Method for recovering R-mandelic acid from ticagrelor production waste liquid

Abstract

The invention provides a method for recovering R-mandelic acid from ticagrelor production waste liquid, which comprises the following steps: 1) adding methylbenzene into a to-be-recovered water phase for extraction, after extraction, slowly dropwise adding concentrated hydrochloric acid while stirring the water phase to adjust the pH value to 1-3, keeping the temperature at 0-30 DEG C, adding a halogenated hydrocarbon solvent or a ketone solvent into the system to extract the water phase for three times, merging organic phases, and collecting the organic phases; washing once; 2) adding a decolorizing agent, stirring, filtering, and distilling until no distillation is generated; 3) adding toluene, cooling to 0-10 DEG C, stirring for 1-3 hours, filtering, and washing with toluene at 0-10 DEG C; and drying at 40-60 DEG C until the weight is not reduced any more to obtain a solid product. The method is mild in process condition and easy to control, the yield of the obtained product is 90% or above, the purity is larger than 99.0%, the method can be used for the three-membered ring intermediate preparation process, and the production cost of ticagrelor is reduced while the waste liquid treatment cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of waste liquid recycling technology, and relates to a method for recovering R-mandelic acid from ticagrelor production waste liquid. Background Technology

[0002] Ticagrelor is a novel, selective small-molecule anticoagulant developed by AstraZeneca. It is a reversible inhibitor of the P2Y12 receptor, making it particularly suitable for patients requiring prior anticoagulation therapy before surgery. Its structure is as follows:

[0003]

[0004] The synthesis route is as follows:

[0005]

[0006] The three-membered ring intermediate used in the production of ticagrelor is R-mandelate. After the reaction is complete, a mixed solution of R-mandelate potassium salt, other inorganic salts, and organic impurities is obtained. R-mandelate is expensive. If it is not separated, purified and recycled, it will not only pollute the environment, but also increase production costs to treat a large amount of wastewater, resulting in waste. Summary of the Invention

[0007] The purpose of this invention is to provide a method for recovering R-mandelic acid from ticagrelor production waste liquid, which has stable process, easy-to-control reaction conditions, low cost, high recovery rate and is easy to industrialize.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] Methods for recovering R-mandelic acid from ticagrelor production wastewater include:

[0010] 1) Add toluene to the aqueous phase to be recovered (to extract organic impurities soluble in toluene, and separate the layers after stirring) for extraction. After extraction, slowly add concentrated hydrochloric acid dropwise to adjust the pH value to 1-3 while stirring the aqueous phase, and keep the temperature between 0-30℃. Add halogenated hydrocarbon solvent or ketone solvent to the system to extract the aqueous phase three times, combine the organic phases, and wash with water once.

[0011] 2) Add decolorizing agent, stir, filter, distill, and continue distilling until no more distillate is produced;

[0012] 3) Add toluene, cool to 0-10℃ and stir for 1-3 hours, filter, wash with toluene at 0-10℃; dry at 40-60℃ until the weight no longer decreases, to obtain a solid product.

[0013] Preferably, in step 1), the weight percentage content of R-mandelic acid in the aqueous phase to be recovered is 4-8%.

[0014] Preferably, in step 1), the weight of toluene added is 0.05-0.15 times the weight of the aqueous phase to be recovered.

[0015] Preferably, in step 1), the temperature during the dropwise addition of concentrated hydrochloric acid is controlled to not exceed 50°C.

[0016] Preferably, in step 1), the volume ratio of the added halogenated hydrocarbon solvent or ketone solvent to the aqueous phase to be recovered is 0.5-1.5:1. Here, the volume of the halogenated hydrocarbon solvent or ketone solvent refers to the total volume of the halogenated hydrocarbon solvent or ketone solvent used in the three extractions.

[0017] Preferably, in step 2), the decolorizing agent is activated carbon or silica gel.

[0018] Preferably, in step 2), the amount of the decolorizing agent is 1-5% of the weight of the R-mandelic acid to be recovered.

[0019] Preferably, in step 2), the decolorization temperature is 0-30℃.

[0020] Preferably, in step 2), the distillation temperature is below 60°C. Vacuum distillation or atmospheric distillation can be selected depending on the properties of the different solvents.

