Preparation method and application of cefepime ester side chain

Abstract

The application discloses a preparation method of high-purity cephalosporin bipu ester side chain (1a), and a reaction route is shown as follows. The method is characterized in that 2a is used as a starting material to react with triphosgene to generate compound 3a, and then the compound 3a is used to react with p-nitrophenol to generate compound 1a. The product has high purity and high reaction yield, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of synthesis. Specifically, this invention relates to a method for preparing high-purity cefepime side chains. Background Technology

[0002] Cefop-pyroxel (2b) is a novel cephalosporin antibiotic, Chemicalbook, jointly developed by Basilea Pharma-ceutica and Johnson & Johnson. Its active ingredient is cefotobiprole. Ceffotobiprole is a broad-spectrum cephalosporin antibiotic, effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA), and is currently the only cephalosporin antibiotic effective against both MRSA and VRSA.

[0003]

[0004] The synthetic process of cefepime (2b) is disclosed in documents WO2009127623A1 and WO2010136423A1. The synthetic process uses compound 1b and side chain 1a (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methyl 4-nitrophenyl carbonate) as raw materials to synthesize cefepime (2b), where 1a is an important side chain of cefepime.

[0005]

[0006]

[0007] Literature WO2021035360A1 reports a synthetic method for compound 1a, which uses p-nitrobenzene chloroformic acid as a raw material (3) and reacts with 4-(hydroxymethyl)-5-methyl-[1,3]dioxanepentadien-2-one (2a) to generate the target product 1a with a yield of 54%. However, 1a synthesized according to the current method contains a large number of impurities, resulting in impurities in the final synthesized cefepime ester product, which in turn leads to unsatisfactory yield and quality of the final product.

[0008] Therefore, there is an urgent need in the field for a new synthetic route to synthesize 1a, which can significantly improve the reaction yield and quality of the final product, cefepime. Summary of the Invention

[0009] The purpose of this invention is to provide a novel synthetic method for cefoprepti ester side chain 1a, which significantly improves the purity of the cefoprepti ester side chain 1a obtained by the method, thereby enabling the high yield and high quality of the final product, cefoprepti ester.

[0010] Another object of the present invention is to provide a method for synthesizing cefoplastin using the cefoplastin side chain 1a obtained by the above method.

[0011] In a first aspect, the present invention provides a method for preparing cefepime, the method comprising:

[0012] 1) Compound 2a reacts with triphosgene to form compound 3a;

[0013] 2) Compound 3a reacts with p-nitrophenol (4a) to generate compound 1a;

[0014] The reaction pathways for steps 1) and 2) are shown below:

[0015]

[0016] 3) Prepare cefepime as shown in 2b using the compound shown in 1a obtained in step 2);

[0017]

[0018] In a specific embodiment, in step 1), compound 2a reacts with triphosgene in solvent S1, wherein S1 is selected from toluene, dichloromethane or dichloroethane; preferably dichloromethane.

[0019] In a specific embodiment, in step 1), compound 2a reacts with triphosgene under alkaline B1 conditions, wherein alkaline B1 is triethylamine, pyridine, or N,N-dimethylaniline; preferably N,N-dimethylaniline.

[0020] In a specific embodiment, in step 1), compound 2a reacts with triphosgene at a temperature T1, wherein the temperature T1 is 0°C to 40°C, preferably 0°C to 5°C.

[0021] In a preferred embodiment, the content of impurity 100 with the structure shown below in the compound 3a obtained in step 1) is less than 2.0%.

[0022]

[0023] In a specific embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) in solvent S2, wherein the solvent is tetrahydrofuran, dichloromethane or dichloroethane; preferably dichloromethane.

[0024] In a specific embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) at a temperature T2, wherein the temperature T2 is 0°C to 40°C; preferably 10°C to 15°C.

[0025] In a specific embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) under base B2 conditions, wherein base B2 is triethylamine, pyridine, or diisopropylethylamine; preferably pyridine.

[0026] In a specific embodiment, the method further includes step 2') between step 2) and step 3), in which the 1a compound obtained in step 2) is purified in solvent S3 to obtain the 1a finished product.

[0027] In a specific implementation, in step 2'), S3 is toluene, ethyl acetate, or acetonitrile; preferably ethyl acetate.

[0028] In a preferred embodiment, the purification in the S3 solvent refers to recrystallizing the 1a compound obtained in step 2) using the S3 solvent.

