The Synthesis Of The Derivatives Of 4-amidino-benzylamine

Factor Xa (Fxa) is a trypsin-like serine protease and plays a pivotal role in the blood coagulation cascade. Recent researches have indicated that FXa is a very attractive target. FXa and its inhibitors are of great importance to the development of orally active antithrombotic agents.The traditional anticoagulants, such as warfarin,heparin and low molecular weight heparin, in the prevention and treatment of arterial and venous thromboembolic disorders, have some disadvantages. Therefore alternatives are sought with low molecular weight inhibitors of the coagulation enzymes, especially of thrombin and FXa. A particular advantage of FXa inhibitors in comparison with thrombin inhibitors could be the lower tendency to bleeding which has been shown in various animal experiments. Thus the bleeding time is only minimally influenced in antithrombotically effective doses.In the recently, some reaserches find that the pharmacophore molecule models of these compounds which have a oral activity are with characteristics of peptide. For example, the new listed FXa inhibitor Ximelagatran which conjunct a dericative of 4-amidino benzylamine in the dipeptide molecule of carbon side. Such compounds are one of the new hot spots of study reaserch and expected to reaserch and develop for a high activity and selective factor Xa inhibitor which can be treatmented for cardiovascular disease and thrombotic events.This paper attempts to synthesize the group of anticoagulant of dipeptide compounds, Benzylsulfonyl-Ser(Bz)-Gly-4-amidinobenzylamide and its derivatives. After experimental methods of synthesis, we gain the main intermediates, which give reliable experimental datas and methods for further reaserch.Objective: The aim is to synthesize the dericatives of 4-amidino-benzylamine.Methods: In this paper, you will see the part of synthesis of dipeptide compound with active to inhibitting blood-clotting. The starting compound 4-cyanobenzylamine(â…¢) is prepared from 4-cyanobenzyl chlorine(â… ) via Gabriel synthesis. The Boc-protected acetyloxamidino-benzylamine(â…£) is obtained from the 4-cyanobenzylamine and reacts with hydroxylanine hydrochloric acid. The Boc on the Boc-4-acetyloxamidino-benzylamide(â…¥) which gained from the last procedure is removed in HCl/AcOH and reacts with a amino acid. Then couple with the glycine and serine which have a Boc protection to obtain compoundsâ…¨and compoundsâ…©â…£Now there are two reaction lines to the following reaction:(1)In literature the acetoxy on the compoundsâ…¨andâ…©â…£can be removed with catalytic hydrogenation(10%Pd/C). Then remove the Boc protection group with HCl/AcOH or F₃CCOOH and couple with another amino acid. (2)We don't know the degree of catalytic hydrogenation and directly do the next reaction. Finally, remove the acetoxy on the compoundsâ…¨andâ…©â…£with catalytic hydrogenation. In the two lines of the reactions, most of the products crystallize well and can be simply purified. The purification of the target compound is carried out in the last stage by means of preparative reversed-phase HPLC. We attempted to use column chromatography and thin layer chromatography to gain the pure products, but failed. The part of separation need further reaserch.The goal of this kind of inhibitor is suitable for oral with high effectiveness and bioavailability.Results: 1.The synthesis of the dericatives of 4-amidino-benzylamine and some amino acids with the protection group are accomplished and the synthetic conditions are optimized.2. The ¹H-NMR of some compounds(1)The ¹H-NMR of compoundâ…¥Name: Boc-4-acetyloxamidinobenzylamide The date of synthesis:061208 Solvent:CDCl₃δ(ppm):1.46(9H, s, -Boc), 2.25(3H, s, -CH3), 4.34(2H, d, -CH2-), 4.92(1H, s, -NH-), 5.08(2H, s, -NH2), 7.29(2H, d, Ar-H), 7.66(2H,d,Ar-H)(2)The ¹H-NMR of compoundâ…¨ Name: Boc-Gly-4-acetyloxamldinobenzylamide The date of synthesis: 070508 Solvent:CDCl₃δ(ppm)1.43(9H,s,-Boc),2.22(3H, s, -CH₃), 3.78-3.79(2H, d,-CH₂-), 4.38-4.40(2H,d,-CH₂-),5.28(2H, s, -NH₂), 5.44(1H, s,-NH-), 7.03(1H, t, -NH-),7.23(2H, d, Ar-H), 7.55(2H, d, Ar-H)(3)The ¹H-NMR of compoundâ…©â…£Name: Boc-Ser-4-acetyloxamldinobenzylamide The date of synthesis: 071115 Solvent:d-DMSOδ(ppm):1.40(9H, s, -Boc), 2.13(3H, s, -CH₃), 3.61(2H, t, -CH₂-OH), 4.00(1H, q, -CH-), 4.33(2H, m, -CH₂-), 4.88(1H, t, -OH), 6.71(1H, d, -NH-), 6.79(2H, s, -NH₂), 7.31(2H, d, Ar-H), 7.43(4H, d, Ar-H), 8.42(H, t, -NH-)(4)The ¹H-NMR of compoundâ…«Name: Benzylsulfonyl-Ser-OH The date of synthesis: 070807 Solvent:d-DMSOδ(ppm):3.62(2H, d, -CH₂-), 3.89(H, m, -CH), 4.33(H, s, -CH-), 5.01 (H, s, -NH-), 7.35-7.41 (1H, -OH), 7.35-7.41 (5H, m, Ar-H)Conclusion: 1.The dericatives of 4-amidino-benzylamine are synthesized. The synthesis can be runned smoothly and efficiently on a large scale. The materials are cheap and available easily.2. Some amino acids with the protection group are synthesised, which is of great significance to continue to reaserch the subject.