A method for recovering intermediate TK-1 from a mother liquor of intermediate TK-1 in ticagrelor

Abstract

The application belongs to the technical field of medicine production and specifically relates to a method for recovering intermediate TK-1 from a TK-1 mother liquor in a ticagrelor intermediate. The TK-1 crystallization mother liquor is concentrated to obtain a concentrated mother liquor; the concentrated mother liquor is stirred and crystallized, and then solid-liquid separation is performed; the obtained solid product is dried and then dissolved in acetonitrile to obtain a crude solution; the crude solution is cooled to a first temperature and then kept at the first temperature; the solution after keeping is subjected to solid-liquid separation to obtain a liquid phase product; the liquid phase product is concentrated, and the obtained concentrate is dissolved in a good solvent to obtain a concentrate solution; a poor solvent is added to the concentrate solution to precipitate a solid product, and then the solid product is subjected to solid-liquid separation and dried to obtain the intermediate TK-1. The application can improve the molar yield of the intermediate TK-1, reduce the production cost of the intermediate TK-1, simultaneously reduce the post-treatment pressure of the intermediate TK-1 mother liquor, reduce the harmless treatment cost of the mother liquor, and relieve the environmental protection pressure.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing technology, and specifically relates to a method for recovering intermediate TK-1 from the mother liquor of ticagrelor intermediate TK-1. Background Technology

[0002] AstraZeneca began developing ticagrelor in 1999. The European Society of Cardiology (ESC) first presented the results of a Phase III trial of ticagrelor at its 2009 annual meeting, detailing its efficacy in patients with acute coronary syndrome (ACS). In December 2010, ticagrelor received EU approval for the prevention of atherosclerotic thrombotic events in adult patients with ACS. In January 2011, ticagrelor was officially marketed in all EU member states under the brand name Brilique, available in 60-tablet packs of 90mg each. On July 20, 2011, the FDA approved ticagrelor for reducing cardiovascular death and heart attacks in patients with ACS. On November 22, 2012, the State Food and Drug Administration (SFDA) approved ticagrelor (Brinda) for marketing in China. The current mainstream synthetic routes for ticagrelor in China are as follows:

[0003]

[0004] This route uses inexpensive and readily available starting materials. The entire route is relatively short, the reaction operation is simple, and it avoids harsh reactions involving high temperatures, low temperatures, or pressure, as well as the use of certain solvents and highly toxic chemicals. It has low cost and is suitable for industrial production. The drawback of this route is that the yield of intermediate TK-1 in step 1 is relatively low, with a molar yield of only 60-70%. The synthesis process of intermediate 1 is as follows:

[0005]

[0006] 120 kg of ethylene glycol was added to a reaction vessel, and stirring was started. Then, 33 kg of triethylamine, 22.0 kg of TK-01, and 18 kg of TK-03 were added sequentially. Heating was initiated, and the temperature was raised to 90–110 °C and maintained with stirring for 4–6 hours. The mixture was transferred to a reaction vessel pre-filled with 120 kg of ethyl acetate and 200.0 kg of purified water, stirred, and allowed to stand for separation. The liquid was separated, and the solvent was removed under reduced pressure to obtain a viscous concentrate. 64.0 kg of ethyl acetate and 195.0 kg of n-heptane were added; the mixture was then stirred and centrifuged while maintaining the temperature to obtain approximately 17.7 kg of intermediate TK-1, with a molar yield range of 60–70%.

[0007] Therefore, since about 10-20 wt% (mass content) of intermediate TK-1 product failed to precipitate in the TK-1 crystallization mother liquor, the yield of intermediate TK-1 in the ticagrelor production process is low, resulting in high production cost of intermediate TK-1. At the same time, it also makes the post-processing of TK-1 crystallization mother liquor difficult, costly, and puts great pressure on the environment. Summary of the Invention

[0008] The purpose of this invention is to provide a method for recovering intermediate TK-1 from the mother liquor of ticagrelor intermediate TK-1. The method provided by this invention can improve the molar yield of intermediate TK-1, reduce the production cost of intermediate TK-1, reduce the post-processing pressure of intermediate TK-1 mother liquor, reduce the cost of harmless treatment of mother liquor, and alleviate environmental pressure.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] This invention provides a method for recovering intermediate TK-1 from mother liquor of ticagrelor intermediate TK-1, comprising the following steps:

