Preparation method and application of ligustrazine and salt thereof

Abstract

The invention provides a preparation method and application of ligustrazine and salts thereof. According to the method disclosed by the invention, a mode of dropwise adding part of reaction materials is adopted, so that the phenomenon of rapid temperature rushing in the preparation of ligustrazine is avoided, the risks of material spraying and explosion of a reaction system in large-scale production are avoided, and the personal safety is effectively protected. In addition, the method provided by the invention has the advantages of simple and easily available raw materials, low price, short reaction time, high total yield, good product purity, reduction of three wastes, energy conservation and environmental protection, and is especially suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a preparation method of ligustrazine and a salt thereof and application thereof. Background Art

[0002] Ligustrazine, also known as tetramethylpyrazine (see the structure of Formula I below), has the effects of anti-platelet aggregation, dilation of arterioles, improvement of microcirculation, blood circulation and blood stasis, and has a depolymerization effect on aggregated platelets. Currently, the marketed products include ligustrazine hydrochloride and ligustrazine phosphate, and the dosage forms include injections, dripping pills, capsules, tablets, etc. The therapeutic indications include occlusive cerebrovascular diseases such as cerebral insufficiency, cerebral thrombosis, cerebral embolism and other ischemic vascular diseases such as coronary heart disease, vasculitis, etc.

[0003]

[0004] The currently reported preparation methods of ligustrazine are not suitable for large-scale industrial production. The development of a production process of ligustrazine with the advantages of safety, environmental protection, energy saving, and high efficiency has important industrial value. Summary of the invention

[0005] An object of one aspect of the present invention is to provide a method for preparing ligustrazine, the method comprising:

[0006] (1) 3-Hydroxy-2-butanone reacts with ammonium acetate and hydrogen peroxide to generate ligustrazine, wherein the reaction solvent is water and the reaction temperature is 80-110°C.

[0007] (2) post-treatment to obtain ligustrazine,

[0008] In the step (1), any one of 3-hydroxy-2-butanone, ammonium acetate and hydrogen peroxide is added dropwise, or any two of 3-hydroxy-2-butanone, ammonium acetate and hydrogen peroxide are added dropwise to the reaction system separately and simultaneously or after mixing, dropwise.

[0009] The dropping is performed by first heating the reaction system to 60-70°C and then dropping, and the temperature is controlled not to exceed 90°C during the dropping process.

[0010] In a preferred embodiment of the present invention, the molar ratio of 3-hydroxy-2-butanone to ammonium acetate is 1:1.4-2.0, preferably 1:1.6-1.8, and more preferably 1:1.7.

[0011] In a preferred embodiment of the present invention, the content of hydrogen peroxide in hydrogen peroxide is 25-35 wt %, preferably 28-32 wt %, and more preferably 30 wt %.

[0012] In a preferred embodiment of the present invention, the molar ratio of 3-hydroxy-2-butanone to hydrogen peroxide is 1:0.2-0.8, preferably 1:0.4-0.6, and more preferably 1:0.57.

[0013] In a preferred embodiment of the present invention, the weight volume ratio (g / ml) of 3-hydroxy-2-butanone to water is 1:1.5-4.5, preferably 1:2-4, and more preferably 1:3.

[0014] In a preferred embodiment of the present invention, the reaction temperature of step (1) is 90-100°C.

[0015] In a preferred embodiment of the present invention, the reaction time of step (1) is 30 min-120 min, preferably 30 min-60 min, more preferably 30 min-45 min.

[0016] In a preferred embodiment of the present invention, the post-treatment of step (2) is specifically: cooling to crystallize, filtering, and washing the filter cake to obtain a solid.

[0017] In a preferred embodiment of the present invention, the temperature is lowered to -5 to 5°C for crystallization in step (2).

[0018] In a preferred embodiment of the present invention, the filter cake is washed with water in step (2).

[0019] In a preferred embodiment of the present invention, the specific operation of the method is: adding water to a reaction container, adding 3-hydroxy-2-butanone and ammonium acetate under stirring, heating to 60-70° C., adding hydrogen peroxide dropwise, reacting at 90-100° C. for 30 min-45 min, cooling and crystallizing, filtering, washing the filter cake, and obtaining a solid.

