Development of a Practical Synthesis of ERK Inhibitor GDC-0994

Linghu, Xin; Wong, Nicholas; Iding, Hans; Jost, Vera; Zhang, Haiming; Koenig, Stefan G.; Sowell, C. Gregory; Gosselin, Francis

doi:10.1021/acs.oprd.7b00006

Cited by 17 publications

(3 citation statements)

References 26 publications

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“…A total biocatalyst loading up to 10 % w/w can lead to acceptable levels of foaming and emulsification in extractive work‐ups [93–94] . In addition to this, less than 5 % w/w total biocatalyst loading has previously been adopted in two‐enzyme processes for pharmaceutical manufacturing employing lyophilised clarified cell‐free extracts [95–102] . The selected thresholds for final product concentration [51] and biocatalyst loading (Table 6) lead to target biocatalyst yield ranging from 10—50 g product /g biocatalyst .…”

Section: Towards Industrial Utilitymentioning

confidence: 99%

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

et al. 2021

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Polyphosphate kinases (PPKs) have emerged as valuable candidates to address the unmet need for scalable recycling of the common enzyme cofactor adenosine‐5’‐triphosphate (ATP) because they use cheap, freely available and stable polyphosphate (polyP) salts as the phosphate donor. The aim of this review is not only to present recent efforts in the characterisation of PPKs but also to provide an overview of the challenges associated with their implementation in chemical manufacturing. In assessing the current status of polyP‐driven biocatalysts, we identify gaps that need to be filled for successful adoption of these biocatalysts in industry. Guidelines for a wider adoption of PPKs are also provided.

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Section: Towards Industrial Utilitymentioning

confidence: 99%

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

et al. 2021

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“…The safe operation temperature is very close to the reaction temperature by the test of TSU. We strongly recommend to please ensure that the engineering control is in place to strictly follow the parameters in the procedure . Ammonium molybdate tetrahydrate (43.9 kg, 35.5 mol, 0.03 equiv) was added to H 2 O 2 (439 kg, 27.5 wt %, 3.55 kmol, 3 equiv).…”

Section: Experimental Sectionmentioning

confidence: 99%

Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Hæffner

Wang

et al. 2021

Org. Process Res. Dev.

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Route evaluation, process development, and large-scale manufacturing of 4-chloro-N-(1-methyl-1H-pyrazol-4yl)pyrimidin-2-amine (1) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)pyrimidine ( 11) to 4-chloro-2-(methylsulfonyl)pyrimidine ( 7) and displacement of the sulfonyl with N-(1-methyl-1Hpyrazol-4-yl)formamide (10) under basic conditions followed by in situ hydrolysis of the N-formyl intermediate to deliver compound 1. N-(1-Methyl-1H-pyrazol-4-yl)formamide (10) was readily prepared from 1-methyl-1H-pyrazol-4-amine (4) via reaction with formic acid. The route allows for large-scale production of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1). Density functional theory (DFT) calculations were carried out to better understand the observed reactivity and selectivity.

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“…A small molecule inhibitor, GDC-0994, targeting the extracellular-signal-regulated kinases (ERK) was recently discovered as a promising candidate to treat patients with locally advanced or metastatic solid tumors. , To support preclinical and clinical studies, we developed and reported an efficient asymmetric multi-kilogram scale synthesis of the target molecule (Scheme ). , The key intermediate for this transformation was 4-heteroarylpyridone 1 . Herein, we describe the development of an efficient and scalable process toward 1 that relies on an efficient Kumada–Corriu cross-coupling reaction.…”

Section: Introductionmentioning

confidence: 99%

Kumada–Corriu Heteroaryl Cross-Coupling for Synthesis of a Pharmaceutical Intermediate: Comparison of Batch Versus Continuous Reaction Modes

Linghu¹,

Wong²,

Jost

et al. 2017

Org. Process Res. Dev.

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Pyridone 1, a key intermediate in the preparation of ERK inhibitor GDC-0994, was synthesized via a cross-coupling/hydrolysis sequence from commercially available starting materials. C–C bond formation was achieved via an efficient palladium catalyzed Kumada–Corriu cross-coupling reaction. However, the 4-pyridylmagnesium halide reagent generated in situ was found to be unstable at the reaction temperature, leading to inconsistent results on scale. In order to address process robustness issues associated with the cross-coupling reaction, we investigated both flow chemistry and a low temperature Kumada–Corriu coupling reaction. Finally, a basic hydrolysis process of 2-fluoropyridine was developed to avoid formation of toxic and corrosive hydrofluoric acid, resulting in a safe and scalable process toward 1.

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Development of a Practical Synthesis of ERK Inhibitor GDC-0994

Cited by 17 publications

References 26 publications

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

Recent Developments and Challenges for the Industrial Implementation of Polyphosphate Kinases

Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Kumada–Corriu Heteroaryl Cross-Coupling for Synthesis of a Pharmaceutical Intermediate: Comparison of Batch Versus Continuous Reaction Modes

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