A method for preparing a z-form cefditoren pivoxil core

Abstract

The application discloses a preparation method of Z-form cefditoren pivoxil mother nucleus, which comprises the following steps: after 7-ACA is reacted with benzeneacetyl chloride, the reaction product is subjected to silanization by HMDS, is reacted with triphenylphosphine and TMSI to generate a quaternary phosphonium salt, is subjected to Wittig reaction with 4-methyl-5-formylthiazole under the action of lithium acetate and BSA, and is subjected to salt formation with 2-pentanone and cyclohexylamine to remove E-form and Delta3-form compound A, so as to obtain compound B; and the compound B is subjected to enzymolysis to obtain Z-form cefditoren pivoxil mother nucleus (7-ATCA), wherein the purity of the Z-form cefditoren pivoxil mother nucleus is greater than or equal to 99.2%, the content of E-form isomer is less than or equal to 0.15%, and the content of Delta3-form isomer is less than or equal to 0.10%. The whole preparation method has high yield, small residual amount of by-products and small content of E-form and Delta3-form isomers.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing Z-type cefotaxime nucleus from 7-ACA as a raw material through condensation, silanization, substitution, wittiging, salt formation, and hydrolysis. Background Technology

[0002] Cefditoren Pivoxil (ME-1207) is a novel oral third-generation cephalosporin antibiotic developed by Meiji Seika Co., Ltd. of Japan. It was launched in Japan in 1994 under the brand name Meiact, and was subsequently approved by the FDA in September 2001. Cefditoren Pivoxil is tervavalerate methyl ester of cefotaxime. After absorption, it is hydrolyzed to the active form cefotaxime, thus exerting its antibacterial effect. It has strong antibacterial activity against both Gram-positive and Gram-negative bacteria, and exhibits high activity against certain drug-resistant strains.

[0003] Its structural formula is as follows:

[0004]

[0005] Ceftoram sodium is a key raw material for the synthesis of cefotaxime. Ceftoram sodium exists in two structures, Z and E, with the chemical structural formula shown in Formula 1. The Z structure is the active structure we need.

[0006]

[0007] Formula 1

[0008] Ceftorand sodium exists in three chemical structures: Z-form, E-form, and Δ3-form. These are mainly due to the presence of the parent nucleus 7-ATCA, specifically Z-form, E-form, and Δ3-form 7-ATCA, as shown in Equation 2.

[0009]

[0010] Formula 2

[0011] Several papers have reported on the preparation methods of 7-ATCA. The main starting materials include 7-aminocephalosporanic acid (7-ACA), D-7-ACA, and p-methoxybenzyl 7-phenylacetamido-3-chloromethylcephalosporanic acid (GCLE), GCLH, etc. Existing routes typically involve constructing the 3-position side chain via the Wittig reaction, followed by deprotection, condensation with the active AE ester, and esterification with iodomethyl terpentine to obtain the target product. However, these methods generally suffer from the following core drawbacks: First, the Wittig reaction is slow (usually requiring 20-24 hours), with low yields and poor stereoselectivity. In addition to the target Z-type isomer, the product inevitably contains E-type and Δ3-type isomer byproducts. These isomers are highly similar to the target product in structure and physicochemical properties, making separation extremely difficult and easily resulting in residues in the final product, cefotaxime, which severely affects the purity and quality of the drug. Second, the deprotection step often uses environmentally hazardous and highly corrosive reagents such as phenol-trifluoroacetic acid and phosphorus pentachloride, resulting in harsh reaction conditions and numerous side reactions, further reducing the reaction yield. Third, to control isomer impurities, existing processes often employ multiple purification and recrystallization methods, leading to a significant decrease in product yield and increasing the industrial production cost of Z-7-ATCA.

[0012] In their paper "Research on the Synthetic Process of 7-ATCA, a Key Intermediate of Ceftriaxone" (Proceedings of the 13th National Conference on Antibiotics), Chen Lin et al. reported that 7-ATCA was obtained by reacting GCLE with 4-methyl-5-formylthiazole via a Wittig reaction. The DPTC was then obtained by removing the p-methoxybenzyl protecting group at the 2-position of the carboxyl group with phenol and removing the 7-position phenylacetyl protecting group with penicillin G acylase. The total yield was 30%, and the Z-isomer content in the product was 93%, while the E-isomer accounted for no less than 5%.

