Process for the preparation of cefixime side chain ring-opened acid by aqueous phase method

Abstract

The application belongs to the technical field of acyclic compounds, and particularly relates to a method for preparing cefixime side chain ring-opening acid by a water phase method. Compound I, a catalyst and a citric acid solution are added in water to perform a deprotection reaction, so as to obtain an aqueous solution containing compound II and the catalyst; the aqueous solution containing compound II and the catalyst is cooled, and then N-chlorosuccinimide aqueous solution is added to perform a chlorination reaction; alkali is added to adjust the pH value; extraction, separation and layering are performed to obtain an aqueous phase; acid is added in the aqueous phase to adjust the pH value, so that solid is precipitated; suction filtration and vacuum drying are performed to obtain cefixime side chain ring-opening acid. The application uses water as a solvent system, so that environmental problems such as generation of acidic waste gas and VOCs volatilization in the existing process are eliminated, the number of side reactions is small, and the product yield is high.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of acyclic compounds, and particularly relates to a method for preparing cefixime side chain ring-opening acid by a water phase method. BACKGROUND

[0002] Cefixime is a third-generation oral cephalosporin antibiotic. As a broad-spectrum third-generation cephalosporin, it has many outstanding characteristics: stability to beta-lactamase, broad antibacterial spectrum, wide indications, good efficacy, and small dosage.

[0003] The current main synthesis method of cefixime includes cefixime side chain ring-opening acid (CMOBA) acyl chloride method, CMOBA·DFCCS method, active ester method, and cefixime side chain acid acyl chloride method. As an important intermediate for synthesizing cefixime, the synthesis process of CMOBA has attracted widespread attention.

[0004] Chinese patent CN 117510367A discloses a preparation method of cefixime side chain ring-opening acid. Compound I is dissolved in an organic solvent, and HCl is added for acidolysis reaction to obtain a solution containing compound II. A catalyst is added to the solution containing compound II, and chlorination reaction is performed by adding chlorine and HCl. After vacuum distillation, beating, suction filtration, and vacuum drying, cefixime side chain ring-opening acid is obtained. Although this patent recycles the by-product HCl as raw material, the reaction system is still an organic solvent system, which produces a large amount of three wastes, is high in cost, and is difficult to dispose. SUMMARY

[0005] The purpose of the present application is to provide a method for preparing cefixime side chain ring-opening acid by a water phase method, which uses water as a solvent system to eliminate environmental problems such as generation of acidic waste gas and VOCs volatilization in the existing process, has fewer side reactions, and has high product yield.

[0006] The method for preparing cefixime side chain ring-opening acid by a water phase method according to the present application comprises the following steps:

[0007] (1) Compound I, a catalyst, and a citric acid solution are added to water to perform a deprotection reaction, and a water solution containing compound II and the catalyst is obtained;

[0008] (2) The water solution containing compound II and the catalyst obtained in step (1) is cooled, and N-chlorosuccinimide aqueous solution is added to perform a chlorination reaction. Alkali is added to adjust the pH, extraction is performed, and the layers are separated to obtain an aqueous phase;

[0009] (3) The pH of the aqueous phase obtained in step (2) is adjusted by adding acid, and solid is precipitated. After suction filtration and vacuum drying, cefixime side chain ring-opening acid is obtained.

[0010] The structural formula of compound I in step (1) is as follows:

[0011] .

[0012] The mass ratio of compound I and water in step (1) is 1:1.5-2.5, and the mass concentration of the citric acid solution is 15-35%; the ratio of compound I to the citric acid solution is 1:2.7-2.9, wherein the compound I is measured in grams, and the citric acid solution is measured in milliliters.

[0013] The catalyst in step (1) is a mixture of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol, and the mass ratio of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol is 1:0.5-0.8:2-2.2; the mass ratio of the catalyst to compound I is 0.002-0.005:1.

[0014] The deprotection reaction temperature in step (1) is 25-35℃, and the deprotection reaction time is 20-60min.

[0015] In step (2), the temperature is lowered to-10-0℃, the mass concentration of the N-chlorosuccinimide aqueous solution is 25-30%, and the N-chlorosuccinimide aqueous solution is added for 0.5-1.5h.

[0016] In step (2), the mass ratio of the N-chlorosuccinimide aqueous solution to compound I is 2.1-2.6:1.

[0017] In step (2), the chlorination reaction temperature is 15-25℃, and the chlorination reaction time is 2-3h.

