Refining method and application of high-purity epalrestat

Abstract

The invention belongs to the technical field of medicines, and provides a refining method and application of high-purity epalrestat. The refining method of the high-purity epalrestat comprises the following steps: adding an epalrestat crude product into a mixed solvent of a solvent A and a solvent B, stirring and dissolving in a dark place at 60-80 DEG C, stirring and refluxing for 0.5-2 hours, then carrying out gradient cooling to 20-40 DEG C, carrying out heat preservation and stirring crystallization for a certain time, carrying out suction filtration, and drying at 80 DEG C to obtain the epalrestat refined product. The mass volume ratio of the epalrestat crude product to the mixed solvent is (1: 8)-(1: 12). The solvent A is a good solvent, the solvent B is a poor solvent, and the volume ratio of the solvent A to the solvent B is 3: 1.5-3: 10. The yield of the epalrestat refined product prepared by the method is greater than 80%, and the purity is not less than 99.9%. Isomer impurities A and B are not detected, the content of an isomer impurity C is less than 0.05%, and the content of other maximum single impurities is not more than 0.06%.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and provides a purification method and application of high-purity epalrestat. Background Art

[0002] Diabetes is a disease that seriously endangers human health. As people's living standards gradually improve, the incidence of diabetes has an increasing trend. Diabetic neuropathy is one of the common and early complications of diabetes, which has a great impact on the quality of life of patients. It is generally believed that diabetic neuropathy is related to the action of aldose reductase, and epalrestat is an aldose reductase inhibitor that has a strong inhibitory effect on sorbitol in the human lens, sciatic nerve and red blood cells. It is clinically used to treat complications of diabetes such as peripheral neuropathy, vibration paresthesia, and cardiac abnormalities.

[0003] Eparlrestat was developed by Ono Pharmaceuticals of Japan and was first launched in Japan in 1992.

[0004]

[0005] Chinese patent CN 102977047A discloses a method for refining epalrestat: 1. dissolving a crude product in tetrahydrofuran solvent, heating it to completely dissolve it, adding isopropyl ether, cooling it naturally to crystallize, filtering and drying it; 2. dissolving the first refined product in tetrahydrofuran again, heating it until it is completely dissolved, adding petroleum ether, cooling it naturally, crystallizing it and drying it to obtain the refined epalrestat. This refining method requires two recrystallizations, and the total yield of the two refinings is about 65.0%, the refining yield is low, and the material cost is high.

[0006] Chinese patent CN 102516197A discloses a method for refining epalrestat, which includes dissolving a crude product under acidic conditions, refluxing, filtering, cooling and crystallizing to obtain a crude epalrestat fine product, and then dissolving the crude fine product with isopropanol, refluxing, filtering, cooling and crystallizing to obtain a refined epalrestat product. This method first forms a salt, then acidifies, and then recrystallizes, requiring two refining steps, and the yield of salt formation and acidification is low, only 68.5%, and the amount of solvent in the secondary refining is large, the operation is complicated, and the production cost is high.

[0007]

[0008] Moreover, in the prior art, although the purity of the refined epalrestat is significantly improved, the content of impurities therein cannot be effectively controlled, and the content of impurity C is above 0.3%.

[0009] In summary, the purification methods of epalrestat in the prior art all have the following deficiencies: they all require two recrystallizations, a large amount of refining solvent, a large number of solvent types, a low yield, and a high refining cost; and they all need to be hydrochlorinated and then purified with methanol, which is complicated to operate, has a relatively low yield, high labor and material costs, and the impurity content cannot be effectively controlled. Summary of the invention

[0010] The purpose of the present invention is to overcome the shortcomings of the prior art, and to prepare high-purity epalrestat by a specific gradient cooling method using simple operations and easily available solvents, which can not only improve product quality and reduce costs, but also reduce the content of related impurities in the raw material drug while increasing the yield and purity of the refined epalrestat.

[0011] The present invention is achieved through the following technical solutions:

[0012] The present invention provides a method for refining high-purity epalrestat, comprising the following steps:

[0013] The crude product of epalrestat is added to a mixed solvent of solvent A and solvent B, stirred and dissolved at 60-80°C in the dark, stirred and refluxed for 0.5-2 hours, and then gradually cooled to 20-40°C, kept warm and stirred for crystallization for a certain period of time, filtered, and dried at 80°C to obtain the refined product of epalrestat.