[0013] Kenji Sakagami, Kunio Akimoto, Yuichi Yamamoto, et al. ("Synthesis and Oral Activity of Pivaloyloxymethy-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoaceta-mido]-3-(Z)-(4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylate (ME1207) and Its Related Compound", Bulletin of Chemical Pharmacology 39(9) 2433-2436(1991)) prepared chen7-ATCA, in which the ratio of Z-form to E-form was 4.7:1 (E-form / Z + E) accounted for 17.5%.

[0014] US6,288,223 discloses a method for producing the Z isomer of 7-N unsubstituted or substituted amino-3-[2-(4-substituted or unsubstituted thiazolyl-5-yl)vinyl]-3-cephalospora-4-carboxylic acid or an ester thereof, the method using a mixed solvent consisting of one or more chlorinated hydrocarbon solvents and one or more lower alcohols in a volume ratio ranging from 1:3 to 1:0.25. This process, which involves crystallizing the amine salt of the Z / E mixture of 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephalospora-4-carboxylic acid and converting it to 7-amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephalospora-4-carboxylic acid, or by chromatographic separation of the Z / E mixture, is not suitable for commercialization.

[0015] IN2010DE00467 discloses an improved method for preparing ceftorand sodium (Formula (2)). Ceftorand sodium is prepared from a 7-ATCA-DCA salt as a starting material in the presence of MAEM and sodium-2-ethylhexanoic acid. This one-step process yields ceftorand sodium with high purity, rich in the Z-isomer form.

[0016] WO2005 / 003141 A2 discloses an improved process for preparing ceftriaxone (Form I), which includes the following steps: i) converting a (Form II) compound to a (Form III) compound using TPP and sodium iodide in the presence of THF, water, and an alkali; ii) reacting the (Form III) compound with 4-methyl-5-carboxythiazole to generate a (Form IV) compound; iii) deesterifying the (Form IV) compound to obtain a (Form V) compound; iv) converting the (Form V) compound to a (Form VI) compound in the presence of an alkali and a solvent; v) converting the (Form VI) compound to a (Form VII) compound by enzymatic hydrolysis; vi) reacting the (Form VII) compound with the (Form VIII) compound in the presence of a solvent and an alkali to generate a (Form I) compound.

[0017] US6288233 discloses a process for preparing Cefditoren, which involves the condensation reaction of a wittig salt of the cephalosporin moiety with thiazole-5-carboxaldehyde in a chlorinated hydrocarbon and lower alcohol medium. The journal *Chemical Pharmaceutical Bulletin*, Vol. 39 (1991), p. 2433, discloses a process involving the conversion of GCLE(II) to a wittig salt, a wittig reaction with 5-formyl-4-methylthiazole, separation of isomers by stepwise crystallization, followed by column chromatography to deprotect the free amine, then reaction with protected MAEM, and finally deprotection to obtain the free acid (I). The separation of the E / Z isomers involves column chromatography, resulting in low yields.

[0018] IN2003CH00641 discloses a method for preparing 7-aminocephalosporin derivatives. More specifically, the present invention relates to a method for preparing 7-aminocephalosporin (7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephalosporin-4-carboxylic acid), yielding a product with a purity of 87-97%.

[0019] In their paper, "A Scalable Chemienzymatic Process for the Preparation of 7-Amino-3-[Z-2-(4-methylthiazol-5-yl)vinyl]-3-cephalosporin-4-carboxylic acid (ATCA)," Gao Chunhui et al. reported a highly efficient chemienzymatic process for the preparation of 7-amino-3-[Z-2-(4-methylthiazol-5-yl)vinyl]-3-cephalosporin-4-carboxylic acid. This process involves removing the p-methoxybenzyl group with trichloroacetic acid and utilizing immobilized penicillinamidinase to cleave the phenylacetyl E-isomer. The E-isomer of 7-amino-3-[Z-2-(4-methylthiazol-5-yl)vinyl]-3-cephalosporin-4-carboxylic acid can be easily reduced to below 0.2% through salt formation. Literature reports the use of dicyclohexylamine salt, but studies have found that after 7-phenylacetylamino-3-[Z-2-(4-methylthiazolyl-5-yl)vinyl]-3-cephalosporin-4-carboxylic acid forms a salt with dicyclohexylamine via 2-butanone, this salt has very low solubility in water. The subsequent reaction of cleaving the phenylacetyl E-isomer with immobilized penicillinamidinase is relatively slow and not suitable for industrial production.