[0029] In a preferred embodiment, the content of impurity 100 in the compound 1a obtained in step 2') is <0.1%.

[0030] In a preferred embodiment, step 3) prepares cefepime (as shown in 2b) via the reaction route illustrated below.

[0031]

[0032] In a second aspect, the present invention provides a method for preparing the cefoperazone side chain shown in 1a, the method comprising:

[0033] 1) Compound 2a reacts with triphosgene to form compound 3a;

[0034] 2) Compound 3a reacts with p-nitrophenol (4a) to generate compound 1a;

[0035] The reaction pathways for steps 1) and 2) are shown below:

[0036]

[0037] In a preferred embodiment, in step 1), compound 2a reacts with triphosgene in solvent S1, wherein S1 is selected from toluene, dichloromethane or dichloroethane; preferably dichloromethane.

[0038] In a preferred embodiment, in step 1), compound 2a reacts with triphosgene under a base B1 condition, wherein base B1 is triethylamine, pyridine, or N,N-dimethylaniline; preferably N,N-dimethylaniline.

[0039] In a preferred embodiment, in step 1), compound 2a reacts with triphosgene at a temperature T1, wherein the temperature T1 is 0°C to 40°C, preferably 0°C to 5°C.

[0040] In a preferred embodiment, the content of impurity 100 with the structure shown below in the compound 3a obtained in step 1) is less than 2.0%.

[0041]

[0042] In a preferred embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) in solvent S2, wherein the solvent is tetrahydrofuran, dichloromethane, or dichloroethane; preferably dichloromethane.

[0043] In a preferred embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) at a temperature T2, wherein the temperature T2 is 0°C to 40°C; preferably 10°C to 15°C.

[0044] In a preferred embodiment, in step 2), compound 3a reacts with p-nitrophenol (4a) under base B2 conditions, wherein base B2 is triethylamine, pyridine, or diisopropylethylamine; preferably pyridine.

[0045] In a preferred embodiment, the method further includes step 2'), in which the 1a compound obtained in step 2) is purified in solvent S3 to obtain the 1a finished product.

[0046] In a preferred embodiment, in step 2'), S3 is toluene, ethyl acetate, or acetonitrile; preferably ethyl acetate.

[0047] In a preferred embodiment, the purification in the S3 solvent refers to recrystallizing the 1a compound obtained in step 2) using the S3 solvent.

[0048] In a preferred embodiment, the content of impurity 100 in the compound 1a obtained in step 2') is <0.1%.

[0049] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0050] Figure 1 The HPLC chromatogram of product 1a and the HPLC detection method are shown.

[0051] Figure 2 Separation chromatograms of compounds 2a, 3a, and impurity 100 are shown; the HPLC detection method is the same as that of product 1a; the retention time of compound 2a is 19.8 min; the retention time of compound 3a is 23.3 min; and the retention time of impurity 100 is 25.6 min.

[0052] Figure 3 The MS plot of impurity 100 is shown;

[0053] Figure 4 The structural confirmation spectrum of compound 3a is shown;

[0054] Figure 5 The structural confirmation spectrum of compound 1a is shown; the proton spectrum and mass spectrum of compound 1a are shown respectively. Detailed Implementation

[0055] In their research on the synthesis method of cefepime, the inventors discovered that the cefepime side chain compound 1a, synthesized using the conventional method—specifically, by reacting compound 3 with compound 2a—contains a large amount of impurity 11. Furthermore, in the subsequent synthesis of cefepime using compound 1a and compound 1b, impurity 11 also reacts with 1b, generating a large amount of impurity 22. Therefore, the conventional method for synthesizing cefepime results in a final product containing a large amount of impurity 22, leading to unsatisfactory yield and quality.

[0056]

[0057] To address this issue, the inventors creatively developed a novel synthetic process for the cefepime ester side-chain 1a compound, while optimizing the synthetic conditions to improve reaction yield and product quality. Based on this, the present invention was completed.

[0058] The method for synthesizing cefoprene side chains of the present invention

[0059] In the method for synthesizing cefepime 1a side chain compound of the present invention, 2a is used as the starting material and reacted with triphosgene to generate compound 3a, and then 3a reacts with p-nitrophenol (4a) to generate compound 1a (the reaction process is shown below).

[0060]

[0061] Based on the above method, the inventors further optimized the process conditions, thereby significantly improving the yield and quality of compound 1a.

