A methylation synthesis method for a ceftaroline fosamil intermediate

Abstract

The invention discloses a methylation synthesis method of a ceftaroline fosamil intermediate, characterized in that: 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolethioyl]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted with an iodine alkali salt and an acid to obtain a ceftaroline fosamil intermediate. In the reaction process of the invention, the methylation ability is strong, the reaction toxicity is low, and the reaction does not use the toxic reagent iodomethane, thereby solving the potential safety hazard problem in the prior art.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a methylation synthesis method for a ceftaroline fosamil intermediate. Background Art

[0002] 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid benzhydryl ester iodide is a key intermediate of cefuroxime fosamil, usually referred to as cefuroxime intermediate core. The preparation method reported in the existing literature (Bioorg & Med. Chem. 11 (2003), 2427-2437) is as follows:

[0003]

[0004] In this synthesis method, methyl iodide needs low temperature for reaction and is a highly toxic substance and a Class 3 carcinogen. As a liquid with a low boiling point (42°C), it has a great safety hazard when used in the factory production process. At the same time, the reaction yield is low, the purity is not high, and there are many impurities. The purification method after the reaction is completed is complicated. Therefore, a safer and more economical solution is needed now. Summary of the invention

[0005] The present invention aims to overcome the above defects and provide a new method for synthesizing 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide by a methylation method. In the reaction process of the present invention, the methylation ability is strong, the reaction toxicity is low, and the reaction does not use the toxic reagent iodomethane, which solves the safety hazard problem existing in the prior art, while improving the reaction yield and product purity, and only simple post-treatment is required after the reaction is completed.

[0006] The invention provides a methylation synthesis method for a cefuroxime intermediate, which is characterized in that 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted with iodinated alkali salt and acid to obtain a cefuroxime intermediate.

[0007]

[0008] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0009] The mass ratio of the above-mentioned 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester: iodinated alkali salt: acid is 1:0.1-1:0.1-1.

[0010] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0011] The reaction temperature is 0-40°C, and the reaction time is 1-8 hours.

[0012] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0013] The reaction is carried out in a polar solvent.

[0014] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0015] The polar solvent is selected from one or a mixture of ethers, alkylamides, alkylnitriles, ketones and halogenated hydrocarbons.

[0016] Such as: tetrahydrofuran, dimethylformamide, acetonitrile, acetone, chloroform and other similar solvents.

[0017] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0018] The mass ratio of the above-mentioned 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester to the polar solvent is 1:2-10.

[0019] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0020] The reaction product is purified by dissolving in an ester solvent, filtering and drying.

[0021] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0022] The mass ratio of the above-mentioned 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester to the ester solvent is 1:1-5.

[0023] Furthermore, the present invention provides a methylation synthesis method of a ceftaroline fosamil intermediate, which is also characterized in that:

[0024] The drying temperature is not higher than 40°C.

[0025] Functions and effects of the present invention:

[0026] The present invention replaces methyl iodide in the traditional process with a low-toxic and safe methylation method. The method is not only safer, but also has a more stable reaction, less by-products, higher yield, and stronger operability. It is an environmentally friendly chemical raw material that meets the requirements of modern "clean process". BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 . H spectrum of the product of Example 1;

[0028] Figure 2 . HPLC results of the product of Example 1; DETAILED DESCRIPTION

[0029] Example 1

[0030] In a 250ML three-necked flask, add 33.2g potassium iodide, 35mL dimethylformamide, 9.6g methanol, add 67.0g 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid dibenzyl ester, slowly add 10ml concentrated hydrochloric acid, stir the mixture at room temperature 20°C for 3 hours, add 100ml ethyl acetate, filter and dry. The product 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid dibenzyl ester iodide is obtained, the molar yield of the product is 98%, and the purity is 98.7%.