[0011] Step 1) Concentrate the TK-1 crystallization mother liquor to obtain concentrated mother liquor; stir the concentrated mother liquor to precipitate crystals and then separate the solid and liquid components, dry the obtained solid product, and obtain crude mother liquor recovery product;

[0012] Step 2) Dissolve the crude mother liquor recovered product in acetonitrile to obtain a crude product solution; cool the crude product solution from room temperature to a first temperature and keep it at that temperature; separate the solid and liquid phases of the solution after keeping it at that temperature to obtain a liquid phase product; concentrate the liquid phase product to obtain a concentrate.

[0013] Step 3) Dissolve the concentrate in a good solvent to obtain a concentrate solution; add a poor solvent to the concentrate solution to precipitate a solid product; after solid-liquid separation, dry the solid product to obtain the intermediate TK-1.

[0014] Preferably, in step 1): the solvent contained in the TK-1 crystallization mother liquor is ethyl acetate and n-heptane, and the volume ratio of ethyl acetate to n-heptane is 150:600; the concentration is vacuum concentration, and the vacuum concentration temperature is 30-60℃, and the vacuum degree is ≤-0.07Mpa.

[0015] Preferably, in step 1), the volume ratio of the concentrated mother liquor to the TK-1 crystallization mother liquor is 1:(2-4).

[0016] Preferably, in step 1), the stirring crystallization temperature is room temperature, the time is 1 to 4 hours, and the stirring speed is 20 to 100 r / min.

[0017] The drying process is vacuum drying, with a vacuum degree of ≤-0.03 MPa and a temperature of 20–80°C.

[0018] Preferably, in step 2), the mass ratio of the crude mother liquor recovery product to the volume ratio of the acetonitrile is 1 g: (2-3) mL.

[0019] Preferably, in step 2): the first temperature is -5 to 10°C, the time for the temperature to drop from room temperature to the first temperature is 30 to 60 minutes, the heat preservation time is 30 to 120 minutes, and the heat preservation is carried out under stirring conditions with a stirring speed of 20 to 100 r / min.

[0020] Preferably, in step 2), the concentration is vacuum concentration, and the temperature of the vacuum concentration is 20-80℃, and the vacuum degree is ≤-0.03Mpa.

[0021] Preferably, in step 3), the good solvent is one or more of methyl acetate, ethyl acetate and isopropyl acetate, and the mass ratio of the concentrate to the volume of the good solvent is 1 g: (2-4) mL.

[0022] Preferably, in step 3), the undesirable solvent is one or more of petroleum ether, n-pentane, n-hexane, and n-heptane; the volume ratio of the good solvent to the undesirable solvent is 1:(3-5).

[0023] Preferably, in step 3), the drying is vacuum drying, the vacuum degree of the vacuum drying is ≤-0.03Mpa, and the temperature of the vacuum drying is 20~80℃.

[0024] This invention has discovered that during the synthesis of intermediate TK-1 from TK-01 and TK-03, ethylene glycol is used as the reaction solvent. Under the action of basic triethylamine, ethylene glycol reacts with some TK-03 to generate impurity M. Due to the relatively large amount of impurity M, approximately 10-20 wt% of intermediate TK-1 product fails to precipitate from the mother liquor. The reaction equation for the formation of impurity M is as follows:

[0025]

