Method for comprehensive recycling of atorvastatin M4 organic waste

Abstract

The application provides a comprehensive recycling method of atorvastatin M4 organic waste, which comprises the following steps: S1, mixing M4 crude mother liquor and M4 refined mother liquor high-boiling residues generated in the preparation of atorvastatin M4 by a linear method, and adjusting the water content of the system to obtain a mixed system; S2, cooling and standing the mixed system to crystallize, and centrifuging to obtain M4 crude products. The method of the application makes the M4 product be precipitated to the maximum extent by using the solvent and impurity system in the M4 crude mother liquor and M4 refined mother liquor high-boiling residues, significantly improves the yield of the M4 product, simultaneously comprehensively recycles the M4 crude mother liquor and M4 refined mother liquor high-boiling residues, greatly reduces the amount of organic solid waste generated in the production process of atorvastatin M4, improves the comprehensive utilization rate of resources and the level of clean production, reduces the cost of raw materials, and has good economic and social environmental benefits.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to a comprehensive recycling method of atorvastatin M4 organic waste. BACKGROUND

[0002] Atorvastatin M4 is the mother nucleus of atorvastatin calcium, a hypolipidemic drug, and its chemical name is 4-fluoro-alpha-[2-methyl-1-oxopropyl]-gamma-oxo-N, beta-diphenyl phenylbutyramide. At present, the synthesis route of atorvastatin mother nucleus M4 is as follows:

[0003]

[0004] The specific preparation process is: 1) phenylacetyl chloride and fluorobenzene undergo a Friedel-Crafts reaction under the condition of Lewis acid to obtain compound II; 2) compound II is subjected to bromination to obtain compound III; 3) isobutyryl methyl ester (compound IV) is reacted with aniline to obtain amide V; 4) compound V and compound III are synthesized in an alkaline environment to obtain compound VI (atorvastatin mother nucleus M4); wherein, step 4) uses potassium carbonate to provide an alkaline environment, and during the reaction process, alkaline inorganic salts such as potassium carbonate, potassium bicarbonate and potassium bromide are wrapped in compound VI. The above process needs to use a large amount of solvent to refine M4 crude product, so that more organic waste liquid is generated, which not only has a high treatment cost, but also has certain safety hazards, and the level of clean production of the product and the comprehensive utilization rate of resources are low.

[0005] Therefore, the present application is proposed. The present application adopts a linear synthesis route, and comprehensively recycles the generated organic waste liquid. SUMMARY

[0006] The present application aims to provide a comprehensive recycling method of atorvastatin M4 organic waste, which significantly improves the yield of M4 product, greatly reduces the amount of organic solid waste generated in the production process of atorvastatin M4, and improves the comprehensive utilization rate of resources and the level of clean production.

[0007] The present application provides a comprehensive recycling method of atorvastatin M4 organic waste, comprising the following steps:

[0008] S1: mixing M4 crude mother liquor and M4 refined mother liquor high-boiling residue generated in the preparation of atorvastatin M4 by a linear method, and adjusting the water content of the system to obtain a mixed system;

[0009] S2: cooling and standing the mixed system for crystallization, and centrifuging to obtain M4 crude product.

[0010] In step S1, the mass ratio of M4, solvent and impurities in the M4 crude mother liquor is 1:(15-20):(2-4), for example 1:18:3; wherein the solvent includes isopropyl alcohol, and the impurities include catalyst, triethylamine hydrobromide, p-fluorobenzaldehyde, defluorinated impurities, o-fluorinated impurities, difluorinated impurities, methyl diketone, M3, triethylamine and other known impurities and unknown impurities.

[0011] The mass ratio of M4, solvent and impurities in the M4 refined mother liquor high-boiling residue is 1:(2-4):(1-1.5), for example 1:3:1.15; wherein the solvent includes dichloromethane, and the impurities include p-fluorobenzaldehyde, defluorinated impurities, o-fluorinated impurities, difluorinated impurities, methyl diketone, M3, glacial acetic acid and other known impurities and unknown impurities.

[0012] When mixing, the mass ratio of the M4 crude mother liquor to the M4 refined mother liquor high-boiling residue can be controlled to be (5-7):1; in addition, the water content of the system can be adjusted by adding water, isopropyl alcohol containing water and other solvents, and the water content of the isopropyl alcohol containing water can be 10-12%, and the water content of the system can be adjusted to 5-10%, for example 5-7%.

[0013] In the present application, the linear method for preparing atorvastatin M4 includes: reacting M3 and p-fluorobenzaldehyde in the presence of a thiazole salt catalyst and triethylamine; recovering the triethylamine after the reaction, adding isopropyl alcohol for stirring and crystallization, and centrifuging to obtain a M4 crude mother liquor and a M4 crude product.