[0014] In the epalrestat purification method of the present invention, the solvent A is a good solvent, selected from one or more of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, methyl acetate, and dichloromethane, preferably tetrahydrofuran or 1,4-dioxane; the solvent B is a poor solvent, selected from one or more of anhydrous methanol, anhydrous ethanol, water, acetonitrile, isopropanol, n-butanol, ether, isopropyl ether, acetone, n-hexane, and cyclohexane, preferably anhydrous ethanol, anhydrous methanol, isopropanol, and acetone.

[0015] The mass volume ratio of the crude epalrestat to the mixed solvent is 1:8 to 1:12, preferably 1:8 to 1:10.

[0016] In the mixed solvent, the volume ratio of solvent A to solvent B is 3:1.5 to 3:10, preferably 3:5 to 3:10, and more preferably 3:5 to 3:7.

[0017] Furthermore, in the method for refining epalrestat of the present invention, the mixed solvent is preferably tetrahydrofuran-anhydrous methanol, tetrahydrofuran-anhydrous ethanol, tetrahydrofuran-isopropanol, and most preferably tetrahydrofuran-anhydrous methanol, and the volume ratio of tetrahydrofuran to anhydrous methanol is 3:5 to 3:7.

[0018] The gradient cooling is as follows: cooling by 1 to 10°C every 10 to 60 minutes, preferably cooling by 4 to 6°C every 20 to 30 minutes; and keeping warm and stirring for 10 to 60 minutes after each cooling, preferably keeping warm for 30 to 50 minutes.

[0019] After the temperature is gradually reduced to 20-40°C, the crystallization is carried out by stirring and heat preservation for 1-12 hours. Preferably, the temperature is gradually reduced to 20-30°C, and the crystallization time is preferably 2-5 hours.

[0020] The present invention preferably adopts the following technical solutions:

[0021] The crude epalrestat product is added to a mixed solvent of tetrahydrofuran-anhydrous methanol in a volume ratio of 3:5 to 3:7, stirred and dissolved at 60 to 80° C. in the dark, and then the temperature is gradually reduced by 4 to 6° C. every 20 to 30 minutes, and the temperature is kept warm for 30 to 50 minutes after each cooling. After the temperature is gradually reduced to 20 to 30° C., the mixture is kept warm and stirred for crystallization for 2 to 5 hours, filtered, and dried at 80° C. to obtain a refined epalrestat product, wherein the mass ratio of the crude epalrestat product to the mixed solvent of tetrahydrofuran-anhydrous methanol is 1:8 to 1:10.

[0022] The yield of the prepared refined epalrestat is greater than 80%, and the purity is not less than 99.9%.

[0023] Compared with the prior art, the method for refining high-purity epalrestat provided by the present invention has the following advantages:

[0024] 1) The solvent used for recrystallization is relatively small, and the yield of the refined epalrestat is greater than 80%.

[0025] 2) The operation is simple, the operability of the scaled-up production is strong, the total material cost is low, the refining time is short, and the purity can reach more than 99.9% after only one refining. The refining method is not only low in cost, but also high in yield and purity.

[0026] 3) The epalrestat raw material is unstable to light and heat, and the two double bonds in its structure are easily isomerized to produce three isomeric impurities. Therefore, the control of isomeric impurities in its refining process is crucial. The use of this refining method can greatly improve the quality of epalrestat refined products. The total impurity of the refined products is <0.1%; isomeric impurities A and B are not detected, the content of isomeric impurity C is less than 0.05%, and the maximum content of other single impurities is no more than 0.06%. Description of the drawings:

[0027] Figure 1 HPLC spectrum of crude epalrestat in the examples.

[0028] Figure 2 This is the HPLC spectrum of the refined epalrestat prepared in Example 1.

[0029] Figure 3 This is the HPLC spectrum of the refined epalrestat prepared in Example 2.

[0030] Figure 4 This is the HPLC spectrum of the refined epalrestat prepared in Example 3. DETAILED DESCRIPTION

[0031] The following examples are intended to illustrate the present invention in detail, but not to limit the present invention. Under the guidance of the disclosed content of the present invention, the technical personnel can modify and improve the present invention without departing from the main purpose and premise of the spirit of the invention, and these will fall within the scope of the present invention.

[0032] Process Screening Process

[0033] Process 1: Add the crude epalrestat to a mixed solvent of solvent A and solvent B, stir and dissolve at 60°C in the dark, stir and reflux for 2 hours, turn off the heating and slowly cool to 20-30°C, keep warm and stir to crystallize for 2 hours, filter with suction, and dry at 80°C to obtain the refined epalrestat; the mass volume ratio of the crude epalrestat to the mixed solvent is 1:8.

