Integrated Approach to the Development and Understanding of the Borane Reduction of a Carboxylic Acid

Lobben, Paul C.; Leung, Simon Shun-Wang; Tummala, Srinivas

doi:10.1021/op049910h

Cited by 17 publications

(11 citation statements)

References 7 publications

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“…As the mixture was subsequently warmed, a second exotherm initiated at ∼4 °C that rapidly heated the reactor contents to 9 °C despite jacket cooling. This result was consistent with the accumulation and exothermic sequential reduction of an acyloxyborane intermediate . In order to achieve conditions in which accumulation of intermediates was not significant, the reduction was performed at higher temperature.…”

Section: Resultssupporting

confidence: 79%

Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Walker

Borths

DiVirgilio

et al. 2011

Org. Process Res. Dev.

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Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4 0 -(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (()-1. An efficient and scalable synthesis of (()-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum's acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step SuzukiÀMiyaura couplingÀbromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.

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Section: Resultssupporting

confidence: 79%

Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Walker

Borths

DiVirgilio

et al. 2011

Org. Process Res. Dev.

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show abstract

“…42 The BTHF reduction of a carboxylic acid shown in Scheme 25 had a delayed exotherm during scale-up. The carbonyl reduction is about 3.5 times more exothermic than the initial diacyloxyborane formation.…”

Section: Carboxylic Acid Reductionmentioning

confidence: 99%

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

2006

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“…The value proposition for PAT in early process development, as an enabler of increased mechanistic and process understanding, has already been validated by academia and the broader scientific community over decades. The rich data sets that PAT enables can be often combined with modeling tools to obtain in-depth mechanistic understanding in an efficient manner. , Recent advances in PAT have continued to lower the barriers for their use while simultaneously increasing the level of knowledge that can be gained, leading to increased adoption. For example, advances in inline mid-IR probe technology have led to “flexible” silver halide (AgX) and virtually eliminated the need for cumbersome probe alignment, something that was essential even five years ago.…”

Section: Perspective On the Value Proposition Of Pat In Various Phase...mentioning

confidence: 99%

Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review

Simon

Pataki

Marosi

et al. 2015

Org. Process Res. Dev.

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352

238

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This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

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Integrated Approach to the Development and Understanding of the Borane Reduction of a Carboxylic Acid

Cited by 17 publications

References 7 publications

Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review

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