[0018] In step (2), the base is sodium carbonate, the pH is adjusted to 10-12; the extraction is carried out using ethyl acetate, and the extraction temperature is 15-25℃.

[0019] In step (3), the acid is hydrochloric acid, the mass concentration of the hydrochloric acid is 15-22%, and the pH is adjusted to 3.2-4.

[0020] In the present application, the catalyst is efficient in catalyzing the deprotection reaction and the chlorination reaction. In the deprotection reaction, compound I is dispersed in water, and citric acid solution is added under the action of the catalyst to carry out deprotection. After the deprotection is completed, an aqueous solution containing compound II and the catalyst is obtained. In the chlorination reaction, N-chlorosuccinimide (NCS) aqueous solution is added to the aqueous solution containing compound II and the catalyst to carry out the reaction. After the reaction is completed, the product is treated by using the specific carboxyl functional group, alkali is added to adjust the pH to alkaline, ethyl acetate is used for extraction to remove impurities, hydrochloric acid is added to adjust the pH to acidic, and the target product is precipitated in the form of a solid. After filtration and vacuum drying, the cefixime side chain ring-opening acid is obtained.

[0021] The reaction equation of the present application is as follows:

[0022]

[0023] Deprotection reaction: benzyltriethylammonium chloride as a phase transfer catalyst, citric acid (weak acid, pKa≈3.1) provides protons (H + ) to the hydrophobic tert-butyl protected substrate, achieving mild protonation to generate a carbocation intermediate. The hydrophobic phosphine group of trihexyl( tetradecyl) phosphonium chloride captures the carbocation, accelerates the leaving group dissociation through nucleophilic assistance, and inhibits side reactions. The hydrogen bond network formed by polyethylene glycol and citric acid carboxyl groups enhances the dispersibility of the hydrophobic substrate in water, stabilizes the active structure of trihexyl( tetradecyl) phosphonium chloride, and reduces the hydrolysis energy barrier, accelerating the cleavage of the protecting group. Since citric acid is a weak acid, it can maintain the weak acidity of the system, avoiding the cleavage of sensitive groups caused by strong acid; in addition, citric acid can co-construct a dynamic hydrophilic microenvironment with the ether oxygen atoms of polyethylene glycol, improving the phase transfer efficiency of benzyltriethylammonium chloride.

[0024] Chlorination reaction: benzyltriethylammonium chloride transfers the active chlorine species generated by N-chlorosuccinimide in the aqueous phase to the interface of the hydrophobic substrate. The hydrophobic phosphine group of trihexyl( tetradecyl) phosphonium chloride stabilizes the active chlorine species through electrostatic interaction, while forming a micellar microenvironment to enrich the hydrophobic substrate, accelerating the electrophilic substitution or radical chlorination pathway. Polyethylene glycol coats the trihexyl( tetradecyl) phosphonium chloride micelles through a hydrogen bond network, inhibiting the hydrolysis of phosphonium salt and enhancing the mass transfer efficiency of the substrate in the micellar core.

[0025] The reaction system in the present application is water, and the compounded catalyst has a synergistic catalytic effect, which has a large positive catalytic effect on both reactions, greatly enhancing the mass transfer efficiency.

[0026] The reaction conditions of the present application are mild, and the reaction system is changed from the existing organic solvent system to the water system. In the prior art, when hydrochloric acid is used to remove the tert-butyl group, it must be carried out under anhydrous conditions. If it is carried out in an aqueous phase, another active functional group, the methyl ester bond, will be broken, producing a byproduct, a dicarboxylic compound. The reaction rate of the present application is fast, the reaction time is short, the reaction time in the existing organic solvent system is greatly shortened, the reaction selectivity is high, the formation of the dicarboxylic byproduct by the cleavage of the methyl ester bond is greatly reduced, and the selectivity of the chlorination reaction is poor. The formation of polychlorinated byproducts is greatly reduced. Citric acid selectively removes the tert-butyl protecting group without selectivity to the other active functional group, the methyl ester bond, greatly reducing the side reaction of methyl ester bond cleavage; N-chlorosuccinimide has specific selectivity during electrophilic chlorination, and there are few polychlorinated byproducts; at the same time, the post-treatment is simple, and the target product is purified by acid-base washing using the unique carboxyl functional group of the open ring acid, resulting in high product purity.

