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Process for refining bendazac lysine and analogs thereof

A technology of analogues, bentaxic acid, which is applied in the field of chemical drug preparation, can solve problems such as poor removal of impurities, impact on the quality of bentaxaric acid, and products that do not meet quality requirements, achieving short reaction time and low impurity Less, good crystal form effect

Inactive Publication Date: 2011-10-05
JILIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Further studies have found that, in the refining process of this synthesis method, salt is formed in an aqueous solution of ethanol, and then recrystallized in an aqueous solution of ethanol. Such a refining method makes the above-mentioned impurities not well removed, even according to this method. Recrystallization, the resulting product still does not meet the quality requirements, seriously affecting the quality of Bendalysine

Method used

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  • Process for refining bendazac lysine and analogs thereof
  • Process for refining bendazac lysine and analogs thereof
  • Process for refining bendazac lysine and analogs thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the comparison of the implementation effect of salt-forming solvent and recrystallization solvent

[0041] 1. Comparison of salt-forming solvents:

[0042] 141g (0.5mol) of bentacic acid (0.5mol) and 73g (0.5mol) of L-lysine were weighed in 5 parts respectively, added in the reactor successively, and then respectively measured 90% (v / v) methanol, ethanol, acetone, Aqueous solutions of tetrahydrofuran and acetonitrile were sequentially added to the reactor, stirred, heated to reflux for 10 minutes, filtered hot, the filtrate was cooled to room temperature, filtered, and the filter cake was dried and weighed to obtain a crude product. The relevant experimental data are shown in Table I.

[0043] Table I

[0044]

[0045] Data in table 1 shows: compare two kinds of polar protic solvents of methanol and ethanol, use acetone, THF, acetonitrile three kinds of polar aprotic solvents in the salt-forming step, the related substance of gained product is low, an...

Embodiment 2

[0054] Embodiment 2: the comparison of salt-forming solvent concentration

[0055] 282 grams (1mol) of benzylic acid, 146 grams (1mol) of L-lysine, and the aqueous solution of acetonitrile were placed in the reactor together, stirred, heated to reflux for 10 minutes, heated and filtered, the filtrate was cooled to room temperature, filtered, and The filter cake was dried to obtain the crude product, which was weighed. The relevant experimental data of different aqueous solutions of acetonitrile (v / v) are shown in Table IV.

[0056] Table IV

[0057]

[0058] Data in Table IV shows that when the acetonitrile concentration is 90-95% (v / v), the volume of the reaction solution is moderate, and the related substances of the resulting product are low, the content is high, and the productive rate is high.

Embodiment 3

[0059] Embodiment 3. Comparison of recrystallization solvent concentration

[0060] Weigh the crude product obtained in Experiment 6-3 in the previous step, weigh 4 parts, each 100g, add to the reactor respectively, add aqueous solutions of ethanol with different concentrations (v / v), stir, heat and reflux for 10 minutes, and heat filter , the filtrate was naturally cooled to room temperature, placed for 12 hours, filtered, washed with absolute ethanol, dried, collected, and weighed. The experimental data obtained are shown in Table V.

[0061] Table V

[0062]

[0063] The data in Table V shows that: when the ethanol concentration is 91-94% (v / v), the volume of the reaction solution is moderate, the related substances of the obtained product are low, the content is high, and the yield is high.

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Abstract

The invention provides a process for refining bendazac lysine and analogs thereof, belonging to the technical field of chemical drug preparation. The process comprises the steps of adopting bendazac or bendazac analogs and L-lysine or L-histidine as raw materials; reacting the raw and salifying the materials in an aqueous solution of a polar aprotic solvent so as to obtain a crude product; and then recrystallizing the crude product in an aqueous solution of a polar protic solvent, wherein the polar aprotic solvent preferably selected from acetonitrile while the polar protic solvent is preferably selected from ethanol. The bendazac lysine and the analogs thereof which are finally prepared by using the invention are both white crystalline powders with yield of more than 80% and content of 99.6-101%, wherein the content of 3-hydroxyl-1-benzyl indazole is lower than 0.1%; or even no 3-hydroxyl-1-benzyl indazole is detected; and the total content of impurities does not exceed 0.2%. The refining process provided by the invention has the advantages of simple method, mild condition, short reaction time, low product cost, high purity and high yield, is beneficial for large-scale production and can be also can be used for refining commercial bendazac lysine raw materials.

Description

technical field [0001] The invention relates to the technical field of preparation of chemical medicines, in particular to a refining process of bendalysine and its analogues. Background technique [0002] Cataract is a common and frequently-occurring disease of the elderly, and it is one of the main blinding eye diseases, which seriously affects the quality of life of the elderly. Except for cataract extraction surgery, previous drug treatments have not had a certain effect. [0003] Bendazac lysine (bendazac lysine, BDZL), chemical name: L-lysine (1-benzyl-1H-indazol-3-yl) acetate, its structural formula is as follows: [0004] [0005] Bendalysine was developed and researched by Angelini Pharmaceutical Group as an anti-cataract drug. It was first launched in Italy in 1983. There are two types of tablets and eye drops, and it has been marketed in many countries. As an aldose reductase inhibitor, the drug is not only effective for sugar cataracts, but also prevents and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/42C07D233/64C07C227/18C07D231/56C07C229/26
Inventor 王丽萍修志明
Owner JILIN UNIV
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