Synthetic Approaches to the New Drugs Approved During 2022.

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Synthetic Approaches to the New Drugs Approved During 2020.

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

Ruthenium(0)-Catalyzed C-C Coupling of Alkynes and 3-Hydroxy-2-oxindoles: Direct C-H Vinylation of Alcohols.

Upon exposure to a ruthenium(0) catalyst, N-benzyl-3-hydroxy-2-oxindoles react with diverse alkynes to form products of C-H vinylation with complete control of regioselectivity and olefin geometry. This method contributes to a growing body of catalytic processes that enable direct conversion of lower alcohols to higher alcohols in the absence of stoichiometric organometallic reagents.

Redox-triggered C-C coupling of diols and alkynes: synthesis of β,γ-unsaturated α-hydroxyketones and furans by ruthenium-catalyzed hydrohydroxyalkylation.

Direct ruthenium-catalyzed CC coupling of alkynes and vicinal diols to form β,γ-unsaturated ketones occurs with complete levels of regioselectivity and good to complete control over the alkene geometry. Exposure of the reaction products to substoichiometric quantities of p-toluenesulfonic acid induces cyclodehydration to form tetrasubstituted furans. These alkyne-diol hydrohydroxyalkylations contribute to a growing body of merged redox-construction events that bypass the use of premetalated reagents and, hence, stoichiometric quantities of metallic by-products.

Ruthenium-catalyzed hydrohydroxyalkylation of acrylates with diols and α-hydroxycarbonyl compounds to form spiro- and α-methylene-γ-butyrolactones.

Under the conditions of ruthenium(0)-catalyzed hydrohydroxyalkylation, vicinal diols 1a-1l and methyl acrylate 2a are converted to the corresponding lactones 3a-3l in good to excellent yield. The reactions of methyl acrylate 2a with hydrobenzoin 1f, benzoin didehydro-1f, and benzil tetradehydro-1f form the same lactone 3f product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters 2a-2h participate in spirolactone formation, as illustrated in the conversion of N-benzyl-3-hydroxyoxindole 1o to cycloadducts 4a-4h.

Chiral-anion-dependent inversion of diastereo- and enantioselectivity in carbonyl crotylation via ruthenium-catalyzed butadiene hydrohydroxyalkylation.

The ruthenium catalyst generated in situ from H(2)Ru(CO)(PPh(3))(3), (S)-SEGPHOS, and a TADDOL-derived phosphoric acid promotes butadiene hydrohydroxyalkylation to form enantiomerically enriched products. Notably, the observed diastereo- and enantioselectivity is the opposite of that observed using BINOL-derived phosphate counterions in combination with (S)-SEGPHOS, the same enantiomer of the chiral ligand. Match/mismatch effects between the chiral ligand and the chiral TADDOL-phosphate counterion are described.

Enantioselective C-H crotylation of primary alcohols via hydrohydroxyalkylation of butadiene.

The direct, by-product-free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 × 10(6) metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products.

Amplification of anti-diastereoselectivity via Curtin-Hammett effects in ruthenium-catalyzed hydrohydroxyalkylation of 1,1-disubstituted allenes: diastereoselective formation of all-carbon quaternary centers.

Under the conditions of ruthenium-catalyzed transfer hydrogenation, 1,1-disubstituted allenes 1a-c and alcohols 2a-g engage in redox-triggered generation of allylruthenium-aldehyde pairs to form products of hydrohydroxyalkylation 3a-g, 4a-g, and 5a-g with complete branched regioselectivity. By exploiting Curtin-Hammett effects, good to excellent levels of anti-diastereoselectivity (4:1 to >20:1) are obtained. Thus, all carbon quaternary centers are formed in a diastereoselective fashion upon carbonyl addition from the alcohol oxidation level in the absence of premetalated nucleophiles or stoichiometric byproducts.

Allenamide hydro-hydroxyalkylation: 1,2-amino alcohols via ruthenium-catalyzed carbonyl anti-aminoallylation.

Exposure of alcohols to allenamides in the presence of RuHCl(CO)(PPh(3))(3) and dippf [dippf = bis(diisopropylphosphino)ferrocene] results in hydrogen transfer to generate aldehyde-allylruthenium pairs, which engage in C-C coupling to form products of carbonyl aminoallylation as single anti-diastereomers.