Heterogeneous catalytic oxidation preparation method of penem antibiotic intermediate

Abstract

The invention discloses a heterogeneous catalytic oxidation preparation method of a penem antibiotic intermediate. A raw material compound is subjected to a catalytic oxidation reaction in an organic solvent under the action of a catalyst and an oxidizing agent to generate a target product, wherein the catalyst is a ruthenium-based heterogeneous metal catalyst, and the oxidizing agent is peracetic acid. The preparation method disclosed by the invention has the characteristics of economy, high efficiency, convenience in separation and recovery and high yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a heterogeneous catalytic oxidation preparation method for penem antibiotic intermediates. Background Technology

[0002] (3R,4R)-4-acetoxy-3-[(R)-1'-tert-butyldimethylsiloxane]-2-azacyclobutanone (4-AA) is a key intermediate in the synthesis of penem drugs. Penem drugs belong to the third-generation β-lactam antibiotics and were developed in the 1980s. They are among the broadest-spectrum and most potent antibiotics to date. They exhibit strong antibacterial activity against Gram-positive and Gram-negative bacteria, as well as aerobic and anaerobic bacteria, and are characterized by their broad spectrum, high efficacy, and low incidence of bacterial resistance. Therefore, they have become a research hotspot in clinical drug development.

[0003] Currently, there are eight penem drugs on the market globally, listed in order of their market launch date: imipenem, panipenem, meropenem, faropenem, ertapenem, biapenem, doripenem, and telbipenem. Among them, meropenem is the largest product in the global penem drug market, and its market demand continues to grow.

[0004]

[0005] (3R,4R)-4-acetoxy-3-[(R)-1'-tert-butyldimethylsiloxane]-2-azacyclobutanone (4-AA), composed of a β-lactam ring and three chiral centers, is the key active center for the chiral fused-ring core of penem antibiotic molecules. Currently, the synthesis of penem antibiotics mainly relies on total synthesis; therefore, the cost of 4-AA directly affects the final drug price.

[0006] In the asymmetric synthesis of 4-AA, a homogeneous catalytic system of ruthenium trichloride is mainly used, the catalyst is difficult to separate and recycle, a large amount of polluting wastewater is generated in the post-treatment, and the post-treatment cost is high. The research on the preparation of 4-AA by catalyst loading is relatively less. In the existing reports, the carriers used for the heterogeneous catalytic oxidation synthesis of 4-AA include: carbon (S. Murahashi, T. Naota, T. Kuwabara, et al. Ruthenium-catalyzed oxidation of amides and lactams with peroxides. J. Am. Chem. Soc. 1990 112 (21), 7820-7822), graphite, alumina (European Patent Organization, EP509821A1 1992-10-21), fluorapatite (India, IN2008CH02844 A 2010-06-25). These methods cannot realize catalyst recycling or have low reaction yield. Therefore, finding a suitable catalyst carrier that can ensure synthesis yield and realize recycling has become a new research hotspot. SUMMARY

[0007] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, the abstract and the title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0008] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0009] One of the purposes of the present application is to provide a heterogeneous catalytic oxidation preparation method of an intermediate of a penam antibiotic, which adopts a heterogeneous catalytic system, can realize recycling of the catalyst, reduces process cost and reduces environmental pollution caused by heavy metals in wastewater and residues.

[0010] To solve the above technical problems, the present application provides the following technical scheme: a heterogeneous catalytic oxidation preparation method of an intermediate of a penam antibiotic, comprising: under the action of a catalyst and an oxidizing agent, a raw material compound shown in formula I is subjected to catalytic oxidation reaction in an organic solvent to generate a product shown in formula II;

[0011]

[0012] The catalyst is a ruthenium-based heterogeneous metal catalyst, and the oxidizing agent is peroxoacetic acid.

