Preparation method and application of cefepiprox pivoxil side chain

Abstract

The invention discloses a preparation method of a high-purity cefepiprox pivoxil side chain (1a). The reaction route is shown in the specification. According to the method, 2a is taken as an initial raw material and reacts with triphosgene to generate a compound 3a, and the compound 3a reacts with p-nitrophenol to generate a compound 1a. The method is high in product purity, high in reaction yield and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of synthesis. Specifically, the present invention relates to a method for preparing a high-purity side chain of ceftobiprole ester. Background Art

[0002] Ceftobiprole ester (2b) is a new cephalosporin antibiotic jointly developed by Basilea Pharmaceutica and Johnson & Johnson. Its active ingredient is ceftobiprole. Ceftobiprole is a broad-spectrum cephalosporin antibiotic, and its antibacterial spectrum includes methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA), etc. It is currently the only cephalosporin antibiotic effective against MRSA and VRSA.

[0003]

[0004] The synthetic processes of ceftobiprole ester (2b) are disclosed in documents WO2009127623A1 and WO2010136423A1. In this synthetic process, ceftobiprole ester (2b) is synthesized using compound 1b and side chain 1a ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate) as raw materials, where 1a is an important side chain of ceftobiprole ester.

[0005]

[0006]

[0007] Document WO2021035360A1 reports a synthetic method of compound 1a. In this method, p-nitrophenyl chloroformate (3) and 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (2a) are reacted to generate the target product 1a, with a yield of 54%. However, there are a large number of impurities in 1a synthesized by the current method, resulting in impurities in the finally synthesized ceftobiprole ester product, and further leading to unsatisfactory yields and quality of the final product.

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

[0009] The purpose of the present invention is to provide a new synthetic method for the side chain 1a of ceftobiprole ester. The purity of the side chain 1a of ceftobiprole ester synthesized by this method is significantly improved, so that the final product, ceftobiprole ester, can be obtained in high yield and high quality.

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

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

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

[0013] 2) Reacting compound 3a with p-nitrophenol (4a) to form compound 1a;

[0014] The reaction routes of steps 1) and 2) are as follows:

[0015]

[0016] 3) Preparing ceftobiprole ester shown as 2b using the compound 1a prepared in step 2);

[0017]

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

[0019] In a specific embodiment, in step 1), compound 2a reacts with triphosgene under the condition of base B1, and the base 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 temperature T1, and the temperature T1 is 0°C to 40°C, preferably 0 to 5°C.

[0021] In a preferred embodiment, the content of impurity 100 with the following structure 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, and 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 temperature T2, and the temperature T2 is 0°C to 40°C; preferably 10 to 15°C.

[0025] In a specific embodiment, in step 2), the compound 3a reacts with p-nitrophenol (4a) under the condition of base B2, and the 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), and the compound 1a obtained in step 2) is refined in the S3 solvent to obtain the finished product of 1a.

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

[0028] In a preferred embodiment, the refining in the S3 solvent means recrystallizing the compound 1a obtained in step 2) with 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 ceftobiprole ester shown as 2b through the following reaction route

[0031]

[0032] In a second aspect, the present invention provides a method for preparing the side chain of ceftobiprole ester shown as 1a, and the method includes:

[0033] 1) The compound 2a reacts with triphosgene to generate the compound 3a;

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

[0035] The reaction routes of step 1) and 2) are as follows:

[0036]

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

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

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

[0040] In a preferred embodiment, the content of impurity 100 having the following structure in the 3a compound obtained in step 1) is less than 2.0%:

[0041]

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

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

[0044] In a preferred embodiment, in step 2), the 3a compound reacts with p-nitrophenol (4a) under the condition of base B2, and the 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 refined in solvent S3 to obtain the 1a finished product.

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

[0047] In a preferred embodiment, the refining in solvent S3 means recrystallizing the 1a compound obtained in step 2) with solvent S3.