[0027] The beneficial effects of the present application are as follows:

[0028] (1) The present application uses water as a solvent system, citric acid to remove the carboxyl protecting group, and N-chlorosuccinimide for chlorination reaction, with less side reactions and greatly improved overall yield.

[0029] (2) The reaction system of the present application is water, and most of the hazardous waste is salt solution, which eliminates the environmental problems such as generation of acidic waste gas and VOCs volatilization in the existing process, greatly reduces the environmental pressure, and is more in line with green atomic economic benefits. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the liquid chromatogram of the cefixime side chain ring-opening acid prepared in Example 1. 1 H NMR spectrum.

[0031] Figure 2 is the liquid chromatogram of the cefixime side chain ring-opening acid prepared in Example 1.

[0032] Figure 3 is the liquid chromatogram of the cefixime side chain ring-opening acid prepared in Example 1. 1 H NMR spectrum. DETAILED DESCRIPTION

[0033] The present application is further described below in conjunction with examples.

[0034] Example 1

[0035] (1) 320 g of water was added with 160 g of compound I and 0.48 g of catalyst, the catalyst was a mixture of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol, the mass ratio of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol was 1:0.5:2, 450 ml of 18% citric acid solution was added dropwise at 25℃, and the deprotection reaction was carried out at 25℃ for 60 min to obtain an aqueous solution containing compound II and catalyst; compound II was separated from the aqueous solution containing compound II and catalyst for structure characterization, and the yield of compound II was 99.5%. 1 The H NMR spectrum of compound II is shown in Figure 1 The H NMR spectrum of compound II is shown in 1 The H NMR spectrum parameters of compound II are as follows: 1 H NMR (600 MHz, DMSO) δ 2.51 (s, 1.05H), 3.89 (s, 1.00H), 4.91 (s, 0.64H);

[0036] (2) After cooling the aqueous solution containing compound II and catalyst obtained in step (1) to -8℃, 343.28g of N-chlorosuccinimide aqueous solution with a mass concentration of 30% was added dropwise. The temperature was controlled at -8℃ and the addition was completed in 1h. The temperature was raised to 20℃ for chlorination reaction for 2.5h. Sodium carbonate was added to adjust the pH to 12. 450ml of ethyl acetate was added and extracted once at 20℃. The layers were separated to obtain the aqueous phase.

[0037] (3) The pH of the aqueous phase obtained in step (2) was adjusted to 3.6 by adding 15% hydrochloric acid, and a solid precipitated. The solid was then filtered, dried under vacuum, and the side-chain open-ring acid of cefixime was obtained with a molar yield of 95.61% (based on compound I) and an HPLC purity of 99.58%. The HPLC chromatogram of the side-chain open-ring acid of cefixime is shown below. Figure 2 Cefixime side-chain open-chain acid 1 The H NMR spectrum is shown in [reference]. Figure 3 .

[0038] Example 2

[0039] (1) Add 160g of compound I and 0.8g of catalyst to 400g of water. The catalyst is a mixture of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphine chloride and polyethylene glycol. The mass ratio of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphine chloride and polyethylene glycol is 1:0.7:2.1. Add 464ml of citric acid solution with a mass concentration of 15% at 30°C. Carry out the deprotection reaction at 30°C for 40min to obtain an aqueous solution containing compound II and catalyst.

[0040] (2) After cooling the aqueous solution containing compound II and catalyst obtained in step (1) to 0°C, 411.94 g of N-chlorosuccinimide aqueous solution with a mass concentration of 25% was added dropwise. The temperature was controlled at 0°C and the addition was completed in 1.5 h. The temperature was then raised to 15°C for chlorination reaction for 3 h. Sodium carbonate was added to adjust the pH to 11. 500 ml of ethyl acetate was added and extracted once at 15°C. The layers were separated to obtain the aqueous phase.

[0041] (3) Add 22% hydrochloric acid to the aqueous phase obtained in step (2) to adjust the pH to 3.2, precipitate solid, filter, and vacuum dry to obtain cefixime side chain open ring acid with a molar yield of 96.23% (based on compound I) and HPLC purity of 99.67%.