[0021] Preferably, in step 3), the volume ratio of toluene added in both the first and second steps to the R-mandelic acid to be recovered is 0.5-2.0:1.

[0022] The beneficial effects of this invention are as follows:

[0023] The process conditions of this invention are mild and easy to control, yielding a product yield of over 90% and a purity greater than 99.0%, meeting the quality standards for industrial R-mandelic acid. It can be used in the preparation of three-membered ring intermediates. Recovering usable R-mandelic acid from ticagrelor waste reduces waste treatment costs and lowers the production cost of ticagrelor. Attached Figure Description

[0024] Figure 1 The above is the liquid chromatogram result of Example 1 of the present invention.

[0025] Figure 2 This is the liquid chromatogram result of Example 4 of the present invention.

[0026] Figure 3 The above is the liquid chromatogram result of Example 6 of the present invention. Detailed Implementation

[0027] The present invention will now be described in detail with reference to specific embodiments. These specific embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. Unless otherwise specified, all reagents and materials used below are commercially available.

[0028] Example 1

[0029] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene to extract organic impurities soluble in toluene, and perform one extraction. Slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be approximately 2. Maintain the temperature at approximately 25℃ and extract the aqueous phase three times with chloroform (400 mL, 200 mL, 200 mL). Combine the organic phases, wash with 50 mL of water, add 1 g of activated carbon, stir for 0.5 hours, filter, and recover the chloroform by vacuum distillation at a temperature below 60℃ until no more distillate is produced. Add 50 mL of toluene, cool to approximately 4℃, maintain the temperature and stir for 2 hours, filter, wash with 50 mL of toluene at 4℃, and dry at 50℃ until the weight no longer decreases. 55.0 g of white solid is obtained. Yield: 96%. See the liquid chromatogram below. Figure 1 The purity of the product meets the requirements for industrial R-mandelic acid.

[0030] Example 2

[0031] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene, extract once, and slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be 1-2, maintain the temperature at approximately 0℃, and extract the aqueous phase three times with dichloromethane (400 mL, 400 mL, 200 mL). Combine the organic phases, wash with 50 mL of water, add 1 g of activated carbon, stir for 0.5 hours, filter, and recover the dichloromethane by atmospheric distillation until no more distillate is produced. Add 60 mL of toluene, cool to 0℃, maintain the temperature and stir for 1 hour, filter, wash with 50 mL of toluene at 0℃, and dry at 40℃ until the weight no longer decreases. 53.0 g of white solid is obtained. Yield: 93%. The purity of the product meets the requirements for industrial R-mandelic acid.

[0032] Example 3

[0033] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene, extract once, and slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be 2-3, maintain the temperature at about 30℃, and extract the aqueous phase three times with chloroform (300 mL, 300 mL, 200 mL). Combine the organic phases, wash with 60 mL of water, add 2 g of industrial-grade silica gel for column chromatography, stir for 0.5 hours, filter, and recover the chloroform by vacuum distillation at a temperature below 60℃ until no more distillate is produced. Add 60 mL of toluene, cool to 10℃, maintain the temperature and stir for 3 hours, filter, wash with 50 mL of toluene at 10℃, and dry at 60℃ until the weight no longer decreases. 54.0 g of white solid is obtained. Yield: 95%. The purity of the product meets the requirements for industrial R-mandelic acid.

[0034] Example 4

[0035] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene, extract once, and slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be around 2, maintain the temperature at about 25℃, and extract the aqueous phase three times with dichloromethane (400 mL, 300 mL, 300 mL). Combine the organic phases, wash with 60 mL of water, add 2 g of industrial-grade silica gel for column chromatography, stir for 0.5 hours, filter, and recover the dichloromethane by atmospheric distillation until no more distillate is produced. Add 60 mL of toluene, stir, cool to about 4℃, maintain the temperature and stir for 3 hours, filter, wash with 50 mL of toluene at 4℃, and dry at 50℃ until the weight no longer decreases. 54.5 g of white solid is obtained. Yield: 96%. See the liquid chromatogram below. Figure 2 The purity of the product meets the requirements for industrial R-mandelic acid.