[0020] In a preferred embodiment of the present invention, the specific operation of the method is: dissolving ammonium acetate in a portion of purified water for standby use; adding the remaining purified water and hydrogen peroxide to a reaction container, adding 3-hydroxy-2-butanone under stirring, heating to 60-70° C., and dropwise adding the prepared ammonium acetate aqueous solution, reacting at 90-100° C. for 30-45 minutes after the dropwise addition, cooling for crystallization, filtering, and washing the filter cake to obtain a solid.

[0021] In a preferred embodiment of the present invention, the specific operation of the method is: dissolving 3-hydroxy-2-butanone in a portion of purified water for standby use; adding the remaining purified water and hydrogen peroxide to a reaction container, adding ammonium acetate under stirring, heating to 60-70° C., and dropwise adding the prepared 3-hydroxy-2-butanone aqueous solution. After the dropwise addition, reacting at 90-100° C. for 30 min-45 min, cooling for crystallization, filtering, and washing the filter cake to obtain a solid.

[0022] In a preferred embodiment of the present invention, the specific operation of the method is: dissolving ammonium acetate in a portion of purified water for standby use; adding the remaining purified water and 3-hydroxy-2-butanone to a reaction container, starting stirring, heating to 60-70° C., and simultaneously adding the prepared ammonium acetate aqueous solution and hydrogen peroxide solution dropwise, reacting at 90-100° C. for 30-45 minutes after the addition, cooling for crystallization, filtering, and washing the filter cake to obtain a solid.

[0023] In a preferred embodiment of the present invention, the time difference between the completion of the dropwise addition of the aqueous ammonium acetate solution and the hydrogen peroxide solution is no more than 5-20 minutes.

[0024] In a preferred embodiment of the present invention, the time difference between the completion of the dropwise addition of the aqueous ammonium acetate solution and the hydrogen peroxide solution is no more than 5-10 minutes.

[0025] In a preferred embodiment of the present invention, the specific operation of the method is: dissolving ammonium acetate in a portion of purified water for standby use, mixing the prepared aqueous ammonium acetate solution with hydrogen peroxide to form a mixed solution 1, adding the remaining purified water and 3-hydroxy-2-butanone to the reaction container, starting stirring, heating to 60-70° C., and dropwise adding the above mixed solution 1, after the dropwise addition, reacting at 90-100° C. for 30 min-45 min, cooling for crystallization, filtering, and washing the filter cake to obtain a solid.

[0026] In a preferred embodiment of the present invention, the prepared ligustrazine is further reacted with an acid to generate a ligustrazine salt.

[0027] Another object of the present invention is to provide application of the above preparation method in industrial preparation of ligustrazine.

[0028] Another object of the present invention is to provide the application of the above preparation method in the industrial preparation of ligustrazine salt.

[0029] In a preferred embodiment of the present invention, the prepared ligustrazine salt is ligustrazine phosphate.

[0030] In a preferred embodiment of the present invention, the prepared ligustrazine salt is ligustrazine hydrochloride.

[0031] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage (ml / g); when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage (g / ml); the rest are weight / weight percentages.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The raw materials for preparing ligustrazine of the present invention are simple, easily available, low in price, short in reaction time, high in overall yield and good in product purity. The process of the present invention reduces the generation of three wastes, is energy-saving and environmentally friendly, and is particularly suitable for large-scale production.

[0034] The present invention adopts the method of adding part of the reaction materials dropwise, thereby avoiding the rapid temperature surge phenomenon in the preparation of ligustrazine, avoiding the risk of material spraying and explosion in the reaction system in large-scale production, and effectively protecting personal safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Mass spectrum of ligustrazine prepared for Example 1.

[0036] Figure 2 This is the hydrogen spectrum of ligustrazine prepared in Example 1.

[0037] Figure 3 This is the carbon spectrum of ligustrazine prepared in Example 1. DETAILED DESCRIPTION

[0038] The following are some specific embodiments to illustrate the present invention. It is necessary to point out that the following specific embodiments are only used to further illustrate the present invention and do not limit the protection scope of the present invention. Some non-essential modifications and adjustments made by others based on the present invention still fall within the protection scope of the present invention.

