High diastereoselectivity synthesis method of avibactam intermediate III
By using reducing agents such as sodium cyanoborohydride in the solution of Avebactam Intermediate II and adding acid to perform borohydration reduction reaction, the problem of low yield of Avebactam Intermediate III was solved, and synthesis of high diastereoelectivity and high purity was achieved, reducing costs.
Patent Information
- Application Number
- CN202510218106.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-26
- Publication Date
- 2025-06-13
AI Technical Summary
In the prior art, the yield of avibactam intermediate III is low, and the reaction is more inclined to produce avibactam intermediate IV, resulting in low purity and yield and high prices.
A highly diastereoelective synthesis method is adopted, by adding sodium cyanoborohydride and other reducing agents to the solution containing Avebactam intermediate II, and then adding acid to perform borohydride reduction reaction, ensuring that the reaction only goes through one reaction process, thereby improving the generation of Avebactam intermediate III.
The high yield and high purity of Avebactam intermediate III were achieved, with the dr value reaching (5-8):1 and the purity can reach 75-78%, reducing the purchase cost of Avebactam intermediate III.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a method for highly diastereoselective synthesis of avibactam intermediate III. Background Art
[0002] Avibactam belongs to diazabicyclooctanone compounds and is a non-β-lactam inhibitor. It has no obvious antibacterial activity itself, but can inhibit type A (including ESBL and KPC) and type C β-lactamases. Therefore, when combined with various cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially significant antibacterial activity against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamase, Escherichia coli containing excessive Amp C enzyme, and Escherichia coli containing both Amp C and extended-spectrum β-lactamase.
[0003] The structural formulas of avibactam and avibactam sodium intermediate I are shown as follows respectively:
[0004]
[0005] Avibactam sodium intermediate I, chemically named: (2S,5R)-5-[(phenylmethoxy)amino]-2-piperidinecarboxylic acid ethyl ester oxalate, CAS: 1416134-48-9, is a key intermediate for the synthesis of avibactam sodium. Its purity, chiral purity, and impurities directly affect the purity and impurity content of other intermediates and even avibactam sodium, thus directly affecting the efficacy of the drug. Avibactam intermediate III and avibactam intermediate IV are diastereoisomers generated during the synthesis of avibactam sodium intermediate I, and are very important for the in-process control positioning, analysis of purity, etc. of the reaction process for synthesizing avibactam sodium intermediate I. Conventional avibactam intermediate III is obtained from the mother liquor of the post-treatment of synthesizing avibactam sodium intermediate I. The operation method is as follows: First, add concentrated sulfuric acid to acidify the avibactam intermediate II system, and then add sodium borohydride to the system for borohydride reduction. After adjusting the pH to neutral, add oxalic acid dihydrate for recrystallization to form a salt to obtain avibactam intermediate I. After filtering off the crystal, add dilute sulfuric acid to the mother liquor to adjust the pH to 2-3, cool down to crystallize to obtain the sulfate crystal of avibactam intermediate III, neutralize with alkali, and concentrate the organic layer to obtain avibactam intermediate III. The specific synthesis route is shown as follows:
[0006]
[0007] However, the yield of avibactam intermediate III under the borohydride reduction conditions of the above synthesis method is low, and the reaction tends to produce avibactam intermediate IV. The HPLC detection results show that the relative peak area ratio of avibactam intermediate III and IV is about 1:4, that is, the dr value is about 1:4. The yield ratio of avibactam intermediate III and avibactam intermediate IV obtained in the actual reaction process is also about 1:4. Generally, the method to obtain avibactam intermediate III is to carry out post-treatment after borohydride reduction and further process the mother liquor to obtain it. Due to the lack of an effective and feasible direct synthesis method for avibactam intermediate III, the production efficiency, yield and purity of avibactam intermediate III are low (in general industrial production, the purity of avibactam intermediate III is 15-20% by HPLC in-process control of the reaction solution), and the price remains high.