[0042] Example 3

[0043] (1) 240 g water was added with 160 g of compound I and 0.32 g of catalyst, the catalyst was a mixture of benzyltriethylammonium chloride, trihexyl (tetradecyl) phosphonium chloride and polyethylene glycol, the mass ratio of benzyltriethylammonium chloride, trihexyl (tetradecyl) phosphonium chloride and polyethylene glycol was 1:0.8:2.2, 432 ml of 35% mass concentration citric acid solution was added dropwise at 35℃, and the deprotection reaction was carried out at 35℃ for 20 min to obtain an aqueous solution containing compound II and catalyst;

[0044] (2) The aqueous solution containing compound II and catalyst obtained in step (1) was cooled to -10℃, and 385.72 g of 28% mass concentration N-chlorosuccinimide aqueous solution was added dropwise, the temperature was controlled at -10℃, and the dropwise addition was completed in 0.5 h, then the temperature was increased to 25℃ and the chlorination reaction was carried out for 2 h, sodium carbonate was added to adjust the pH to 10, 450 ml of ethyl acetate was added for extraction at 25℃, and the aqueous phase was obtained after separation;

[0045] (3) The aqueous phase obtained in step (2) was added with 17% mass concentration hydrochloric acid to adjust the pH to 4, and the solid was precipitated, then filtered and vacuum dried to obtain cefixime side chain ring-opening acid, the molar yield was 96.15% (calculated from compound I), and the HPLC purity was 99.71%.

[0046] Comparative Example 1

[0047] Without adding benzyltriethylammonium chloride, the other steps were the same as in Example 1. The molar yield of cefixime side chain ring-opening acid was 81.25% (calculated from compound I), and the HPLC purity was 99.11%.

[0048] Comparative Example 2

[0049] Without adding trihexyl (tetradecyl) phosphonium chloride, the other steps were the same as in Example 1. The molar yield of cefixime side chain ring-opening acid was 83.21% (calculated from compound I), and the HPLC purity was 99.17%.

[0050] Comparative Example 3

[0051] Without adding polyethylene glycol, the other steps were the same as in Example 1. The molar yield of cefixime side chain ring-opening acid was 88.53% (calculated from compound I), and the HPLC purity was 99.21%.

Claims

1. A process for the preparation of cefixime side chain ring-opened acid by aqueous phase method, characterized by It comprises the following steps: (1) adding compound I, catalyst and citric acid solution in water to carry out deprotection reaction, obtaining an aqueous solution containing compound II and catalyst; (2) cooling the aqueous solution containing compound II and catalyst obtained in step (1) and adding N-chlorosuccinimide aqueous solution to carry out chlorination reaction, adding alkali to adjust pH, extracting, separating layers, obtaining an aqueous phase; (3) adding acid to the aqueous phase obtained in step (2) to adjust pH, precipitating solid, suction filtering, vacuum drying, obtaining cefpodoxime proxetil side chain ring-opening acid; The structural formula of compound I in step (1) is as follows: ； The structural formula of compound II in step (1) is as follows: ； The catalyst in step (1) is a mixture of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol, and the mass ratio of benzyltriethylammonium chloride, trihexyl(tetradecyl)phosphonium chloride and polyethylene glycol is 1:0.5-0.8:2-2.

2.

2. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1 wherein The mass ratio of compound I and water in step (1) is 1:1.5-2.5, and the mass concentration of citric acid solution is 15-35%; the ratio of compound I to citric acid solution is 1:2.7-2.9, wherein the compound I is measured in g and the citric acid solution is measured in ml.

3. A process for the preparation of cefixime side chain ring opened acid by aqueous phase method as claimed in claim 1 wherein The mass ratio of catalyst to compound I in step (1) is 0.002-0.005:

1.

4. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1, wherein The deprotection reaction temperature in step (1) is 25-35℃, and the deprotection reaction time is 20-60 min.

5. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1 wherein In step (2), the temperature is cooled to-10—0℃, the mass concentration of N-chlorosuccinimide aqueous solution is 25-30%, and the N-chlorosuccinimide aqueous solution is added for 0.5-1.5 h.

6. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1, wherein The mass ratio of N-chlorosuccinimide aqueous solution to compound I in step (2) is 2.1-2.6:

1.

7. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1, wherein the process is characterized by The chlorination reaction temperature in step (2) is 15-25℃, and the chlorination reaction time is 2-3 h.

8. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1 wherein In step (2), the alkali is sodium carbonate, the pH is adjusted to 10-12; the extraction is carried out with ethyl acetate, and the extraction temperature is 15-25℃.

9. A process for the preparation of cefixime side chain ring opened acid by aqueous phase process as claimed in claim 1 wherein In step (3), the acid is hydrochloric acid, the mass concentration of hydrochloric acid is 15-22%, and the pH is adjusted to 3.2-4.

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