Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3H)-pyrimidones, a pharmacokineticsdriven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

A novel synthetic route for making (−)-CBD and its derivatives bearing various C4′-side chains is developed by a late-stage diversification method. Starting from commercially available phloroglucinol, the key intermediate (−)-CBD-2OPiv-OTf is efficiently and regioselectively prepared and further undergoes Negishi cross-coupling to furnish (−)-CBD. This approach allowed an efficient synthesis of (−)-CBD in a five-step total 52% yield on a 10 g scale. Furthermore, diversification on the C4′-side chain with this method can be realized in a wide range.

A one-pot process for preparing molnupiravir from cytidine was developed. The advantages of this synthesis were as follows: (1) The presence of N,N-dimethylformamide dimethyl acetal (DMF-DMA) facilitated the selective protection of 2′,3′-dihydroxyls and amino of cytidine, which eliminated the negative impact of these groups on the following isobutyrylation at 5′-hydroxyl. (2) Degradations of the product in the deprotection stage were avoided since a mild condition was used. (3) The achievement of deprotection and hydroxyamination in one single step improved the synthetic efficiency. (4) Molnupiravir with high purity (purity up to 99.7% analyzed by high-performance liquid chromatography (HPLC)) was obtained in a yield of 63% through crystallization.

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The development of an industrially scalable synthetic route for 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid (1), a key starting material for lifitegrast, is described. This route includes the following features: (1) tetrahydroisoquinoline 19 was prepared in three steps from readily commercially available 3,5-dichlorobenzoyl chloride and 2-aminoethanol in a high total yield of 76%; (2) formaldehyde instead of triphenylmethyl chloride was employed in the protection of the secondary amine, resulting in much higher atom economy; (3) the target compound 1 was produced in an overall yield of 66% with an HPLC purity of 99% by area.

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