An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical ...cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)–C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.
A general Rh(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide N-oxides as substrates. In general, ...high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures.
Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino ...acid-linker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody-maytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure-activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens.
A highly efficient and regioselective halogenation reaction of unsymmetrical pyridine N-oxide under mild conditions is described. The methodology provides a practical access to various ...2-halo-substituted pyridines, which are pharmaceutically important intermediates.
The development of a flow chemistry process for asymmetric propargylation using allene gas as a reagent is reported. The connected continuous process of allene dissolution, lithiation, Li‐Zn ...transmetallation, and asymmetric propargylation provides homopropargyl β‐amino alcohol 1 with high regio‐ and diastereoselectivity in high yield. This flow process enables practical use of an unstable allenyllithium intermediate. The process uses the commercially available and recyclable (1S,2R)‐N‐pyrrolidinyl norephedrine as a ligand to promote the highly diastereoselective (32:1) propargylation. Judicious selection of mixers based on the chemistry requirement and real‐time monitoring of the process using process analytical technology (PAT) enabled stable and scalable flow chemistry runs.
Go with the flow: Continuous flow is used for the practical preparation of highly reactive allenyllithium from allene gas under non‐cryogenic conditions. On‐line process analytical technologies such as FlowIR allowed real‐time monitoring of the formation of reactive intermediates.
The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard ...reagent, N-methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (OC(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt. In addition to the connected plug flow reactor system, the Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, was also prepared continuously in CSTR as a more soluble LiCl adduct in THF (Turbo Grignard).
A general inversion-stereospecific, N-selective alkylation of substituted 2-pyridones (and analogues), amides, and carbamates using chiral α-chloro- or bromocarboxylic acids in the presence of KOt-Bu ...(or KHMDS) and Mg(Ot-Bu)2 is reported. The resulting α-chiral carboxylic acid products were isolated by crystallization in good chemical yields and in high ee (>90% ee). Mechanistic evidence suggests that the reaction proceeds through 2-pyridone O-coordinated Mg carboxylate intermediates, which afford the product through an intramolecular SN2 alkylation.
We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this ...reactor is extracted into nitrogen gas from the liquid reaction mixture, effectively removing it from reagents and byproducts that may interfere in subsequent reactions. Vertically oriented tubular reactors were used to produce and consume diazomethane in situ. Key features of this reactor include high productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min) and a commercially available gas/liquid separator equipped with a selectively permeating hydrophilic membrane. The design of the reactor keeps the inventory below 53 mg of CH2N2 during normal operation. The reactor was demonstrated by generating CH2N2 that was used in a connected continuous reactor. We evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor and achieved high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.
A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with ...consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.
A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel ...bench-stable Vilsmeier reagent, methoxymethylene-N,N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).
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