Study On Diastereoselective Synthesis Of Chiral M Receptor Antagonists

Muscarinic acetylcholine receptors are members of the huge superfamily of G-protein-coupled receptors (GPCRs). To date, five pharmacologically distinct receptor subtypes (M1-M5) have been defined. Many vital diseases such as Parkinsonian syndromes, Alzheimer's disease(AD), chronic obstructive pulmonary disease(COPD) and irritable bowel syndrome(IBS) are associated with M receptors. However, the lack of receptor subtype selectivity or organ specificity of M receptor antagonists limited their clinical utility and the therapeutic applicability. It has been well established that the receptor subtype selectivity and organ specificity not only depends on the chemical properties but also the stereochemical properties. In order to improve the selcetivities and reduce side effects of muscarinic receptor antagonists, it is very important to study the stereostructure-activity relationship of these antagonists.Phencynonate hydrocloride (8021) and Penehyclidine hydrocloride (8018) are two new anti-cholinerigic M receptor antagonists developed by our research institute. 8021 exhibited good curative effect for motion sickness and its active optical isomer adopted R configuration. 8018 exhibited good curative effect for the pesticides poison of organic phosphorus. Furthermore, 8018 had far greater selectivity for M3 over Ml receptor subtype, which makes it has potentially use in the treatment of respiratory disorders such as COPD. The optical isomer of 8018 with R configuration is the active one. However, no any diastereoselective synthetic methods for 8021 and 8018 optical isomers were reported. This paper is focused on the study of diastereoselective synthetic methods of 8021 and 8018. Then a series of new class of M receptor antagonists were designed and synthesized by utilizing the chiral intermediate, a-Cyclopentyl-a- hydroxy phenyl acetic acid, as the key structural unit. Project supported by the National Natural Science Foundation of China. The results are showed as follow.1. Diastereoselective synthetic methods of 8021 and 8018 a-Cyclopentyl-a-hydroxy phenyl acetic acid 5, the key intermediate for the synthesis of 8021 and 8018, was firstly synthesized through a practical diastereoselective method by utilizing thereadily available and inexpensive starting materials, (S) or (R)-mandelic acid and cyclopentanone (Scheme a). Then the aimed optical pure products of 8021 were synthesized through esterification and ester-change reaction for the first time in this paper (Scheme b). The ee values of 8021 optical isomers were over 99.9%.Scheme b Synthetic route of 8021 and its optical pure derivatives After attempting some unsuccessful synthetic routes for the preparation of Penehyclidine hydrocloride (8018), a practical diastereoselective synthetic method for 8018 four enantiopure isomers was developed by utilizing the ring opening of epoxide intermediate If for the first time. The epoxide intermediate 19 was synthesized from the reduction of chiral tertiary a-hydroxy acid 5, the mono-sulfonation of diol and intramolecular Williamson ether synthetic method (Scheme c). The four optical isomers were obtained with moderate yields in 99-100% ee values.Scheme c Synthetic route of 8018 and its optical pure derivatives2. Diastereoselective synthesis of 8021 and 8018 derivatives The aimed optical pure products of 8021 derivatives were synthesized through ester-change reaction by utilizing the methyl ester of chiral tertiary α-hydroxy acid 5 and corresponding optical alcohol as starting materials (Scheme b). The optical purity of these aimed products were determined by High Performance Capillary Electrophoresis (HPCE) and with over 99.9% ee values, respectively. Moreover, in order to study the effects of aromatic heterocyclic on the bioactivity of 8021, two optical isomers of Thiencynonate Hydrochloride were synthesized through resolution method.The optical 8018 derivatives with piperidine structures were synthesized through ring opening reaction of epoxide 19 with corresponding 4-hydroxy piperidine derivatives (Scheme c). The isomers were obtained with moderate yields in 99-100% ee values. The preliminary biological results suggested that the piperidine derivatives with R configuration were active optical isomers, in which the competitive inhibitory rate of compounds 20a, 20e, 20f, 20j, 20k with QNB at 1 × 10-5mol/L could reach 91%, 88%, 78%, 77% and 83%, respectively. However, the affinity on M receptor of these piperidine derivatives reduced significantly compared to their parent compound 8018.3. Diastereoselective synthesis of M receptor antagonists with C-N bond Based on the synthetic methods of 8021 and 8018 optical isomers, a simplepractical diastereoselective method for the synthesis of a new class of M receptor antagonists with C-N linker bond was designed and developed for the first time.Thirty compounds with R and S configuration were synthesized through condensation, hydrogenation, reductive amination and the amide intermediate reduction by utilizing the chiral tertiary α-hydroxy acid 5 as starting materials (Scheme d).Because the reaction did not involve the changing of chiral center of chiral tertiary α-hydroxy acid, the ee values of these aimed products have the same ee values as the starting materials chiral tertiary α-hydroxy acid with 99.9% ee values. The results also suggested that solvents significantly affected the yields of reduction process of amides, and toluene was the suitable solvent for this reaction.Scheme d Synthetic route of chiral M receptor antagonists with C-N bond...