Search

The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine...

[Image: see text] A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene (“MPB”) payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the “MPB” binding component and guided structure–activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody–drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.

A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided ...

We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dus...

Two approaches to a 1-aryl-4-trifluoromethyltriazole are described. Initially, a late-stage trifluoromethylation of the corresponding 1-aryl-4-iodotriazole using methyl fluorosulfonyldifluoroacetat...

Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that the addition of sub-stoichiometric cerium(III)...

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (8-FDC) fragment of OPC-167832 in 41 % yield and in > 99 % purity over 4 steps from 3-amino-4-fluorophenol. The key feature of this process is the development of a telescoped one pot synthesis of the quinolone via a chemoselective amidation and easier product isolation without the need for a column chromatography.

Propylphosphonic anhydride has been shown to be an effective reagent for the synthesis of substituted [1,2,4]triazolo[1,5-a]pyridines from the corresponding N′-hydroxy-N-formimidamides. The reactio...

A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography.

We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO3. Sulfolane emerged as the solvent of choice for this transformation due to its high stability toward strongly acidic and oxidizing conditions. The specific hazards of this reaction were studied, and the nitration was efficiently and safely conducted leveraging flow conditions.

A safe and scalable synthesis of 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrobromide is described. A process safety-driven synthetic strategy was employed for the selection of thermally stable compounds en route to the target 1,2,4-oxadiazole. Application of process safety principles and tools for predicting the stability of process streams, isolated compounds, and for defining optimum reaction parameters are discussed in detail. The effect of protecting groups on the thermal stability of isolated intermediates is also highlighted.

The large-scale synthesis of ethyl 4-bromocyclohex-3-enecarboxyalate, using a mild brominating reagent derived from triphenyl phosphite and bromine, is reported. The development and comparison of both continuous and batch processes are described. A modified addition sequence was developed based on the knowledge garnered from flow-processing, resulting in a safe and efficient process for the in situ generation of the unstable active reagent and its immediate reaction with the ketone in a batch mode process.

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 iso-octyl-3-mercaptopropionate as a 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 a 20 kg scale.

Zinc salts have been shown to promote the Buchwald–Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

This article describes a systematic approach used to streamline the process for the isolation of bosutinib monohydrate, a promiscuous solvate former. A thorough understanding of the complex solid form landscape was garnered, and this knowledge was used to develop a process that routinely delivered the correct solid form and excellent purity at the end of the last bond-formation step, without the need for additional recrystallization and/or solid form conversion steps.

Many metal-mediated cross-couplings involve the use of organic halides, which are usually accessed by halogenation reactions. Cross-couplings are sensitive to the presence of impurities in the hali...

A new scalable enzymatic resolution approach to both enantiomers of trans-2-hydroxycyclohexanecarbonitrile (9 and 11) was developed. Treatment of the racemic mixture (4) with succinic anhydride in the presence of Novozym 435 led to selective acylation of one enantiomer to the corresponding hemisuccinate, which was separated from the unreacted enantiomer by a simple basic extraction. This procedure produced the desired enantiomer in high ee, while obviating the need for chromatography or expensive catalysts and ligands. The application of this protocol to the large-scale synthesis of an androgen receptor antagonist (1) is described.

This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.

The reaction of internal 1,2-diols with catalytic n-Bu2SnO, p-TsCl (1.05 equiv.) and Et3N (1.1 equiv.) led to selective monotosylation. In the case of cyclic substrates, the cis-1,2-diol moiety appeared best suited for optimal results, supporting the intermediacy of a five-membered chelate.

Nitroxyl radicals can be oxidized to N-oxo ammonium salts that are themselves useful oxidants for primary and secondary alcohols. Several computational methods were investigated in order to predict the redox potential of nitroxyl radicals and to better understand the behavior of different nitroxides as catalysts for alcohol oxidation. The difference in calculated heats of formation for N-oxo ammonium ions and nitroxyl radicals using AM1 did not lead to a useful correlation with experimental redox potential as measured by cyclic voltammetry. However, when both the N-oxo ammonium ion and the nitroxyl radical were evaluated using the Cramer-Truhlar solvation model (SM2), a linear correlation was observed between the difference in heats of formation and the experimental redox values. This correlation may be used to correctly predict the redox potential of new nitroxyl radicals.

The reaction of substituted glycols with catalytic dibutyltin oxide, stoichiometric p-toluenesulfonyl chloride, and triethylamine in CH2Cl2 resulted in the complete and rapid sulfonylation at the primary alcohol. The α-heterosubstituted primary alcohol moiety appeared optimal for best results, supporting the intermediacy of a five-membered chelate. The role of the amine is discussed, in addition to catalyst requirements and solvent effects.

Lai's protocol for the synthesis of nitroxides has been extended to the synthesis of several new chiral piperazine and morpholine nitroxides. This strategy utilizes the Bargellini reaction as the key bond-forming step. Several optically pure nitroxides incorporating alpha-aromatic and alpha-spiro centers were prepared by this route. These chiral nitroxides will be of interest as enantioselective oxidants, as traps for prochiral radicals, and in the preparation of new materials. One of these nitroxides, compound 43, was found to racemize under mild oxidizing conditions. The mechanism for this unusual racemization reaction was investigated.

The chemical reactivity of cryptophycin 52 towards sulfur and phosporous nucleophiles under different conditions was explored to reveal the differential reactivity of the epoxide and olefinic centers. Under basic conditions 1,4-addition to the enone is favored, while under acidic conditions the epoxide is more reactive.

Lai's protocol for the synthesis of nitroxides has been extended to the synthesis of several new chiral piperazine and morpholine nitroxides. This strategy utilizes the Bargellini reaction as the key bond-forming step. Several optically pure nitroxides incorporating α-aromatic and α-spiro centers were prepared by this route. These chiral nitroxides will be of interest as enantioselective oxidants, as traps for prochiral radicals, and in the preparation of new materials. One of these nitroxides, compound 43, was found to racemize under mild oxidizing conditions. The mechanism for this unusual racemization reaction was investigated.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.

The reaction of internal 1,2-diols with catalytic n-Bu2SnO, p-TsCl (1.05 equiv.) and Et3N (1.1 equiv.) led to selective monotosylation. In the case of cyclic substrates, the cis-1,2-diol moiety appeared best suited for optimal results, supporting the intermediacy of a five-membered chelate.