Deprotection preparation method of avibactam intermediate

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a deprotection preparation method of an avibactam intermediate, which comprises the following steps: reacting a compound I with formate in a solvent under the catalysis of palladium carbon and the existence of acid to prepare a product, and post-treating the product to obtain an avibactam intermediate compound II, the method is mild in condition, high in safety, simple and convenient to operate, high in reaction purity, few in impurity and easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and particularly relates to a method for the deprotection preparation of an avibactam intermediate. Background Technology

[0002] The original process for avibactam (such as WO2012086241A1) has significant drawbacks: it is lengthy (more than 15 steps), has a low overall yield (about 30%), requires the use of dangerous hydrogenation debenzylation reactions and expensive protective agents (such as Fmoc-Cl), and the purification of intermediates depends on column chromatography, which makes it difficult to meet the needs of large-scale production.

[0003] Avibactam, a non-β-lactamase inhibitor, significantly enhances the antibacterial activity of cephalosporins by inhibiting resistance enzymes such as AmpC and KPC, making it an important drug for combating multidrug-resistant bacterial infections. Its molecular structure contains a diazabicyclooctone skeleton and requires a multi-step protection / deprotection reaction for construction, with the deprotection of benzyloxyamino group being a key step. The specific structure is as follows: Several publications have reported on the deprotection of avibactam, such as WO2015023123A1, CN107501255A, and CN103649051A. These publications highlight issues such as the presence of alkaline or strong environmental conditions leading to numerous reaction impurities, difficulty in process control, and high costs. Summary of the Invention

[0004] The purpose of this invention is to provide a method for the deprotection preparation of avibactam intermediates. This method is characterized by mild conditions, high safety, simple operation, high reaction purity, low impurities, and ease of industrial production.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for deprotecting and preparing an avibactam intermediate involves reacting compound I with a formate in a solvent under palladium-on-carbon catalysis and in the presence of an acid to obtain the product. The product is then post-treated to obtain avibactam intermediate compound II. The structures of compounds I and II are as follows: Compound I ; Compound II .

[0006] Furthermore, the formate is one of sodium formate, ammonium formate, potassium formate, and cesium formate, with ammonium formate being preferred.

[0007] Furthermore, the acid is one or more of formic acid, acetic acid, methanesulfonic acid, and trichloroacetic acid, preferably formic acid.

[0008] Furthermore, the solvent is a mixture of methanol, ethanol, isopropanol and water, preferably isopropanol as the reaction solvent.

[0009] Furthermore, the mass ratio of compound I to formate is 1:(0.01~2.4), preferably 1:(0.031~0.5).

[0010] Furthermore, the mass ratio of compound I to palladium on carbon is 1:(0.01~2.2), preferably 1:(0.025~0.5).

[0011] Furthermore, the mass-to-volume ratio of compound I to acid, expressed in g / mL, is 1:(0.01~3), preferably 1:(0.07~1).

[0012] Furthermore, the mass-volume ratio of compound I to solvent, expressed in g / mL, is 1:(5~50) or 1:(10~30).

[0013] Furthermore, the reaction temperature is 10~40℃, preferably 20~35℃; the reaction time is 0.5~6h, preferably 2~4h.

[0014] Further post-processing steps: After the reaction is complete, palladium on carbon is filtered, the filtrate is concentrated, water is added to the concentrated solid to dissolve it, and then it is extracted with an organic solvent to recover the organic phase. After the organic phase is dried, it is concentrated to obtain avibactam intermediate compound II.

[0015] Preparation mechanism: This method uses in-situ hydrogen gas as a hydrogen source for hydrogenation debenzylation, and selects formic acid, ammonium formate and other active α-hydrogen compounds as hydrogen sources to remove benzyl groups under noble metal catalysis.

