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Factor Xa is a serine protease, play a key role in the blood clotting process. Recent studies have shown, to the Xa factor can be used as a new target of anticoagulant drugs play an important role in the development of oral anticoagulants. The traditional anticoagulants such as warfarin, unfractionated heparin and low-molecular-weight heparin, there are a number of shortcomings in the prevention and treatment of arterial or venous thromboembolic disease. For example, warfarin overdose can cause bleeding in any part of the body, more common in the local tissues and organs (tumor, ulcer disease, cerebral aneurysms) bleeding; monitoring anticoagulant therapy process needs, and these drugs are generally orally active or oral low activity. Therefore, the search for the toxic side effects of thrombin inhibitors and factor Xa inhibitor, has become the new hot spot of recent studies. Factor Xa inhibitor and thrombin inhibitor, compared to their advantage: different animal tests, have lower bleeding tendency. Accordingly, in the effective dose of the anticoagulant, the bleeding time is the minimum, is a class of promising anti-clotting compounds. Recent studies have found that the use of oral factor Xa inhibitor peptide with the characteristics of its pharmacophore model molecule has a peptide bond. E.g. new oral listed directly anti-thrombin inhibitor ximelagatran, belonging to a new generation of anticoagulant drugs and in the C-terminal of the two peptide molecules, and even has an anticoagulant activity of the derivatives of 4 - amidino benzyl amine . These compounds is a new research focus, expected research and development to the treatment of cardiovascular disease and antithrombotic activity, highly selective factor Xa inhibitor anticoagulant. This paper attempts to design and synthesis of dipeptides anticoagulant compound benzylsulfonyl - seryl (benzyl) - Glycyl -4 - amidino benzyl amine and its derivatives. After the study of the experimental method, the synthesis has been the main intermediate target, to provide a reliable experimental methods of operation and data for further research. Objective: To establish 4. Amidino benzyl amine derivative of the synthesis method. Method: The paper design a synthesis method of these compounds: The compounds 4 - cyanobenzyl chloride as raw materials, to give 4 - cyanobenzylamine by the Gabe Riel reaction, then tert-butyl dicarbonate (di -Boc), to give the Boc-protected 4 - cyano-benzylamine. And then reacted with hydroxylamine hydrochloride to give 4 - (N-acetoxy) amidino-N-t-butoxycarbonyl benzyl amine (VI). Compound (VI) in 1N HCl in acetic acid solution was stripped of the protective group, and then with glycine and serine condensation with Boc to give the compound (N-tert-butoxycarbonyl) glycyl [4 - (of N-acetyl oxy) amidino] benzyl amine (IX) and the compound (N-tert-butoxy carbonyl) seryl-[4 - (N-acetoxy) amidino] the benzylamine (Ⅹ IV). Compound Ⅸ Ⅹ Ⅳ subsequent reaction using two synthetic route: (1) literature methods: using a palladium / carbon above acetoxy compound obtained by catalytic hydrogenation, and then the Boc protecting group on the amino acid in a 1N HCl acetic acid solution or 90 Solutions% trifluoroacetic acid solution, and at last with a part of the group of the amino acid condensation; (2) Since in the subject process can not be determined whether the catalytic hydrogenation of the palladium / carbon, directly off of the amino acid on the compound Ⅸ Ⅹ Ⅳ Boc reaction, and then condensed with the amino acid with a part of the group, and finally subjected to catalytic hydrogenation. Two routes during the reaction most of the product easy purification, were used in the current literature on the handling of the final compounds by high performance liquid preparation method, the subject tries to use of column chromatography or thin chromatography, etc. separated and purified, but failed to give final compounds pure, pending further study of the part. The ultimate goal is to get that type of inhibitor studies have orally active and have efficient, high bioavailability compounds. Results: 1. The established method for the synthesis of 4 - amidino benzyl amine derivative, to improve the yield of the part of the intermediate product, reduce costs, reduce pollution, and synthesized with the protecting group of the amino acid and the intermediate (VI) and (X Ⅳ). 2. Some compounds 1 H-NMR data: (1) compound Ⅵ 1 H-NMR: Name: 4 - (N-acetoxy) amidino-(N- tert-butoxycarbonyl) benzylamine preparation date: 061 208 Solvent: the CDCl 3 chemical shift δ (ppm), and its hydrogen vest: 1.46 (9H, s, C-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) Compound IX 1 H-NMR: Name: N-tert-butoxycarbonyl Gan glycyl - acetyloxymethyl amidino benzylamine preparation date: 070 508 Solvent: CDCl 3 chemical shift δ (ppm), and its hydrogen vest: 1.43 (9H, s, C-Boc), 2.22 (3H, s,-CH 3 ) ,3.78-3 .79 (2H, d,-CH 2 -) ,4.38-4 .40 (2H, d ,-CH 2 -), 5.28 (2H, s,-NH 2 ), 5.44 (1H, s,-NH-), 7.03 (1H, t,-NH-), 7.23 (2H, d, Ar-H), 7.55 (2H, d, Ar-H) (3) Compound Ⅹ Ⅳ 1 H -NMR: Name: N-tert-butyl oxycarbonyl Jisi glycyl - acetoxymethyl amidino benzylamine Preparation Date: 07,115 solvent: d-DMSO chemical shift δ (ppm) and its hydrogen vest: 1.40 (9H, s, - Boc), 2.13 (3H, s,-CH 3 ), 3.61 (2H, t,-CH 2 -OH), 4.00 (1H , q,-CH-), 4.33 (2H, m,-CH 2 -), 4.88 (1H, t,-OH), 6.71 (1H, d, - NH-), 6.79 (2H, s,-NH 2 ), 7.31 (2H, d, Ar-H), 7.43 (4H, d, Ar-H), 8.42 (H, t,-NH-) (4) the compound Ⅻ 1 H-NMR: Name: N-benzyl sulfonamide - serine preparation date: 070 807 solvent: d-DMSO chemical shift δ (ppm) and its hydrogen vest: 3.62 (2H, d,-CH 2 -), 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: a result of this study is to establish the method for the synthesis of 4 - amidino benzyl amine derivative. The synthetic route used, raw materials readily available, easy to operate, easy to handle. 2 Synthesis of the part of the belt-protecting group of the amino acid, provides a reliable experimental methods and data for the subject to continue.
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