[0039] The preparation process of ligustrazine of the present invention is as follows:

[0040]

[0041] Example 1 Preparation of Ligustrazine

[0042] To the reaction bottle, add 180ml purified water and 45g 30wt% hydrogen peroxide, add 60g 3-hydroxy-2-butanone and 90g ammonium acetate under stirring, heat to 90-100°C for 30min, TLC detection reaction is complete, cool to -5-5°C for crystallization, filter, and wash the filter cake with purified water to obtain 53.9g ligustrazine solid, with a water content of 23%, a ligustrazine yield of 89.5%, a purity of 98.3%, [M+H] + :137.1, 1 H-NMR(DMSO-d6): δ2.33(S,12H), 13 C-NMR (DMSO-d6): δ147.8, 20.9, mass spectrum, hydrogen spectrum, carbon spectrum are shown in Figure 1-3 A rapid temperature surge was observed in the reaction.

[0043] Example 2 Preparation of Ligustrazine

[0044] In a 100L reactor, 30kg purified water and 7.4kg 30wt% hydrogen peroxide were added, 10kg 3-hydroxy-2-butanone and 15kg ammonium acetate were added under stirring, the temperature was raised to 90-100°C for 30min, TLC detected that the reaction was complete, the temperature was lowered to -5-5°C for crystallization, filtered, and the filter cake was washed with purified water to obtain 9.2kg ligustrazine, with a water content of 24%, a ligustrazine yield of 90.5%, and a purity of 98.6%. It was observed that the reaction quickly rushed to about 130°C, and spraying occurred.

[0045] Example 3 Preparation of Ligustrazine

[0046] In a reaction flask, add 180ml of purified water, add 60g of 3-hydroxy-2-butanone and 90g of ammonium acetate under stirring, heat to 60-70°C, dropwise add 45g of 30wt% hydrogen peroxide, control the temperature during the dropwise addition to not exceed 90°C, after dropwise addition, react at 90-100°C for 30min, TLC detection shows that the reaction is complete, cool to -5-5°C for crystallization, filter, wash the filter cake with purified water, and obtain 53.2g of ligustrazine, with a water content of 22%, a ligustrazine yield of 89.5%, and a purity of 99.8%. The temperature of the reaction rises slowly and controllably during the dropwise addition.

[0047] Example 4 Preparation of Ligustrazine

[0048] 90g of ammonium acetate was dissolved in 100ml of purified water for standby use. 80ml of purified water and 45g of 30wt% hydrogen peroxide were added to the reaction bottle, 60g of 3-hydroxy-2-butanone was added under stirring, the temperature was raised to 60-70°C, and the prepared aqueous solution of ammonium acetate was added dropwise, the temperature of the addition process was controlled not to exceed 90°C, after the addition was completed, the reaction was carried out at 90-100°C for 30min, and the reaction was complete by TLC detection, the temperature was lowered to -5-5°C for crystallization, filtered, and the filter cake was washed with purified water to obtain 51.8g of ligustrazine, with a water content of 23%, a ligustrazine yield of 86.0%, and a purity of 99.7%. The temperature of the reaction rose slowly and was controllable during the addition process.

[0049] Example 5 Preparation of Ligustrazine

[0050] 60g 3-hydroxy-2-butanone was dissolved in 100ml purified water for standby use. 80ml purified water and 45g 30wt% hydrogen peroxide were added to the reaction bottle, 90g ammonium acetate was added under stirring, the temperature was raised to 60-70°C, and the prepared 3-hydroxy-2-butanone aqueous solution was added dropwise, the temperature of the addition process was controlled not to exceed 90°C, after the addition was completed, the reaction was carried out at 90-100°C for 30min, the reaction was completely detected by TLC, the temperature was lowered to -5-5°C for crystallization, filtered, and the filter cake was washed with purified water to obtain 53.3g ligustrazine, with a water content of 21%, a ligustrazine yield of 90.8%, and a purity of 99.9%. The temperature of the reaction rose slowly and was controllable during the addition process.