[0016] The advantages of this invention are: 1. Formate is inexpensive and has low processing costs; formate is safe and does not require special storage; formate is a weak acid-weak base salt, so it does not have high requirements for equipment and operation. 2. Formate has relatively weak activity and will not react with functional groups such as ester groups, resulting in fewer byproducts, high product purity, and no need for additional purification steps; 3. Formic acid is a weak acid; avoid making the solution too acidic to prevent impurities from forming. 4. The synthesis method of the present invention avoids the problems of large safety hazards, difficult process control and many impurities in the existing strong acid process methods. The reaction conditions of the present invention are mild, the operation is simple, the process operation is safe, the yield is high and the product purity is high, which is suitable for industrial production. Attached Figure Description

[0017] Figure 1 This is the mass spectrum of the avibactam intermediate prepared in Example 1 of this invention. Detailed Implementation

[0018] Example 1 A method for deprotecting and preparing an avibactam intermediate involves reacting compound I with formate in the presence of palladium on carbon catalysis and acid to prepare reactant compound II, as follows: Compound I Compound II 5.0 g of compound I was added to 75 ml of isopropanol, along with 0.56 g of palladium on carbon, 0.62 g of ammonium formate, and 1.38 ml of formic acid. The mixture was reacted at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated by rotary evaporation. Water was added to the concentrated solid, and the mixture was extracted with dichloromethane. The lower layer of dichloromethane was recovered, and the upper layer of the reaction mixture was concentrated by rotary evaporation to obtain compound II. Weight: 3.027 g; Yield: 91.2%; Purity: 98.44%. MS (m / z): 186.1 [M+1] + The mass spectrum of the product is as follows: Figure 1 As shown, the hydrogen spectrum data (MS(m / z): 186.1 [M+1]) + This allows for analysis and confirmation of the target product, further validating the results.

[0019] Example 2: 5.0 g of compound I was added to 50 ml of methanol, along with 0.56 g of palladium on carbon, 0.62 g of ammonium formate, and 1.38 ml of formic acid. The mixture was reacted at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated by rotary evaporation. Water was added to the concentrated solid, and the mixture was extracted with dichloromethane. The lower layer of dichloromethane was recovered, and the upper layer of the reaction mixture was concentrated by rotary evaporation to obtain compound II. Weight: 3.027 g; Yield: 85.2%; Purity: 97.35%.

[0020] Example 3: 5.0 g of compound I was added to 75 ml of isopropanol, along with 0.56 g of palladium on carbon, 0.93 g of sodium ammonium formate, and 1.38 ml of formic acid. The mixture was reacted at 30 °C for 3 h. The mixture was filtered, and the filtrate was concentrated by rotary evaporation. Water was added to the concentrated solid, and the mixture was extracted with dichloromethane. The lower layer of dichloromethane was recovered, and the upper layer of the reaction mixture was concentrated by rotary evaporation to obtain compound II. Weight: 3.027 g; Yield: 95.2%; Purity: 99.17%.

[0021] Example for comparison: 5.0 g of compound I was added to 75 ml of isopropanol and 75 ml of water, along with 0.56 g of palladium on carbon. The mixture was reacted with hydrogen gas at 30 °C for 8 h. The mixture was filtered, and the filtrate was concentrated by rotary evaporation. The concentrate was extracted with dichloromethane, and the lower layer of dichloromethane was recovered. The upper layer of the reaction mixture was concentrated by rotary evaporation to obtain compound II. Weight: 2.89 g; Yield: 90.9%; Purity: 99.3%.

Claims

1. A method for preparing an avibactam intermediate through deprotection, characterized in that: Compound I was reacted with formate in a solvent under palladium-on-carbon catalysis and in the presence of acid to prepare the product. The product was then post-treated to obtain avibactam intermediate compound II. The structures of compounds I and II are as follows: Compound I ; Compound II .

2. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The formate is one of sodium formate, ammonium formate, potassium formate, and cesium formate.

3. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The acid is one or more of formic acid, acetic acid, methanesulfonic acid, and trichloroacetic acid.

4. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The solvent is a mixture of methanol, ethanol, isopropanol and water.

5. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The mass ratio of compound I to formate is 1:(0.01~2.4).

6. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The mass ratio of compound I to palladium on carbon is 1:(0.01~2.2).

7. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The mass-to-volume ratio of compound I to acid, expressed in g / mL, is 1:(0.01~3).

8. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The mass-to-volume ratio of compound I to solvent, expressed in g / mL, is 1:(5~50).

9. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: The reaction temperature is 10~40℃, and the reaction time is 0.5~6h.

10. The method for preparing the avibactam intermediate as described in claim 1, characterized in that: Post-processing steps: After the reaction is complete, palladium on carbon is filtered, the filtrate is concentrated, water is added to the concentrated solid to dissolve it, and then it is extracted with an organic solvent. The organic phase is recovered, dried, and concentrated to obtain avibactam intermediate compound II.

Images