Acid addition salts of abemaciclib, processes for their preparation and uses

Abstract

This invention provides acid addition salts of abexicillin, their preparation methods, and applications, relating to the field of medicinal chemistry. The abexicillin acid addition salts provided by this invention, particularly benzylsulfonate, can be used as intermediates in the preparation of abexicillin active pharmaceutical ingredient (API). Preparing free abexicillin via abexicillin acid addition salts can significantly reduce palladium and other related substances (impurities) in the product, obtaining high-purity API, avoiding the extensive use of conventional palladium removal agents such as mercaptosilicone, reducing production costs, improving production efficiency, and being environmentally friendly. In particular, compared with other salt forms, abexicillin benzylsulfonate has a high yield and high removal efficiency of palladium and related substances, making it an ideal intermediate for the industrial production of abexicillin API. The method of preparing free abexicillin using abexicillin benzylsulfonate can be used in the de novo synthesis of abexicillin, as well as in the purification process of crude abexicillin, suitable for industrial production to promote the production and application of abexicillin.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to the acid addition salt of abexicillin, its preparation method and uses. Background Technology

[0002] Abemaciclib is a novel oral CDK4 / 6 inhibitor that selectively inhibits cyclin-dependent kinase 4 / 6 (CDK4 / 6), restores cell cycle regulation, and inhibits tumor cell proliferation. It is indicated for the treatment of postmenopausal or premenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor (HER-2)-negative, advanced or metastatic breast cancer that has progressed after endocrine therapy. Its brand name is Verzenio.

[0003] Abecitabine's chemical name is N-ethyl-N'-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amino-2-pyridine-5-methyl)piperazine. In the prior art, the synthesis of abecitabine requires a palladium catalyst in multiple steps, resulting in excessive palladium residue in the active pharmaceutical ingredient. In the prior art, palladium removal agents, such as mercaptosilanol, are commonly used to remove palladium from abecitabine for palladium control in the final active pharmaceutical ingredient. This method of removing palladium through adsorption has the following drawbacks: (1) it is expensive and not conducive to cost control; (2) it is inefficient and often requires multiple adsorptions, reducing production efficiency and further increasing production costs; (3) it generates solid waste pollution, which is not environmentally friendly. Patent CN102264725B describes the addition of methanesulfonic acid to a solution of crude abecitabine in DCM and methanol, followed by vacuum concentration to remove the solvent, and then grinding with the addition of MTBE to obtain abecitabine methanesulfonate. During the research process, the inventors discovered that the method used a large amount of methanesulfonic acid, and vacuum concentration could not directly precipitate solids. Moreover, after the solvent was concentrated to dryness, MTBE was added for grinding, but there was no crystallization process, so the removal effect on palladium and impurities was very limited. Summary of the Invention

[0004] One of the objectives of this invention is to provide acid addition salts of abexicillin, through which free abexicillin can be prepared. This can significantly reduce palladium and other related substances in the product, obtain high-purity active pharmaceutical ingredient, avoid the extensive use of conventional palladium removal agents such as mercaptosilicone, reduce production costs, improve production efficiency, and is environmentally friendly. It is an ideal intermediate for the industrial production of abexicillin active pharmaceutical ingredient.

[0005] Another object of the present invention is to provide a method for preparing abexilic acid addition salts, including but not limited to hydrochloride, maleate, succinate, malate, benzenesulfonate, benzoate, D-di-p-methoxybenzoyl tartrate, D-di-p-methylbenzoyl tartrate, citrate or p-toluenesulfonate.

[0006] Another object of the present invention is to provide a method for preparing abexicillin benzylsulfonate and its use, wherein the method is used to prepare abexicillin benzylsulfonate and can be used to prepare free abexicillin.

[0007] The technical solution adopted in this invention is as follows:

[0008] Acid addition salts of abecilibi, wherein the acid is selected from any one of hydrochloric acid, maleic acid, succinic acid, malic acid, benzenesulfonic acid, benzoic acid, D-di-p-methoxybenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, citric acid, or p-toluenesulfonic acid.

[0009] This invention provides abexicillin benzenesulfonate as shown in the following formula:

[0010]

[0011] The preparation method of abexilic acid addition salt involves adding acid and solvent to crude abexilic acid, heating to dissolve, and then cooling to precipitate the solid.

