A process for the preparation of cefodizime and intermediates thereof

Abstract

The application discloses a preparation method of cefodizole and an intermediate thereof, and the method comprises the following steps: condensation reaction of 2-chloro-3,4-dihydroxybenzoic acid and 2-(pyrrolidine-1-yl)ethane-1-amine in a mixed solution of polyethylene glycol and water in the presence of a condensing agent and an alkali, then adding an alkali, a halide salt and a hydroxyl protection reagent, and performing a protection group reaction to generate a compound shown in formula (I), wherein R is a hydroxyl protection group; the method can not only synthesize a target product with a better step, but also has a shorter step, less industrial wastewater, and especially can obtain an excellent total yield, is suitable for industrial production, and can be used in a process for preparing cefodizole.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing cefdil and its intermediates. Background Technology

[0002] Cefdil is a broad-spectrum oral antibiotic belonging to the cephalosporin class. It has antibacterial activity and can be used to treat diseases caused by various bacterial infections. Cefdil primarily exerts its antibacterial effect by inhibiting bacterial cell wall synthesis. It binds to bacterial target sites and prevents bacteria from synthesizing the enzymes required for cell wall synthesis, thereby leading to bacterial death or inhibiting their reproduction. Cefdil has some activity against both Gram-positive and Gram-negative bacteria, including Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus. 2-Chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide is an important intermediate in the synthesis of cefdil. Currently, there are three main methods for synthesizing this intermediate compound:

[0003] (1) Using 2-chloro-3,4-dimethoxybenzoic acid as raw material, the final product is synthesized in 5 steps: demethylation, methyl esterification, phenolic hydroxyl protection, ester hydrolysis and amidation. This method requires carboxyl protection and deprotection processes. Although the overall yield is high, the steps are too long and the post-processing is complicated. In addition, water-soluble polar aprotic solvents such as DMF and THF are used in multiple steps, resulting in a lot of wastewater.

[0004]

[0005] (2) Using 2-chloro-3,4-dimethoxybenzoic acid as a raw material, the reaction proceeds through demethylation, nucleophilic substitution / esterification (one-pot two-reaction), ester hydrolysis, and amidation. This method reduces the ester protection step, but requires an ester hydrolysis process, the amidation reaction yield is low, and it still requires the use of water-soluble polar aprotic solvents such as DMF;

[0006]

[0007] (3) The final product was synthesized from 2-chloro-3,4-dimethoxybenzaldehyde via demethylation, hydroxyl protection, oxidation, and amidation. This reaction has a relatively short duration, but since it uses an aldehyde as a raw material, the reaction needs to be carried out under a nitrogen atmosphere, and the amidation reaction has a particularly low yield.

[0008] Summary of the Invention

[0009] The purpose of this invention is to overcome one or more deficiencies in the prior art and provide an improved method for preparing a cefdil intermediate (the compound shown in formula (I)) with fewer steps and higher yield.

[0010] The present invention also provides a method for preparing cefdil.

[0011] To achieve the above objectives, the present invention employs the following technical solution:

[0012] A method for preparing a cefdil intermediate, wherein the cefdil intermediate is a compound represented by formula (I). In formula (I), R is a hydroxyl protecting group. The preparation method includes: condensing 2-chloro-3,4-dihydroxybenzoic acid and 2-(pyrrolidone-1-yl)ethane-1-amine in a mixed solution of polyethylene glycol and water in the presence of a condensing agent and a first base; then adding a second base, a halide salt and a hydroxyl protecting agent to react with the protecting group to generate the compound shown in formula (I); wherein the volume ratio of polyethylene glycol to water is 1:0.8-2.0.

[0013] The reaction route of this invention is as follows:

[0014]

[0015] Among them, the compound shown in formula (Ⅰ) is the product of the condensation reaction.

[0016] According to some preferred aspects of the invention, the polyethylene glycol has a molecular weight of 200-600. Further, in some embodiments of the invention, the polyethylene glycol is one or more combinations selected from PEG-200, PEG-400, and PEG-600.

[0017] According to some preferred aspects of the invention, the volume ratio of the polyethylene glycol to the water is 1:0.8-1.5.

[0018] According to some preferred aspects of the invention, the condensing agent is one or more selected from N,N-carbodiimidazole (CDI), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (TCFH), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl).

[0019] According to some preferred aspects of the invention, the condensation reaction is controlled to proceed at 25-60°C. Further, the condensation reaction is controlled to proceed at 45-60°C.

[0020] According to some preferred aspects of the present invention, the first base and the second base are each independently selected from one or more combinations of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0021] According to some preferred aspects of the invention, the upper protecting group reaction is controlled to be carried out at 25-60°C. Further, the upper protecting group reaction is controlled to be carried out at 45-60°C.