[0031] Proton spectrum data such as Figure 1 As shown: 1 HNMR (CDCl3, 300MHz) δ (ppm): 3.51 (2H, dd), 3.76 (2H, brs), 4.37 (3H, d), 5.13 (1 H,d), 5.94(1H,d), 6.96(1H,s), 7.19-7.42(15H,m), 7.75(3H,m), 8.67(2H,dd).

[0032] like Figure 1 As shown,

[0033] Serial number When reserved Peak area Peak height Analysis Column efficiency Separation Tailing Factor 1 3.0 Room 73 87823 678 0.03%2 541.594 9.887 0.9 sub 23 2 4.383 19371 136 0.007 1544.75 4.570 0.966 3 5.093 23597 120 0.009 1287.02 2.380 0.829 4 6.700 2714581 796226 98.677 3497.21 5.348 1.665 5 12.257 256484 683 0.093 1138.47 9.908 1.193 6 13.437 880955 2120 0.320 761.816 1.180 1.019 7 16.833 2371009 4130 0.862 1244.03 2.994 1.001

[0034] Example 2

[0035] In a 250ML three-necked flask, add 33.2g potassium iodide, 200mL tetrahydrofuran, 19.2g methanol, add 67.0g 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester, slowly add 10ml concentrated hydrochloric acid dropwise, the mixture is stirred at 0℃ for 5 hours, and then 80ml ethyl acetate is added for crystallization, filtered and dried.

[0036] The product 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide was obtained, and the molar yield of the product was 96% and the purity was 97.5%.

[0037] Example 3

[0038] In a 250ML three-necked flask, add 33.2g potassium iodide, 300mL acetone, 28.8g methanol, add 67.0g 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester, slowly add 10ml concentrated hydrochloric acid dropwise, the mixture is stirred at 35°C for 1 hour, most of the acetone is evaporated by rotary evaporation, and then 80ml ethyl acetate is added for crystallization, filtered and dried.

[0039] The product 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide was obtained, and the molar yield of the product was 97.6% and the purity was 96.1%.

[0040] Example 4

[0041] In a 250ML three-necked flask, add 33.2g potassium iodide, 400mL chloroform, 19.2g methanol, add 67.0g 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester, slowly add 10ml concentrated hydrochloric acid dropwise, the mixture is stirred at room temperature 20℃ for 1 hour, most of the chloroform is evaporated by rotary evaporation, and then 100ml ethyl acetate is added for crystallization, filtered, and dried at room temperature.

[0042] The product 7β-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide was obtained, and the molar yield of the product was 98.5% and the purity was 97.1%.

[0043] It can be found from the above embodiments that, compared with the traditional process, the process adopted in this embodiment is simple, has a safe production process, is convenient for post-processing, has a high yield rate and good purity.

Claims

1. A methylation synthesis method for a ceftaroline fosamil intermediate, characterized in that: 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester is reacted with methanol under the action of iodine alkali salt and hydrochloric acid to obtain a ceftaroline fosamil intermediate; The iodide alkali salt is potassium iodide; The reaction temperature is 0-40°C and the reaction time is 1-8 hours; The mass ratio of the 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester: iodinated alkali salt: acid is 1:0.1-1:0.1-1.

2. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 1, characterized in that: The reaction is carried out in a polar solvent.

3. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 2, characterized in that: The polar solvent is selected from one of ethers, alkylamides, alkylnitriles, ketones, and halogenated hydrocarbons, or a mixture of several of them.

4. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 3, characterized in that: The mass ratio of the 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester to the polar solvent is 1:2-10.

5. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 1, characterized in that: The reaction product is purified by dissolving in an ester solvent, filtering and drying.

6. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 5, characterized in that: The mass ratio of the 7-phenylacetylamino-3-[4-(1-methyl-4-pyridine)-2-thiazolylthio]-3-cephem-4-carboxylic acid diphenylmethyl ester to the ester solvent is 1:1-5.

7. The methylation synthesis method of a ceftaroline fosamil intermediate according to claim 5, characterized in that: The drying temperature is no higher than 40°C.

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