[0014] The synthesis reaction equation of the linear method for preparing atorvastatin M4 is as follows:

[0015]

[0016] In the linear method for preparing atorvastatin M4, the molar ratio of M3 to p-fluorobenzaldehyde is 1:(1.0-1.5), the reaction temperature is 70-90°C, and the reaction time is 6-10h; more specifically, the mass ratio among M3, p-fluorobenzaldehyde, thiazole salt catalyst and triethylamine can be 1:(0.55-0.65):(0.1-0.15):(0.6-0.7).

[0017] The linear method for preparing atorvastatin M4 described above has high reaction conversion rate, simple post-treatment and less wastewater and waste residue.

[0018] Further, after dissolving the M4 crude product in dichloromethane, the pH value of the system is adjusted to 5.5-6.5 by glacial acetic acid, decolorization is performed by activated carbon, the activated carbon is removed by filtration, the filtrate is concentrated and crystallized, and centrifuging is performed to obtain a refined mother liquor and a M4 refined product; after recovering the dichloromethane solvent and part of the M4 product in the refined mother liquor, a M4 refined mother liquor high-boiling residue is obtained.

[0019] In step S2, after cooling to 15 DEG C or below, the solution is crystallized at 0-15 DEG C for 6 hours or more. The crystallization time is for example 7-10 hours.

[0020] In step S2, the solvent in the centrifugal filtrate is recovered. The solvent can be recovered by vacuum concentration, and the temperature during the vacuum concentration can be 60-70 DEG C.

[0021] In the present application, the content refers to the HPLC purity unless otherwise specified.

[0022] It is found that the M4 crude mother liquor is a saturated solution of M4, and the solution system is stable. The residual M4 is difficult to be further refined by conventional methods. Meanwhile, the residual M4 in the M4 refined mother liquor high-boiling residue is also difficult to be extracted. Only a small amount of M4 product can be extracted by repeated conventional refining methods, which not only has a low extraction rate and is difficult to improve the yield of M4 product, but also has a poor quality of the extracted M4 product, which is not conducive to improving the quality of the M4 product.

[0023] Based on the above problems, it is found that the M4 crude mother liquor and the M4 refined mother liquor high-boiling residue generated in the preparation of atorvastatin M4 by the linear method are mixed and the water content of the system is adjusted. The specific solvent and impurity system of the M4 crude mother liquor and the M4 refined mother liquor high-boiling residue can be used for dissolving and refining impurities. The M4 in the M4 crude mother liquor and the M4 refined mother liquor high-boiling residue can be maximized, and the impurity content in the M4 product is low. The yield of the M4 product is significantly improved, and the quality of the M4 product is guaranteed. In particular, the above method can comprehensively reuse the organic waste M4 crude mother liquor and the M4 refined mother liquor high-boiling residue generated in the preparation of atorvastatin M4. Therefore, the amount of solid waste generated in the production of atorvastatin M4 is significantly reduced, the comprehensive utilization rate of resources is greatly improved, the level of clean production is improved, the cost of raw materials is reduced, and good economic and social environmental benefits are obtained.

[0024] The economic benefits of the method of the present application are as follows:

[0025] According to the annual production capacity of 350t, the organic waste liquid is reduced by 493t per year. The new M4 product is 18648kg per year, and the benefit is 3730000 yuan. The treatment cost of the organic waste liquid is saved by 986000 yuan. The total economic benefit is 4716000 yuan.

[0026] The social and environmental benefits of the method of the present application are as follows:

[0027] The application maximizes the precipitation of M4 in the M4 crude mother liquor and M4 refined mother liquor high-boiling residue by mixing the M4 crude mother liquor and M4 refined mother liquor high-boiling residue and adjusting the moisture content of the system, thereby greatly improving the yield and quality of the M4 product; at the same time, the M4 crude mother liquor and M4 refined mother liquor high-boiling residue are developed and comprehensively utilized in the above manner, the M4 organic solid waste is reasonably disposed of on the basis of improving the yield and quality of the M4 product, about 493 tons of organic waste liquid can be reduced in generation and discharge per year, storage resources (400 plastic barrels of 200 kg of packaging) and storage space (50 m 2 ) are saved, organic waste gas is reduced, organic waste fire safety hazards are alleviated, environmental pressure is reduced, and the environmental benefits are significant. DETAILED DESCRIPTION

[0028] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0029] It should be noted that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, the singular form also includes the plural form unless the context clearly indicates otherwise, and furthermore, it should be understood that when the terms "comprise" and / or "include" are used in the specification, there is a reference to the presence of a feature, step, operation, device, component and / or combinations thereof.