[0012] In a preferred embodiment of the present invention, the solvent is methanol or tetrahydrofuran, and the acid is selected from any one of hydrochloric acid, maleic acid, succinic acid, malic acid, benzenesulfonic acid, benzoic acid, D-di-p-methoxybenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, citric acid, or p-toluenesulfonic acid.

[0013] In a preferred embodiment of the present invention, the temperature is raised to 40-80°C for dissolution, and the temperature is lowered to 0-15°C to precipitate the solid.

[0014] The preparation method of abexicillin benzenesulfonate adopts the following synthetic route:

[0015]

[0016] The operation steps are as follows:

[0017] (1) Add tert-amyl alcohol to the reaction vessel and purge with nitrogen. Then add potassium carbonate, compound 3, compound 4 and Xantphos in sequence. Rinse the vessel wall with tert-amyl alcohol, turn on the stirrer, replace with nitrogen and add Pd2(dba)3. Then heat to 95-105℃ for reaction. After the reaction is qualified, cool down and add dichloromethane to the system. After cooling to room temperature, filter and take the filtrate.

[0018] (2) Purify the filtrate to obtain a refined filtrate;

[0019] (3) Add benzenesulfonic acid or its monohydrate to the filtrate, heat and stir to react, then cool down under stirring to precipitate solid, separate the solid, wash with cold methanol and dry to obtain abexicillin benzenesulfonate.

[0020] In a preferred embodiment of the present invention, in step (1), potassium carbonate is in powder form.

[0021] In a preferred embodiment of the present invention, the particle size of the powdered potassium carbonate satisfies D95≤100μm.

[0022] In a preferred embodiment of the present invention, the purification process in step (2) includes purification with N-acetyl-L-cysteine, activated carbon, and mercaptosilicone in sequence.

[0023] In a preferred embodiment of the present invention, in step (3), the temperature is raised to 60-65°C for reaction, and after the reaction is complete, the temperature is lowered to 45-50°C and stirred for 0.5-2 hours. Finally, the temperature is lowered to 0-15°C to precipitate solid.

[0024] The preparation method of abexicillin involves first preparing abexicillin benzenesulfonate using the aforementioned preparation method, then dissolving the abexicillin benzenesulfonate in a mixed solvent consisting of water and an organic solvent, adjusting the pH of the aqueous phase to 11-12, allowing it to stand and separate into layers, taking the organic phase, concentrating it, distilling it with acetone, concentrating it again, then adding acetone and refluxing, crystallizing at low temperature, and filtering to obtain abexicillin.

[0025] In a preferred embodiment of the present invention, the organic solvent is composed of water and dichloromethane in a volume ratio of 1:0.8-2.

[0026] The beneficial effects of this invention are as follows:

[0027] The abecilibric acid addition salts provided by this invention, particularly benzyl sulfonate, can be used as intermediates in the preparation of abecilib active pharmaceutical ingredient (API). Preparing free abecilib via abecilibric acid addition salts can significantly reduce palladium and other related substances (impurities) in the product, resulting in high-purity API. This avoids the extensive use of conventional palladium removal agents such as mercaptosilicone, reducing production costs, improving production efficiency, and being environmentally friendly. In particular, compared to other salt forms, abecilib benzyl sulfonate exhibits high yield and high removal efficiency of palladium and related substances, making it an ideal intermediate for the industrial production of abecilib API. The method of preparing free abecilib using abecilib benzyl sulfonate can be used in the de novo synthesis of abecilib, as well as in the purification process of crude abecilib, making it suitable for industrial production and promoting the production and application of abecilib. Attached Figure Description

[0028] Figure 1-3These are the HPLC detection chromatograms of different samples in Example 2;

[0029] Figure 4-8 The HPLC detection chromatograms of different samples in Example 4 are shown.

[0030] Figure 9-11 The images show the HPLC detection chromatograms of different samples in Example 5. Detailed Implementation

[0031] In this invention, unless otherwise specified, crude abecitabine is synthesized by referring to the synthesis method provided in patent CN102264725B.

[0032] In this invention, unless otherwise specified, benzenesulfonic acid may refer to benzenesulfonic acid or its monohydrate.

[0033] In this invention, palladium in the sample was determined by inductively coupled plasma mass spectrometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0412). Specifically:

[0034] Solvent (blank solution): 2% hydrochloric acid solution.

