Timolol maleate compound and preparation method thereof

Abstract

The invention provides a timolol maleate compound and a preparation method thereof, and the method comprises the following steps: sequentially adding a methanol and ethanol mixed solution and timolol maleate into a reaction pot, and starting stirring for dissolving; cooling to 20-24 DEG C, slowly adding a mixed solution of diethyl ether and cyclohexane while stirring, and continuously stirring after adding to obtain a material; and transferring to a crystallization kettle, cooling to 2-4 DEG C at a speed of 4-5 DEG C / min, filtering to obtain a filter cake, drying, and crushing the filter cake to obtain the timolol maleate dihydrate. The inventor accidentally obtains the novel timolol maleate compound and the preparation method thereof in a large number of research processes on timolol maleate for a long time, and the timolol maleate compound prepared by the method has extremely high quality stability, and the hygroscopicity is reduced.

Description

Technical Field

[0001] The invention relates to the field of compounds, in particular to a timolol maleate compound and a preparation method thereof. Background Art

[0002] Timolol maleate, chemical formula is C 17 H 28 N4O7S, chemical name: (-)-1-(tert-butylamino)-3-[(4-morpholinyl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate, is a β-adrenergic receptor blocking drug. The commonly used dosage forms in clinical practice are tablets and eye drops. Timolol maleate eye drops are used to treat glaucoma: no membrane stabilization effect, no local anesthetic effect, can reduce aqueous humor production, significantly reduce intraocular pressure, especially for primary open-angle glaucoma. The intraocular pressure begins to drop 20 minutes after the eye drops are applied, and the maximum effect is achieved after 1 to 2 hours, and the effect can last for 24 hours. It has no effect on pupil size, light reaction and vision. Timolol maleate eye drops have significant efficacy and are widely used in clinical practice. Further improving the quality of timolol maleate has positive significance for its clinical use.

[0003] The inventors unexpectedly obtained a new timolol maleate compound and a preparation method thereof during a long-term and extensive study on timolol maleate. The timolol maleate compound prepared by the method has extremely high quality stability and reduced hygroscopicity, which is significantly superior to the prior art. Summary of the invention

[0004] The invention aims to provide a timolol maleate compound and a preparation method thereof. The compound is timolol maleate dihydrate, has good stability and low hygroscopicity, is convenient for the preparation of pharmaceutical preparations, and improves the safety of medication.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] In a first aspect of the present invention, a method for preparing timolol maleate dihydrate is provided, the method comprising:

[0007] S1. Add a mixed solution of methanol and ethanol and timolol maleate into a reaction pot in sequence, and stir to dissolve; wherein the weight ratio of the mixed solution of timolol maleate, methanol and ethanol is 1:(2-3); the weight ratio of methanol and ethanol is: methanol:ethanol=4:1;

[0008] S2, cooling to 20-24°C, slowly adding a mixed solution of ether and cyclohexane while stirring, and continuing to stir after adding to obtain a material; wherein the amount of the mixed solution added is 6-8 times the weight of the mixed solution of methanol and ethanol in S1; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1

[0009] S3, transferring the material obtained in S2 to a crystallization kettle, cooling the temperature to 2-4°C at 4-5°C / min, filtering to obtain a filter cake, and washing the filter cake with ether;

[0010] S4, drying the filter cake obtained in S3 and then crushing the filter cake to obtain timolol maleate dihydrate.

[0011] Furthermore, in S1, the weight ratio of the mixed solution of timolol maleate, methanol and ethanol is 1:2.5.

[0012] Furthermore, in S2, the weight of the mixed solution of ether and cyclohexane is 7 times the weight of the mixed solution of methanol and ethanol in S1.

[0013] Furthermore, in S2, the stirring speed is maintained at 110 to 130 rpm.

[0014] Furthermore, in S3, during the washing, the filter cake is washed twice with 2 times the weight of ether.

[0015] Furthermore, in S4, the drying condition is: drying at 58° C. to 64° C. for 6-8 hours.

[0016] In the second aspect of the present invention, provided is timolol maleate dihydrate prepared by the method.

[0017] The timolol maleate dihydrate of the present invention has the molecular formula: 17 H 28 N4O7S·2H2O.

[0018] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0019] 1. The present invention provides a timolol maleate dihydrate and a preparation method thereof. The inventors unexpectedly obtained a new timolol maleate dihydrate and a preparation method thereof during a long-term and extensive study on timolol maleate. The timolol maleate dihydrate prepared by the method has extremely high quality stability and reduced hygroscopicity, which is significantly superior to the prior art.