[0034] 1. Choice of solvent type:

[0035] The composition of the mixed solvent was changed to investigate the effects of different mixed solvents on the content of impurity C, the yield and purity of the refined epalrestat. The results are shown in Table 1:

[0036] Table 1 Effect of different mixed solvents on the purity and yield of epalrestat refined products

[0037]

[0038]

[0039] The results show that when tetrahydrofuran is selected as solvent A and anhydrous methanol is selected as solvent B, and the ratio of the two is 3:1.5-3:10, the purity of the refined epalrestat is above 99%, and the content of impurity C is less than 0.7%. When the ratio of the two is 3:5-3:10, the content of impurity C is less than 0.6%, and the yield of the refined epalrestat with a purity of more than 99% is more than 65%. When the ratio of the two is 3:5, the content of impurity C is the lowest. When 1,4-dioxane is used as solvent A and anhydrous methanol or anhydrous ethanol is used as solvent, the yield is equivalent to that of epalrestat prepared by tetrahydrofuran-anhydrous methanol as a mixed solvent, the purity is less than 99%, and the content of impurity C is significantly increased.

[0040] 2. Investigation of the amount of mixed solvent:

[0041] Using tetrahydrofuran-anhydrous methanol with a volume ratio of 3:5 as a mixed solvent, changing the amount of the mixed solvent, and keeping the other conditions the same as process 1, the effect of the amount of the mixed solvent on the content, yield and purity of impurity C in the refined epalrestat was investigated. The results are shown in Table 2:

[0042] Table 2 Effect of mixed solvent dosage on yield and purity of epalrestat refined product

[0043] Serial number Epalrestat crude product: mixed solvent mass volume ratio Impurity C(%) purity(%) Yield (%) 1 1：8 0.37 99.43 68.3 2 1：9 0.38 99.38 65.4 3 1：10 0.35 99.40 59.8 4 1：12 0.42 99.32 50.5

[0044] The results show that when the mass volume ratio of crude epalrestat: mixed solvent is 1:8-12, there is no significant difference in the detection amount and purity of impurity C, but the larger the amount of solvent, the lower the yield. Therefore, the present invention preferably has a mass volume ratio of crude epalrestat: mixed solvent of 1:8-10. At this time, the content of impurity C is less than 0.4%, and the yield of refined epalrestat is about 60% or more. When the mass volume ratio of the mixed solvent is 1:8-9, the yield of epalrestat can reach more than 65%.

[0045] In general, when the mass volume ratio of crude epalrestat: mixed solvent was 1:8-10, there was no significant effect on the yield, purity and impurity C content of epalrestat.

[0046] 3. Investigation of crystallization temperature: Tetrahydrofuran-anhydrous methanol (3:5) and 1,4-dioxane-anhydrous methanol (3:5) were used as mixed solvents, the mass volume ratio of crude epalrestat: mixed solvent was 1:8, the crystallization temperature was changed, and other conditions were the same as process 1. The effect of crystallization temperature on the yield and purity of refined epalrestat was investigated. The results are shown in Tables 3 and 4:

[0047] Table 3 Effect of crystallization temperature on the yield and purity of refined epalrestat (mixed solvent is tetrahydrofuran-anhydrous methanol 3:5)

[0048] Serial number Crystallization temperature(℃) Impurity C(%) purity(%) Yield (%) 1 10～20 0.58 98.15 65.7 2 20～30 0.37 99.43 68.3 3 30～40 0.29 99.58 60.3

[0049] Table 4 Effect of crystallization temperature on the yield and purity of epalrestat refined product (mixed solvent is 1,4-dioxane-anhydrous methanol 3:5)

[0050] Serial number Crystallization temperature(℃) Impurity C(%) purity(%) Yield (%) 1 10～20 1.21 97.32 58.1 2 20～30 0.73 98.33 59.3 3 30～40 0.80 98.12 50.4

[0051] The results showed that when tetrahydrofuran-anhydrous methanol (3:5) was used as a mixed solvent, the content of impurity C was different at different crystallization temperatures, and the yield and purity of the prepared epalrestat refined product were also different. When the crystallization temperature was 20-40°C, not only was the content of impurity C low, but the purity of epalrestat could reach more than 99%, and the yield was more than 60%. When the crystallization temperature was 30-40°C, the detection amount of impurity C was the lowest, but the yield decreased. Taking all factors into consideration, the crystallization temperature is preferably 20-30°C.