[0022] In some preferred and specific embodiments of the present invention, the reaction time of the condensation reaction is controlled to be 1-4 hours.

[0023] In some preferred and specific embodiments of the present invention, the reaction time of the upper protecting group reaction is controlled to be 4-12 hours.

[0024] According to some preferred aspects of the invention, the halide salt is sodium iodide and / or potassium iodide.

[0025] According to some preferred aspects of the present invention, the hydroxyl protecting agent is one or more combinations selected from p-methoxybenzyl chloride, benzyl chloride, benzyl bromide, benzyl iodide, 2-methylpropene, benzyl chloromethyl ether, triphenyl chloromethane, p-nitrobenzoyl chloride, acetyl chloride, methoxymethyl chloride, 2-methyl-4-acetoxy-2-naphthol, trimethylchlorosilane, hexamethyldisilazane, and tert-butyldimethylchlorosilane.

[0026] According to some preferred aspects of the present invention, the molar ratio of the 2-chloro-3,4-dihydroxybenzoic acid, the 2-(pyrrolid-1-yl)ethane-1-amine, the condensing agent and the first base is 1:1-1.5:1.5-3:1.5-3.

[0027] According to some preferred aspects of the invention, the concentration of the 2-chloro-3,4-dihydroxybenzoic acid in the mixed solution is controlled to be 0.1-1.5 mol / L.

[0028] According to some preferred aspects of the present invention, the molar ratio of the 2-chloro-3,4-dihydroxybenzoic acid, the hydroxyl protecting agent, the second base, and the halide salt is 1:2-4:2-4:0.5-1.5.

[0029] In some preferred embodiments of the present invention, the preparation method of the cefdil intermediate is a one-pot method, the implementation of which includes:

[0030] Add 2-chloro-3,4-dihydroxybenzoic acid, 2-(pyrrolidone-1-yl)ethane-1-amine, a condensing agent, and a first base to a mixed solution of polyethylene glycol and water. Stir and then heat to react. After the reaction is complete, cool to room temperature, add a second base, a halide salt, and a hydroxyl protecting agent, and then heat to react.

[0031] In some embodiments of the present invention, the method for preparing the cefdil intermediate further includes a post-processing step, which includes filtering, washing, and drying the reaction mixture solution after the reaction is completed.

[0032] According to one specific aspect of the invention, the cefdil intermediate is 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide.

[0033] Another technical solution provided by the present invention: a method for preparing cefdil, the method for preparing cefdil includes a step of preparing the compound shown in formula (I), wherein the step of preparing the compound shown in formula (I) adopts the method for preparing cefdil intermediates described above.

[0034] In this invention, the starting material 2-chloro-3,4-dihydroxybenzoic acid is used as a raw material, and it is prepared by a demethylation reaction (e.g., patent: CN 200980143827.5).

[0035] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0036] This invention addresses the problems of cumbersome procedures, excessive wastewater, and difficulty in achieving optimal overall yield in the preparation of cefodil intermediates, particularly 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide, caused by the reagents used in existing technologies. Based on extensive experimental research, the inventors of this invention unexpectedly discovered that using 2-chloro-3,4-dihydroxybenzoic acid as a raw material, condensing it with 2-(pyrrolidine-1-yl)ethane-1-amine in a mixed solution of polyethylene glycol and water, followed by the addition of a hydroxyl protecting group, not only allows for the synthesis of the target product in a better manner but also results in shorter steps, less industrial wastewater, simpler post-treatment, and a more environmentally friendly solvent. In particular, it also achieves excellent overall yield, making it suitable for industrial production. Attached Figure Description

[0037] Figure 1 The 1H NMR spectrum of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide prepared in Example 1 of this invention. Detailed Implementation

[0038] The above-mentioned solution will be further described below with reference to specific embodiments; it should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments; the implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0039] Unless otherwise specified in the following examples, all raw materials are commercially available or prepared by conventional methods in the art.

[0040] Example 1

[0041] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0042] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of a PEG-400 / H2O mixed solution (volume ratio 1:1). The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to obtain 4.62 g of the target compound (its 1H NMR spectrum is shown in [reference needed]). Figure 1 (As shown), purity 94%, yield 88%.

[0043] Example 2

[0044] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0045] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of HATU (5.7 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of a mixed solution of PEG-400 / H2O (volume ratio 1:1). The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 4.31 g of the target compound with a purity of 94% and a yield of 82%.

[0046] Example 3

[0047] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0048] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of triethylamine (2.02 g) were added to 10 mL of a PEG-400 / H2O mixed solution (1:1 v / v). The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 4.36 g of the target compound with a purity of 92% and a yield of 83%.

[0049] Comparative Example 1

[0050] The process is basically the same as in Example 1, except that only water is added as the solvent for the condensation reaction.

