Microreactor Assisted Synthesis Of Sinomenine Derivatives And Anti-rheumatoid Arthritis Activity

Rheumatoid Arthritis (RA) is a common systemic autoimmue disease with the main performance of chronic inflammatory of joint tissue, which affects about 0.8% of adult population worlfwide. The diseased joint mainly attends by sustained and recurrent inflammatory cell infiltration, synovial hyperplasia, pannus formation, and incidental cartilage and bone injury. In our country, about 0.26%-0.5% people are suffering from RA, onset typically occurs between 45-50 years old, and more in female. Almost all the RA patients will lose working ability due to the loss of the joint function, and this will bring on serious social problems.Microfluidics synthesis is a new technology in organic chemistry in recent years. Microreactor possess excellent mass and heat transfer capabilities that can not be achieved in traditional reactors, and can obtain much better result, for example, significantly higher yields and purity, less reaction time, lower potential danger and greater product selectivity.Although the studies on structure modified and biological activity of sinomenine increased recent years, modification at A-ring, especially at 1 position, and inhibition of NO, were not studied efficiently. In this thesis, microreactor was extensively used to perform Suzuki reaction of aryl chlorides at first, and then applied for the modification of sinomenine and its reduction product of C-tetrahydrosinomenine at 1 position. The inhibitory activitiy of the synthesized derivatives on lipopolysaccharide (LPS)-induced NO production was also evaluated using the RAW264.7 cells.1. The Suzuki reaction of aryl chlorides in microreactorThe high efficient Suzuki reaction of aryl chlorides with aryl boric acid was performed in microreactor. All the substrates gave low to moderate conversions after 4h in batch reaction, while in microreactor, nearly quantitative conversions were present to almost all the substrates, reached or exceeded the conversions of 24h in batch reaction.2. Synthesis of sinomenine derivatives in microreactorThe synthesis of target molecules were divided into five categories:the halogenosinomenine and halogeno-C-tetrahydrosinomenine; derivatives of cinnamate esters at 1 position at A-ring of sinomenine and C-tetrahydrosinomenine; derivatives of isoxazoline at 1 position at A-ring of sinomenine and C-tetrahydrosinomenine.The C-tetrahydrosinomenine was got via Clemmensen reduction of hydrochloride sinomenine, and then 1-halogenosinmenine was got via halogenation reaction. In microreactor, the 1-idiosinomenine and 1-idio-C-tetrahydrosinomenine reacted with acrylic ester via Heck reaction, gave derivatives of cinnamate esters at 1 position at A-ring of sinomenine and C-tetrahydrosinomenine. Compared to the batch reactions, the reactions in microreactor gave higher conversions in less time. In assembled microreactor, the 1-idiosinomenine and 1-idio-C-tetrahydrosinomenine transformed to methyl cinnamate at 1 position at A-ring of sinomenine and C-tetrahydrosinomenine in M1, and then reacted with aryl nitro oxides given in M2 via 1,3-Dipolar Cycloaddition reaction in M3, to give isoxazoline derivatives at 1 position at A-ring of sinomenine and C-tetrahydrosinomenine. The assembled microreactor provided the target moleculues without any isolation of intermideiates.3. Evaluation of the inhibitory activity of the sinomenine derivate on LPS-induced NO production in RAW264.7 cells.The inhibition activity of the synthesized sinomenine derivatives was evaluated on LPS-induced NO production using RAW264.7 cells culture system. (1) Halogenosinomenine and halogeno-C-tetrahydrosinomenine exhibited a lower activity than sinomenine; (2) derivatives of cinnamate esters at 1 position at A-ring of sinomenine exhibited moderate activity, the activity was stronger than sinomenine in moderate and high concentration; (3) the activity ofC-tetrahydrosinomenine was lower than sinomenine, the derivatives of the cinnamate esters at 1 position showed more potent activity than the corresponding derivatives of sinomenine, suggested that the hydrogenation of C-ring is propitious to increase the activities of derivatives. (4) The derivatives of isoxazoline of sinomenine exhibited moderate activity; the Cl and Br substituted derivatives were more active than -CH3 and -OCH3 substituted derivatives in low concentration; a majority of the isomer-a were more active than isomer-b. (5) Derivatives of isoxazoline of C-tetrahydrosinomenine exhibited a better good activity than sinomenine. In high concentration, both exhibited a strong activity.