[0020] US patent 5233035 discloses a process for preparing p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazol-5-yl)-vinyl-3-cephalospora-4-carboxylic acid ester, comprising the following steps: reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephalospora-4-carboxylic acid ester with triphenylphosphine in dimethylformamide in the presence of sodium iodide; then reacting the resulting product with 5-formaldehyde-4-methylthiazole in methyl chloride. The resulting p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazol-5-yl)-vinyl-3-cephalospora-4-carboxylic acid ester is purified by silica gel column chromatography eluted with chloroform. This process suffers from low yield, poor quality, and high content of the E isomer.

[0021] CN109180704 discloses a method for synthesizing cefotaxime. The method involves reacting D-7ACA with an oxidizing agent to obtain compound 1; silanizing compound 1 to obtain compound 2; iodination of 4-methylthiazol-5-methanol and NaI under a small amount of sulfuric acid catalysis, followed by the addition of triphenylphosphine to obtain compound 3; adding compound 3 to the solution of compound 2 for reaction, concentrating the solution, adding methanol and a small amount of concentrated hydrochloric acid for deprotection, and then crystallizing to obtain the cefotaxime core; reacting 7-ATCA and AE active ester under alkaline conditions to crystallize and obtain wet cefotaxime sodium; reacting the wet cefotaxime sodium with methyl iodide tervastatin in the presence of a phase transfer catalyst to crystallize and obtain crude cefotaxime sodium.

[0022] CN103695522 B discloses a method for preparing an intermediate of cefotaxime. This method uses 7-phenylacetamido-3-chloromethylcephalosporanic acid p-methoxybenzyl ester (GCLE) as the starting material, undergoes a Wittig reaction to generate formula Π, followed by deprotection to generate formula I. While this method is simple and easy to operate, the Wittig reaction has a low yield, is slow (generally 20-24 hours), and has poor selectivity. The Z-type product is mixed with E-type isomer byproducts, which are difficult to separate due to their similar structures and properties, and may even remain in the final cefotaxime, affecting drug efficacy and safety. Furthermore, the deprotection of formula Π uses environmentally harmful reagents such as phenol-trifluoroacetic acid, and the reaction conditions are harsh, resulting in low yields.

[0023] EP0175610 discloses a method using GCLE as a raw material, which involves a Wittig reaction followed by combination with 4-methylthiazol-5-carboxaldehyde to remove carboxyl protection, followed by salt formation and reaction with iodomethyl tervastatin. Then, phosphorus pentachloride and pyridine are used to remove the 7-amino group protection, and the resulting product reacts with aminothiazolium acid with the amino group protected to yield triphenylmethylcefotaxime. After removing the triphenylmethyl group protection, the final product is obtained. However, this route lacks selectivity in attaching the 3-side chain, resulting in approximately 20% E-isomer impurities in the final product, making purification difficult. Furthermore, it requires the use of phosphorus pentachlor, which is highly corrosive. The subsequent sodium salt formation reaction, requiring alkaline sodium isooctanoate, easily forms the Δ3-isomer, which, due to its similar structure and properties, is difficult to separate, leading to a decrease in both the yield and purity of the target product.

[0024] WO2005016936 publicly reported a process using 7-phenylacetamido-3-chloromethylcephalosporanic acid p-methoxybenzyl ester (GCLE) as the starting material. The process involved a Wittig reaction followed by a reaction with 4-methylthiazol-5-carboxaldehyde, removal of the 7-position protecting group, reaction with an AE active ester, removal of the 4-position protecting group, and reaction with iodomethyl tervastatin. The resulting product had a purity of 96.8% and contained 0.78% of the E isomer. The product obtained by this method has relatively low purity and a high content of E-isomers, with a total molar yield of 26.3-30.4%. Highly volatile and corrosive reagents such as trifluoroacetic acid and phenol are used in the C-4 deprotection process. The subsequent sodium salt formation reaction requires alkaline conditions with sodium isooctanoate, which can damage the amide bonds in the product. Furthermore, the sodium salt of cefotaxime is not suitable for storage and has poor stability, resulting in low purity of the product. In the final reaction step, the use of the alkaline catalyst NaHCO3 easily generates the Δ3-isomer of cefotaxime, which is difficult to remove. Trifluoroacetic acid is expensive, and phenol is environmentally unfriendly.