[0062] In specific embodiments, compound 2a reacts with triphosgene in a solvent selected from the group consisting of toluene, dichloromethane, or dichloroethane; preferably dichloromethane. In specific embodiments, compound 2a reacts with triphosgene in the presence of a base selected from the group consisting of triethylamine, pyridine, or N,N-dimethylaniline; preferably N,N-dimethylaniline. In specific embodiments, compound 2a reacts with triphosgene at a temperature of 0°C to 40°C, preferably 0°C to 5°C.

[0063] The inventors discovered that compound 3a, obtained by reacting compound 2a with triphosgene, contains impurity 100 with the structure shown below:

[0064]

[0065] Through process optimization, the content of impurity 100 in compound 3a can be lower than 2.0%.

[0066] In specific embodiments, compound 3a reacts with p-nitrophenol (4a) in a solvent selected from the group consisting of tetrahydrofuran, dichloromethane, or dichloroethane; preferably dichloromethane. In specific embodiments, compound 3a reacts with p-nitrophenol (4a) at a temperature of 0°C to 40°C; preferably 10°C to 15°C. In specific embodiments, compound 3a reacts with p-nitrophenol (4a) in the presence of a base selected from the group consisting of triethylamine, pyridine, or diisopropylethylamine; preferably pyridine.

[0067] After obtaining compound 1a, compound 1a can be further purified and refined to obtain the final product, 1a. In a specific embodiment, the purification and refinement refers to recrystallizing the obtained compound 1a. For example, the compound 1a can be recrystallized in toluene, ethyl acetate, or acetonitrile, preferably ethyl acetate.

[0068] After further purification and refinement, the purity of compound 1a was further improved. In a specific embodiment, the content of impurity 100 in compound 1a was <0.1%.

[0069] The method for synthesizing cefepime of the present invention

[0070] The cefepime side chain obtained using the above method can be further used to synthesize cefepime. Based on common knowledge in the art, those skilled in the art will know how to synthesize cefepime using the cefepime side chain. For example, cefepime shown in 2b can be prepared via the reaction route shown below:

[0071]

[0072]

[0073] Advantages of this invention:

[0074] 1. This invention provides a novel method for synthesizing cefepime side chain 1a compounds;

[0075] 2. The reaction yield and product quality of the method of the present invention are significantly improved;

[0076] 3. The reaction conditions of the method of the present invention are mild, which is conducive to industrial production.

[0077] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0078] Example 1: Synthesis of compound 3a

[0079] 500 mL of dichloroethane, 65.1 g (0.5 mol) of compound 2a, and 49.5 g (0.167 mol) of triphosgene were added to three reaction flasks respectively.

[0080] 50.6 g (0.5 mol) of triethylamine was added dropwise to reaction 1;

[0081] 39.6 g (0.5 mol) of pyridine was added dropwise to reaction 2;

[0082] 60.6 g (0.5 mol) of N,N-dimethylaniline was added dropwise to reaction 3.

[0083] After the three reactions were added dropwise, the reaction was carried out at 20-25℃ until complete. After the reaction was complete, the mixture was washed twice with ice water, and the organic layer was dried with anhydrous sodium sulfate. The mixture was filtered and distilled to obtain compound 3a. The area percentage (Area%) of compound 3a and impurity 100 was calculated as shown in the table below.

[0084] Table 1

[0085]

[0086]

[0087] Example 2: Synthesis of compound 3a

[0088] Add 500 mL of dichloroethane, 65.1 g (0.5 mol) of compound 2a, and 49.5 g (0.167 mol) of triphosgene to three reaction flasks, respectively. After the addition is complete, add 60.6 g (0.5 mol) of N,N-dimethylaniline dropwise.

[0089] Reacting in reaction flask No. 1 at 0-5℃ until compound 2a is completely reacted;

[0090] Reacting in reaction flask No. 2 at 10-15℃ until compound 2a is completely reacted;

[0091] Reacting in reaction flask #3 at 20-25℃ until compound 2a is completely reacted;

[0092] After the reaction was complete, the mixture was washed twice with ice water, and the organic layer was dried with anhydrous sodium sulfate. The mixture was then filtered and distilled to obtain compound 3a. The area percentage (Area%) of compound 3a and impurity 100 was calculated as shown in the table below.