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

[0049] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Brief Description of the Drawings

[0050] Figure 1 Shows the HPLC chromatogram of product 1a and the HPLC detection method;

[0051] Figure 2 Shows the separation diagram of compounds 2a, 3a and impurity 100; among them, 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; the retention time of impurity 100 is 25.6 min;

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

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

[0054] Figure 5 The spectrum for structural confirmation of compound 1a is shown; wherein the hydrogen spectrum and the mass spectrum of compound 1a are respectively shown. Detailed implementation manners

[0055] In the research on the synthesis method of ceftobiprole ester products by the present inventors, it was found that in the ceftobiprole ester side chain compound 1a synthesized by using a conventional method, that is, by reacting a compound of formula 3 with a compound of formula 2a, a large amount of impurity 11 was present. And in the subsequent synthesis of ceftobiprole ester by reacting compound 1a with compound 1b, impurity 11 would also react with 1b, thereby generating a large amount of impurity 22. Therefore, the conventional method for synthesizing ceftobiprole ester would cause a large amount of impurity 22 to be contained in the final product, resulting in unsatisfactory yield and quality.

[0056]

[0057] In view of this, the present inventors creatively developed a completely new synthesis process for the ceftobiprole ester side chain compound 1a, and at the same time optimized the synthesis process conditions, improving the reaction yield and the quality of the product. Based on this, the present invention was completed.

[0058] The method for synthesizing the ceftobiprole ester side chain of the present invention

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

[0060]

[0061] On the basis of the above method, the present inventors further optimized the process conditions, so that the yield and quality of compound 1a were both significantly improved.

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

[0063] The inventor of the present invention has found that there is an impurity 100 with the following structure in the 3a compound obtained by reacting the 2a compound with triphosgene:

[0064]

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

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

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

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

[0069] The method for synthesizing ceftobiprole ester of the present invention

[0070] The ceftobiprole ester side chain synthesized by using the above method can be further synthesized into ceftobiprole ester. Based on the common general knowledge in the art, those skilled in the art can know how to synthesize ceftobiprole ester by using the ceftobiprole ester side chain. For example, ceftobiprole ester shown in 2b is prepared through the following reaction route:

[0071]

[0072]

[0073] Advantages of the present invention:

[0074] 1. The present invention provides a new method for synthesizing the ceftobiprole ester side chain 1a compound;

[0075] 2. The reaction yield and the quality of the product 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 beneficial to industrial production.

[0077] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following embodiments can be obtained from commercial channels without special instructions.

[0078] Example 1: Synthesis of Compound 3a

[0079] 500 mL of dichloroethane and 65.1 g (0.5 mol) of Compound 2a were added to each of the 3 reaction flasks, and then 49.5 g (0.167 mol) of triphosgene was added. After addition,

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

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

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

[0083] After the addition in the three reactions was completed, the reaction was carried out at 20 - 25 °C until completion. After the reaction, it was washed twice with ice water, and the organic layer was dried with anhydrous sodium sulfate. After filtration and distillation, Compound 3a was obtained. The area percentages (Area%) of Compound 3a and Impurity 100 were calculated as shown in the following table.

[0084] Table 1

[0085]

[0086]

[0087] Example 2: Synthesis of Compound 3a

[0088] 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 each of the 3 reaction flasks. After addition, 60.6 g (0.5 mol) of N,N-dimethylaniline was added dropwise. After the addition was completed,

[0089] The reaction in the 1st reaction flask was carried out at 0 - 5 °C until Compound 2a was completely reacted;

[0090] The reaction in the 2nd reaction flask was carried out at 10 - 15 °C until Compound 2a was completely reacted;

[0091] The reaction in the 3rd reaction flask was carried out at 20 - 25 °C until Compound 2a was completely reacted;

[0092] After the reaction, wash twice with ice water and dry the organic layer with anhydrous sodium sulfate. Filter and distill to obtain Compound 3a. Calculate the area percentages (Area%) of Compound 3a and Impurity 100 as shown in the following table.