[0035] Test solution: Take an appropriate amount of this product, accurately weigh it, dissolve it in 2% hydrochloric acid solution and dilute it quantitatively to prepare a solution containing about 1 mg of abexilide per 1 ml.

[0036] Reference solutions: Accurately measure an appropriate amount of palladium single-element standard solution (containing 1000 μg of palladium per 1 ml), and quantitatively dilute it with 2% hydrochloric acid solution to prepare solutions containing 0 ng, 1 ng, 2.5 ng, 5 ng, 10 ng, 15 ng, 20 ng, and 30 ng of palladium per 1 ml, as a series of reference solutions.

[0037] Internal standard solution: Accurately measure an appropriate amount of mixed internal standard solution (containing 100 μg of indium per 1 ml) and quantitatively dilute it with 2% hydrochloric acid solution to prepare a solution containing 100 ng of indium per 1 ml.

[0038] Assay: Accurately measure blank solution, a series of control solutions, and the test solution for injection, while simultaneously adding internal standard online using a peristaltic pump. Palladium mass number is 10⁵, and indium mass number is 11⁵; calculations are performed using the standard curve method calibrated with internal standard.

[0039] In this invention, abexicillin and related substances were detected by high performance liquid chromatography (HPLC) under the following chromatographic conditions: octadecylsilane-bonded silica gel was used as the packing material; 0.01 mol / L ammonium formate buffer (pH adjusted to 10.0 with ammonia) was used as mobile phase A, and acetonitrile was used as mobile phase B; linear gradient elution was performed according to the elution program shown in Table 1; the flow rate was 1.0 ml per minute; the detection wavelength was 235 nm; the column temperature was 30 °C; and the injection volume was 10 μl.

[0040] Table 1 Elution Procedure

[0041]

[0042] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0043] Example 1

[0044] In this embodiment, the yield and palladium removal efficiency of different salt forms of abexicillin were tested. Specific method: 2g of crude abexicillin was taken in multiple portions, and different acids (1.0 eq) were added to each portion, followed by different solvents to form salts. The salt yield was calculated, and palladium residue in each salt was detected. The salt formation process and results for each combination are shown in Table 2.

[0045] Table 2. Salt formation process, yield, and palladium removal effect of different salt types and solvents.

[0046]

[0047]

[0048] Table 2 shows that, under the same salt-forming method, the salt-forming process of crude abexicillin differs depending on the type of acid used, indicating variations in dissolution state, reaction process, and / or crystallization state in different solvents. Furthermore, the palladium residue after salt formation varies considerably depending on the acid and solvent used. All salts exhibit some palladium removal efficiency, with hydrochloride, maleate, succinate, malate, benzenesulfonate, benzoate, D-di-p-methoxybenzoyl tartrate, D-di-p-methylbenzoyl tartrate, and citrate showing particularly good palladium removal effects. Methanol or tetrahydrofuran is preferred as the salt-forming solvent, with methanol being more preferred as it balances salt yield and palladium removal efficiency.

[0049] Example 2

[0050] This embodiment provides a method for preparing abexicillin. The method first obtains abexicillin benzenesulfonate, and then the free abexicillin benzenesulfonate is used to obtain abexicillin. The synthetic route is shown below:

[0051]

[0052] Specific synthesis steps:

[0053] Step 1: Add 4L of tert-amyl alcohol to the reactor and purge with nitrogen for at least 0.5 hours. Then, add 640g of potassium carbonate (granular), 680g of compound 3 (629-1), 1000g of compound 4 (5054-2), and 14.34g of Xantphos sequentially. Rinse the reactor wall with 1L of tert-amyl alcohol, start stirring, purge with nitrogen, and then add 11.35g of Pd2(dba)3. Purge with nitrogen three times, then heat to 95-105℃. After the reaction is successful, add dichloromethane to the system, cool to room temperature, filter (sampling point 1), and collect the filtrate.

[0054] Step 2: Add N-acetyl-L-cysteine ​​aqueous solution and sodium hydroxide solution to the filtrate in sequence to adjust the pH to 11-12. Add hydrochloric acid to the organic layer after separation, separate the liquid and liquid, add activated carbon to the aqueous phase, stir for 1 hour, filter and collect the filtrate.

