The Role of New Technologies in Defining a Manufacturing Process for PPARα Agonist LY518674

Abstract

The impact of several new technologies on the development of a manufacturing process for LY518674 is described. Extensive use of process analytical technology (PAT) throughout development, both at laboratory and pilot-plant scale, enabled data-rich experiments, shortened development cycle times, and obviated the requirement of PAT for process control at larger scale. In situ ReactIR was used to develop a kinetic model for a one-pot preparation of a semicarbazide intermediate. Parallel crystallizers fitted with online focused-beam reflectance measurement (FBRM) and particle vision and measurement (PVM) probes were used in the development of several challenging crystallization processes. Application of the process knowledge afforded by these technologies, combined with the principles of Quality by Design, resulted in excellent purity control throughout the four-step process. A single, 5-min, MSfriendly method capable of separating over 30 components was developed using a combination of chromatography modeling software, sub-2 µm column technology, and higher-pressure LC equipment. The method was used across all four processing steps, greatly facilitating impurity tracking, and reducing assay time and solvent use by 85% and 93%, respectively.

N2-Alkylation of semicarbazones. A general and efficient protocol for the synthesis of 2-alkylsemicarbazides from semicarbazide

“…Similarly, 2-benzyl-2h,i,k and 2-(4-methoxybenzyl)-substituted semicarbazones of aliphatic aldehydes 2j,l were prepared in 66-78% yields by alkylation of semicarbazones of propanal, butanal, or 2-methylpropanal 1e,f, (E)-1g after their deprotonation with NaH in MeCN (entries [11][12][13][14][15]. Only a single stereoisomer of 2h-l presumably with (E)-configuration was obtained in each case.…”

“…10 The second approach involves carbamoylation of the corresponding monosubstituted hydrazines with trimethylsilyl isocyanate, 4,[11][12][13] urea, 14 or cyanic acid generated by reaction of Brønsted acid and metal cyanate. [15][16][17][18] Scheme 1. Commonly used approaches to 2-alkylsemicarbazides.…”

A New Efficient Route to 2-Alkylsemicarbazides

“…The first is based on nitrosonation of N-alkylureas with nitrous acid or its anhydride, followed by reduction of the nitroso group in the obtained N-Alkyl-N-nitrosoureas with Zn in aqueous AcOH [6][7][8], H2 over Pd/C [9], or using the electrochemical method [10]. The second approach involves carbamoylation of the corresponding monosubstituted hydrazines with trimethylsilyl isocyanate [4,[11][12][13], urea [14], or cyanic acid generated by reaction of Brønsted acid and metal cyanate [15][16][17][18]. In addition, there are some particular syntheses of 2-alkylsemicarbazides.…”

In Situ Raman Spectroscopy: A Process Analytical Technology Tool to Monitor a De-protection Reaction Carried Out in Aqueous Solution

“…There are many scientific publications as well and the interested reader is referred to some recent publications in the field of applying PAT to the development of active pharmaceutical ingredients (APIs). 1–4 At the root of all work involving PAT is some type of measurement data, device, or system. Although the analytical data or method can be based, in principle at least, on any analytical measurement, in the case of development of a manufacturing process for APIs, this field seems to be dominated by the use of mid-infrared (mid-IR) spectroscopy.…”