Preparation of a rhodium solid phase catalyst and its application in the preparation of penem intermediates

Abstract

The present invention relates to the preparation of a rhodium solid phase catalyst and its application in catalytic preparation of a penem intermediate. First, rhodium ions are loaded onto a cationic resin by ion exchange to obtain a rhodium solid phase catalyst; then the rhodium solid phase catalyst is used to catalyze the reaction of a compound of formula (2) to obtain a penem intermediate compound of formula (1). The self-made rhodium solid phase catalyst of the present invention is used for the reaction for the first time, and the catalyst can be recycled, avoiding the complicated recovery of homogeneous catalysts and the high residual rhodium metal in the product. The post-treatment operation is simple and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of a rhodium solid phase catalyst and an application method thereof in catalytically preparing a penem intermediate. Background Art

[0002] The structure of a penem intermediate compound of formula (1) according to the present invention is shown below: .

[0003] Its chemical name is (5R,6S)-6-[1R-1-hydroxyethyl]-3,7-dioxo-1-aminobicyclo[3.2.0]heptane-2-carboxylic acid p-nitrobenzyl ester. This intermediate is a key intermediate in the synthesis of penem antibiotics, such as meropenem and ertapenem. The synthesis of this compound generally adopts the compound of formula (2) prepared by rhodium catalysis. It is an industrial synthesis method of mainstream manufacturers, as described in patents CN103059025B and CN108948086B. The synthesis route is as follows: .

[0004] However, the current processes all use homogeneous rhodium catalysts, such as rhodium acetate and rhodium octanoate. Homogeneous rhodium catalysts have the advantages of fast reaction speed and low dosage, but also have some disadvantages: First, it is easy to deactivate. The homogeneous rhodium catalyst gradually deactivates during the reaction, and the catalyst cannot be applied after the reaction. Second, it is difficult to recover. Rhodium is an expensive rare metal. The homogeneous rhodium catalyst is still dissolved in the reaction system after the reaction is completed. The recovery process is complicated. The recovered rhodium requires a complex preparation process to be re-made into rhodium acetate or rhodium octanoate, and the recovery rate is low, resulting in the loss of rhodium metal; Third, the rhodium remaining in the product is difficult to completely remove, resulting in excessive rhodium in the product, affecting the product quality of penicillin drugs. Summary of the invention

[0005] In view of the shortcomings of homogeneous rhodium catalysts in the process of preparing compounds of formula (1), the present invention provides a method for preparing a heterogeneous rhodium solid phase catalyst, and successfully applies it to the preparation of compounds of formula (1) for the first time. The technical solution of the present invention is as follows.

[0006] A method for preparing a rhodium solid phase catalyst is characterized by: dissolving rhodium chloride, rhodium acetate or rhodium octanoate in water, ethanol, ethyl acetate, acetone or toluene, adding a cation exchange resin, stirring for 6 to 48 hours at a temperature of 20 to 90 DEG C, cooling to room temperature, filtering, and obtaining the rhodium solid phase catalyst; wherein the weight ratio of rhodium chloride, rhodium acetate or rhodium octanoate to the cation exchange resin is 1:10 to 50, the amount of water, ethanol, ethyl acetate, acetone or toluene is 10 to 30 times the weight of the cation exchange resin, and the model of the cation resin is 732 H, Amberlite IR120H, Amberjet 1000H, Amberjet 1200H, Mitsubishi UBK08 H, Mitsubishi UBK10 H, Mitsubishi PK216 or Mitsubishi PK208 H.

[0007] A preparation method of a penem intermediate, characterized in that: under nitrogen protection, a compound of formula (2) and a rhodium solid phase catalyst are added to dichloromethane, ethyl acetate, acetone or toluene, the temperature is raised to 40-110°C for reaction for 1-8 hours, after the reaction is completed, the temperature is cooled to 15-25°C, filtered, the filtrate is decompressed and distilled to dryness, petroleum ether, isopropyl ether or n-heptane is added, stirred and crystallized for 1-6 hours, filtered, and dried to obtain a penem intermediate compound of formula (1); wherein the amount of the rhodium solid phase catalyst is 0.1-0.5 times the weight of the compound of formula (2), the amount of dichloromethane, ethyl acetate, acetone or toluene is 3-20 times the weight of the compound of formula (2), and the amount of petroleum ether, isopropyl ether or n-heptane is 2-8 times the weight of the compound of formula (2).