[0026] This invention provides a method for recovering intermediate TK-1 from the mother liquor of ticagrelor intermediate TK-1, comprising the following steps: Step 1) Concentrating the TK-1 crystallization mother liquor to obtain concentrated mother liquor; stirring the concentrated mother liquor to precipitate crystals and then separating the solid and liquid phases, drying the obtained solid product to obtain a crude mother liquor recovery product; Step 2) Dissolving the crude mother liquor recovery product in acetonitrile to obtain a crude product solution; cooling the crude product solution from room temperature to a first temperature and maintaining the temperature; separating the solid and liquid phases of the solution after maintaining the temperature to obtain a liquid phase product; concentrating the liquid phase product to obtain a concentrate; Step 3) Dissolving the concentrate in a good solvent to obtain a concentrate solution; adding a poor solvent to the concentrate solution to precipitate a solid product, separating the solid and liquid phases, and drying the solid product to obtain intermediate TK-1. This invention recovers intermediate TK-1 from TK-1 crystallization mother liquor, wherein TK-1 crystallization mother liquor is the mother liquor from which ethylene glycol is removed by extraction after the reaction of TK-01 and TK-03, and TK-1 crystallization mother liquor contains the aforementioned impurity M and unprecipitated intermediate TK-1. This invention first recovers a solid crude product from the mother liquor of TK-1 crystallization by concentration and stirring crystallization. The recovered crude mother liquor contains impurity M and intermediate TK-1. Then, utilizing the different solubilities of acetonitrile for impurity M and intermediate TK-1, a cooling crystallization method is used to remove impurities, allowing impurity M to precipitate as much as possible under the first temperature condition, thereby effectively separating impurity M and intermediate TK-1. The resulting concentrate is the crude intermediate TK-1. Finally, the concentrate is purified by anti-solvent recrystallization using a combination of a good solvent and a poor solvent for intermediate TK-1, yielding pure intermediate TK-1 with a yield of 60-70% and a purity of over 98.5%. In summary, the method provided by this invention can improve the molar yield of intermediate TK-1, reduce the production cost of intermediate TK-1, reduce the post-processing pressure of intermediate TK-1 mother liquor, reduce the cost of harmless treatment of mother liquor, and alleviate environmental pressure. Attached Figure Description

[0027] Figure 1 A flowchart for recovering intermediate TK-1 from the mother liquor of ticagrelor intermediate TK-1 provided by the present invention;

[0028] Figure 2 The liquid chromatogram of intermediate TK-1 recovered in Example 1 of this invention;

[0029] Figure 3 The liquid chromatogram of intermediate TK-1 recovered in Example 2 of this invention;

[0030] Figure 4 The liquid chromatogram of intermediate TK-1 recovered in Example 3 of this invention;

[0031] Figure 5This is a liquid chromatogram of intermediate TK-1 recovered in Comparative Example 1 of the present invention;

[0032] Figure 6 This is a liquid chromatogram of intermediate TK-1 recovered in Comparative Example 2 of the present invention;

[0033] Figure 7 This is a liquid chromatogram of intermediate TK-1 recovered in Comparative Example 3 of the present invention. Detailed Implementation

[0034] This invention provides a method for recovering intermediate TK-1 from mother liquor of ticagrelor intermediate TK-1, comprising the following steps:

[0035] Step 1) Concentrate the TK-1 crystallization mother liquor to obtain concentrated mother liquor; stir the concentrated mother liquor to precipitate crystals and then separate the solid and liquid components, dry the obtained solid product, and obtain crude mother liquor recovery product;

[0036] Step 2) Dissolve the crude mother liquor recovered product in acetonitrile to obtain a crude product solution; cool the crude product solution from room temperature to a first temperature and keep it at that temperature; separate the solid and liquid phases of the solution after keeping it at that temperature to obtain a liquid phase product; concentrate the liquid phase product to obtain a concentrate.

[0037] Step 3) Dissolve the concentrate in a good solvent to obtain a concentrate solution; add a poor solvent to the concentrate solution to precipitate a solid product; after solid-liquid separation, dry the solid product to obtain intermediate TK-1.

[0038] In this invention, unless otherwise specified, all raw materials / components used in the preparation are commercially available products well known to those skilled in the art.

[0039] This invention involves concentrating the TK-1 crystallization mother liquor (hereinafter referred to as the first concentration) to obtain a concentrated mother liquor; then, the concentrated mother liquor is stirred to induce crystallization, followed by solid-liquid separation (hereinafter referred to as the first solid-liquid separation), and the resulting solid product is dried (hereinafter referred to as the first drying) to obtain a crude mother liquor recovery product. In this invention, the TK-1 crystallization mother liquor is the mother liquor from which ethylene glycol is removed by extraction after the reaction of TK-01 and TK-03.

