Development of a Potential Manufacturing Route to PF-00610355: A Novel Inhaled β₂-Adrenoreceptor Agonist

Abstract

The development of a practical, scalable route to PF-00610355 (8) is described. In this convergent approach, amine 9 is coupled to protected bromohydrin 1 to give the doubly protected intermediate 26. TBS-Deprotection of 26 affords the benzyl protected penultimate intermediate 25 which is crystallized as the corresponding hemifumarate salt 25a. On the basis of solubility data, the final debenzylation was conducted in aqueous THF, and the API (8) is isolated from acetonitrile by an unusual distillative crystallization process. The development of an efficient process to prepare amine 9 is also described.

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…Twiddle and co-workers at Pfizer used CDI for an improved amide coupling in the synthesis of β-2 adrenoreceptor agonist 137 (Scheme ). In a previous commercial route, the condensation of acid 133 and benzylamine 134 was mediated by EDC·HCl and HOBt in CH 2 Cl 2 , but this combination of reagents and solvent led to a protracted aqueous workup. Alternatively, a revised coupling with CDI in EtOAc streamlined the aqueous workup via easy-to-purge byproducts (imidazole) and facilitated solvent exchange to chloroacetonitrile and TFA for a telescoped Ritter reaction.…”

Optimization of the Manufacturing Route to PF-610355 (1): Synthesis of Intermediate 5

“…This process was employed to generate 35 kg of PF-610355 (Scheme 1) to support early clinical development. 3 As the candidate progressed, continual development work was performed on the synthetic process and is discussed herein. This article focuses solely on the synthesis of 5, the first isolated intermediate in the original process.…”

“…The conditions employed for the desired reaction required an excess of thiourea (4.2 equiv) in neat acetic acid (11 L/kg wrt 1) at 70 °C, conditions that were not ideal for large scale manufacture. 3 This was in addition to the problematic workup involving filtration of the solid sideproduct 18 (diaminothiazole) and byproduct 20 (pseudothiohydantoin) as discussed earlier. The isolation of 4 as a crystalline solid eliminated the problem associated with the carryover of chloroacetonitrile, and this allowed the thiourea charge to be lowered to 1.2 equiv and simplified the workup considerably through the minimization of waste.…”

“…1 The candidate progressed through the development phases with publications documenting the enabling chemistry 2 and alternative route investigations. 3 This paper documents the development work performed to afford a synthetic process suitable for commercial scale manufacture of intermediate 5.…”

“…A summary of the discovery and synthesis of a range of β-2 adrenoreceptor agonists culminating in the identification of PF-610355 as a clinical candidate has recently been published . The candidate progressed through the development phases with publications documenting the enabling chemistry and alternative route investigations . This paper documents the development work performed to afford a synthetic process suitable for commercial scale manufacture of intermediate 5 .…”