[0093] Table 2

[0094]

[0095] Example 3: Synthesis of Compound 3a

[0096] Take 3 reaction flasks, where:

[0097] Add 500 mL of dichloroethane to the 1st reaction flask;

[0098] Add 500 mL of toluene to the 2nd reaction flask;

[0099] Add 500 mL of dichloromethane to the 3rd reaction flask;

[0100] Then add 65.1 g (0.5 mol) of Compound 2a and 49.5 g (0.167 mol) of triphosgene to the three reaction flasks respectively. After adding, add 60.6 g (0.5 mol) of N,N-dimethylaniline dropwise at 0 - 5°C. After the dropwise addition, control the temperature at 0 - 5°C and react until complete. After the reaction, wash twice with ice water and dry the organic layer with anhydrous sodium sulfate. Filter and distill to obtain Compound 3a. Calculate the area percentages (Area%) of Compound 3a and Impurity 100 as shown in the following table.

[0101] Table 3

[0102]

[0103]

[0104] Example 4: Synthesis of Compound 3a

[0105] Add 5 L of dichloromethane and 650.5 g (5 mol) of Compound 2a and 495 g (1.67 mol) of triphosgene to the reaction kettle. After adding, add 605.9 g (5 mol) of N,N-dimethylaniline dropwise. After the dropwise addition, control the temperature at 0 - 5°C and react until Compound 2a is completely reacted. After the reaction, wash twice with ice water and dry the organic layer with anhydrous sodium sulfate. Filter and distill to obtain 923.6 g of Compound 3a with a yield of 95.9% and the Area% of Impurity 100 being 0.51%.

[0106] Example 5: Synthesis of 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 each of the 3 reaction flasks. After adding, among them:

[0108] In the 1st experimental group, add dropwise 10.1 g (0.1 mol) of triethylamine;

[0109] In the 2nd experimental group, add dropwise 7.9 g (0.1 mol) of pyridine;

[0110] In the 3rd experimental group, add dropwise 12.9 g (0.1 mol) of diisopropylethylamine.

[0111] After the dropwise addition, control the reaction of the raw materials to be complete at 20 - 25°C respectively. After the reaction is detected by HPLC, wash with water 2 times, dry the organic layer, filter and concentrate to obtain the crude product of 1a. Calculate the area percentages (Area%) of compound 1a and impurity 100 as shown in the following table.

[0112] Table 4

[0113]

[0114] Example 6: Synthesis of compound 1a

[0115] 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 each of the 3 reaction flasks. After adding, add dropwise 8.3 g (0.105 mol) of pyridine. After the dropwise addition, among them:

[0116] Control the temperature of the 1st reaction flask at 0 - 5°C and react until the raw materials are complete;

[0117] Control the temperature of the 2nd reaction flask at 10 - 15°C and react until the raw materials are complete;

[0118] Control the temperature of the 3rd reaction flask at 20 - 25°C and react until the raw materials are complete;

[0119] After HPLC detection of the three reactions, wash with water 2 times, dry the organic layer, filter and concentrate to obtain the crude product of 1a. Calculate the area percentages (Area%) of compound 1a and impurity 100 as shown in the following table.

[0120] Table 5

[0121]

[0122] Example 7: Synthesis of compound 1a

[0123] Take 3 reaction flasks, among which:

[0124] Add 50 ml of tetrahydrofuran to the 1st reaction flask;

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

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

[0127] Then, add 19.3 g (0.1 mol) of Compound 3a, 13.9 g (0.1 mol) of Compound 4a to the three reaction flasks respectively. After adding, add 8.3 g (0.105 mol) of pyridine dropwise. After the dropwise addition, react at 10 - 15 °C until the raw materials are completely reacted. After the reaction is detected by HPLC, wash twice with water, dry the organic layer, filter and concentrate to obtain the crude product of 1a. Calculate the area percentages (Area%) of Compound 1a and Impurity 100 as shown in the following table.