[0051] Specifically:

[0052] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0053] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of water. The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 1.94 g of the target compound with a purity of 63% and a yield of 37%.

[0054] Comparative Example 2

[0055] The process is basically the same as in Example 1, except that only polyethylene glycol is added as the solvent for the condensation reaction.

[0056] Specifically:

[0057] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0058] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of polyethylene glycol. The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 3.30 g of the target compound with a purity of 81% and a yield of 63%.

[0059] Comparative Example 3

[0060] The process is basically the same as in Example 1, except that the volume ratio of polyethylene glycol to water is adjusted to 1:3.

[0061] Specifically:

[0062] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0063] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of a PEG-400 / H2O mixed solution (volume ratio 1:3). The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g), 30 mmol of sodium carbonate (3.18 g), and 10 mmol of NaI (1.5 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 3.78 g of the target compound with a purity of 95% and a yield of 72%.

[0064] Comparative Example 4

[0065] The process is basically the same as in Example 1, except that NaI is not added during the reaction of the upper protecting group.

[0066] Specifically:

[0067] This example provides a method for preparing 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidone-1-yl)ethyl)benzamide, which includes:

[0068] 10 mmol of 2-chloro-3,4-dihydroxybenzoic acid (1.88 g), 15 mmol of 2-(pyrrolidone-1-yl)ethane-1-amine (1.71 g), 15 mmol of EDCI (2.88 g), and 20 mmol of pyridine (1.58 g) were added to 10 mL of a PEG-400 / H2O mixed solution (volume ratio 1:1). The mixture was stirred at room temperature for 5 min, then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and 30 mmol of p-methoxybenzyl chloride (4.70 g) and 30 mmol of sodium carbonate (3.18 g) were added directly without post-treatment. The mixture was then heated to 50 °C and reacted for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the precipitated solid was filtered, washed with petroleum ether, and dried to give 3.62 g of the target compound with a purity of 75% and a yield of 69%.

[0069] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0070] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for preparing a cefdil intermediate, wherein the cefdil intermediate is a compound represented by formula (I), In formula (I), R is a hydroxyl protecting group, characterized in that, The preparation method includes: 2-Chloro-3,4-dihydroxybenzoic acid and 2-(pyrrolidone-1-yl)ethane-1-amine were condensed in a mixed solution of polyethylene glycol and water in the presence of a condensing agent and a first base. Then, a second base, a halide salt and a hydroxyl protecting agent were added to react with a protecting group to produce the compound shown in formula (Ⅰ). The volume ratio of polyethylene glycol to water is 1:0.8-2.

0. The molecular weight of the polyethylene glycol is 200-600; The condensing agent is one or more combinations selected from N,N-carbazide imidazole, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; The first base and the second base are each independently selected from one or more combinations of triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; The halide salt is sodium iodide and / or potassium iodide; The hydroxyl protecting agent is selected from one or more of p-methoxybenzyl chloride, benzyl chloride, benzyl bromide, and benzyl iodide.

2. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The volume ratio of polyethylene glycol to water is 1:0.8-1.

5.

3. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The condensation reaction is controlled to be carried out at 25-60°C.

4. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The reaction of the upper protecting group is controlled to be carried out at 25-60°C; and / or, the reaction time of the condensation reaction is controlled to be 1-4 h; and / or, the reaction time of the upper protecting group reaction is controlled to be 4-12 h.

5. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The molar ratio of the 2-chloro-3,4-dihydroxybenzoic acid, the 2-(pyrrolid-1-yl)ethane-1-amine, the condensing agent, and the first base is 1:1-1.5:1.5-3:1.5-3; and / or, the concentration of the 2-chloro-3,4-dihydroxybenzoic acid in the mixed solution is controlled to be 0.1-1.5 mol / L; and / or, the molar ratio of the 2-chloro-3,4-dihydroxybenzoic acid, the hydroxyl protecting agent, the second base, and the halide salt is 1:2-4:2-4:0.5-1.

5.

6. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The preparation method of the cefdil intermediate is a one-pot method, and its implementation includes: Add 2-chloro-3,4-dihydroxybenzoic acid, 2-(pyrrolidone-1-yl)ethane-1-amine, a condensing agent, and a first base to a mixed solution of polyethylene glycol and water. Stir and then heat to react. After the reaction is complete, cool to room temperature, add a second base, a halide salt, and a hydroxyl protecting agent, and then heat to react.

7. The method for preparing the cefdil intermediate according to claim 1, characterized in that, The cefodil intermediate is 2-chloro-3,4-bis((4-methoxybenzyl)oxy)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide.

8. A method for preparing cefdil, the method comprising the step of preparing the compound shown in formula (I), characterized in that, The preparation process of the compound shown in formula (I) adopts the method for preparing the cefodil intermediate according to any one of claims 1-7.

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