[0055] Step 3: Add 100g of mercaptosilica to the filtrate, stir for about 5-15 hours, and then filter. Add dichloromethane (or n-butanol) and sodium hydroxide solution to the filtrate, adjust the pH to 11-12, and retain the organic phase (sampling point 2).

[0056] Step 4: After concentrating the organic phase to dryness, add methanol and distill twice (i.e., azeotropic distillation). Then add methanol and heat to 40-50℃ to dissolve the solids. Add benzenesulfonic acid monohydrate, heat to 60-65℃ and stir for 0.5h. Then cool to 45-50℃ and stir for 1h. Finally, cool to 0-15℃ and continue stirring for 1h. Centrifuge, wash the filter cake with cold methanol, and finally dry to obtain abexicillin benzenesulfonate (sampling point 3).

[0057] Step 5: Add abexicillin benzenesulfonate to 5 times the volume of water and 6 times the volume of dichloromethane, stir at 0-15℃ for 15-25 minutes, add sodium hydroxide aqueous solution to adjust the pH of the aqueous phase to 11-12, then let it stand to separate into layers, retain the organic phase, concentrate the organic phase, and distill the residue three times with acetone, concentrate it again, and finally add 5-6 times the volume of acetone and reflux for 8-12 hours, then lower the temperature to 0-15℃ and filter to obtain the abexicillin product.

[0058] Samples were taken at the above sampling points, and the obtained samples were analyzed. The results are shown in Table 3 and Appendix. Figure 1-3 As shown, among which, appendix Figure 1-3 The images show the HLPC analysis spectra of the samples obtained at sampling points 1-3.

[0059] Table 3. Detection results (%) for each sample

[0060]

[0061] Note: In Table 3, " / " indicates that it was not detected.

[0062] From Table 3 and Figure 1-3 The results showed that after purification with N-acetyl-L-cysteine, activated carbon, and mercaptosilica gel in steps 2 and 3, the sample at sampling point 2 was obtained. Ten impurities were detected in both sampling points 1 and 2, with almost no difference in the types and amounts of impurities. However, after salting abexicillin, the number of impurities decreased significantly, leaving only three, all with amounts below 0.10%. This demonstrates that salting abexicillin effectively removes related substances generated during the process, and the related substances in the salted product meet the requirements of ICH Q3A guidelines, with unknown impurities all below 0.10%.

[0063] Furthermore, the inventors discovered during the research and development process that the shape of the material affects the reaction process. Specifically, in step 1 of this embodiment, the use of granular potassium carbonate hindered the reaction process to some extent, resulting in a lower abexilin content and a relatively higher impurity content at sampling point 1. Using powdered potassium carbonate promotes the reaction, affects the impurity profile, reduces impurity content, and increases product yield; specific data can be found in Example 5. Further, the researchers found that when the particle size of potassium carbonate meets the requirement of D95 ≤ 100 μm, and preferably D95 ≤ 80 μm, it can better promote the improvement of product yield.

[0064] Example 3

[0065] This embodiment provides a comparison of the palladium removal effects of different palladium removal methods on the abexilide reaction solution. The palladium removal methods used include: ① re-adsorption with 10% activated carbon; ② acid-water alkalization extraction followed by washing with N-acetyl-L-cysteine ​​aqueous solution; ③ adsorption with mercaptosilicone; ④ acid-water alkalization extraction followed by concentration, and then palladium removal by benzenesulfonic acid salt formation.

[0066] Referring to the synthesis route and process of Example 2, the filtrate obtained in step (2) was collected, divided into 4 equal portions, and processed as follows:

[0067] System 1: Add 10% activated carbon to the filtrate, heat to 40-50℃, stir for 1 hour, filter, concentrate the filtrate and measure palladium.

[0068] System 2: The pH of the filtrate was adjusted to 11-12 with sodium hydroxide solution, extracted with dichloromethane, and extracted with 4% N-acetyl-L-cysteine ​​aqueous solution. The mixture was stirred at 10-25℃ for 30±10 min, allowed to stand and separate into layers, and a small amount of the organic phase was taken and concentrated under reduced pressure to obtain a solid. Palladium residue was then detected.

[0069] System 3: Add 10% mercaptosilica to the filtrate to remove palladium for 8 hours, filter, and dry the filtrate to determine palladium.