[0051] Example 6 Preparation of Ligustrazine

[0052] 90g of ammonium acetate was dissolved in 100ml of purified water for standby use. In a reaction flask, 80ml of purified water and 60g of 3-hydroxy-2-butanone were added, stirring was started, the temperature was raised to 60-70°C, and the prepared aqueous solution of ammonium acetate and 45g of 30wt% hydrogen peroxide were added dropwise at the same time, the temperature of the addition process was controlled not to exceed 90°C, and the difference in the end time of the two additions was not more than 5-10min, the dropwise addition was completed, the reaction was carried out at 90-100°C for 30min, the reaction was complete by TLC detection, the temperature was lowered to -5-5°C for crystallization, filtered, and the filter cake was washed with purified water to obtain 57.2g of ligustrazine, with a water content of 22%, a ligustrazine yield of 96.2%, and a purity of 99.8%. The temperature of the reaction rose slowly and was controllable during the addition process.

[0053] Example 7 Preparation of Ligustrazine

[0054] Dissolve 90g of ammonium acetate in 100ml of purified water, and mix the above solution with 45g of 30wt% hydrogen peroxide to form a mixed solution 1. Add 80ml of purified water and 60g of 3-hydroxy-2-butanone to the reaction bottle, start stirring, heat to 60-70°C, and dropwise add the above mixed solution 1. The temperature during the dropwise addition process is controlled not to exceed 90°C. After the dropwise addition is completed, react at 90-100°C for 30min. The reaction is complete by TLC detection, and the temperature is lowered to -5-5°C for crystallization, filtered, and the filter cake is washed with purified water to obtain 51.9g of ligustrazine, with a water content of 20%, a ligustrazine yield of 89.6%, and a purity of 99.7%. The temperature of the reaction rises slowly and controllably during the dropwise addition process.

[0055] Example 8 Preparation of Ligustrazine

[0056] 90kg of ammonium acetate was dissolved in 100kg of purified water for standby use. 80kg of purified water and 60kg of 3-hydroxy-2-butanone were added to a 500L reactor, stirring was started, the temperature was raised to 60-70°C, and the prepared aqueous solution of ammonium acetate and 45kg of 30wt% hydrogen peroxide were added dropwise at the same time, the temperature of the dropwise addition process was controlled not to exceed 90°C, and the difference in the end time of the two dropwise additions was not more than 5-10min. After the dropwise addition was completed, the reaction was carried out at 90-100°C for 30min, and the reaction was complete by TLC detection, and the temperature was lowered to -5-5°C for crystallization, filtered, and the filter cake was washed with purified water to obtain 58.1kg of ligustrazine, with a water content of 23%, a ligustrazine yield of 96.5%, and a purity of 99.9%. The temperature of the reaction rose slowly and was controllable during the dropwise addition process.

[0057] Example 9 Preparation of Ligustrazine Phosphate

[0058] Add 10 g of the wet product of ligustrazine prepared in Example 8 and 100 ml of anhydrous ethanol into the reaction bottle, stir to dissolve, add 7.2 g of phosphoric acid dropwise, stir for 30 min, cool to 0-10°C for crystallization, filter, and dry to obtain 12.47 g, with a yield of 91%.

[0059] Example 10 Preparation of Ligustrazine Hydrochloride

[0060] Add 10 g of the wet product of ligustrazine prepared in Example 8 and 100 ml of ethyl acetate into the reaction bottle, stir to dissolve, add 2.7 g of hydrochloric acid ethanol solution dropwise at room temperature, stir for 30 min, cool to 0-10°C for crystallization, filter, and dry to obtain 10.20 g, with a yield of 90%.

[0061] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing ligustrazine, comprising: (1) 3-Hydroxy-2-butanone reacts with ammonium acetate and hydrogen peroxide to generate ligustrazine, wherein the reaction solvent is water and the reaction temperature is 80-110°C. (2) post-treatment to obtain ligustrazine, In the step (1), any one of 3-hydroxy-2-butanone, ammonium acetate and hydrogen peroxide is added dropwise, or any two of 3-hydroxy-2-butanone, ammonium acetate and hydrogen peroxide are added dropwise to the reaction system separately and simultaneously or after mixing, dropwise. The dropping is performed by first heating the reaction system to 60-70°C and then dropping, and the temperature is controlled not to exceed 90°C during the dropping process.