[0040] The chemical structural formula of TK-01 is as follows:

[0041]

[0042] The chemical structural formula of TK-03 is as follows:

[0043]

[0044] The chemical structural formula of TK-1 is:

[0045]

[0046] In this invention, the TK-1 crystallization mother liquor contains the aforementioned impurity M and the unprecipitated intermediate TK-1. The solvents in the TK-1 crystallization mother liquor are preferably ethyl acetate and n-heptane. In the TK-1 crystallization mother liquor: ethyl acetate... Kazumasa The volume ratio of heptane is preferably 150:600. The mass content of TK-1 in the TK-1 crystallization mother liquor is preferably 10-20 wt%, and the mass content of impurity M is preferably 3-6 wt%.

[0047] The chemical structural formula of impurity M is:

[0048]

[0049] In this invention, the first concentration is preferably vacuum concentration, the vacuum concentration temperature is preferably 30-60℃, and the vacuum degree is preferably ≤-0.07 MPa. The volume ratio of the concentrated mother liquor to the TK-1 crystallization mother liquor is preferably 1:(2-4), specifically preferably 1:3. The stirring crystallization temperature is preferably room temperature, the time is preferably 1-4 hours, more preferably 1-3 hours; the stirring speed is preferably 20-100 r / min, more preferably 40-60 r / min. During the stirring crystallization process, impurities M and intermediate TK-1 in the concentrated mother liquor precipitate out together from the concentrated mother liquor. The first solid-liquid separation is preferably filtration. The first drying is preferably vacuum drying, the vacuum degree of the vacuum drying is preferably ≤-0.03 MPa, more preferably ≤-0.07 MPa; the vacuum drying temperature is preferably 20-80℃, more preferably 40-60℃.

[0050] After obtaining the crude mother liquor recovery product, the present invention dissolves the crude mother liquor recovery product in acetonitrile to obtain a crude product solution; the crude product solution is cooled from room temperature to a first temperature and kept at that temperature; the solution after keeping at that temperature undergoes solid-liquid separation (hereinafter referred to as second solid-liquid separation) to obtain a liquid phase product; the liquid phase product is concentrated (hereinafter referred to as second concentration) to obtain a concentrate. In the present invention, the mass ratio of the crude mother liquor recovery product to the volume of the acetonitrile is preferably 1 g:(2-3) mL, more preferably 1 g:3 mL. The dissolution temperature is preferably room temperature, and the first temperature is preferably -5 to 10°C, more preferably 0 to 5°C. The time for cooling from room temperature to the first temperature is preferably 30 to 60 min, more preferably 35 to 55 min. The cooling is preferably uniform cooling. The holding time is preferably 30 to 120 min, more preferably 60 to 90 min. The holding is carried out under stirring conditions, and the stirring speed is preferably 20 to 100 r / min, more preferably 40 to 60 r / min. The second solid-liquid separation is preferably filtration. The solid product obtained from the second solid-liquid separation is impurity M, and the liquid product obtained is an acetonitrile solution of intermediate TK-1. The second concentration is preferably vacuum concentration, and the temperature of the vacuum concentration is preferably 20–80°C, more preferably 30–70°C; the vacuum degree is preferably ≤-0.03 MPa.

[0051] After obtaining the concentrate, the present invention dissolves the concentrate in a good solvent to obtain a concentrate solution; a poor solvent is added to the concentrate solution to precipitate a solid product, and after solid-liquid separation (hereinafter referred to as the third solid-liquid separation), the solid product is dried (hereinafter referred to as the third drying) to obtain intermediate TK-1.

[0052] In this invention, the good solvent is preferably one or more of methyl acetate, ethyl acetate, and isopropyl acetate. The mass ratio of the concentrate to the volume of the good solvent is preferably 1 g:(2-4) mL, more preferably 1 g:3 mL. The poor solvent is preferably one or more of petroleum ether, n-pentane, n-hexane, and n-heptane. The volume ratio of the good solvent to the poor solvent is preferably 1:(3-5), more preferably 1:4. The addition is preferably dropwise. The dropwise addition is carried out under stirring. The third drying is preferably vacuum drying, the vacuum degree of which is preferably ≤-0.03 MPa, more preferably ≤-0.07 MPa; the temperature of the vacuum drying is preferably 20-80°C, more preferably 40-60°C.

[0053] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0054] The following embodiments are all in accordance with Figure 1The process shown recovers intermediate TK-1 from the mother liquor of ticagrelor intermediate TK-1.

