Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind

An antithrombin and non-peptide technology, which is applied in the field of synthesis of new antithrombin inhibitors, can solve the problems of low total yield, high price, and low yield, and achieve high total yield and short route , the effect of separating simple

Inactive Publication Date: 2009-07-08
FUDAN UNIV
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  • Abstract
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Problems solved by technology

[0010] Utilize this method, start with the raw material 1 with higher price, have used N,N-dimethylformamide (DMF) that post-treatment is troublesome as solvent to synthesize compound 2; Compound 4 is synthesized compound 5 under the effect of CDI, And after acid hydrolysis of compound 5, add (NH 4 ) 2 CO 3 Compound 6 is obtained by ammoniation, and the two-step yield is low, which brings inconvenience to production
And the overall yield of this synthetic route is low (11.1%)

Method used

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  • Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind
  • Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind
  • Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Synthesis of ethyl 3-(pyridine-2-imine)-propionate (10)

[0040]Under the protection of nitrogen, add ethyl acrylate (27.5 g, 0.275 mol) to compound 9 (A=H, X=N) - 2-aminopyridine (22.5 g, 0.25 mol), stir and reflux at higher than 100 ° C After 24 hours, the precipitate was filtered off, and the residue was concentrated and purified by a silica gel column to obtain a white solid 10 (38 g, 72%).

[0041] Synthesis of 1-(4-cyano-phenylimine)-acetic acid (12)

[0042] Add 150ml of water to compound 11 (6.0g, 0.05mol) and 1-chloroacetic acid (10g, 0.11mol) and heat to reflux until a large amount of yellow solid precipitates, filter at room temperature, and rinse with water, absolute ethanol, and anhydrous ether, respectively. After washing, yellow solid 12 (6.4 g, 73%) was obtained.

[0043] Synthesis of 4-aminomethyl-3-nitro-benzoic acid (1)

[0044] 150ml of 25%-30% methylamine aqueous solution was added to compound 13 (25g, 0.124mol), and the system was reacted at a t...

Embodiment 2

[0060] Synthesis of ethyl 3-(4-fluorophenyl-1-imine)-propionate (10')

[0061] Under nitrogen protection, add ethyl acrylate (27.5 g, 0.275 mol) to compound 9' (A=F, X=H) - 4-fluoroaniline (23.5 g, 0.25 mol), add 10 ml of absolute ethanol and 10 ml of Triethylamine was stirred and refluxed at higher than 100°C for 24h, the precipitate was filtered off, and the residue was concentrated and purified by a silica gel column to obtain a light red solid 10' (43g, 77%).

[0062] Synthesis of 3-[(4-aminomethyl-3-nitro-benzoyl)-(4-fluorobenzene)-2-imine]-propionic acid ethyl ester (3')

[0063] Compound 10' (10.5g, 0.05mol) was dissolved in 30ml CH 2 Cl 2 and 30ml triethylamine, slowly add the CH of compound 2 at room temperature 2 Cl 2 solution. The mixed system was reacted at room temperature for 12 h, the precipitate was filtered off, and the residue was concentrated and purified by a silica gel column to obtain a yellow oily liquid 3' (19.0 g, 98%).

[0064] Synthesis of 3-[(...

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Abstract

The invention belongs to the field of chemical synthesis, and relates to a synthesis method of an inhibitor containing a heterocyclic compound, especially an achiral, a Synthesis of peptide antithrombin inhibitors. The present invention uses cheap and easy-to-obtain 3-nitro-4-chlorobenzoic acid as a starting material, a highly efficient and high-yield synthetic raw material compound and a condensing agent with better effect to finally synthesize the target compound antithrombin inhibitor BIBR- 953 and BIBR-1048 and its analogs. The method of the invention has simple step operation and separation, high yield of each step, cheap and easy-to-obtain reagents, short route and high total yield of the target compound, which is nearly 50%.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a method for synthesizing inhibitors containing heterocyclic compounds, especially a novel antithrombin with 1,2,5-trisubstituted benzimidazole as the central skeleton or a fluorine atom Synthesis of Inhibitors. Background technique [0002] Thromboembolism is a leading cause of disease and death in Western societies. An important cause of this symptom is the overexpression of hemagglutination. Coagulation behavior involves two crucial steps, including: 1). Prothrombin complex activation generates thrombin; 2). Thrombin hydrolyzes fibrinogen to form insoluble fibrous coagulum. In addition, thrombin mediates platelet activation, which triggers a wide range of thrombogenic secondary effects, such as proliferation of vascular smooth muscle cells and fibroblasts, monocyte chemotaxis, and neutrophil adhesion. [0003] Current clinical anticoagulant therapy mainly includes the use of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
Inventor 林国强马景毅徐亮孙逊孙智华王进义
Owner FUDAN UNIV
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