[0030] The technical solutions of the present application will be described below in conjunction with the embodiments, obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0031] Example 1

[0032] The synthesis reaction equation of atorvastatin M4 prepared by linear method is as follows:

[0033]

[0034] 920 kg of M3 was mixed with 550 kg of p-fluorobenzaldehyde, then 115 kg of thiazole salt catalyst and 590 kg of triethylamine were added, the mixture was uniformly mixed and reacted at 80℃ for 8h; after the reaction, 560 kg of triethylamine was recovered, 1440 kg of isopropyl alcohol was added and stirred to crystallize, and centrifugation was performed to obtain 1750 kg of M4 crude mother liquor and 1300 kg of M4 crude product.

[0035] The M4 crude product was dissolved in dichloromethane, the pH value of the system was adjusted to about 6.0 by glacial acetic acid, and activated carbon was used for decolorization. The activated carbon was removed by filtration, the filtrate was concentrated and crystallized, and centrifugation was performed to obtain 1330 kg of fine product mother liquor and 1050 kg of M4 fine product. After recovering the dichloromethane solvent and part of the M4 product from the fine product mother liquor, 250 kg of M4 refined mother liquor high-boiling residue was obtained.

[0036] It was detected that the composition of the M4 crude product mother liquor was as follows: the mass ratio of M4, solvent and impurities was 1:18:3. The solvent included isopropyl alcohol, and the impurities included catalyst, triethylamine hydrobromide, p-fluorobenzaldehyde, defluorinated impurities, m-fluorinated impurities, o-fluorinated impurities, difluorinated impurities, methyl diketone, M3, triethylamine and unknown impurities.

[0037] The composition of the M4 refined mother liquor high-boiling residue was as follows: the mass ratio of M4, solvent and impurities was 1:3:1.15. The solvent included dichloromethane, and the impurities included p-fluorobenzaldehyde, defluorinated impurities, o-fluorinated impurities, difluorinated impurities, methyl diketone, M3, glacial acetic acid and unknown impurities.

[0038] The structures, sources and control strategies of the impurities are shown in Table 1.

[0039] Table 1 Structures, sources and control strategies of the impurities

[0040]

[0041]

[0042] Example 2

[0043] Atorvastatin M4 was prepared according to the method of Example 1. 1250 kg of M4 crude product mother liquor and 250 kg of M4 refined mother liquor high-boiling residue were taken.

[0044] The 250 kg of M4 refined mother liquor high-boiling residue was added to the 1250 kg of M4 crude product mother liquor, 85 kg of water and 500 kg of aqueous isopropyl alcohol (containing 10% of water) were added to make the water content of the system about 6.5%, and stirring was performed. The system was slowly cooled to 15°C, and crystallization was performed at 15°C for 7 hours. Centrifugation was performed to obtain 72 kg of M4 crude product with a purity of 98%, and 57.8 kg of M4 fine product with a purity of 99.8% after refining. The filtrate was concentrated at 70°C under reduced pressure to recover 1080 kg of aqueous isopropyl alcohol, which could be recycled. The remaining 405 kg was organic waste, which was disposed of as waste liquid. The yield of M4 was increased by 5.5%, and the resource utilization rate was 73%.

[0045] Example 3

[0046] Atorvastatin M4 was prepared according to the method of Example 1. 1500 kg of M4 crude product mother liquor and 250 kg of M4 refined mother liquor high-boiling residue were taken.

[0047] Add 250 kg M4 refined mother liquor high-boiling residue into 1500 kg M4 crude mother liquor, add 72 kg water and 400 kg water-containing isopropyl alcohol (water content 10%), so that the water content of the system is about 5%, stir, slowly cool to 10°C, and crystallize at 10°C for 7 h. Centrifuge to obtain 76 kg M4 crude (61 kg M4 fine can be obtained after refining). Concentrate the filtrate at 70°C under reduced pressure, recycle the water-containing isopropyl alcohol. The remaining 437.5 kg is organic waste, which is disposed of as waste liquid. The yield of M4 synthesis is increased by 5.8%, and the resource utilization rate is 75%.

[0048] Example 4

[0049] Prepare atorvastatin M4 according to the method of Example 1, take 1750 kg M4 crude mother liquor, and 250 kg M4 refined mother liquor high-boiling residue.

[0050] Add 250 kg M4 refined mother liquor high-boiling residue into 1750 kg M4 crude mother liquor, add 120 kg water, so that the water content of the system is about 5.7%, stir, slowly cool to 10°C, and crystallize at 10°C for 7 h. Centrifuge to obtain 70 kg M4 crude (56 kg M4 fine can be obtained after refining, 99.5). Concentrate the filtrate at 70°C under reduced pressure, recycle the water-containing isopropyl alcohol. The remaining 520 kg is organic waste, which is disposed of as waste liquid. The yield of M4 synthesis is increased by 5.3%, and the resource utilization rate is 74%.

[0051] Example 5

[0052] Prepare atorvastatin M4 according to the method of Example 1, take 1500 kg M4 crude mother liquor, and 250 kg M4 refined mother liquor high-boiling residue.