[0055] Example 1

[0056] Step 1) 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) was concentrated to 240 mL under reduced pressure at 50 °C and a vacuum degree ≤ -0.07 MPa. The concentrated mother liquor was then stirred at room temperature for 2 hours at a stirring speed of 60 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree ≤ -0.03 MPa and a temperature of 60 °C, yielding 8.2 g of crude mother liquor recovery product.

[0057] Step 2) Add 8.2 g of crude mother liquor recovered from Step 1) to 24.6 mL of acetonitrile, stir to dissolve, then cool from room temperature to 1°C at a constant rate over 30 minutes, keep warm and stir for 40 minutes, filter, and concentrate the filtrate under reduced pressure at a temperature of 50°C and a vacuum degree of ≤-0.03 MPa; 6.1 g of concentrate is obtained.

[0058] Step 3) Dissolve 6.1 g of the concentrate obtained in Step 2) in 18.3 mL of ethyl acetate, and add 73.2 mL of n-heptane dropwise under stirring. A large amount of solid precipitates. After solid-liquid separation and drying, 4.1 g of intermediate TK-1 is obtained, with a yield of 67.2% and a purity of 99.61%. The intermediate TK-1 prepared in this example can be used to prepare subsequent intermediates and finished products.

[0059] Figure 2 This is the high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Example 1, obtained by... Figure 2 It can be seen that the purity of the intermediate TK-1 recovered in this embodiment is 99.61%.

[0060] Example 2

[0061] Step 1) 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) was concentrated to 220 mL under reduced pressure at 40 °C and a vacuum degree ≤ -0.07 MPa. The concentrated mother liquor was then stirred at room temperature for 3 hours at a stirring speed of 60 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree ≤ -0.03 MPa and a temperature of 60 °C, yielding 8.3 g of crude mother liquor recovery product.

[0062] Step 2) Add 8.3 g of crude mother liquor recovered from Step 1) to 24.9 mL of acetonitrile, stir to dissolve, then cool from room temperature to 1°C at a constant rate over 30 minutes, keep warm and stir for 40 minutes, filter, and take the filtrate for vacuum concentration at a temperature of 60°C and a vacuum degree ≤ -0.03 MPa; 6.2 g of concentrate is obtained.

[0063] Step 3) Dissolve 6.2 g of the concentrate obtained in Step 2) in 19 mL of ethyl acetate, and add 76 mL of n-hexane dropwise under stirring. A large amount of solid precipitates. After solid-liquid separation and drying, 4.2 g of intermediate TK-1 is obtained, with a yield of 67.74% and a purity of 98.92%. The intermediate TK-1 prepared in this example can be used to prepare subsequent intermediates and finished products.

[0064] Figure 3 The high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Example 2 is shown below. Figure 3 It can be seen that the purity of the intermediate TK-1 recovered in this embodiment is 98.92%.

[0065] Example 3

[0066] Step 1) 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) was concentrated to 250 mL under reduced pressure at 45°C and a vacuum degree ≤ -0.07 MPa. The concentrated mother liquor was then stirred at room temperature for 2 hours at a stirring speed of 50 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree ≤ -0.03 MPa and a temperature of 60°C, yielding 8 g of crude mother liquor recovery product.

[0067] Step 2) Add 8 grams of crude mother liquor recovered from Step 1) to 24 mL of acetonitrile, stir to dissolve, then cool from room temperature to 1°C at a constant rate over 50 minutes, keep warm and stir for 40 minutes, filter, and take the filtrate for vacuum concentration at a temperature of 60°C and a vacuum degree ≤ -0.03 MPa; 6.0 grams of concentrate are obtained.

[0068] Step 3) Dissolve 6.0 g of the concentrate obtained in Step 2) in 18 mL of ethyl acetate, and add 72 mL of n-heptane dropwise under stirring. A large amount of solid precipitates out. After solid-liquid separation and drying, 4.1 g of intermediate TK-1 is obtained, with a yield of 68.3% and a purity of 98.95%. The intermediate TK-1 prepared in this example can be used to prepare subsequent intermediates and finished products.

[0069] Figure 4 The high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Example 3 is shown below. Figure 4It can be seen that the purity of the intermediate TK-1 recovered in this embodiment is 98.95%.

[0070] Comparative Example 1

[0071] The preparation method is basically the same as in Example 1, except that tetrahydrofuran is used instead of acetonitrile in step 2).

