Hans; Haenggi, Ruedi; Reyes, Jesús Navarro; Seeger-Weibel, Manuela; Gallou, Fabrice

doi:10.1021/op700222r

Cited by 9 publications

(3 citation statements)

References 10 publications

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“…Given the poor efficiency of this oxidation process (in total, 10 equiv of the oxidant KHSO 5 were required, when only 2 are theoretically needed) the use of alternative oxidants has been briefly examined. Both sodium tungstate/hydrogen peroxide and peracetic acid have given promising preliminary results and will be the focus of further development.…”

Section: Introductionmentioning

confidence: 99%

Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

Bradley

Koning

Johnson

et al. 2009

Org. Process Res. Dev.

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The development and implementation of a scaleable process for the manufacture of the nonsteroidal progesterone receptor antagonist 8 is described. Key aspects of the synthesis include (i) a telescoped chlorination−etherification sequence to prepare diketone 4 and (ii) separation of pyrazole regioisomers 6 and 7 through formation of their hydrogen sulfate salts and selective crystallization, followed by oxidation to 8.

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Section: Introductionmentioning

confidence: 99%

Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

Bradley

Koning

Johnson

et al. 2009

Org. Process Res. Dev.

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“…As an alterative to m -CPBA, aqueous hydrogen peroxide has been shown in the literature to be one of cheap and green oxidants . Sulfone synthesis via a molybdate- or tungstate-catalyzed sulfide oxidation with aqueous hydrogen peroxide has been well-documented. − We then quickly evaluated the efficiency of Na 2 WO 4 -catalyzed oxidation of sulfide 6 with 30% aqueous H 2 O 2 in a variety of solvents (Table ). It was found that EtOH (entry 1) gave an incomplete conversion after 7 h. Reactants were not completely soluble in this solvent system, resulting in a heterogeneous reaction.…”

Section: Discussion and Resultsmentioning

confidence: 99%

Development of a Practical Synthesis of ERK Inhibitor GDC-0994

Linghu¹,

Wong²,

Iding

et al. 2017

Org. Process Res. Dev.

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The process development of a synthetic route to manufacture ERK inhibitor GDC-0994 on multikilogram scale is reported herein. The API was prepared as the corresponding benzenesulfonate salt in 7 steps and 41% overall yield. The synthetic route features a biocatalytic asymmetric ketone reduction, a regioselective pyridone SN2 reaction, and a safe and scalable tungstate-catalyzed sulfide oxidation. The end-game process involves a telescoped SNAr/desilylation/benzenesulfonate salt formation sequence. Finally, the development of the API crystallization allowed purging of process-related impurities, obtaining >99.5A% HPLC and >99% ee of the target molecule.

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“…2 Since the seminal work of Erlenmeyer and Darzens, the methodology has been extensively used for aromatic aldehydes as well as for aromatic and aliphatic ketones. 3 During the reaction, a carbonyl is reacted with an a-halo ester in the presence of a base to give an epoxide.…”

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confidence: 99%

Development of a Robust and Practical Process for the Darzens Condensation and α,β-Epoxide Rearrangement: Scope and Limitations of the Methodology

Zimbron¹,

Seeger-Weibel²,

Hirt³

et al. 2008

Synthesis

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A practical and robust process for the Darzens condensation of substituted benzaldehydes and subsequent a,b-epoxy rearrangement is reported. The process developed is both amenable to large scale and parallel synthesis. While electron-poor benzaldehydes gave mixtures of aryl ketones and 2-substituted aryl ketones in mediocre to low yields, electron-rich benzaldehydes were found to react in high yields with complete regioselectivity to form 2-substituted aryl ketones.In the course of one of our development program, we became interested in the well-documented Darzens condensation. 2 Since the seminal work of Erlenmeyer and Darzens, the methodology has been extensively used for aromatic aldehydes as well as for aromatic and aliphatic ketones. 3 During the reaction, a carbonyl is reacted with an a-halo ester in the presence of a base to give an epoxide. Of particular interest for us was the opening of the latter and decarboxylation upon thermolysis, to afford the corresponding one-carbon homologue of the starting aldehyde or ketone. 3,4 Development of a practical and robust metal-free one-carbon homologation process for access to ketone 1 from substituted and readily available benzaldehydes 2 (Scheme 1) was our initial objective. The stereochemistry of the Darzens condensation was of no relevance in this process. Scheme 1 Retrosynthetic analysisA series of potent candidates containing a sulfone moiety was first brought to our attention (R 2 = CH 3 SO 2 in Scheme 1). Under classical conditions, we found that the desired product 5a did not form from the benzaldehyde 3a. Interestingly, the 4-methylsulfanyl-substituted benzaldehyde 3b reacted smoothly under identical conditions and afforded the desired ketone 5b in 73% isolated yield at the first attempt (Scheme 2). Careful investigation revealed that the Darzens condensation was not proceeding at all in the case of the sulfone 3a. A thorough literature search revealed that only sparse results suggesting an electronic bias in the Darzens reaction of aromatic aldehydes were reported. 5 Our project was a perfect opportunity to probe the substrate scope of the reaction while streamlining our process. Particular attention was paid to the practicality and robustness of the overall process to illustrate the importance of the methodology in process development.In the case of aldehyde 3b, the reaction was found to proceed well with the inexpensive (±)-2-chloropropionic acid methyl ester 4 and sodium methoxide at 0°C in a toluene-R 3

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Development of a Practical Route for the Manufacture of N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide

Cited by 9 publications

References 10 publications

Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

Development of a Practical Synthesis of ERK Inhibitor GDC-0994

Development of a Robust and Practical Process for the Darzens Condensation and α,β-Epoxide Rearrangement: Scope and Limitations of the Methodology

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