[0093] Table 2

[0094]

[0095] Example 3: Synthesis of compound 3a

[0096] Take 3 reaction flasks, of which:

[0097] Add 500 ml of dichloroethane to reaction flask No. 1;

[0098] Add 500 ml of toluene to reaction flask No. 2;

[0099] Add 500 ml of dichloromethane to reaction flask No. 3;

[0100] Then, 65.1 g (0.5 mol) of compound 2a and 49.5 g (0.167 mol) of triphosgene were added to the three reaction flasks, respectively. After the addition was complete, 60.6 g (0.5 mol) of N,N-dimethylaniline was added dropwise at 0-5℃. After the addition was complete, the reaction was carried out at 0-5℃ until complete. After the reaction was complete, the mixture was washed twice with ice water, and the organic layer was dried with anhydrous sodium sulfate. The mixture was filtered and distilled to obtain compound 3a. The area percentage (Area%) of compound 3a and impurity 100 was calculated as shown in the table below.

[0101] Table 3

[0102]

[0103]

[0104] Example 4: Synthesis of compound 3a

[0105] 5 L of dichloromethane was added to a reaction vessel, followed by 650.5 g (5 mol) of compound 2a and 495 g (1.67 mol) of triphosgene. After the addition was complete, 605.9 g (5 mol) of N,N-dimethylaniline was added dropwise. The reaction was continued at 0-5 °C until compound 2a was completely reacted. After the reaction was complete, the mixture was washed twice with ice water, and the organic layer was dried with anhydrous sodium sulfate. The mixture was filtered and distilled to obtain 923.6 g of compound 3a, with a yield of 95.9% and impurities of 0.51% per 100 area.

[0106] Example 5: Compound 1a

[0107] Add 50 mL of tetrahydrofuran, 19.3 g (0.1 mol) of compound 3a, and 13.9 g (0.1 mol) of compound 4a to three separate reaction flasks. After addition, the following results were obtained:

[0108] 10.1 g (0.1 mol) of triethylamine was added dropwise to experimental group 1;

[0109] 7.9 g (0.1 mol) of pyridine was added dropwise to experimental group 2;

[0110] 12.9 g (0.1 mol) of diisopropylethylamine was added to experimental group 3.

[0111] After the addition was complete, the reaction was maintained at 20-25℃ until complete. After HPLC analysis, the mixture was washed twice with water, the organic layer was dried, filtered, and concentrated to obtain crude compound 1a. The area percentage (Area%) of compound 1a and impurity 100 was calculated as shown in the table below.

[0112] Table 4

[0113]

[0114] Example 6: Compound 1a

[0115] 50 mL of tetrahydrofuran, 19.3 g (0.1 mol) of compound 3a, and 13.9 g (0.1 mol) of compound 4a were added to three reaction flasks, respectively. After the addition was complete, 8.3 g (0.105 mol) of pyridine was added dropwise. After the addition was complete, the following was observed:

[0116] The temperature of reaction flask No. 1 is controlled at 0-5℃ until the reaction proceeds to completion.

[0117] In reaction flask No. 2, the temperature is controlled at 10-15℃, and the reaction continues until the reactants are fully reacted.

[0118] In reaction flask No. 3, the temperature is controlled at 20-25℃, and the reaction continues until the reactants are completely reacted.

[0119] After HPLC analysis of the three reactions, the mixture was washed twice with water, the organic layer was dried, filtered, and concentrated to obtain crude compound 1a. The area percentage (Area%) of compound 1a and impurity 100 was calculated as shown in the table below.

[0120] Table 5

[0121]

[0122] Example 7: Compound 1a

[0123] Take 3 reaction flasks, of which:

[0124] Add 50 mL of tetrahydrofuran to reaction flask No. 1;

[0125] Add 50 ml of dichloroethane to reaction flask No. 2;

[0126] Add 50 ml of dichloromethane to reaction flask No. 3;

[0127] Then, 19.3 g (0.1 mol) of compound 3a and 13.9 g (0.1 mol) of compound 4a were added to three reaction flasks, respectively. After the addition was complete, 8.3 g (0.105 mol) of pyridine was added dropwise. After the addition was complete, the mixture was reacted at 10-15 °C until the starting material was completely removed. After the reaction was completed, the mixture was washed twice with water by HPLC, the organic layer was dried, filtered, and concentrated to obtain crude compound 1a. The area percentage (Area%) of compound 1a and impurity 100 were calculated as shown in the table below.