[0025] CN108084212A discloses a method for preparing cefotaxime, which includes the following steps: using 7-ACA as the starting material, after silanization protection, an iodination and Wittig reaction occurs to generate the cefotaxime core 7-ATCA; after amino protection by ethyl aminothiazolate, it reacts with the cefotaxime core 7-ATCA under AlMe3 catalysis to generate compound 2; compound 2 undergoes esterification with methyl iodopentanoate under the action of a phase transfer catalyst and an acid adsorbent, and then undergoes deamination protection to obtain the target product cefotaxime. Studies have found that after 7-ACA reacts with trimethyliodosilane, it reacts with triphenylphosphine and then with 4-methyl-5-formylthiazolium via a Wittig reaction at room temperature. A certain amount of E-form-7ATCA is subsequently quenched with methanol to remove the 7-position trimethylsilyl group protection, which easily leads to excessive condensation reaction with 4-methyl-5-formylthiazolium and the 7-position amino group, resulting in increased impurities and a darker product color.

[0026] CN109336904A discloses a method for preparing cefotaxime, which includes the following steps: using 7-ACA as the starting material, after silanization protection in benzene reagent, a series of reactions such as iodination occur to generate the cefotaxime core 7-ATCA; this compound first reacts with sodium isooctanoate to form a sodium salt, and then reacts with ethyl aminothiazolate under the catalysis of immobilized penicillin acylase to generate compound 2, namely cefotaxime sodium; then reacts with methyl iodide tervastatin to obtain the target product cefotaxime. In the direct silanization of 7-ACA with HMDS in the benzene system, benzene is a carcinogen with extremely strict residue limits in pharmaceuticals. Trifluoroethoxyphosphate is highly toxic and environmentally unfriendly. In step 1), the molar ratio of 7-ACA, hexamethyldisilazane, trimethyliodosilane, phosphate, sodium hexamethyldisilazane, and 15-crown-5 is 1:1.0–1.4:1–1.2:0.8–1.1:0.8–1.0:1.0–2.0. Trifluoroethoxyphosphate is used, with a boiling point of 186°C–189°C, resulting in high processing or recovery costs. The catalysts 15-crown-5 and sodium hexamethyldisilazane are used in large quantities and are expensive. Overall, the process is not suitable for commercial production.

[0027] Meanwhile, based on the chemical reaction mechanism of ylide and wittig:

[0028] 7-ACA undergoes a substitution reaction with TMSI (trimethyliodosilane) in a first-order reaction to produce the iodinated product. It then reacts with a phosphonite ester to form a quaternary phosphine salt reagent. This quaternary phosphine salt then undergoes a Wittig reaction with 4-methyl-5-formylthiazole under alkaline catalysis to yield the target product. Theoretically, CN109336904A uses trifluoroethoxyphosphate as a reactant and should not react with the iodinated product; this is because the phosphorus electron orbitals of trifluoroethoxyphosphate are completely substituted, preventing further quaternary phosphine salt reactions with the iodinated product. The feasibility of using trifluoroethoxyphosphate prepared from phosphine oxychloride and trifluoroethanol as a catalyst in patent CN109336904A warrants further consideration.

[0029] Summary of the Invention

[0030] The purpose of this invention is to address the shortcomings of existing technologies by providing a new preparation process suitable for industrial production. This preparation process uses cheaper and more environmentally friendly reagents, and can improve the purity of the product, effectively reduce the content of impurities, and produce a light-colored final product.

[0031] The technical solution of this invention is implemented as follows:

[0032] A method for preparing a Z-type cefotaxime core includes the following steps:

[0033] Step 1: 3-Acetylcephalosporanic acid (7-ACA) reacts with phenylacetyl chloride in an organic solvent to generate 7-(2-phenylacetamido)-3-(acetoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (7-PA-ACA). The reaction formula is as follows:

[0034]

[0035] Step 2: In a solvent containing silyl ether, 7-PA-ACA is first protected with hydroxyl groups, then forms a phosphorus ylide reagent with TMSI and PPh3, and then undergoes a wittig reaction with 4-methyl-5-formylthiazole. By controlling the wittig reaction temperature, Z-form A product, a small amount of E-form A product and Δ3-form A product are generated.