[0013] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the carrier of the ruthenium-based heterogeneous metal catalyst is one of α-Al2O3, β-Al2O3, γ-Al2O3, activated carbon powder, α-MnO2, β-MnO2, hydroxyapatite, and SiO2.

[0014] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the method for synthesizing the ruthenium-based heterogeneous metal catalyst comprises impregnation, ion exchange, and the like. In one embodiment, the ruthenium precursor of the ruthenium-based catalyst is RuCl3xH2O.

[0015] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the molar number of ruthenium in the ruthenium-based heterogeneous metal catalyst is 1-10 mol% of the molar number of the starting compound of Formula I.

[0016] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the concentration of the peracetic acid solution is not less than 30%.

[0017] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: in one embodiment, the oxidant peracetic acid is prepared from acetic anhydride and hydrogen peroxide.

[0018] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the molar ratio of the starting compound of Formula I to the oxidant is 1:2-10.

[0019] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the temperature of the catalytic oxidation reaction is -15-20°C.

[0020] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: the organic solvent is acetonitrile, ethyl acetate, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol, or a combination thereof.

[0021] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: 5-30 mL of the organic solvent is required per gram of the starting compound of Formula I.

[0022] As a preferred embodiment of the method for preparing the intermediate of the penam antibiotic according to the present application by heterogeneous catalytic oxidation, wherein: sodium acetate and glacial acetic acid are further added in the catalytic oxidation reaction.

[0023] As a preferred scheme of the preparation method of the penam antibiotic intermediate by heterogeneous catalytic oxidation of the present application, the molar ratio of the raw material compound of formula I to sodium acetate is 1:1-10, and the amount of glacial acetic acid is 1-5 mL per gram of the raw material compound of formula I.

[0024] As a preferred scheme of the preparation method of the penam antibiotic intermediate by heterogeneous catalytic oxidation of the present application, after the catalytic oxidation reaction is completed, the reaction needs to be quenched, and the quenching solution is sodium thiosulfate solution, sodium bisulfite solution, sodium sulfite solution, sodium bisulfite solution, sodium bicarbonate solution or pure water. In an embodiment, the amount of the quenching solution is 5-20 mL per gram of the raw material I.

[0025] Compared with the prior art, the present application has the following beneficial effects:

[0026] The present application realizes the recycling and reuse of the catalyst while maintaining the yield. The recycling and reuse of the catalyst greatly reduces the cost and achieves better economic benefits. The discharge of heavy metal waste liquid in the post-treatment is reduced, and the degree of environmental pollution is greatly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor. Among them:

[0028] Figure 1 is a schematic diagram of the scanning electron microscope (SEM) and mapping diagram of the Ru / α-MnO2 catalyst prepared in Example 4 of the present application, wherein (a) is the SEM diagram of Ru / α-MnO2, and (b) is the mapping diagram of Ru / α-MnO2.

[0029] Figure 2 is a schematic diagram of the X-ray diffraction (XRD) diagram of α-MnO2, β-MnO2, Ru / α-MnO2 and Ru / β-MnO2 prepared in Example 4 of the present application, wherein (a) is the XRD diagram of α-MnO2 and Ru / α-MnO2 and the standard PDF card, and (b) is the XRD diagram of β-MnO2 and Ru / β-MnO2 and the standard PDF card.

[0030] Figure 3Figure 1 is a schematic diagram of X-ray diffraction (XRD) patterns of HAP, Ru / HAP, and Ru / α-MnO2cycled once prepared in accordance with embodiments 2 and 5 of the present application, wherein (a) is the XRD patterns of HAP and Ru / HAP and standard PDF cards, and (b) is the XRD patterns of Ru / α-MnO2and Ru / α-MnO2cycled once and standard PDF cards.

[0031] The attached figures can prove that the metal ruthenium is successfully loaded and uniformly distributed on the carrier, and no obvious metal clusters appear after the catalyst is used. DETAILED DESCRIPTION

[0032] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific embodiments of the present application will be described in detail below in combination with the description examples.