[0008] Therefore, there is an urgent need to develop a synthesis method for avibactam intermediate III with high yield. Summary of the Invention
[0009] The present invention aims to solve at least one of the technical problems existing in the above prior art. For this purpose, the present invention provides a highly diastereoselective synthesis method for avibactam intermediate III. The synthesis method for avibactam intermediate III provided by the present invention is more inclined to produce avibactam intermediate III. After the reaction, the reaction solution is controlled by HPLC, and the purity of avibactam intermediate III can reach 75-78%. The diastereoselectivity is relatively high, the dr value is as high as (5-8):1, and the yield of avibactam intermediate III is high.
[0010] The first aspect of the present invention provides a highly diastereoselective synthesis method for avibactam intermediate III.
[0011] Specifically, a highly diastereoselective synthesis method for avibactam intermediate III includes the following steps:
[0012] (1) Take a solution containing avibactam intermediate II and mix it with a reducing agent to obtain a mixed reaction solution;
[0013] (2) Add an acid to the mixed reaction solution in step (1) to carry out a borohydride reduction reaction to obtain the avibactam intermediate III;
[0014] In step (1), the reducing agent is at least one of sodium cyanoborohydride, borane dimethyl sulfide, and borane pyridinium salt;
[0015] In step (1), the solvent in the solution containing avibactam intermediate II is at least one of ethyl acetate (EA), dichloromethane, and tetrahydrofuran.
[0016] In the synthesis method of the present invention, a reducing agent is first added to a solution containing Avibactam intermediate II to cause the imine raw material (Avibactam intermediate II) to undergo a hydroboration reaction to generate an intermediate, and then an acid is added for acidification to provide a hydrogen source for further reaction of the intermediate. Such an operation method ensures that the reaction proceeds through only one reaction process, that is, the reducing agent first nucleophilically attacks the imine carbon-nitrogen double bond, and at this time, the configuration of the product is completely determined by the steric hindrance of the reducing agent. The reducing agent used in the present invention has a larger steric hindrance compared to the conventionally used sodium borohydride. Then, an acid is added for reduction, which is beneficial to obtaining a product with a high degree of diastereoselectivity and is more inclined to generate Avibactam intermediate III.
[0017] dr value: It refers to the ratio of two stereoisomers. Specifically, the dr value of the present invention refers to the ratio of the mass of Avibactam intermediate III to the mass of Avibactam intermediate IV.
[0018] Preferably, in step (1), the acid is at least one of sulfuric acid, methanesulfonic acid, tartaric acid, and acetic acid.
[0019] Preferably, in step (2), the temperature of the hydroboration reduction reaction is 0 - 5°C, and / or the time of the hydroboration reduction reaction is 0.5 - 2 h.
[0020] Preferably, the equivalent ratio of Avibactam intermediate II, the reducing agent, and the acid is 1:(1 - 2):(3 - 8).
[0021] Preferably, in step (1), Avibactam intermediate II is first dissolved in an organic solvent and then mixed with the reducing agent.
[0022] Preferably, the mass ratio of Avibactam intermediate II to the organic solvent is 1:(5 - 10).
[0023] Preferably, in step (1), the temperature when Avibactam intermediate II is mixed with the reducing agent is 0 - 5°C.
[0024] Preferably, in step (1), after Avibactam intermediate II is mixed with the reducing agent, it is stirred for 1 - 2 h.
[0025] Preferably, in step (2), the temperature during the process of adding the acid is 0 - 5°C.
[0026] Preferably, in step (2), after adding the acid, it is stirred for 1 - 2 h.
[0027] Preferably, in step (2), after the hydroboration reduction reaction, a reaction solution is obtained, and the reaction solution is detected by liquid chromatography to obtain the purity of Avibactam intermediate III in the reaction solution as 75 - 78%.