[0070] System 4: The pH of the filtrate was adjusted to 11-12 with sodium hydroxide solution, extracted with dichloromethane, the organic phase was concentrated and distilled with methanol, then methanol was added and the temperature was raised to 40-50℃ to dissolve it, benzenesulfonic acid monohydrate was added, the temperature was raised to 60-65℃ and stirred for 0.5h, then the temperature was lowered to 45-50℃ and stirred for 1h, and finally the temperature was lowered to 0-15℃ and stirred for another 1h. After filtration and drying, palladium was measured.

[0071] The palladium removal effects of the different palladium removal methods mentioned above are shown in Table 4.

[0072] Table 4. Palladium removal efficiency of different palladium removal methods

[0073]

[0074] Table 4 shows that the palladium content of the products obtained from the same filtrate through different palladium removal methods varies significantly. Re-application of activated carbon and N-acetyl-L-cysteine ​​aqueous solution only removes about 50% of the palladium. Adsorption with mercaptosilicone is more effective than activated carbon and N-acetyl-L-cysteine ​​aqueous solution, but still leaves nearly 30% palladium residue. The product obtained through benzenesulfonate formation achieves a palladium removal rate exceeding 90%, significantly higher than the other three methods, resulting in a lower palladium content and more reliable quality in the final product.

[0075] Example 4

[0076] Using the same batch of crude product, different acids were used to form salts, and the effects of salt formation on impurity removal were compared. The results are shown in Table 5. Figure 4-8 As shown, where, Figure 4 This is the HPLC chromatogram of the crude product solution. Figure 5-8 The corresponding HPLC detection chromatograms are shown in sections 6.1-6.4.

[0077] 6.1 Add crude abexicillin and mesylate to tetrahydrofuran, stir until dissolved, heat to 50-70℃ until the solid remains, then cool 0-15℃. Filter and dry at 50℃ to obtain abexicillin mesylate.

[0078] 6.2 Add crude abexicillin and p-toluenesulfonic acid to tetrahydrofuran, stir until dissolved, heat to 50-70℃ until the solid remains, then cool to 0-15℃. Filter and dry at 50℃ to obtain abexicillin methanesulfonate.

[0079] 6.3 Add crude abexicillin and benzenesulfonic acid monohydrate to tetrahydrofuran, stir to precipitate solid, heat to 50-70℃, if the solid is not completely dissolved, cool to 0-15℃, filter, and dry at 50℃ to obtain abexicillin benzenesulfonate.

[0080] 6.4 Add crude abexicillin and benzenesulfonic acid monohydrate to methanol, stir to precipitate solid, heat to 50-70℃, dissolve the solid, cool to 0-15℃, filter, and dry at 50℃ to obtain abexicillin benzenesulfonate.

[0081] Table 5. Impurity removal effect of different salt types

[0082]

[0083] Note: In Table 5, " / " indicates that it was not detected.

[0084] From Table 5 and Figure 4-8 It can be seen that benzenesulfonate, methanesulfonate, and p-toluenesulfonate have similar removal effects on most impurities. However, for the RRT0.98 impurity in crude abexicillin, p-toluenesulfonate and benzenesulfonate have significant removal effects on this impurity, while methanesulfonate has almost no removal effect on this impurity.

[0085] Example 5

[0086] Referring to the process of Example 2 (in step 1, granular potassium carbonate was replaced with powder), in step (4), methanesulfonic acid and benzenesulfonic acid (or monohydrate) were selected for salt formation, and the palladium removal and impurity removal effects of abexicillin benzenesulfonate and abexicillin methanesulfonate were compared. The results are shown in Table 6 and Figure 9-11 As shown, where, Figure 9 This is the HPLC chromatogram of the sample before salt formation. Figure 10-11 The images show the HPLC chromatograms of the samples after conversion to benzenesulfonic acid and methanesulfonate, respectively.

[0087] Table 6. Palladium and impurity removal effects of different salt types

[0088]

[0089] Note: In Table 6, " / " indicates not detected, N / A indicates not applicable, and the sample before salt formation was filtrate, so palladium content was not detected.

[0090] From Table 6 and Figure 9-11 The results show that abexicillin benzenesulfonate has a significant advantage over methanesulfonate in the removal of RRT0.127, 5054-1B, 5054-2J, 5054-1J and RRT2.23. Furthermore, the palladium content in the benzenesulfonate is lower than that in the methanesulfonate. Therefore, abexicillin benzenesulfonate has a better overall removal effect on organic impurities and palladium than abexicillin methanesulfonate.