[0033] In the following description, a large number of specific details are set forth in order to facilitate a thorough understanding of the present application, but the present application can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without departing from the connotation of the present application, therefore the present application is not limited by the specific examples disclosed below.

[0034] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is independent of or mutually exclusive with other embodiments.

[0035] Unless otherwise specified, the raw materials used in the examples are commercially purchased.

[0036] Example 1

[0037] (1) Preparation of peroxyacetic acid

[0038] At -15°C, hydrogen peroxide (10 g, 50%) was added dropwise to acetic anhydride (15 g), and then concentrated sulfuric acid was slowly added. After stirring for 1 h, the reaction was carried out at room temperature for 3 h, and then left overnight to obtain 30% peroxyacetic acid.

[0039] (2) Preparation of Ru / Al2O3 catalyst

[0040] Taking Ru / α-Al2O3 as an example, RuCl3xH2O (136 mg) was weighed and dissolved in a beaker with deionized water. Then α-Al2O3 powder (1 g) was weighed and added to the RuCl3solution. The mixture was stirred for 3 h, dried at 80°C for 6 h, and finally calcined at 500°C for 3 h under Ar2atmosphere and H2atmosphere (100 mL·min -1Reduced at 500℃ for 2 hours, yielding 5% Ru / α-Al2O3.

[0041] (3) Preparation of 4-acetoxyazolidinone

[0042]

[0043] Azacyclobutanone (115 mg, 0.5 mmol), sodium acetate (164 mg, 2 mmol), and Ru / α-Al₂O₃ (50 mg, 5 mol%) were dissolved in ethyl acetate (1 mL) and glacial acetic acid (0.2 mL). A 30% peracetic acid solution (0.5 mL) was slowly added dropwise at 0 °C, maintaining the reaction at 0 °C. The reaction progress was monitored by TLC. After the reaction was completed, saturated sodium sulfite solution was added to quench the reaction. The catalyst was recovered by filtration, and the filtrate was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column purification separated the product 4-AA as white crystals. The calculated yield was 73%.

[0044] 1H NMR spectrum of the target product: 1 H NMR (500MHz, CDCl3): 6.56 (s, 1H), 5.83 (s, 1H), 4.21 (dd, J = 6.4, 3.5Hz, 1H), 3.1 8(d,J=3.4Hz,1H),2.10(s,3H),1.24(d,J=6.3Hz,3H),0.85(s,9H),0.06(s,6H).

[0045] It should be noted that, following the method in Example 1, replacing α-Al2O3 with γ-Al2O3 as the support can also yield 5% Ru / γ-Al2O3.

[0046] Example 2

[0047] Add 1 g of hydroxyapatite (HAP) support to a round-bottom flask containing 100 mL of acetone and stir at 55 °C. Dissolve 136 mg of RuCl3·xH2O in 15 mL of acetone and slowly add it dropwise to the suspension. Reflux and stir for 24 h, remove acetone by rotary evaporation, and dry overnight at 40 °C. In an H2 atmosphere (100 mL / min... -1 At 280℃ (heating at 1℃ / min) for 3 hours, 5% Ru / HAP was obtained.

[0048] Example 3

[0049] 700 mg of activated carbon powder was stirred with 95 mg of RuCl3·xH2O in ethanol (40 mL), and the mixture was then refluxed for 4 h. After cooling to room temperature, the ethanol solution was removed by rotary evaporation, and the remaining solid was dried under vacuum at 80 °C for 12 h. The solid was then pyrolyzed at 800 °C (10 °C / min increase) for 2 h under an Ar2 atmosphere to obtain 5% Ru / C.

[0050] Example 4

[0051] Taking Ru / α-MnO2 as an example, 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 13.6 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and vigorously stirred at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring was continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 200 °C for 1 h to obtain 5% Ru / α-MnO2.