[0072] Step 1) 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) was concentrated to 240 mL under reduced pressure at 50 °C and a vacuum degree ≤ -0.07 MPa. The concentrated mother liquor was then stirred at room temperature for 2 hours at a stirring speed of 60 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree ≤ -0.03 MPa and a temperature of 60 °C, yielding 8.2 g of crude mother liquor recovery product.

[0073] Step 2) Add 8.2 g of crude mother liquor recovered from Step 1) to 24.6 mL of tetrahydrofuran, stir to dissolve, then cool from room temperature to 1°C at a constant rate over 30 minutes, keep warm and stir for 40 minutes, filter, and take the filtrate for vacuum concentration at a temperature of 50°C and a vacuum degree ≤ -0.03 MPa; 6.5 g of concentrate is obtained.

[0074] Step 3) Dissolve 6.5 g of the concentrate obtained in Step 2) in 18.3 mL of ethyl acetate, and add 73.2 mL of n-heptane dropwise under stirring. A large amount of solid precipitates. After solid-liquid separation and drying, 4.6 g of intermediate TK-1 is obtained, with a yield of 70.8% and a purity of 90.57%. The purity of the prepared intermediate TK-1 does not meet the quality requirements of subsequent processes.

[0075] Figure 5 The high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Comparative Example 1 is shown below. Figure 5 It can be seen that the purity of the intermediate TK-1 recovered in this embodiment is 90.57%.

[0076] Comparative Example 2

[0077] The preparation method is basically the same as that in Example 1, except that the cooling time in step 2) is 10 minutes, and the temperature is reduced from room temperature to 1°C.

[0078] Step 1) Concentrate 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) under reduced pressure to 2 ppm. 40 mL of concentrated mother liquor was collected under reduced pressure at a temperature of 50°C and a vacuum degree of ≤-0.07 MPa. The concentrated mother liquor was stirred at room temperature for 2 hours at a stirring speed of 60 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree of ≤-0.03 MPa and a temperature of 60°C, yielding 8.3 g of crude mother liquor recovery product.

[0079] Step 2) Add 8.3 g of crude mother liquor recovered from Step 1) to 24.6 mL of acetonitrile, stir to dissolve, then cool from room temperature to 1°C at a constant rate over 10 minutes, keep warm and stir for 40 minutes, filter, and concentrate the filtrate under reduced pressure at a temperature of 60°C and a vacuum degree of ≤-0.03 MPa; 6.2 g of concentrate is obtained.

[0080] Step 3) Dissolve 6.2 g of the concentrate obtained in Step 2) in 18.3 mL of ethyl acetate, and add 73.2 g of ethyl acetate dropwise under stirring. The yield was 67.74%, and the purity was 93.30%. The purity of the prepared intermediate TK-1 did not meet the quality requirements of subsequent processes.

[0081] Figure 6 The high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Comparative Example 2 is shown below. Figure 6 It can be seen that the purity of the intermediate TK-1 recovered in this comparative example is 93.30%.

[0082] Comparative Example 3

[0083] The preparation method is basically the same as that in Example 1, except that in step 2), when the temperature is lowered to 1°C, it is kept warm and stirred for 10 minutes.

[0084] Step 1) Concentrate 750 mL of TK-1 crystallization mother liquor (containing 150 mL ethyl acetate, 600 mL n-heptane, TK-1 content of 20 wt%, and impurity M content of 6%) under reduced pressure to 2 ppm. 4 0 mL of concentrated mother liquor was collected under reduced pressure at a temperature of 50°C and a vacuum degree of ≤-0.07 MPa. The concentrated mother liquor was stirred at room temperature for 2 hours at a stirring speed of 60 r / min. Solid-liquid separation was performed, and the resulting solid product was vacuum dried at a vacuum degree of ≤-0.03 MPa and a temperature of 60°C to obtain 8 g of crude mother liquor recovery product.

[0085] Step 2) Add 8 grams of crude mother liquor recovered from Step 1) to 24 mL of acetonitrile, stir to dissolve, and then allow to cool to room temperature. 3 The solution was cooled to 1°C at a constant rate for 0 minutes, kept warm and stirred for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure at a temperature of 50°C and a vacuum degree of ≤-0.03 MPa; 6.3 grams of concentrate were obtained.