[0128] Table 6

[0129]

[0130] Example 8: Compound 1a

[0131] 192.6 g (1 mol) of compound 3a, 500 mL of dichloromethane, and 139.1 g of compound 4a were added to a reaction flask. After the addition was complete, 83 g (1.05 mol) of pyridine was added dropwise. The reaction was carried out at 10-15 °C until the reactants were completely removed. After HPLC analysis, the mixture was washed twice with 350 mL of water (2 x 2). The organic layer was dried, filtered, and concentrated to obtain crude product 1a. The crude product 1a was divided into three equal parts: a, b, and c.

[0132] Part a was purified with toluene to obtain the recrystallized product 1a;

[0133] Part b was purified with ethyl acetate to obtain the recrystallized product of 1a;

[0134] Part c was purified with acetonitrile to obtain the recrystallized product of 1a;

[0135] The area percentage (Area%) of compound 1a and impurity 100 are calculated separately as shown in the table below.

[0136] Table 7

[0137]

[0138] Example 9: Compound 1a

[0139] 192.6 g (1 mol) of compound 3a, 500 mL of dichloromethane, and 139.1 g of compound 4a were added to a reaction flask. After the addition was complete, 83 g (1.05 mol) of pyridine was added dropwise. The reaction was carried out at 10-15 °C until the reactants were completely removed. After the reaction was complete, the mixture was washed twice with 350 mL of water (2 mL each). The organic layer was dried, filtered, and concentrated to obtain crude compound 1a. The crude compound was purified with ethyl acetate to obtain 263.3 g of compound, with a yield of 89.2% and an HPLC purity of 99.89%.

[0140] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing Cefpodoxime Proxetil, which comprises: 1) reacting compound 2a with triphosgene in the presence of base B1 to form compound 3a, wherein base B1 is N,N-dimethylaniline; 2) reacting compound 3a with p-nitrophenol (4a) to form compound la; The reaction route of steps 1) and 2) is shown as follows: 3) using compound la prepared in step 2) to prepare Cefpodoxime Proxetil shown as compound 2b In step 1), the content of impurity 100 shown as the structure below in compound 3a obtained is less than 2.0%: The method further comprises step 2'), purifying compound la obtained in step 2) in solvent S3 to obtain finished product la; In step 2'), S3 is ethyl acetate; The purification in solvent S3 means recrystallization of compound la obtained in step 2) using solvent S3; The content of impurity 100 in compound la obtained in step 2') is less than 0.1%.

2. The method of claim 1, wherein, In step 1), compound 2a is reacted with triphosgene in solvent S1, wherein S1 is selected from toluene, dichloromethane or dichloroethane.

3. The method of claim 2, wherein, S1 is dichloromethane.

4. The method of claim 1 or 2, wherein, In step 1), compound 2a is reacted with triphosgene at temperature T1, wherein T1 is 0-40°C.

5. The method of claim 4, wherein, T1 is 0-5°C.

6. The method of claim 1, wherein, In step 2), compound 3a is reacted with p-nitrophenol (4a) in solvent S2, wherein the solvent is tetrahydrofuran, dichloromethane or dichloroethane.

7. The method of claim 6, wherein, The solvent is dichloromethane.

8. The method of claim 1, wherein, In step 2), compound 3a is reacted with p-nitrophenol (4a) at temperature T2, wherein T2 is 0-40°C.

9. The method of claim 8, wherein, T2 is 10-15°C.

10. The method of claim 1, wherein, In step 2), compound 3a is reacted with p-nitrophenol (4a) in the presence of base B2, wherein B2 is triethylamine, pyridine or diisopropylethylamine.

11. The method of claim 10, wherein, B2 is pyridine.

12. A method for preparing the side chain of Cefpodoxime Proxetil shown as compound la, which comprises: 1) reacting compound 2a with triphosgene in the presence of base B1 to form compound 3a, wherein base B1 is N,N-dimethylaniline; 2) reacting compound 3a with p-nitrophenol (4a) to form compound la; The reaction route of steps 1) and 2) is shown as follows: In step 1), the content of impurity 100 shown as the structure below in compound 3a obtained is less than 2.0%: The method further comprises step 2'), purifying compound la obtained in step 2) in solvent S3 to obtain finished product la; In step 2'), S3 is ethyl acetate; The purification in solvent S3 means recrystallization of compound la obtained in step 2) using solvent S3; The content of impurity 100 in compound la obtained in step 2') is less than 0.1%.

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