[0052] Alternatively, by replacing α-MnO2 with β-MnO2 as the support according to the method in Example 4, 5% Ru / β-MnO2 can also be obtained.

[0053] The scanning electron microscope (SEM) image and mapping image of the Ru / α-MnO2 catalyst prepared in Example 4 are shown below. Figure 1 As shown. The X-ray diffraction (XRD) patterns of α-MnO2, β-MnO2, Ru / α-MnO2, and Ru / β-MnO2 prepared in Example 4 are shown below. Figure 2 As shown, (a) is the XRD pattern of α-MnO2 and Ru / α-MnO2 and the standard PDF card, and (b) is the XRD pattern of β-MnO2 and Ru / β-MnO2 and the standard PDF card. The figures demonstrate that metallic ruthenium was successfully loaded and uniformly distributed on the support.

[0054] Example 5

[0055] The 5% ruthenium-based metal catalysts prepared in Examples 1-4 based on different supports were then used to prepare 4-acetoxyazinobutanone according to the method described in step (3) of Example 1. The yields are shown in Table 1.

[0056] Table 1. Yields of ruthenium-based catalysts with different supports

[0057] Catalyst Mol % Yield (%) [Ru / alpha-Al2O3] 5 73 [Ru / γ-Al2O3] 5 76 Ru / C 5 60 Ru / HAP 5 78 [Ru / α-MnO2] 5 80 [Ru / β-MnO2] 5 78

[0058] As can be seen from Table 1, under the same reaction conditions, except for the catalyst with C as the support which has a low yield, the ruthenium-based catalysts with other supports can all obtain high yields.

[0059] Schematic diagrams of X-ray diffraction (XRD) patterns of HAP, Ru / HAP, and Ru / α-MnO2 after one cycle prepared in Examples 2 and 5, where (a) shows the XRD patterns of HAP and Ru / HAP and the standard PDF card, and (b) shows the XRD patterns of Ru / α-MnO2 and Ru / α-MnO2 after one cycle and the standard PDF card. It can be seen that no obvious metal clusters appeared after catalyst use.

[0060] Example 6

[0061] The ruthenium-based metal catalysts prepared with different supports in Example 5 were recycled and reused. Then, 4-AA was synthesized again according to the method described in step (3) of Example 1. The yield and recycling effect are shown in Table 2.

[0062] Table 2. Cycling performance of ruthenium-based catalysts with different supports

[0063] Catalyst First time yield (%) One cycle yield (%) [Ru / alpha-Al2O3] 73 / [Ru / γ-Al2O3] 76 15 Ru / C 60 20 Ru / HAP 78 18 [Ru / α-MnO2] 80 45 [Ru / β-MnO2] 78 30

[0064] As can be seen from Table 2, only the Ru / α-MnO2 catalyst showed good recycling performance.

[0065] Example 7

[0066] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 13.6 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 300 °C for 1 h to obtain 5% Ru / α-MnO2.

[0067] Example 8

[0068] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 8.0 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 200 °C for 1 h to obtain 3% Ru / α-MnO2.

[0069] Example 9

[0070] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 8.0 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 300 °C for 1 h to obtain 3% Ru / α-MnO2.

[0071] Example 10

[0072] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 19.5 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 200 °C for 1 h to obtain 7% Ru / α-MnO2.

[0073] Example 11

[0074] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 19.5 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 300 °C for 1 h to obtain 7% Ru / α-MnO2.

[0075] Example 12

[0076] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 28.7 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 200 °C for 1 h to obtain 10% Ru / α-MnO2.

[0077] Example 13

[0078] 100 mg of α-MnO2 was dispersed in 20 mL of H2O and sonicated for 30 min. Then, 28.7 mg of RuCl3·xH2O was dissolved in 20 mL of H2O and stirred vigorously at room temperature. The RuCl3 solution was then added to the α-MnO2 suspension, and the pH was adjusted to 13 with 1 M NaOH solution. Stirring continued for 12 h, followed by vacuum filtration and washing with deionized water until neutral. After drying in an oven at 80 °C, the product was further annealed in air at 300 °C for 1 h to obtain 10% Ru / α-MnO2.