[0036]

[0037] Step 3: The product from step 2 is reacted with cyclohexylamine in an organic solvent to form a salt, generating product B;

[0038]

[0039] Step 4: The product from step 3 is reacted to remove phenylacetic acid, and the pH is adjusted to 3.3-4.5 to generate Z-form 7-ATCA;

[0040]

[0041] The temperature of the second Wittig reaction is controlled below -10°C.

[0042] This invention primarily reduces the content of E and Δ3 configurations in the product by first protecting it with phenylacetyl chloride in the first step, and then lowering the reaction temperature in the Wittig reaction in the second step, while ensuring the purity of the Z configuration required in subsequent products.

[0043] In the first step,

[0044] To avoid the condensation reaction between the 7-amino group of the 7-ACA raw material and 4-methyl-5-carboxythiazole, we use phenylacetyl chloride as a protecting group to protect the amino group, thus avoiding the side reaction with 4-methyl-5-carboxythiazole during the Wittig reaction.

[0045] The reaction process is as follows:

[0046] 7-ACA was prepared by adding BSA to dichloromethane and stirring until dissolved. Then, phenylacetyl chloride was added, and after the reaction was complete, dichloromethane was distilled off under reduced pressure. Ethyl acetate and water were added, and after stirring to precipitate the solid, 7-(2-phenylacetamido)-3-(acetoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (abbreviated as 7-PA-ACA) was obtained; the yield was higher than 98%.

[0047] The solvent for the first step reaction in this invention is dichloromethane; the reaction temperature range for 7-ACA and BSA is 20~35℃; and the molar ratio of 7-ACA, BSA, and phenylacetyl chloride is 1:1~1.2:1.1~1.3.

[0048] In the second step,

[0049] In the second step of this invention, the reaction solvent is a mixture of dichloromethane and hexamethyldisilether. The amount of dichloromethane used is 5 to 6 times the weight of 7-PA-ACA, and the amount of hexamethyldisilether used is 0.1 times the weight of dichloromethane. Using this mixed solvent not only ensures high reaction efficiency but also effectively avoids the use and residue of benzene.

[0050] In the second step of this invention, the molar ratio of 7-PA-ACA:triphenylphosphine:HMDS:TMSI:N,N-diethylaniline is 1:1.1:1~1.3:1.1~1.5:2.0~2.2, the reaction temperature is 38~43℃, and the reaction time is 7~9h.

[0051] In the second step of the Wittig reaction of this invention, the amount of BSA used is 1 to 1.2 times the weight of 7-PA-ACA; the amount of DMSO used is 0.1 to 0.2 times the weight of BSA; the inorganic base used is anhydrous lithium acetate (moisture content ≤ 0.1%), and the amount of anhydrous lithium acetate used is 2 to 3 times the molar amount of 7-PA-ACA; the molar ratio of 7-PA-ACAC and 4-methyl-5-formylthiazole in the second step of the reaction of this invention is 1.0:2.0 to 3.0, the reaction temperature is -20 to -25°C, and the reaction time is 30 to 48 hours. The reaction quencher for the Wittig reaction is an alcohol: anhydrous ethanol is selected, and the amount of ethanol used is 4 to 6 times the weight of 7-PA-ACA.

[0052] Preferably, the specific process is as follows:

[0053] 7-PA-ACA, triphenylphosphine, and hexamethyldisilazane (HMDS) were added to dichloromethane and hexamethyldisilazane and refluxed for 2-3 hours. The mixture was then cooled to 0-5°C, and N,N-diethylaniline and trimethyliodosilane were added. After the reaction was complete, the mixture was cooled, and DMSO, BSA, and anhydrous lithium acetate were added. Studies showed that at 0-10°C, the Wittig reaction with 4-methyl-5-formylthiazole yielded an E-form A product ratio of 10%-12% and a Δ3-form A product ratio of 5%-8%. The proportions of E-form A and Δ3-form A products gradually decreased with decreasing temperature, but the reaction time needed to be extended. We selected -20℃ to -25℃ and carried out a Wittig reaction with 4-methyl-5-formylthiazole for 48 hours. The E-form A product ratio was less than 4%, the Δ3-form A product ratio was less than 1%, and the intermediate raw material residue was less than 2%. Dichloromethane was concentrated under reduced pressure, and ethanol was added dropwise at a controlled temperature of 20~30℃. The precipitated yellow solid was filtered (A), with a yield of 89%~91%. The E-form A product:E / E+Z ratio was less than 4%, and the Δ3-form A product ratio was less than 1%.