[0020] 2. In the preparation method of timolol maleate dihydrate provided by the present invention, the ratio of timolol maleate, methanol, ethanol, ether and cyclohexane, the reaction temperature, the cooling rate, the time and the like are crucial to obtaining the timolol maleate compound of the present invention. According to a large number of experiments conducted by the applicant, the timolol maleate compound described in the present invention cannot be obtained by changing the relevant parameters of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description are some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0022] Figure 1 This is the X-ray powder diffraction pattern of the timolol maleate compound prepared in Example 1. DETAILED DESCRIPTION

[0023] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0024] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0025] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained by existing methods.

[0026] The timolol maleate used can be synthesized according to known techniques or purchased from the market.

[0027] The present application will be described in detail below with reference to embodiments and experimental data.

[0028] Example 1. Preparation of Timolol Maleate Compound

[0029] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 4:1;

[0030] (2) Cooling to 20°C, maintaining a stirring speed of 110 rpm, slowly adding 150 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1;

[0031] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 2°C at 4°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0032] (4) The filter cake obtained in step (3) was placed in a drying oven at 58° C. and dried for 6 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0033] X-ray powder diffraction pattern is attached Figure 1 .

[0034] Example 2 Preparation of Timolol Maleate Compound

[0035] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 4:1;

[0036] (2) Cooling to 22°C, maintaining a stirring speed of 120 rpm, slowly adding 175 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1;

[0037] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 3°C at a rate of 4.5°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0038] (4) The filter cake obtained in step (3) was placed in a drying oven at 61° C. and dried for 7 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0039] The X-ray powder diffraction pattern was consistent with that of Example 1.

[0040] Example 3 Preparation of Timolol Maleate Compound

[0041] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 4:1;

[0042] (2) Cooling to 24°C, maintaining a stirring speed of 130 rpm, slowly adding 200 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1;

[0043] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 4°C at a rate of 5°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0044] (4) The filter cake obtained in step (3) was placed in a drying oven at 64° C. and dried for 8 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0045] The X-ray powder diffraction pattern was consistent with that of Example 1.

[0046] Comparative Example 1

[0047] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 5:1;

[0048] (2) Cooling to 20°C, maintaining a stirring speed of 110 rpm, slowly adding 150 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 6:1;

[0049] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 2°C at 4°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0050] (4) The filter cake obtained in step (3) was placed in a drying oven at 58° C. and dried for 6 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0051] Comparative Example 2

[0052] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 4:1;

[0053] (2) Cooling to 20°C, maintaining a stirring speed of 110 rpm, slowly adding 125 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1;

[0054] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 2°C at 4°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0055] (4) The filter cake obtained in step (3) was placed in a drying oven at 58° C. and dried for 6 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0056] Comparative Example 3

[0057] (1) 25 kg of a mixed solution of methanol and ethanol and 10 kg of timolol maleate were added to a reaction pot in sequence and stirred to dissolve; the weight ratio of methanol to ethanol was: methanol: ethanol = 4:1;

[0058] (2) Cooling to 24°C, maintaining a stirring speed of 140 rpm, slowly adding 150 kg of a mixed solution of ether and cyclohexane while stirring, and continuing to stir for 30 minutes after the addition; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1;

[0059] (3) The material of step (2) was transferred to a crystallization kettle, cooled to 1°C at 6°C / min, filtered to obtain a filter cake, and the filter cake was rinsed twice with 2 times the weight of ether;

[0060] (4) The filter cake obtained in step (3) was placed in a drying oven at 58° C. and dried for 6 hours, then the filter cake was crushed to obtain a timolol maleate compound.

[0061] Experimental Example 1: Study on the properties of timolol maleate dihydrate

[0062] 1. Elemental analysis

[0063] The elemental analysis of the timolol maleate dihydrate prepared by the method of the embodiment of the present invention was performed, and the results were: C: 43.57%, H: 6.85%, N: 11.94%, S: 6.86% (accurate to two decimal places), which is consistent with the theoretical value of timolol maleate dihydrate. The theoretical value of timolol maleate dihydrate is: C: 43.59%, H: 6.84%, N: 11.96%, S: 6.84% (accurate to two decimal places).

[0064] 2. Differential thermal analysis

[0065] The timolol maleate dihydrate prepared by the method of the present invention was subjected to differential thermal analysis and compared with timolol maleate, a raw material for preparing timolol maleate dihydrate. The results showed that timolol maleate dihydrate had an absorption peak between 140 and 145° C., indicating that there was crystal water or crystallization solvent in the sample, while the reference substance had no absorption peak, indicating that there was no crystal water or crystallization solvent in the sample.

[0066] 3. Moisture analysis

[0067] The water content of the timolol maleate dihydrate of the present invention was measured by Karl Fischer water determination method, and the result was between 7.70% and 7.72%, which was consistent with the theoretical water content of timolol maleate dihydrate of 7.69%, and the two results were consistent. This indicates that the sample contains only water and no other solvents.

