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A kind of production method of anticoagulant drug intermediate

A tungsten disulfide, modified technology, applied in chemical instruments and methods, chemical/physical processes, physical/chemical process catalysts, etc. The particle size is uniform, the particle size is large, and the effect of reducing production costs

Inactive Publication Date: 2020-09-22
THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Therefore, although there are a large number of documents reporting on this reduction step at present, it does not solve the common problems at present: 1. The noble metal catalyst is easy to be poisoned, and the traditional metal reduction consumes a large amount, which produces a large amount of metal waste water and causes great environmental pollution; 2. Catalyst reaction selection Poor properties, resulting in a large number of by-products (mainly incompletely reacted transition states, such as hydroxylamine, dimers in different states), the product is mostly oily, which is inconvenient to separate, and high-purity solid products cannot be obtained; Potential impurities generated during the reaction have not been studied in detail, and the reaction cannot be optimized from the reaction process

Method used

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  • A kind of production method of anticoagulant drug intermediate
  • A kind of production method of anticoagulant drug intermediate
  • A kind of production method of anticoagulant drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of tungsten disulfide modified Pt / Ni bimetallic highly dispersed nanocatalyst:

[0043] 1) Add different molar amounts of platinum acetylacetonate (Pt(acac) 2 ), nickel acetylacetonate (Ni(acac) 2 ) and tungsten disulfide (WS 2 ) dispersed in a mixed solution of oleylamine and tetrahydrofuran (calculated by volume: oleylamine / tetrahydrofuran=90:10) and heated to 100-120°C and stirred for 0.5h to obtain a brown-yellow mixed solution; each gram of the composition (Pt(acac) 2 、Ni(acac) 2 and WS 2 Three gross weights and) the amount that adds the mixed solution of oleylamine and tetrahydrofuran is 8ml;

[0044] 2) Transfer the brown-yellow mixed liquid to the high-pressure reactor, feed nitrogen, replace the air in the high-pressure reactor with nitrogen three times, and then replace the nitrogen in the high-pressure reactor with hydrogen for three times, and raise the temperature to 200±20°C after the replacement , pass in hydrogen and react for 1-2h under...

Embodiment 2

[0050] Catalytic performance evaluation is carried out to the catalyst of the different proportioning ratio that above-mentioned embodiment prepares, and method is as follows: Add 3-[(4-methylamino-3-nitro-benzamide group) (pyridine-2- base)] ethyl propionate (3.72g, 10mmol, HPLC purity is 98.9%), anhydrous methanol 50ml, the different catalysts (0.372g, 10wt%) that embodiment 1 prepares, adopt the air in the nitrogen replacement kettle, then adopt hydrogen Replace the nitrogen in the kettle, feed hydrogen, and react at 45°C under a hydrogen pressure of 1MPa. When the substrate is no longer converted and the product is no longer increased by HPLC detection, the reaction is stopped to calculate the conversion rate of the substrate and the selectivity of the target product. Statistics The results are shown in Table 2:

[0051] Catalytic effect of different catalysts in table 2

[0052] sequence catalyst Reaction time / h Conversion rate / % selectivity / % 1 C...

Embodiment 3

[0055] After identifying the Cat-Pt 80 / Ni 10 / W 5 When being a catalyst, the influence of different solvents, different hydrogen pressures, and different catalyst consumptions (based on the weight of the substrate) on the reaction was investigated, and the preparation process is as follows:

[0056] Add ethyl 3-[(4-methylamino-3-nitro-benzamido)(pyridin-2-yl)]propionate (3.72g, 10mmol, HPLC purity 98.9%) to the high-pressure hydrogenation reactor , solvent 50ml, Cat-Pt 80 / Ni 10 / W 5 (0.372g, 10wt%), adopt nitrogen to replace the air in the still, then adopt hydrogen to replace the nitrogen in the still, pass into hydrogen and react at 45°C under different hydrogen pressures, HPLC detects that when the substrate is no longer converted and the product is no longer increased , stop the reaction to calculate the substrate conversion rate and the selectivity of the target product, and the statistical results are as shown in Table 3:

[0057] Table 3 The influence of differe...

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Abstract

The invention belongs to the technical field of the preparation of new drugs, and particularly relates to a production method of an anticoagulant drug dabigatran etexilate intermediate. According to the method, platinum is taken as a main catalyst, nickel is taken as a second catalyst, tungsten sulfide is taken as a catalyst additive, so as to form a high-dispersion nano-catalyst, 3-[(4-methylamino-3-nitryl-benzamido) (pyridine-2-base)] ethyl propionate can be efficiently catalyzed under low pressure to produce 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino] ethyl propionate, almost 100 percent conversion is basically realized, and the product selectivity reaches greater than 97 percent.

Description

technical field [0001] The invention belongs to the technical field of new drug preparation, and in particular relates to a production method of an anticoagulant drug dabigatran etexilate intermediate. Background technique [0002] Dabigatran etexilate, the chemical name is 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl Base-1H-benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] ethyl propionate, the medicinal ingredient is its mesylate, and the structural formula is as shown in formula (1): [0003] [0004] The drug is a new type of oral anticoagulant drug developed by Boehringer Ingelheim, Germany. It is a non-peptide thrombin inhibitor. Dabigatran etexilate is the prodrug of dabigatran, which is converted into dabigatran with direct anticoagulant activity under the action of enzymes in the body, and the latter binds to the fibrin-specific binding site of thrombin to prevent fibrin Cleavage of proproteins to fibrin blocks the final s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01J27/045C07D213/75
CPCB01J27/045C07D213/75
Inventor 王景浩张逸强高瑞王波刘佳琪
Owner THE FIRST AFFILIATED HOSPITAL OF JINAN UNIV
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