[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0029] In the present invention, Avibactam intermediate II is first mixed with a reducing agent, and then an acid is added to carry out a borohydride reduction reaction to obtain Avibactam intermediate III. The synthesis method provided by the present invention has high diastereoselectivity. The purity of Avibactam intermediate III in the reaction solution is as high as 75-78% when controlling the time, and the dr value of the obtained Avibactam intermediate III in the reaction system is (5-8):1. The method provided by the present invention can directly synthesize Avibactam intermediate III, and has a high yield, which can reduce the purchase cost of Avibactam intermediate III. Description of the Drawings
[0030] Figure 1 1H NMR spectrum of Avibactam intermediate III after column chromatography purification prepared in Example 1 of the present invention;
[0031] Figure 2 13C NMR spectrum of Avibactam intermediate III after column chromatography purification prepared in Example 1 of the present invention;
[0032] Figure 3 High performance liquid chromatography (HPLC) chart of the reaction solution after the reaction in step (2) of Example 1 of the present invention is controlled. Detailed Embodiments
[0033] In order to make those skilled in the art more clearly understand the technical solutions described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.
[0034] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels, or can be obtained by existing known methods.
[0035] Example 1
[0036] A synthesis method of Avibactam intermediate III, comprising the following steps:
[0037] (1) A four-necked flask containing an ethyl acetate solution (solute mass fraction 10%) of 560 g of Avibactam intermediate II is placed at 0 °C, and 17.9 g of sodium cyanoborohydride is slowly added thereto, and the temperature is controlled at 0 °C and stirred for 1 h;
[0038] (2) Then, at 0 °C, 187 g of concentrated sulfuric acid (solute mass fraction 98%) is added to the reaction system, the temperature is controlled at 0-2 °C, and the reaction is carried out for 1 h. TLC (thin layer chromatography) monitoring is carried out. After the raw materials are consumed and the reaction is completed, the reaction solution is sent for inspection and HPLC detection is carried out.
[0039] The main synthesis route involved above is as follows:
[0040]
[0041] Example 2
[0042] A method for synthesizing avibactam intermediate III, comprising the following steps:
[0043] (1) Place a four-necked flask containing 560 g of an ethyl acetate solution of avibactam intermediate II (solute mass fraction 10%) at 0 °C, and slowly add 17.9 g of sodium cyanoborohydride thereto, and control the temperature at 0 °C and stir for 1 h;
[0044] (2) Then, at 0 °C, add 104.4 g of methanesulfonic acid to the reaction system, control the temperature at 0 - 2 °C, react for 1 h, perform TLC monitoring, and after the raw materials are consumed, send the reaction solution for HPLC detection after the reaction ends.
[0045] Example 3
[0046] A method for synthesizing avibactam intermediate III, comprising the following steps:
[0047] (1) Place a four-necked flask containing 560 g of an ethyl acetate solution of avibactam intermediate II (solute mass fraction 10%) at 0 °C, and slowly add 142.6 mL of borane dimethyl sulfide (using tetrahydrofuran as a solvent and the solute borane dimethyl sulfide concentration is 2 mol / L) thereto, and control the temperature at 0 °C and stir for 1 h;
[0048] (2) Then, at 0 °C, add 104.4 g of methanesulfonic acid to the reaction system, control the temperature at 0 - 2 °C, react for 1 h, perform TLC monitoring, and after the raw materials are consumed, send the reaction solution for HPLC detection after the reaction ends.
[0049] Example 4
[0050] A method for synthesizing avibactam intermediate III, comprising the following steps:
[0051] (1) Place a four-necked flask containing 560 g of an ethyl acetate solution of avibactam intermediate II (solute mass fraction 10%) at 0 °C, and slowly add 142.6 mL of borane dimethyl sulfide thereto, and control the temperature at 0 °C and stir for 1 h;
[0052] (2) Then, at 0 °C, add 187 g of concentrated sulfuric acid (solute mass fraction 98%) to the reaction system, control the temperature at 0 - 2 °C, react for 1 h, perform TLC monitoring, and after the raw materials are consumed, send the reaction solution for HPLC detection after the reaction ends.
[0053] Example 5
[0054] A method for synthesizing avibactam intermediate III, comprising the following steps:
[0055] (1) Place a four-necked flask containing a 10% (by mass) ethyl acetate solution of 560 g of avibactam intermediate II at 0 °C, and slowly add 17.9 g of sodium cyanoborohydride thereto, and stir at 0 °C for 1 h;
[0056] (2) Then, at 0 °C, add 114.5 g of glacial acetic acid to the reaction system, control the temperature at 0 - 2 °C, react for 1 h, perform TLC monitoring, and after the raw materials are consumed, send the reaction solution for HPLC detection after the reaction ends.
