Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4-triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladium-catalyzed C–N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

A short and efficient synthesis of the nucleoside fragment contained in the NS5B nucleoside inhibitor BMS-986094 was achieved in 23% overall yield on a gram scale. The synthesis uses the widely available starting material guanosine via a short sequence ending in a Mukaiyama hydration reaction to establish the key tertiary alcohol moiety and set the C-2' methyl stereogenic center. This work resulted in a robust and scalable approach to this complex nucleoside.

We report research focused on the preparation of an advanced intermediate in the synthesis of a novel antiretroviral. This manuscript describes the development of an efficient oxidation of a 6-azaindole derivative, the bromination of the resulting N-oxide using PyBroP, the removal of the protecting group, and the isolation of the brominated azaindole product. The work reported herein has been successfully implemented in the multikilogram scale to fund development and clinical activities of BMS-663068.

The discovery, development, and optimization of an Ullmann–Goldberg–Buchwald coupling reaction is described. This complex process represents a key transformation in the development of a commercially viable synthesis of the HIV attachment inhibitor prodrug BMS-663068. In this reaction, high regioselectivities were obtained for the coupling of a 1,2,4-triazole and a 7-bromoazaindole, preparing BMS-626529, the antepenultimate in good yield and quality. Key challenges associated with developing commercially viable conditions for this copper-mediated coupling include achieving the desired level of regiochemical control, identifying robust isolation conditions and controlling residual copper levels in the isolated product.

We report research focused on the construction of the 6-azaindole core, a key intermediate in the synthesis of the clinical candidate BMS-663068. The work describes an efficient and scalable method to access the 6-azaindole from a protected 3-ketopyrrole via a Pictet–Spengler cyclization and a radical-mediated aromatization. The process reported herein has been successfully implemented on the multikilogram scale to support preclinical development and clinical studies of BMS-663068.

During the development of a Friedel–Crafts acylation for the preparation of a key pyrrole intermediate in the synthesis of the HIV attachment inhibitor, BMS-663068-03, a significant scale dependence was found. A precipitous drop in yield was observed for the acylation of a protected pyrrole with chloroacetyl chloride upon scale-up. Spectroscopic studies to mitigate this scale dependence led to the identification of the complex effect of dissolved hydrogen chloride (HCl) as well as the poor reactivity of the acylating agent, chloroacetyl chloride. At this point, the counterintuitive choice to switch to a longer, but scale-independent, three-step route was made. By changing the acylating agent to acetyl chloride, a more robust process was obtained. Rapid development of a high yielding α-chlorination then provided the common α-chloroketone intermediate required to generate the desired α-amide ketopyrrole. The improved yield and scalability of this three-step process supported the addition of one linear step to the route, and it was demonstrated successfully at scale.

During the process of developing a synthesis to a complex molecule, multiple decisions are made regarding the strategies and tactics used to prepare key bonds. In this article, we preface a series of papers describing the development of the commercial synthesis of BMS-663068 (a potential new treatment for HIV), with an in-depth discussion of the important strategic decisions made during the process of designing and demonstrating the proposed commercial synthesis of this complex clinical candidate. We discuss the key strategic disconnections and the key experimental data used to drive our tactical decisions during development. In the remaining articles in this series, we outline the development of these enabling chemical processes into scalable procedures ready to support commercialization of this promising new medicine.

An electrochemical C–H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity is described; it uses inexpensive and readily available materials and represents a scalable allylic C–H oxidation that could be adopted in large-scale industrial settings without substantial environmental impact. Allylic C–H oxidation has been used widely in the syntheses of natural product variants, medicines and new materials. One disadvantage of the reaction is that it requires highly toxic reagents or expensive catalysts. In this manuscript, the authors describe an electrochemical alternative to conventional allylic oxidation. The new method utilizes inexpensive and readily available materials, has broad substrate scope, operational simplicity, and high chemoselectivity, all with minimal environmental impact. New methods and strategies for the direct functionalization of C–H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials1. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C–H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials2. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as “classics”3. Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium)2. These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C–H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C–H oxidation (demonstrated on 100 grams), enabling the adoption of this C–H oxidation strategy in large-scale industrial settings without substantial environmental impact.

The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a ∼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).

以正十八醇和表氯醇、二甲胺等合成N-(3-十八烷氧基-2-羟丙基)-N,N-二甲基甜菜碱(JHD-18),并对其表面活性以及与OP-10的复配性能进行了研究.结果表明,JHD-18在25℃的临界胶束浓度为500 mg/L,临界表面张力为28.94 mN/m,JHD-18与OP-10的摩尔比为3∶7时表现出最佳的复配效果,该复配体系的临界胶束浓度为450 mg/L,临界表面张力为20.47 mN/m,并可使油水界面张力降低至超低(10-3 mN/m)数量级.复配体系与地层水配伍性好,抗盐能力较强,当Ca2+浓度高达16000 mg/L时,该体系与原油仍可达到超低界面张力(10-3 mN/m);在不同渗透率(0.32× 10-3～3.14×10-3 μm2)岩心的驱替实验中,水驱后注入0.3 PV、质量浓度为1500 mg/L的复配体系(JHD-18与OP-10的摩尔比为3∶7)最大可提高驱油效率15.72％.

The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.

A short and efficient process for the preparation of high-quality dicyclopropylamine HCl salt is described. An oxygen-mediated Chan-Lam coupling of N-cyclopropyl 4-nitrobenzenesulfonamide with cyclopropylboronic acid was followed by an optimized p-nosyl deprotection with 1-decanethiol, providing the title compound in high chemical yield. This process addresses many of the challenges and liabilities inherent in previous synthetic approaches to this challenging molecule. The collection of key safety data enabled implementation of an oxygen-mediated process on-scale and ensured safe operation throughout development, optimization, and processing.

A mild method for the regioselective C2-bromination of fused azine N-oxides is presented, employing tosic anhydride as the activator and tetra-n-butylammonium bromide as the nucleophilic bromide source. The C2-brominated compounds are produced in moderate to excellent yields and with excellent regioselectivity in most cases. The potential extension of this method to other halogens, effecting C2-chlorination with Ts2O/TBACl is also presented. Finally, this method could be incorporated into a viable one-pot oxidation/bromination process, using methyltrioxorhenium/urea hydropgen peroxide as the oxidant.

AbstractA simple, mild, and scalable method for the title reaction is presented which can also be extended to complex molecules [e.g. the antimalarial agent (XIV)] and the incorporation of chlorine using Bu4NCl [viz.