[0008] Compared with the prior art, the present invention has the following advantages: 1. The present invention prepares a rhodium solid phase catalyst and successfully applies it to the preparation of the compound of formula (1), providing a new method for preparing the compound of formula (1); 2. The rhodium solid phase catalyst of the present invention has a simple preparation process, is easy to use, has good catalyst stability, can be reused, and has been used 50 times in the laboratory without obvious activity reduction, which can greatly reduce the cost of use; 3. The post-reaction treatment for preparing the compound of formula (1) is simpler. The rhodium solid phase catalyst can be recovered by simple filtration. The compound of formula (1) can be obtained with high yield and high purity. The residual rhodium is less than 10 ppm, which meets the quality standards of medicines. DETAILED DESCRIPTION

[0009] In order to enable technicians to better understand the present invention, the technical solution of the present invention is specifically described through the following specific embodiments, but it is not intended to limit the protection scope of the present invention.

[0010] 1. Preparation of Rhodium Solid Phase Catalyst Example 1: 10.0 g of rhodium chloride was dissolved in 3000 g of water, 200 g of 732H type cation exchange resin was added, the temperature was controlled at 60°C, the reaction was stirred for 12 h, cooled to room temperature, filtered, the solid was washed with 400 g of water, and dried to obtain a solid phase rhodium catalyst (1).

[0011] Example 2: 10.0 g of rhodium acetate was dissolved in 2500 g of ethanol, 300 g of Amberlite IR120H cation exchange resin was added, the temperature was controlled at 50°C, the reaction was stirred for 30 h, cooled to room temperature, filtered, the solid was washed with 400 g of ethanol, and dried to obtain a solid phase rhodium catalyst (2).

[0012] Example 3: 10.0 g of rhodium octanoate was dissolved in 3000 g of acetone, and 250 g of Mitsubishi PK208 H type cation exchange resin was added. The temperature was controlled at 55°C, and the reaction was stirred for 20 h. The mixture was cooled to room temperature, filtered, and the solid was washed with 600 g of acetone and dried to obtain a solid phase rhodium catalyst (3).

[0013] Example 4: 10.0 g of rhodium octanoate was dissolved in 4000 g of toluene, 200 g of Amberjet 1200H cation exchange resin was added, the temperature was controlled at 70°C, the reaction was stirred for 36 hours, cooled to room temperature, filtered, the solid was washed with 700 g of toluene, and dried to obtain a solid phase rhodium catalyst (4).

[0014] Example 5: 10.0 g of rhodium acetate was dissolved in 3000 g of acetone, 200 g of Mitsubishi UBK08 H type cation exchange resin was added, the temperature was controlled at 55°C, the reaction was stirred for 24 h, cooled to room temperature, filtered, the solid was washed with 600 g of acetone, and dried to obtain a solid phase rhodium catalyst (5).

[0015] (II) Preparation of penem intermediate compound of formula (1) Example 4: Under nitrogen protection, 50 g of the compound of formula (2) and 15 g of the solid phase rhodium catalyst (1) were added to 500 g of dichloromethane, heated to 40°C and reacted for 8 h. After the reaction, the mixture was cooled to 15-25°C, filtered, and the filtrate was distilled to dryness under reduced pressure. 200 g of petroleum ether was added and stirred for crystallization for 2 h. The mixture was filtered and dried to obtain 44.5 g of the compound of formula (1), with a yield of 96.0%, an HPLC content of 99.1%, and a rhodium content of 1.2 ppm.