[0079] Example 14

[0080] Using the Ru / α-MnO2 catalysts prepared under different conditions in Examples 4 and 7-13, 4-AA was synthesized according to the method described in step (3) of Example 1. The catalytic effects are shown in Table 3.

[0081] Table 3 Catalytic effects of Ru / α-MnO2 catalysts under different preparation conditions

[0082] Ru loading (%) Annealing temperature (°C) Yield (%) 3 200 50 3 300 30 5 200 80 5 300 26 7 200 70 7 300 33 10 200 74 10 300 30

[0083] As shown in Table 3, the Ru / α-MnO2 catalysts with Ru loadings of 5%, 7%, or 10%, and annealed at 200℃, exhibited superior catalytic performance.

[0084] Example 15

[0085] The Ru / α-MnO2 catalyst from Example 14 was recycled and reused. Then, 4-AA was synthesized again according to the method described in step (3) of Example 1. The recycling effect is shown in Table 4.

[0086] Table 4. Cyclic reuse efficiency of Ru / α-MnO2 catalysts under different preparation conditions.

[0087]

[0088]

[0089] As can be seen from Table 4, the 5% Ru / α-MnO2 catalyst with annealing at 200℃ has a better recycling effect.

[0090] This invention achieves catalyst recycling and reuse while maintaining yield; the recycling of catalyst greatly reduces costs and improves economic benefits; and the discharge of heavy metal waste liquid in post-treatment is reduced, significantly lowering the degree of environmental pollution.

[0091] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A process for the preparation of an intermediate of a carbapenem antibiotic by heterogeneous catalytic oxidation, characterized in that: The application relates to a method for preparing a product of formula II by catalytic oxidation of a raw material compound of formula I. The catalytic oxidation reaction is carried out in an organic solvent under the action of a catalyst and an oxidant. The catalyst is a ruthenium-based heterogeneous metal catalyst, and the oxidant is peracetic acid.

2. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 1 wherein: The carrier of the ruthenium-based heterogeneous metal catalyst is one of alpha-Al2O3, beta-Al2O3, gamma-Al2O3, activated carbon powder, alpha-MnO2, beta-MnO2, hydroxyapatite and SiO2.

3. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation according to claim 1 or 2, characterized in that: The molar number of ruthenium in the ruthenium-based heterogeneous metal catalyst is 1-10 mol% of the molar number of the raw material compound of formula I.

4. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 1 wherein: The concentration of the peracetic acid solution is not less than 30%.

5. The heterogeneous catalytic oxidation method for preparing penem antibiotic intermediates according to any one of claims 1, 2, and 4, characterized in that: The molar ratio of the raw material compound of formula I to the oxidant is 1:2-10.

6. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 5 wherein: The catalytic oxidation reaction is carried out at a temperature of-15-20 DEG C.

7. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 1 wherein: The organic solvent is acetonitrile, ethyl acetate, dichloromethane, toluene, tetrahydrofuran, methanol, ethanol or a combination thereof.

8. The process for the preparation of an intermediate of a penam antibiotic by heterogeneous catalytic oxidation according to any one of claims 1, 2, 4, 6, 7, characterized in that: 5-30 mL of the organic solvent is needed for each gram of the raw material compound of formula I.

9. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 8 wherein: Sodium acetate and glacial acetic acid are also needed in the catalytic oxidation reaction.

10. The process for the preparation of imipenem intermediate by heterogeneous catalytic oxidation as claimed in claim 9 wherein: The molar ratio of the raw material compound of formula I to sodium acetate is 1:1-10, and the amount of glacial acetic acid needed for each gram of the raw material compound of formula I is 1-5 mL.

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