[0086] Step 3) Dissolve 6.3 g of the concentrate obtained in Step 2) in 18.3 mL of ethyl acetate, and add 73.2 mL dropwise under stirring. The yield is 65.1% and the purity is 94.20%. The purity of the prepared intermediate TK-1 does not meet the quality requirements of subsequent processes.

[0087] Figure 7 The high-performance liquid chromatography (HPLC) chromatogram of intermediate TK-1 prepared in Comparative Example 3 is shown below. Figure 7 It can be seen that the purity of intermediate TK-1 recovered in this comparative example is 94.20%.

[0088] As can be seen from the above embodiments, the method for recovering intermediate TK-1 from the mother liquor of intermediate TK-1 provided by the present invention can increase the molar yield of intermediate TK-1 by about 10%, reduce the production cost of intermediate TK-1, reduce the pressure of mother liquor post-processing, reduce processing costs, and benefit environmental protection.

[0089] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for recovering intermediate TK-1 from mother liquor of ticagrelor intermediate TK-1, characterized in that, Includes the following steps: Step 1) Concentrate the TK-1 crystallization mother liquor to obtain a concentrated mother liquor. The solvent in the TK-1 crystallization mother liquor is ethyl acetate and n-heptane. The volume ratio of ethyl acetate to n-heptane in the TK-1 crystallization mother liquor is 150:

600. The mass content of TK-1 in the TK-1 crystallization mother liquor is 10~20wt%, and the mass content of impurity M is 3~6wt%. After stirring and crystallizing the concentrated mother liquor, solid-liquid separation is performed. The obtained solid product is dried to obtain a crude mother liquor recovery product. The chemical structural formula of impurity M is: ； Step 2) Dissolve the crude mother liquor recovery product in acetonitrile to obtain a crude product solution; cool the crude product solution from room temperature to a first temperature and keep it warm. After heat preservation, the solution is separated into solid and liquid phases to obtain a liquid product; the liquid product is then concentrated to obtain a concentrate. Step 3) Dissolve the concentrate in a good solvent, wherein the good solvent is one or more of methyl acetate, ethyl acetate, and isopropyl acetate, to obtain a concentrate solution; add a poor solvent, wherein the poor solvent is one or more of petroleum ether, n-pentane, n-hexane, and n-heptane, to precipitate a solid product; after solid-liquid separation, dry the solid product to obtain the intermediate TK-1, the chemical structural formula of which is: 。 2. The method according to claim 1, characterized in that, In step 1): the concentration is vacuum concentration, the temperature of the vacuum concentration is 30~60℃, and the vacuum degree is ≤-0.07Mpa.

3. The method according to claim 1 or 2, characterized in that, In step 1), the volume ratio of the concentrated mother liquor to the TK-1 crystallization mother liquor is 1:(2~4).

4. The method according to claim 1 or 2, characterized in that, In step 1): the temperature for stirring and crystallization is room temperature, the time is 1~4h, and the stirring speed is 20~100r / min; The drying process is vacuum drying, with a vacuum degree of ≤-0.03 MPa and a temperature of 20~80℃.

5. The method according to claim 1, characterized in that, In step 2), the mass ratio of the crude mother liquor recovered to the volume of the acetonitrile is 1 g: (2~3) mL.

6. The method according to claim 1, characterized in that, In step 2): the first temperature is -5~10℃, the time from room temperature to the first temperature is 30~60min, the heat preservation time is 30~120min, and the heat preservation is carried out under stirring conditions, with a stirring speed of 20~100r / min.

7. The method according to claim 1, characterized in that, In step 2): the concentration is vacuum concentration, the temperature of the vacuum concentration is 20~80℃, and the vacuum degree is ≤-0.03Mpa.

8. The method according to claim 1, characterized in that, In step 3), the mass ratio of the concentrate to the volume of the good solvent is 1 g: (2~4) mL.

9. The method according to claim 1 or 8, characterized in that, In step 3), the volume ratio of the good solvent to the bad solvent is 1:(3~5).

10. The method according to claim 1, characterized in that, In step 3), the drying is vacuum drying, the vacuum degree of the vacuum drying is ≤-0.03Mpa, and the temperature of the vacuum drying is 20~80℃.

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