[0057] Comparative Example 1
[0058] A method for synthesizing avibactam intermediate III, comprising the following steps:
[0059] (1) Place a four-necked flask containing a 10% (by mass) ethyl acetate solution of 560 g of avibactam intermediate II at 0 °C, and add 187 g of concentrated sulfuric acid (98% by mass) to the reaction system at 0 °C, and stir at 0 °C for 1 h;
[0060] (2) Then, at 0 °C, slowly add 17.9 g of sodium cyanoborohydride thereto, control the temperature at 0 - 2 °C, react for 1 h, perform TLC monitoring, and after the reaction ends, send the reaction solution for HPLC detection. The HPLC purity of avibactam intermediate III in the reaction solution is 17%.
[0061] Comparative Example 2
[0062] A method for synthesizing avibactam intermediate III, the difference between this comparative example and Example 1 is that the reducing agent sodium cyanoborohydride in step (1) is replaced with an equimolar amount of sodium borohydride.
[0063] Comparative Example 3
[0064] A method for synthesizing avibactam intermediate III, the difference between this comparative example and Example 1 is that the reducing agent sodium cyanoborohydride in step (1) is replaced with an equimolar amount of lithium aluminum hydride.
[0065] Comparative Example 4
[0066] A method for synthesizing avibactam intermediate III, the difference between this comparative example and Example 1 is that the solvent ethyl acetate in step (1) is replaced with an equal volume of tetrahydrofuran.
[0067] Comparative Example 5
[0068] A synthesis method of avibactam intermediate III. The difference between this comparative example and Example 1 is that the ethyl acetate solvent in step (1) is replaced with an equal volume of dichloromethane.
[0069] Comparative Example 6
[0070] A synthesis method of avibactam intermediate III. The difference between this comparative example and Example 1 is that concentrated sulfuric acid is not added in step (2).
[0071] Product effect test
[0072] 1. Structure characterization
[0073] The 1H NMR and 13C NMR spectra of the avibactam intermediate III prepared in Example 1 are respectively as Figure 1 and Figure 2 shown. From the figures, it can be judged that the avibactam intermediate III has the following molecular structure:
[0074]
[0075] 2. Purity and dr value
[0076] Both the purity and the dr value are determined by HPLC.
[0077] The HPLC results of the reaction solution after the reaction in Example 1 are as Figure 3 shown. Among them, the purity is the relative peak area of avibactam intermediate III in the liquid phase of the reaction solution; the dr value is the ratio of the relative peak area of avibactam intermediate III to the relative peak area of avibactam intermediate IV. The purity and dr value results of other examples and comparative examples are shown in the following table.
[0078] Table 1 Purity and dr value of each example and comparative example
[0079]
[0080]
[0081] As can be seen from the above table, the purity of avibactam intermediate III controlled in the reaction solutions of Examples 1-5 of the present invention can reach 75-78%, and the dr value is 5.3:1 to 7.1:1, which are all higher than those of Comparative Examples 1-6. This shows that the reaction not only has high diastereoselectivity and good reaction stability, but also has high product purity, and also has the advantages of simple reaction conditions and easy operation.