[0036] Example 5

[0037] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene, extract once, and slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be 1-2, maintain the temperature at approximately 25℃, and extract the aqueous phase three times with methyl isobutyl ketone (400 mL, 300 mL, 100 mL). Combine the organic phases, wash with 50 mL of water, add 2 g of industrial-grade silica gel for column chromatography, stir for 0.5 hours, filter, and recover methyl isobutyl ketone by vacuum distillation at a temperature below 60℃ until no more distillate is produced. Add 50 mL of toluene, cool to 4℃, maintain the temperature and stir for 2 hours, filter, wash with 50 mL of toluene at 4℃, and dry at 50℃ until the weight no longer decreases. 53.4 g of white solid is obtained. Yield: 94%. The purity of the product meets the requirements for industrial R-mandelic acid.

[0038] Example 6

[0039] Take 1000 g of the aqueous phase of ticagrelor intermediate (R-mandelic acid weight percentage: 5.7%), add 100 mL of toluene, extract once, and slowly add concentrated hydrochloric acid dropwise while stirring the aqueous phase, controlling the temperature not to exceed 50℃. After the addition is complete, determine the pH to be 2-3, maintain the temperature at about 25℃, and extract the aqueous phase three times with methyl isobutyl ketone (400 mL, 200 mL, 200 mL). Combine the organic phases, wash with 50 mL of water, add 1 g of activated carbon and stir for 0.5 hours, filter, and recover methyl isobutyl ketone by vacuum distillation at a temperature below 60℃ until no more distillate is produced. Add 60 mL of toluene, cool to 4℃, keep stirring at this temperature for 1 hour, filter, wash with 50 mL of toluene at 4℃, and dry at 50℃ until the weight no longer decreases. 52.5 g of white solid is obtained. Yield: 92%. See the liquid chromatogram below. Figure 3 The purity of the product meets the requirements for industrial R-mandelic acid.

[0040] Obviously, the above embodiments of the present invention are merely examples to illustrate the present invention more clearly, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all implementation methods here. Any obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A method for recovering R-mandelic acid from ticagrelor production wastewater, comprising: 1) Add toluene to the aqueous phase to be recovered for extraction. After extraction, slowly add concentrated hydrochloric acid dropwise to adjust the pH value to 1-3 while stirring the aqueous phase. Keep the temperature between 0-30℃. Add halogenated hydrocarbon solvent or ketone solvent to the system to extract the aqueous phase three times. Combine the organic phases and wash with water once. 2) Add decolorizing agent, stir, filter, distill, and continue distilling until no more distillate is produced; 3) Add toluene, cool to 0-10℃ and stir for 1-3 hours, filter, wash with toluene at 0-10℃; dry at 40-60℃ until the weight no longer decreases, to obtain a solid product.

2. The method according to claim 1, characterized in that, In step 1), the weight percentage content of R-mandelic acid in the aqueous phase to be recovered is 4-8%.

3. The method according to claim 1, characterized in that, In step 1), the weight of toluene added is 0.05-0.15 times the weight of the aqueous phase to be recovered.

4. The method according to claim 1, characterized in that, In step 1), the temperature during the dropwise addition of concentrated hydrochloric acid should not exceed 50°C.

5. The method according to claim 1 or 2, characterized in that, In step 1), the volume ratio of the added halogenated hydrocarbon solvent or ketone solvent to the aqueous phase to be recovered is 0.5-1.5:

1.

6. The method according to claim 1, characterized in that, In step 2), the decolorizing agent is activated carbon or silica gel.

7. The method according to claim 1, 2 or 6, characterized in that, In step 2), the amount of the decolorizing agent is 1-5% of the weight of the R-mandelic acid to be recovered.

8. The method according to claim 1 or 6, characterized in that, In step 2), the decolorization temperature is 0-30℃.

9. The method according to claim 1, characterized in that, In step 2), the distillation temperature is below 60°C.

10. The method according to claim 1, characterized in that, In step 3), the volume ratio of toluene added in both the first and second additions to the R-mandelic acid to be recovered is 0.5-2.0:1.

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