Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834

Abstract

A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless and readily available commodity chemical isooctyl-3-mercaptopropionate as sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on 20 kg scale.

Development of a Scalable Route for a Key Benzothiazole Building Block via a Pd-Catalyzed Migita Coupling with a Nonsmelly Thiol Surrogate

“…The intermediately formed thiophenolate cyclized onto the N -acetyl group to form the desired benzothiazole (Scheme , approach C). A similar thiophenolate release strategy by employing iso -octyl 3-mercaptopropionate ( 7 ) as a thiol surrogate was developed by Pfizer on a multi kg scale for the commercial manufacturing of a diaryl thioether via double Migita coupling . Inspired by these two reports, we started with the development of a benzothiazole formation from nonsmelly thiol surrogates.…”

“…A similar thiophenolate release strategy by employing iso-octyl 3-mercaptopropionate (7) as a thiol surrogate was developed by Pfizer on a multi kg scale for the commercial manufacturing of a diaryl thioether via double Migita coupling. 15 Inspired by these two reports, we started with the development of a benzothiazole formation from nonsmelly thiol surrogates. Despite the elegance of the seminal report by Itoh and Mase, there were several challenges with their original procedure 12 with regard to scale-up: (1) The Migita coupling was run in a full-batch mode by simply mixing all starting materials, reagents and the catalyst at room temperature followed by heating to reflux (110 °C) and aging for 12 h; (2) 1,4-dioxane was used, which is a highly undesirable process solvent, as it has been flagged as a substance of very high concern (SVHC) within the REACH regulations edited by ECHA.…”

Synthesis of Air‐stable, Odorless Thiophenol Surrogates via Ni‐Catalyzed C−S Cross‐Coupling

“…[7] Despite being widely used, both methods rely on aprecious metal catalysta nd employ as trong base in either the cross-coupling reactioni tself or the subsequent deprotection step. [8] Both sulfur nucleophileso ffer poor atom economy [9] (< 20 %), which is compounded by the frequent need for chromatographic purification of the protected thiophenolp rior to its deprotection.N ew general methods for the convenient and scalable synthesis of thiophenols, or their chemicals urrogates, would therefore greatlye xpedite the preparation of more complex aryl-sulfur motifs that form the core of important molecules. [8] Both sulfur nucleophileso ffer poor atom economy [9] (< 20 %), which is compounded by the frequent need for chromatographic purification of the protected thiophenolp rior to its deprotection.N ew general methods for the convenient and scalable synthesis of thiophenols, or their chemicals urrogates, would therefore greatlye xpedite the preparation of more complex aryl-sulfur motifs that form the core of important molecules.…”

“…While the b-thiole sters used in the former methodology are readily available and odorless, triisopropylsilanethiol is expensive, hasl imited availability on scale, and possesses a" pungent rotten egg odor". [8] Both sulfur nucleophileso ffer poor atom economy [9] (< 20 %), which is compounded by the frequent need for chromatographic purification of the protected thiophenolp rior to its deprotection.N ew general methods for the convenient and scalable synthesis of thiophenols, or their chemicals urrogates, would therefore greatlye xpedite the preparation of more complex aryl-sulfur motifs that form the core of important molecules.…”

“…Despite being widely used, both methods rely on a precious metal catalyst and employ a strong base in either the cross‐coupling reaction itself or the subsequent deprotection step. While the β‐thiol esters used in the former methodology are readily available and odorless, triisopropylsilanethiol is expensive, has limited availability on scale, and possesses a “pungent rotten egg odor” . Both sulfur nucleophiles offer poor atom economy (<20 %), which is compounded by the frequent need for chromatographic purification of the protected thiophenol prior to its deprotection.…”