[0082] Compared with Example 1, in Comparative Example 1, the feeding order was changed. The raw materials and acid were mixed first, and the reaction was more inclined to the formation of avibactam intermediate Ⅳ, indicating that the feeding order had a great influence on the reaction process and reaction products. The synthetic route provided by Comparative Example 1 was actually the current conventional method for the borohydride reduction of avibactam intermediate Ⅱ: adding acid to the imine raw material first and then adding sodium borohydride, or adding concentrated sulfuric acid and the reducing agent simultaneously. This would cause the reaction to be more inclined to form avibactam intermediate Ⅳ because there was acid present during the borohydride reduction of the imine by sodium borohydride, resulting in inaccurate control of the reaction mechanism, and two reaction mechanisms would proceed simultaneously (one was that the nitrogen on the carbon-nitrogen double bond of the imine was first protonated by the acid and then a borane nucleophilic addition occurred; the other was that sodium borohydride would perform a nucleophilic addition on the carbon-nitrogen double bond of the imine and then be reduced by the acid). When concentrated sulfuric acid and the reducing agent coexisted, since the energy required for the protonation of the nitrogen on the carbon-nitrogen double bond of the imine was lower than the energy required for the nucleophilic addition of the reducing agent to the carbon-nitrogen double bond of the imine, the former was essentially an electrostatic attraction and binding process, which was fast and reversible, and the system was acidic, so the imine nitrogen atom was easily protonated, while the latter involved partial cleavage of the carbon-nitrogen double bond and the formation of new bonds, requiring higher energy. Therefore, the reaction mechanism in which the nitrogen on the carbon-nitrogen double bond of the imine was first protonated and then a borane nucleophilic addition occurred was dominant. Based on the above, it can be seen that the product of this conventional borohydride reduction method was actually the sum of two reaction mechanisms, and the reaction mechanism in which the nitrogen on the carbon-nitrogen double bond of the imine was first protonated and then a borane nucleophilic addition occurred was dominant, and the final result was a low yield of avibactam intermediate Ⅲ.
[0083] It can be seen from the comparison between Example 1 and Comparative Examples 2 and 3 that when sodium cyanoborohydride was used as the reducing agent, the purity and dr value of the reaction product were higher than those when sodium borohydride and lithium aluminum hydride were used as the reducing agents, indicating that increasing the steric hindrance of the reducing agent was more conducive to improving the diastereoselectivity of the reaction (increasing the yield of avibactam intermediate Ⅲ) and promoting the formation of the product.
[0084] It can be seen from the comparison between Example 1 and Comparative Examples 4 and 5 that the more suitable solvent for the reaction was ethyl acetate. When the solvent was changed to tetrahydrofuran or dichloromethane, the formation of the product would be reduced and the diastereoselectivity would be inhibited, resulting in a decrease in the purity and yield of avibactam intermediate Ⅲ.
[0085] It can be seen from the comparison between Example 1 and Comparative Example 6 that acid was crucial for the borohydride reduction reaction. Without acid, the reaction could not proceed and avibactam intermediate Ⅲ could not be prepared.
Claims
1. A highly diastereoselective synthesis method of avibactam intermediate III, characterized in that: The steps include: (1) taking a solution containing avibactam intermediate II and mixing it with a reducing agent to obtain a mixed reaction solution; (2) adding an acid to the mixed reaction solution of step (1) to carry out a hydroboration reduction reaction to obtain the avibactam intermediate III; In step (1), the reducing agent is at least one of sodium cyanoborohydride, borane dimethyl sulfide, and borane pyridine salt; In step (1), the solvent in the solution containing avibactam intermediate II is at least one of ethyl acetate, dichloromethane and tetrahydrofuran.
2. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (2), the acid is at least one of sulfuric acid, methanesulfonic acid, tartaric acid and acetic acid.
3. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (2), the temperature of the borohydride reduction reaction is 0-5°C, and / or the time of the borohydride reduction reaction is 0.5-2h.
4. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: The equivalent ratio of the avibactam intermediate II, the reducing agent and the acid is 1:(1-2):(3-8).
5. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (1), the avibactam intermediate II is first dissolved in an organic solvent and then mixed with a reducing agent.
6. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: The mass ratio of the avibactam intermediate II to the organic solvent is 1:(5-10).
7. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (1), the temperature at which the avibactam intermediate II is mixed with the reducing agent is 0-5°C.
8. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (1), the avibactam intermediate II is mixed with a reducing agent and stirred for 1-2 hours.
9. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (2), the temperature is controlled at 0-5°C during the process of adding the acid.
10. The highly diastereoselective synthesis method of avibactam intermediate III according to claim 1, characterized in that: In step (2), after the borohydride reduction reaction, a reaction solution is obtained, and the reaction solution is subjected to liquid chromatography detection to obtain a purity of avibactam intermediate III in the reaction solution of 75-78%.