2. The method according to claim 1, characterized in that The molar ratio of the 3-hydroxy-2-butanone to ammonium acetate is 1:1.4-2.0, preferably 1:1.6-1.8, and more preferably 1:1.

7. The content of hydrogen peroxide in the hydrogen peroxide is 25-35wt%, preferably 28-32wt%, and more preferably 30wt%. The molar ratio of the 3-hydroxy-2-butanone to hydrogen peroxide is 1:0.2-0.8, preferably 1:0.4-0.6, and more preferably 1:0.

57. The weight-to-volume ratio (g / ml) of the 3-hydroxy-2-butanone to water is 1:1.5-4.5, preferably 1:2-4, and more preferably 1:

3.

3. The method according to any one of claims 1 to 2, characterized in that: The reaction temperature of step (1) is 90-100°C, the reaction time of step (1) is 30min-120min, preferably 30min-60min, more preferably 30min-45min, and the post-treatment of step (2) is specifically: cooling and crystallizing, filtering, washing the filter cake to obtain a solid, preferably cooling to -5-5°C for crystallization, and preferably washing the filter cake with water.

4. The method according to any one of claims 1 to 3, characterized in that: The specific operation of the method is: adding water to a reaction container, adding 3-hydroxy-2-butanone and ammonium acetate under stirring, heating to 60-70°C, dropping hydrogen peroxide, reacting at 90-100°C for 30-45 minutes, cooling and crystallizing, filtering, washing the filter cake, and obtaining a solid.

5. The method according to any one of claims 1 to 3, characterized in that: The specific operation of the method is as follows: dissolving ammonium acetate in a part of purified water for standby use; adding the remaining purified water and hydrogen peroxide into a reaction container, adding 3-hydroxy-2-butanone under stirring, heating to 60-70° C., adding dropwise the prepared ammonium acetate aqueous solution, reacting at 90-100° C. for 30-45 minutes after the dropping, cooling for crystallization, filtering, washing the filter cake, and obtaining a solid.

6. The method according to any one of claims 1 to 3, characterized in that: The specific operation of the method is: dissolving 3-hydroxy-2-butanone in a part of purified water for standby use; adding the remaining purified water and hydrogen peroxide into a reaction container, adding ammonium acetate under stirring, heating to 60-70° C., dropwise adding the prepared 3-hydroxy-2-butanone aqueous solution, reacting at 90-100° C. for 30-45 minutes after the dropwise addition, cooling for crystallization, filtering, washing the filter cake, and obtaining a solid.

7. The method according to any one of claims 1 to 3, characterized in that: The specific operation of the method is: dissolving ammonium acetate in a part of purified water for standby use; adding the remaining purified water and 3-hydroxy-2-butanone into a reaction container, starting stirring, heating to 60-70° C., and simultaneously adding the prepared ammonium acetate aqueous solution and hydrogen peroxide solution dropwise, reacting at 90-100° C. for 30-45 minutes after the addition, cooling for crystallization, filtering, washing the filter cake, and obtaining a solid, wherein the time difference between the end of the addition of the ammonium acetate aqueous solution and the hydrogen peroxide solution is no more than 5-20 minutes, preferably no more than 5-10 minutes.

8. The method according to any one of claims 1 to 3, characterized in that: The specific operation of the method is as follows: dissolving ammonium acetate in a part of purified water for standby use, mixing the prepared aqueous ammonium acetate solution with hydrogen peroxide to form a mixed solution 1, adding the remaining purified water and 3-hydroxy-2-butanone into a reaction container, starting stirring, heating to 60-70° C., and dropwise adding the mixed solution 1, reacting at 90-100° C. for 30-45 minutes after the dropwise addition, cooling for crystallization, filtering, and washing the filter cake to obtain a solid.

9. The ligustrazine prepared by the method according to any one of claims 1 to 8 is further reacted with an acid to generate a ligustrazine salt.

10. Use of the method described in any one of claims 1 to 8 in the industrial preparation of ligustrazine or the method described in any one of claims 1 to 9 in the industrial preparation of ligustrazine salt, wherein the ligustrazine salt is preferably ligustrazine phosphate or ligustrazine hydrochloride.

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