[0053] Add 250 kg M4 refined mother liquor high-boiling residue into 1500 kg M4 crude mother liquor, add 72 kg water and 400 kg water-containing isopropyl alcohol (water content 10%), so that the water content of the system is about 5%, stir, slowly cool to 5°C, and crystallize at 5°C for 10 h. Centrifuge to obtain 80 kg M4 crude (64 kg M4 fine can be obtained after refining). Concentrate the filtrate at 70°C under reduced pressure, recycle the water-containing isopropyl alcohol. The remaining 433.5 kg is organic waste, which is disposed of as waste liquid. The yield of M4 synthesis is increased by 6.1%, and the resource utilization rate is 75.2%.

[0054] M4 crude mother liquor recovery test of Comparative Example 1

[0055] Comparative Example 1-1

[0056] Take 4 portions of M4 crude mother liquor 1500 kg prepared in Example 1, respectively concentrate isopropyl alcohol 295 kg, 590 kg, 885 kg, 1180 kg, and crystallize by cooling, no M4 precipitates.

[0057] Comparative Example 1-2

[0058] Take 4 portions of M4 crude mother liquor 1500 kg prepared in Example 1, respectively concentrate isopropyl alcohol 295 kg, 590 kg, 885 kg, 1180 kg, and crystallize by cooling, no M4 precipitates.

[0059] Comparative Example 1-3

[0060] Take 3 portions of M4 crude mother liquor 1500 kg prepared in Example 1, concentrate isopropyl alcohol 1180 kg, and then add dichloromethane 500 kg, 950 kg, 1500 kg, respectively, adjust the moisture to 6%, and crystallize by cooling, no M4 precipitates.

[0061] Comparative Example 1-4

[0062] Take 3 portions of M4 crude mother liquor 1500 kg prepared in Example 1, concentrate isopropyl alcohol 1180 kg, and then add methanol 500 kg, 950 kg, 1500 kg, respectively, and crystallize by cooling, no M4 precipitates.

[0063] Comparative Example 2 M4 refined mother liquor high boiling point substance recovery test

[0064] Take M4 refined mother liquor high boiling point substance 250 kg prepared in Example 1, and perform 4 times of refining according to the crude product refining method, to obtain a small amount of M4 crude product (about 5 kg), however, the quality of the M4 crude product is poor, and the purity is only 80%.

[0065] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, and are not limited thereto; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for comprehensive reuse of atorvastatin M4 organic waste, characterized in that, Includes the following steps: S1: Mix the crude M4 mother liquor and the high-boiling point of the refined M4 mother liquor produced by the linear method for preparing atorvastatin M4, adjust the water content of the system, and obtain a mixed system. S2: After cooling the mixed system, allow it to stand and crystallize, then centrifuge to obtain crude product M4; The linear method for preparing atorvastatin M4 includes: reacting M3 and p-fluorobenzaldehyde in the presence of a thiazole salt catalyst and triethylamine; recovering triethylamine after the reaction, adding isopropanol, stirring and crystallizing, centrifuging to obtain crude M4 mother liquor and crude M4 product; Crude M4 was dissolved in dichloromethane, then the pH of the system was adjusted with glacial acetic acid, and then decolorized with activated carbon. The activated carbon was removed by filtration, the filtrate was concentrated and crystallized, and centrifuged to obtain a refined mother liquor and refined M4. After recovering the dichloromethane solvent and part of the M4 product from the refined mother liquor, the high-boiling-point of the refined M4 mother liquor was obtained. The mass ratio of high-boiling-point substances in M4 crude mother liquor to M4 refined mother liquor is (5-7):1; Adjust the moisture content of the system to 5-10%; The structural formulas for M3 and M4 are as follows:

2. The method for comprehensive reuse of atorvastatin M4 organic waste according to claim 1, characterized in that, The mass ratio of M4, solvent and impurities in the crude M4 mother liquor is 1:(15-20):(2-4).

3. The method for comprehensive reuse of atorvastatin M4 organic waste according to claim 1, characterized in that, The mass ratio of M4, solvent and impurities in the high-boiling part of the M4 refined mother liquor is 1:(2-4):(1-1.5).

4. The method for comprehensive reuse of atorvastatin M4 organic waste according to claim 1, characterized in that, The molar ratio of M3 to p-fluorobenzaldehyde is 1:(1.0-1.5), the reaction temperature is 70-90℃, and the reaction time is 6-10h.

5. The method for comprehensive reuse of atorvastatin M4 organic waste according to claim 1, characterized in that, Cool down to below 15℃ and let it stand at 0-15℃ for more than 6 hours to crystallize.

6. The method for comprehensive reuse of atorvastatin M4 organic waste according to claim 1, characterized in that, Step S2 also includes: recovering the solvent from the centrifuged filtrate.

Images