[0052] When 1,4-dioxane-anhydrous methanol (3:5) was used as a mixed solvent and the crystallization temperature was changed, the yield of epalrestat was relatively low compared with that of epalrestat prepared using tetrahydrofuran-anhydrous methanol (3:5) as a mixed solvent, with a purity of less than 99%, and the content of impurity C was significantly higher than that of epalrestat prepared using tetrahydrofuran-anhydrous methanol (3:5) as a mixed solvent.

[0053] 4. Investigation of cooling methods:

[0054] The cooling method was changed, and other conditions were the same as process 1 (the mixed solvent was tetrahydrofuran-anhydrous methanol 3:5 or 1,4-dioxane-anhydrous methanol 3:5). The effects of different cooling methods on the content of impurity C, the yield and purity of epalrestat refined product were investigated. The results are shown in Table 5:

[0055] Table 5 Effect of cooling method on yield and purity of refined epalrestat

[0056]

[0057]

[0058] The results showed that when tetrahydrofuran-anhydrous methanol was used as a mixed solvent, the purity and yield of the refined epalrestat obtained by different cooling methods were different. The yield and purity of epalrestat obtained by turning off the heating and slow cooling and by fast cooling in an ice water bath were similar, but the content of impurity C by turning off the heating and slow cooling was relatively low. When gradient cooling is adopted, the temperature is lowered by 1 to 10°C every 20 to 30 minutes, and the temperature is kept for 30 to 50 minutes after each cooling, the yield of epalrestat is more than 80%, the purity is more than 99%, and the content of impurity C is less than 0.2%; when other conditions remain unchanged, when the temperature is lowered by 1 to 6°C every 20 to 30 minutes, the yield and purity do not change significantly, and the content of impurity C is less than 0.1%; when other conditions remain unchanged, when the temperature is lowered by 4 to 6°C every 20 to 30 minutes, the yield and purity do not change significantly, and the content of impurity C is less than 0.05%; when other conditions remain unchanged, when the temperature is lowered by 5 to 6°C every 20 to 30 minutes, the yield and purity do not change significantly, and the content of impurity C is less than or equal to 0.03%.

[0059] When 1,4-dioxane-anhydrous methanol is used as a mixed solvent in a ratio of 3:5, although the yield of epalrestat is over 75% and the purity is over 99%, the content of impurity C is greater than 0.2%, which is significantly higher than the content of impurity C when tetrahydrofuran-anhydrous methanol is used as a mixed solvent.

[0060] Therefore, the present invention preferably uses tetrahydrofuran-anhydrous methanol as the mixed solvent.

[0061] Example 1

[0062] 3200 g of crude epalrestat was added to the reactor, and 25.6 L of a mixed solvent of tetrahydrofuran-methanol (3:5) was added. The mixture was refluxed and stirred at 70°C in the dark to dissolve. After dissolution, it was stirred and refluxed for 0.5 h. The temperature was slowly lowered. The internal temperature was controlled to slowly lower the temperature based on the internal temperature of the feed liquid. It took 20 to 30 min for each 5°C drop in the internal temperature. After each cooling, the mixture was kept warm and stirred for 30 min until the system dropped to 20 to 30°C. After keeping warm and stirring for 2 to 3 hours to crystallize, the filter cake was dried at 80°C and weighed to obtain 2662.4 g with a purity of 99.92% and a yield of 83.2%.

[0063] Example 2

[0064] 3000 g of crude epalrestat was added to the reactor, and 30 L of a mixed solvent of tetrahydrofuran-methanol (3:5) was added. The mixture was refluxed and stirred at 60°C in the dark to dissolve. After dissolution, it was stirred and refluxed for 2 hours. The temperature was slowly lowered. The internal temperature was controlled to slowly lower the temperature based on the internal temperature of the feed liquid. It took 20 to 30 minutes for each 5°C drop in the internal temperature. After each cooling, the mixture was kept warm and stirred for 30 minutes until the system dropped to 20 to 30°C. After keeping warm and stirring for 2 to 3 hours, the mixture was filtered and dried at 80°C. The filter cake was weighed to obtain 2529.0 g with a purity of 99.92% and a yield of 84.3%.

[0065] Example 3

[0066] 4000 g of crude epalrestat was added to the reactor, and 32 L of a mixed solvent of tetrahydrofuran-methanol (3:7) was added. The mixture was refluxed and stirred at 80°C in the dark to dissolve. After dissolution, it was stirred and refluxed for 0.5 h. The temperature was slowly cooled after each cooling. The internal temperature was controlled to slowly cool down based on the internal temperature of the feed liquid. It took 20 to 30 min for each 5°C drop in the internal temperature. Then, the mixture was kept warm and stirred for 50 min until the system dropped to 20 to 30°C. After keeping warm and stirring for 2 to 3 hours to crystallize, the filter cake was dried at 80°C and weighed to obtain 3408.0 g with a purity of 99.93% and a yield of 85.2%.