[0068] Comprehensive elemental analysis, differential thermal analysis, and water analysis results can prove that the timolol maleate of the present invention contains 2 molecules of crystal water.

[0069] 4. Experimental comparative analysis

[0070] Sample 1: the timolol maleate compound prepared in Example 1 of the present invention;

[0071] Sample 2: Timolol maleate raw material;

[0072] 4.1 Characteristic Study:

[0073] Samples 1-2 were subjected to characteristic research according to the test method of this application. The results are shown in Table 1

[0074] Table 1 Results of the study on the properties of timolol maleate

[0075]

[0076] 4.2 Stability and high humidity test:

[0077] Samples 1-2 were placed under high temperature (60°C), high humidity (RH92.5%±5%), and light (4500lx) conditions for 10 days. Samples were taken on the 10th day to examine the content and moisture content. The results were compared with those on day 0, see Table 2.

[0078] Table 2 Test results of factors affecting timolol maleate dihydrate

[0079]

[0080] The test results in Table 2 show that timolol maleate dihydrate has good stability and low hygroscopicity. The same test was carried out in other embodiments of the present invention and similar results were obtained.

[0081] It can be seen from Table 1-2 that the timolol maleate dihydrate prepared by the present invention has lower hygroscopicity than the anhydrous timolol maleate. Generally, the order of hygroscopicity is hydrate>anhydrous>organic solvate. The timolol maleate compound prepared by the present invention has achieved unexpected technical effects.

[0082] Test Example 2: Comparison of groups

[0083] The timolol maleate compounds prepared in Examples 1-3 of the present invention and Comparative Examples 1-3 were investigated for properties, hygroscopicity and accelerated test stability (40°C ± 2°C, RH 75% ± 5%, placed for 3 and 6 months). The results are shown in Tables 3-5.

[0084] Table 3 Characteristic study

[0085]

[0086] Table 4 Moisture absorption test (RH92.5%±5% for 10 days)

[0087]

[0088] Table 5 Accelerated test results

[0089]

[0090] It can be seen from the results in Tables 3-5 that the timolol maleate compound prepared by the present invention has good stability and low hygroscopicity and has obvious advantages over the prior art. The preparation process parameters of the timolol maleate compound of the present invention are crucial, and even a slight change cannot obtain the timolol maleate compound of the present invention.

[0091] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0092] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0093] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A timolol maleate compound, characterized in that: The timolol maleate compound is timolol maleate dihydrate, and the molecular formula is C 17 H 28 N4O7S·2H2O.

2. The timolol maleate compound according to claim 1, characterized in that The timolol maleate compound is a crystal, and its characteristic peaks in the spectrum are shown in FIG1 , as determined by X-ray powder diffraction.

3. A method for preparing a timolol maleate compound according to claim 1 or 2, characterized in that: The method comprises: S1. Add a mixed solution of methanol and ethanol and timolol maleate into a reaction pot in sequence, and stir to dissolve; wherein the weight ratio of the mixed solution of timolol maleate, methanol and ethanol is 1:(2-3); the weight ratio of methanol and ethanol is: methanol:ethanol=4:1; S2, cooling to 20-24°C, slowly adding a mixed solution of ether and cyclohexane while stirring, and continuing to stir after adding to obtain a material; wherein the amount of the mixed solution added is 6-8 times the weight of the mixed solution of methanol and ethanol in S1; the weight ratio of the mixed solution of ether and cyclohexane is: ether: cyclohexane = 7:1; S3, transferring the material obtained in S2 to a crystallization kettle, cooling the temperature to 2-4°C at 4-5°C / min, filtering to obtain a filter cake, and washing the filter cake with ether; S4, drying the filter cake obtained in S3 and then crushing the filter cake to obtain timolol maleate dihydrate.

4. The preparation method according to claim 3, characterized in that: In S1, the weight ratio of the mixed solution of timolol maleate, methanol and ethanol is 1:2.

5.

5. The preparation method according to claim 3, characterized in that: In S2, the weight of the mixed solution of ether and cyclohexane is 7 times the weight of the mixed solution of methanol and ethanol in S1.

6. The preparation method according to claim 3, characterized in that: The stirring speed in S2 is maintained at 110-130 rpm.

7. The preparation method according to claim 3, characterized in that: The filter cake was rinsed in S3 and rinsed twice with 2 times the weight of ether.

8. The preparation method according to claim 3, characterized in that: The drying conditions in S4 are: drying at 58° C. to 64° C. for 6-8 hours.

9. Timolol maleate dihydrate prepared by the method according to any one of claims 3 to 8.

Images