[0016] Example 5: Under nitrogen protection, 50 g of the compound of formula (2) and 10 g of the solid phase rhodium catalyst (2) were added to 250 g of ethyl acetate, the temperature was raised to 60°C and the reaction was carried out for 3 h. After the reaction, the temperature was cooled to 15-25°C, filtered, and the filtrate was distilled to dryness under reduced pressure. 150 g of isopropyl ether was added and stirred for crystallization for 3 h. The mixture was filtered and dried to obtain 45.1 g of the compound of formula (1). The yield was 97.2%, the HPLC content was 99.0%, and the rhodium content was 0.8 ppm.

[0017] Example 6: Under nitrogen protection, 50 g of the compound of formula (2) and 15 g of the solid phase rhodium catalyst (3) were added to 300 g of acetone, the temperature was raised to 50°C and the reaction was carried out for 4 h. After the reaction, the temperature was cooled to 15-25°C, filtered, and the filtrate was distilled to dryness under reduced pressure. 300 g of n-heptane was added and stirred for crystallization for 4 h. The mixture was filtered and dried to obtain 45.2 g of the compound of formula (1). The yield was 97.4%, the HPLC content was 99.2%, and the rhodium content was 1.5 ppm.

[0018] Example 7: Under nitrogen protection, 50 g of the compound of formula (2) and 10 g of the solid phase rhodium catalyst (4) were added to 500 g of toluene, the temperature was raised to 80°C and the reaction was carried out for 3 h. After the reaction, the temperature was cooled to 15-25°C, filtered, and the filtrate was distilled to dryness under reduced pressure. 200 g of isopropyl ether was added and stirred for crystallization for 3 h. The mixture was filtered and dried to obtain 45.0 g of the compound of formula (1). The yield was 97.0%, the HPLC content was 99.3%, and the rhodium content was 1.1 ppm.

[0019] Embodiment 8: Under nitrogen protection, 50g of the compound of formula (2) and 15g of the solid phase rhodium catalyst (3) were added to 300g of acetone, and the temperature was raised to 50°C for reaction for 4h. After the reaction, the mixture was cooled to 15-25°C, filtered, and the filtrate was distilled to dryness under reduced pressure. Then 300g of n-heptane was added and stirred for crystallization for 4h, filtered, and dried to obtain the compound of formula (1). The solid phase rhodium catalyst (3) obtained by filtration was directly added to the next batch of reactions and used in a cycle. The application results are as follows: .

Claims

1. A method for preparing a rhodium solid phase catalyst, characterized in that: Dissolve rhodium chloride, rhodium acetate or rhodium octanoate in water, ethanol, ethyl acetate, acetone or toluene, add a cation exchange resin, stir for 6 to 48 hours at a temperature of 20 to 90° C., cool to room temperature, and filter to obtain a rhodium solid phase catalyst; wherein the weight ratio of rhodium chloride, rhodium acetate or rhodium octanoate to the cation exchange resin is 1:10 to 50, the amount of water, ethanol, ethyl acetate, acetone or toluene is 10 to 30 times the weight of the cation exchange resin, and the model of the cation resin is 732 H, Amberlite IR120H, Amberjet 1000H, Amberjet 1200H, Mitsubishi UBK08 H, Mitsubishi UBK10 H, Mitsubishi PK216 or Mitsubishi PK208 H.

2. A method for preparing a penem intermediate, characterized in that: Under nitrogen protection, the compound of formula (2) and a rhodium solid phase catalyst are added to dichloromethane, ethyl acetate, acetone or toluene, the temperature is raised to 40-110°C for reaction for 1-8 hours, after the reaction is completed, the temperature is cooled to 15-25°C, filtered, the filtrate is decompressed and distilled to dryness, and then petroleum ether, isopropyl ether or n-heptane is added and stirred for crystallization for 1-6 hours, filtered, and dried to obtain a penem intermediate compound of formula (1); wherein the amount of the rhodium solid phase catalyst is 0.1-0.5 times the weight of the compound of formula (2), the amount of dichloromethane, ethyl acetate, acetone or toluene is 3-20 times the weight of the compound of formula (2), and the amount of petroleum ether, isopropyl ether or n-heptane is 2-8 times the weight of the compound of formula (2).

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