[0067] Example 4 Yield and Purity of the Refined Epalrestat Prepared in Examples 1-3

[0068] Table 6 Yield and purity of the refined epalrestat prepared in Examples 1-3

[0069] Example Feeding amount (g) Yield (g) Yield (%) purity(%) 1 3200 2662.4 83.2 99.92 2 3000 2529.0 84.3 99.92 3 4000 3408.0 85.2 99.93

[0070] The results show that: using the purification method of the present invention, when the volume ratio of the mixed solvent is tetrahydrofuran-anhydrous methanol is 3:5-3:7, the mass volume ratio of the crude epalrestat to the mixed solvent is 1:8-1:10, the temperature for stirring and dissolving in the dark is 60-80°C, and the gradient cooling process is 5-6°C every 20-30 minutes, the yield of the obtained epalrestat is more than 80%, and the purity is more than 99.9%.

[0071] Table 7 Impurity detection in the refined epalrestat prepared in Examples 1-3

[0072]

[0073] The results show that impurities A and B are not detected in the refined epalrestat prepared according to the method of the present invention, the content of impurity C is less than or equal to 0.03%, and the maximum unknown single impurity is less than or equal to 0.06%.

Claims

1. A method for purifying high-purity epalrestat, characterized in that: The steps include: The crude product of epalrestat is added to a mixed solvent of solvent A and solvent B, stirred and dissolved at 60-80° C. in the dark, stirred and refluxed for 0.5-2 hours, and then gradually cooled to 20-40° C., stirred and crystallized, filtered and dried to obtain the product; the solvent A is selected from one or more of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, methyl acetate and dichloromethane, preferably tetrahydrofuran or 1,4-dioxane; the solvent B is selected from one or more of methanol, ethanol, water, acetonitrile, isopropanol, n-butanol, ether, isopropyl ether, acetone, n-hexane and cyclohexane, preferably anhydrous ethanol, anhydrous methanol, isopropanol and acetone.

2. The purification method according to claim 1, characterized in that The mixed solvent is tetrahydrofuran-anhydrous methanol, tetrahydrofuran-anhydrous ethanol, tetrahydrofuran-isopropanol, preferably tetrahydrofuran-anhydrous methanol.

3. The purification method according to claim 1 or 2, characterized in that: The mass ratio of the crude epalrestat to the mixed solvent is 1:8 to 1:12, preferably 1:8 to 1:

10.

4. The refining method according to any one of claims 1 to 3, characterized in that: The volume ratio of solvent A to solvent B in the mixed solvent is 3:1.5 to 3:10, preferably 3:5 to 3:

7.

5. The purification method according to claim 1, characterized in that The gradient cooling is: cooling by 1 to 10°C every 10 to 60 minutes, preferably cooling by 4 to 6°C every 20 to 30 minutes.

6. The purification method according to claim 5, characterized in that After each cooling, the mixture is kept warm and stirred for 10 to 60 minutes, preferably for 30 to 50 minutes.

7. The purification method according to claim 1, characterized in that After the temperature is gradually reduced to 20-40° C., the mixture is stirred and crystallized for 1-12 h. Preferably, the temperature is gradually reduced to 20-30° C., and the mixture is stirred and crystallized for 2-5 h.

8. The purification method according to claim 1, characterized in that The crude epalrestat product is added to a mixed solvent of tetrahydrofuran-anhydrous methanol in a volume ratio of 3:5 to 3:7, stirred and dissolved at 60 to 80°C in the dark, and then gradually cooled by 4 to 6°C every 20 to 30 minutes, and kept warm for 30 to 50 minutes after each cooling. After gradually cooling to 20 to 30°C, the product is kept warm with stirring for 2 to 5 hours for crystallization, filtered and dried to obtain a refined epalrestat product. The mass ratio of the crude epalrestat product to the mixed solvent of tetrahydrofuran-anhydrous methanol is 1:8 to 1:

10.

9. The purification method according to claim 8, characterized in that Reduce the temperature by 5 to 6°C every 20 to 30 minutes.

10. Use of the purification method according to any one of claims 1 to 9 in the preparation of high-purity epalrestat.

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