Synthesis Of A New Immunosuppressant FTY-720 (Second)

Immune drugs developed in the 1970s,are a newly rising class of therapeutic drugs. Immunotherapy through modulation of immune function, and correcting the abnormal immune response to achieve medical purposes. Most of the drugs are acting on the immune system, the role of two sides :immune enhancement and immunosuppression. Immuno suppressants are received widely attention clinically for providing ef-fective therapeutic drugs for rejection of autoallergic disease and organ transplantation.FTY-720 was synthesized by Professor Fujita in 1995 with Yoshitomi Pharmaceutical Company and become a brandnew immunosuppressant. The chemical name is called 2-amino-2- [2-(4-octyl-phenyl) ethyl]-1,3-propanediol hydrochloride, the molecular formula is C19H33NO2HCl and the molecular weight is 343.94U. ISP-1—a sphingosine-like substance was separated from culture medium of Chinese Cordyceps, then synthesized by modificationg the structure of ISP-1.The model results show the following characteristics of FTY-720:①FTY-720 significantly extend allograft survival which has positive correlation with the dose ;②strong immunosuppressive effect, when arriving the identical prolonging allograft survival, the dose of FTY-720 is only 1/30 CsA③FTY-720 can prevent acute rejection and reverse the occurred rejection.Meanwhile, FTY-720 can enhance the immunosuppression of CsA,when two combined, CsA dose only reaching the sub-clinical dose (3mg? kg-1) can be achieved satisfactory co-therapeutic results,thereby easing the liver, kidney toxicity. For the patients with organ failure, organ transplantation has become a routine means of treatment. Development and application of Efficiency, low toxicity, low-cost of new immunosuppressant, plays an important role in promoting organ transplants and will bring good news to organ transplant patients.Its chemical structure and the mechanism is different from the current immunosuppressant, which will reduce the number of B and T lymphocytes in the peripheral blood, thereby weakening the attack on the graft. The decrease in peripheral blood lymphocyte will "homing" in the lymph nodes and intestinal lymph node set, which will not affect the NK cells,granulocyte and monocyte function. FTY-720 could affect chemokine functions, decreasing the access number of T and B cells to transplantation by 70% to 80%, therefore, Xenotransplantation could significantly prolong the sur-vival time,which prevent the occurrence of acute rejection and reverse the occurred rejection .FTY-720 can reduce the infiltration of graft T cell,inhibit the expressions of CD3 mRNA,cytotoxic protein molecules perforation,particle enzyme and FasL mRNA,but not affect the expression of IL-2 mRNA and IFN-γmRNA., which showed that FTY-720 reduced the graft cytotoxic T cell number. Results from the current study shows that FTY-720 react insidious and has high bioavailability.According to the retrosynthesis analysis, the key intermediate of FTY-720 is to be learned compounds 5, FTY-720 are synthesized by reducing ester bond to hydroxy, and then protection, hydrolysis, salification. There are various methods for the synthesis of compounds 5. Durand P reported benzene as raw materials, via five-step reaction: Friedel-Crafts acylation, reduction to octyl benzene, Friedel-Crafts acylation with bromoacetyl bromide, alky-lation,then reduction again . Kiuchi M reportedβ-phenethanol acetates as raw materials, via six-step reactions: Friedel-Crafts acylation,redction to octyl, acetyl hydrolysis to hydroxy, and then sulfonate esteri-fication, iodogenated and alkylation. Gunter S reported S-hydroxyethyl phenol as raw materials,selective protection of hydroxyl first, and then phenolic hydroxyl esterification, as a leaving group coupled with Grignard reagents to get the octyl, iodogenate the protected the hydroxyl and alkylation. Kiuchi M and Gunter S reported multi-steps synthetic routes, rare materials, the high requirements of the equipment, operation difficultly with a total low yield and high-cost. Durand P reports an easy route and its raw materials is easy to get.The yield of key intermediates 5 is 33.3% and FTY-720 is 15.9% .The synthesis of compound 5 have designed by the author based onβ-phenylethanol as raw materials,via four-step reactions: thionyl chloride generated the first to get phenylethyl chloride,then octanoyl Friedel-Crafts acy-lation, halogenated , acetamidobenzoic dietnylmalonate alkylation, reduction carbonyl, the yield is 48.4% which is higher than Durand P. reported of 33.3%.When synthesized from compounds 6 to 7 then hydrolyzed to 8, not to protect the hydroxyl and directly hydrolysis from 6 to 8.The raw materials are easy to get, with a total yield of 23.1% which is higher than Durand P reported of 15.9% .Reaction process is simple to operate, suitable for industrial production. The structures of the key intermediates and the final compound are confirmed by MS, 1H-NMR and 13C-NMR.The eight-step synthesis of novel immunosuppressant FTY-720 with high yield,low costs was described by the author in this paper and suitable for industrial production, bringing good news to the large number of organ transplant patients and patients with autoimmune diseases.