Synthetic Method Optimization Of PDE1 Enzyme Inhibitors

Phosphodiesterase 1 is a therapeutic target for regulation of intracellular signaling pathways, especially in the nervous system and it functions in brain tissue as a regulator of locomotor activity, learning and memory. Studies have shown that, due to the diversity of PDEl genes playing a role in the interaction with Ca and nucleotide signaling pathway, there is positive significance in the treatment of cardiovascular, central nervous system and immune system disorders. PDE1 inhibitors are a special class of experimental drug candidates which are orally effective. Treatments for schizophrenia, Alzheimer's disease and other disorders of the nervous disorders associated with cognitive impairment are now being developed.Both SHP1050 and SHP1098 are selective PDE1 inhibitors developed by Intracellular therapies, INC. in recent years. The PDE1-IC50 value of SHP1050 is between 10 nM and 1 ?M and that of SHP1098 is less than 250 nM. This project is devoted to the improvement of the synthetic routes of these two inhibitors in order to obtain the target compounds of 10 grams scale which are used for the further study of drug activity.Through redesigning the patent synthesis route of SHP1050, we adopt the strategy that the pyrazole ring is first synthesized, followed by the pyrimidine ring, and treat cyclization with carbon disulfide, methylation and oxidation to derive the methyl sulfoxide intermediate with a high substitution activity as key reactions, which overcome the low yield of chloride compound formation, the 2 steps yield of cyclization and methylation reaches 71%. The parent nucleus is obtained efficiently by substitution with the chiral amino-alcohol reagent and intramolecular cyclization from the methyl sulfoxide intermediate. Finally, we take Mitsunobu reaction as a pivotal step to achieve the coupling of the pyrazopyrimidine ring and the benzyl side chain smoothly with a high selectivity and the yield is over 50%. The total yield is up to 8.5% from less than 1% by this 9 steps route and the first 7 steps are simple to work up because all the intermediates are solid and easily precipitated from solvent.The synthesis of SHP1098 is divided into 3 parts based on the structure:synthesizing the pyrazopyrimidine parent nucleus and the benzyl alcohol side chain respectively and then coupling them together. First, we accomplish the synthesis of the parent nucleus according to the patent line and optimize the process conditions, and the total yield of 4 steps reaches 56%. Secondly, facing the fact that the raw material has not been commercialized, we redesign the synthesis route of the side chain and creatively use the tert-butyl sulfinyl protecting group. The synthesis is started from 5-chloropentanoyl chloride, through 5 steps general reactions which contain Friedel-crafts acylation, reductive amination, intramolecular nuclear substitution, aldehyde substitution and reduction in turn to obtain the side chain, overcoming the problems that some protection groups are so unstable, while others are difficult to remove and avoiding the use of high toxic and explosive materials and intermediates, and the total yield of the side chain reaches 22%. Finally, we successfully achieve the splicing of the parent nucleus and the side chain by Mitsunobu reaction, and the target molecule is obtained by the removal of the tert-buty1 sulfiny1 protection group under acidic condition, and the 2 steps synthesis yield is 37%. The overall yield calculated by the longest 7 steps linear synthesis is 8.2%.