The Research On Structural Design And Synthetic Methods Of Novel Retinoids

Retinoids are vital for biologic functions such as embryogenesis, growth, differentiation, vision, and reproduction. At present, retinoids have found clinical utility in the treatment of skin disease and cancer. The aim of this thesis is to research structural design and synthetic methods of novel retinoids. Four results obtained were summarized as follows:1. A highly efficient 4-step synthesis of the retinoid adapalene (1) was developed by adopting a novel Pd-Zn double metal catalyzed cross-coupling reaction as the key step and demonstrated on a pilot scale in 68% overall yield. The most important features are the following: (1) the use of AcOH/H2SO4 to overcome the drawbacks of 98% H2SO4 to afford 4 in quantitative yield; (2) the highly efficient (CH3)2SO4/K2CO3 method to enhance the yield of methylation to 95%; (3) the novel Pd-Zn double metal catalyzed coupling to avoid the preparation of stoichiometric amounts of ArZnBr and give 7 in good yield; (4) the use of toluene to simplify the original chromatographic purification to recrystallization and give 7 in high purity. These make this process a very practical alternative to the existing methods.2. According to the theory for molecule designing of RA, an acetylenic RA (6) with potential RXRs specificity was designed by computer-aided molecule modeling. A directly copper-free sonogashira coupling between iodoaryl acid and phenylacetylene was developed so as to simplify the synthetic procedure of acetylenic RA. Compound 6 was obtained by a 3-step scheme in 52% overall yield and characterized with 1H NMR, 13C NMR, DEPT, IR, and MS. Due to the fact that the reaction is simple and the yield is high, it is applicable to synthesis of other acetylenic RAs.3. On the basis of the special physiological activity of methylene diester prodrugs of biologically active carboxylic acids, methylene diesters (14~17) of RAs were designed and synthesized. Because of that one methylene diester can release two RAs and one formaldehyde by intracellular esterase catalyzed hydrolysis and the released formaldehyde has a pivotal role in inhibiting cancer cell proliferation, it was expected that this type of prodrug will possess higher activity and lower side-effect than the parent RA. A new method for synthesis of methylene diester was also developed. 14～17 were obtained in good yield and in unchanged conformation in part of the unsaturated acyl by using this new method. This method can also was used to esterification of other carboxylic acids with unsaturated polyene structure.4. An improved DCC condensation with DMAP p-toluenesulfonate substitute DMAP as the catalyst was described and applied to the synthesis of 13-cis-RA derivatives 19a～19g. 19a～19g were obtained in 80%-95% yields and in high isomeric purity. The side reaction that converts 13-cis-RA to unreactive N-retinoylurea was completely suppressed. The reaction proceeds under mild conditions and is favored in the acylation of alcohol, amine and carboxylic acid. Among Twenty-six compounds synthesized, thirteen are retinoid compounds.