[0128] Table 6

[0129]

[0130] Example 8: Synthesis of Compound 1a

[0131] Add 192.6 g (1 mol) of Compound 3a, 500 mL of dichloromethane, and 139.1 g of Compound 4a to the reaction flask. After adding, add 83 g (1.05 mol) of pyridine dropwise. After the dropwise addition, react at 10 - 15 °C until the raw materials are completely reacted. After the reaction is detected by HPLC, wash twice with 350 mL × 2 of water, dry the organic layer, filter and concentrate to obtain the crude product of 1a. Divide the obtained crude product of 1a into three equal parts, a, b, and c, where:

[0132] Portion a is refined with toluene to obtain the recrystallized product of 1a;

[0133] Portion b is refined with ethyl acetate to obtain the recrystallized product of 1a;

[0134] Portion c is refined with acetonitrile to obtain the recrystallized product of 1a;

[0135] Calculate the area percentages (Area%) of Compound 1a and Impurity 100 as shown in the following table.

[0136] Table 7

[0137]

[0138] Example 9: Synthesis of 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 addition, 83 g (1.05 mol) of pyridine was added dropwise. After the dropwise addition was completed, the reaction was carried out at 10 - 15 °C until the raw materials were completely reacted. After the reaction was detected by HPLC, it was washed twice with 350 mL × 2 of water. The organic layer was dried, filtered, and concentrated to obtain the crude product of 1a. The crude product was refined with ethyl acetate as the solvent to obtain 263.3 g of the compound, with a yield of 89.2% and an HPLC purity of 99.89%.

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

Claims

1. A method for preparing ceftobiprole ester, the method comprising: 1) Reacting compound 2a with triphosgene to form compound 3a; 2) Reacting compound 3a with p-nitrophenol (4a) to form compound 1a; The reaction routes of steps 1) and 2) are as follows: 3) Preparing ceftobiprole ester shown as 2b using the compound shown as 1a prepared in step 2) 2. The method according to claim 1, wherein In step 1), compound 2a reacts with triphosgene in solvent S1, and the S1 is selected from toluene, dichloromethane or dichloroethane; preferably dichloromethane.

3. The method according to claim 1 or 2, characterized in that, In step 1), compound 2a reacts with triphosgene under the condition of base B1, and the base B1 is triethylamine, pyridine or N,N-dimethylaniline; preferably N,N-dimethylaniline.

4. The method according to any one of claims 1 to 3, characterized in that, In step 1), compound 2a reacts with triphosgene at temperature T1, and the temperature T1 is 0 °C to 40 °C, preferably 0 to 5 °C.

5. The method according to any one of claims 1 to 4, characterized in that, In step 2), compound 3a reacts with p-nitrophenol (4a) in solvent S2, and the solvent is tetrahydrofuran, dichloromethane or dichloroethane; preferably dichloromethane.

6. The method according to any one of claims 1-5, characterized in that, In step 2), compound 3a reacts with p-nitrophenol (4a) at temperature T2, and the temperature T2 is 0 °C to 40 °C; preferably 10 to 15 °C.

7. The method according to any one of claims 1-6, characterized in that, In step 2), compound 3a reacts with p-nitrophenol (4a) under the condition of base B2, and the base B2 is triethylamine, pyridine or diisopropylethylamine; preferably pyridine.

8. The method according to any one of claims 1-7, characterized in that, The method further includes step 2') between step 2) and step 3), refining the compound 1a obtained in step 2) in solvent S3 to obtain the finished product of 1a.

9. The method according to any one of claims 1-8, characterized in that, In step 2'), the S3 is toluene, ethyl acetate or acetonitrile; preferably ethyl acetate.

10. A method for preparing the side chain of ceftobiprole ester shown as 1a, the method comprising: 1) Reacting compound 2a with triphosgene to form compound 3a; 2) Reacting compound 3a with p-nitrophenol (4a) to form compound 1a; The reaction routes of steps 1) and 2) are as follows:

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