[0091] Example 6

[0092] This embodiment provides a method for preparing abexicillin benzylsulfonate from crude abexicillin, as detailed below:

[0093] Take 2g of crude abexicillin, add 0.70g of benzenesulfonic acid monohydrate, add methanol, heat to 40-80℃ and stir to dissolve, cool to 0-15℃, precipitate solid, filter to obtain abexicillin benzenesulfonate.

[0094] Example 7

[0095] This embodiment provides a method for preparing abexicillin benzylsulfonate from crude abexicillin, as detailed below:

[0096] Take 2g of crude abexicillin, add 0.70g of benzenesulfonic acid monohydrate, add tetrahydrofuran, heat to 40-80℃ and stir to dissolve, cool to 0-15℃, precipitate solid, and filter to obtain abexicillin benzenesulfonate.

Claims

1. An acid addition salt of abemaciclib, characterized in that, The acid is selected from any one of hydrochloric acid, maleic acid, succinic acid, malic acid, benzenesulfonic acid, benzoic acid, D-di-p-methoxybenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, citric acid, and p-toluenesulfonic acid.

2. The acid addition salt according to claim 1, characterized in that, It is abexilide benzenesulfonate as shown in the following formula:

3. Process for the preparation of an abemaciclib acid addition salt, characterized in that, Acid and solvent are added to crude abexilide, the mixture is heated to dissolve it, and then cooled to precipitate the solid.

4. The production method according to claim 3, characterized by, The solvent is methanol or tetrahydrofuran, and the acid is selected from any one of hydrochloric acid, maleic acid, succinic acid, malic acid, benzenesulfonic acid, benzoic acid, D-di-p-methoxybenzoyl tartaric acid, D-di-p-methylbenzoyl tartaric acid, citric acid, and p-toluenesulfonic acid.

5. The production method according to claim 3, wherein Dissolve the solid by heating to 40-80℃ and then cooling to 0-15℃ to precipitate the solid.

6. Process for the preparation of abemaciclib besylate, characterized in that, It is synthesized using the following synthetic route: The operation steps are as follows: (1) Add tert-amyl alcohol to the reaction vessel and purge with nitrogen. Then add potassium carbonate, compound 3, compound 4 and Xantphos in sequence. Rinse the vessel wall with tert-amyl alcohol, turn on the stirrer, replace with nitrogen and add Pd2(dba)3. Then heat to 95-105℃ for reaction. After the reaction is qualified, cool down and add dichloromethane to the system. After cooling to room temperature, filter and take the filtrate. (2) Purify the filtrate to obtain a refined filtrate; (3) Add benzenesulfonic acid or its monohydrate to the filtrate, heat and stir to react, then cool down under stirring to precipitate solid, separate the solid, wash with cold methanol and dry to obtain abexicillin benzenesulfonate.

7. The preparation method according to claim 6, characterized in that, In step (1), potassium carbonate is in powder form.

8. The preparation method according to claim 7, characterized in that, The particle size of powdered potassium carbonate meets the requirement of D95≤100μm.

9. The preparation method according to claim 6, characterized in that, In step (2), the purification process includes purification with N-acetyl-L-cysteine, activated carbon, and mercaptosilicone in sequence.

10. The preparation method according to claim 6, characterized in that, In step (3), the temperature is raised to 60-65℃ for reaction. After the reaction is complete, the temperature is lowered to 45-50℃ and stirred for 0.5-2 hours. Finally, the temperature is lowered to 0-15℃ to precipitate solid.

11. A method for preparing abexicillin, characterized in that, Abexicillin benzenesulfonate was first prepared using the preparation method of any one of claims 6-10. Then, abexicillin benzenesulfonate was dissolved in a mixed solvent consisting of water and an organic solvent. The pH of the aqueous phase was adjusted to 11-12, and the phase was allowed to stand and separate. The organic phase was taken, concentrated, and then distilled with acetone. After further concentration, acetone was added and refluxed. The phase was then crystallized at low temperature and filtered to obtain abexicillin.

12. The method for preparing abexicillin according to claim 11, characterized in that, The organic solvent is composed of water and dichloromethane in a volume ratio of 1:0.8-2.

Images