[0054] In the third step,

[0055] Studies on the salt formation of product A with ammonium salts revealed varying effectiveness in removing the E-isomer A. Dicyclohexylamine and cyclohexylamine showed better results in removing both the E- and Δ3 isomers of product A. However, the salt formed by dicyclohexylamine and product A exhibited poor water solubility, hindering the subsequent dephenylacetylation reaction using immobilized penicillin enzyme, which was time-consuming and yielded low results. In contrast, the cyclohexylamine salt of product A (compound B) was readily soluble in water, facilitating a smoother subsequent dephenylacetylation reaction using immobilized penicillin acylase. The study also investigated solvents used in the salt formation process: alcohols and ketones. Alcohols such as methanol, ethanol, and tert-butanol were ineffective in removing the E-isomer A, making ketones a more ideal choice. Acetone was found to have a low boiling point and be highly volatile. Using 2-butanone and acetone, the resulting product B has a fine crystal structure, is difficult to filter, and is unsuitable for production. Using 2-pentanone as a solvent, product A and cyclohexylamine form a salt to obtain product B, which is easy to filter. The yield of Z-form A product reaches over 94%, E-form A compound ≤ 0.15%, and Δ3-form A compound < 0.1%. The removal rate of E-form A product reaches over 99%, and 2-pentanone has a boiling point of 101.7℃, making it easy to recover.

[0056] The solvent used in the third step of this invention is 2-pentanone, the salt-forming agent is cyclohexylamine, and the amount of cyclohexylamine is 1 to 2 times the molar amount of 7-PA-ACA; the pH value of the system is controlled at 8.8 to 9.5; the salt-forming temperature is 0 to 10℃, the E / E+Z ratio is ≤0.15%, and 7-ADCA is ≤0.10%.

[0057] In the fourth step,

[0058] Product B was dissolved in water, immobilized penicillin acylase was added, and 3% sodium bicarbonate was added dropwise to control the pH value at 7.0-8.5. After filtration, the pH was adjusted to 1.0-1.2 with dilute hydrochloric acid, and then adjusted back to 3.3-4.5 with ammonia water. The Z-form 7-ATCA product was obtained with a purity ≥99.2%, E-form 7-ATCA ≤0.15%, Δ3-isomer 7-ATCA ≤0.10%, 7-ADCA ≤0.10%, phenylacetic acid ≤0.1%, and cyclohexylamine residue ≤0.07%.

[0059] In this invention, the solvent system for the fourth step of the reaction is water, and the alkaline solution for the dephenylacetic acid removal process is an aqueous sodium bicarbonate solution. After deprotection, the pH of the system is first adjusted to 0.5, and then adjusted to 3.3-4.5. The research process revealed that directly adjusting the pH of the system to 3.4-4.5 resulted in a cyclohexylamine residue >0.5% in the product. By optimizing the pH of the feed solution system to 1.0-1.2 (precipitation followed by clearing), and then adjusting it back to 3.3-4.5 (crystallization), the cyclohexylamine residue was ≤0.07%, and cyclohexylamine was not detected in the subsequent preparation of ceftriaxone sodium. The total molar yield was ≥80%. The obtained 7-ATCA meets the requirements for the commercial preparation of ceftriaxone pivoxil.

[0060] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0061] This invention improves the yield of Z-form 7-ATCA by protecting the 7-ACA amino group with phenylacetyl chloride, optimizing the Wittig reaction conditions, cyclohexylamine salt formation, and stepwise pH control, thereby achieving a purity of ≥99.2% for the Z-form cefotaximetin core (7-ATCA), with E-isomer ≤0.15% and Δ3-isomer 7-ATCA ≤0.10%. This cefotaximetin core further meets the purity requirements for the synthesis of ceftorax sodium, exhibiting low levels of impurities and conforming to pharmacopoeia requirements. Attached Figure Description

[0062] Figure 1 The HPLC chromatogram of Z-form 7-ATCA obtained in Example 4;

[0063] Figure 2 This is the hydrogen NMR spectrum of ceftriaxone sodium. Detailed Implementation

[0064] The various abbreviations of this invention are as follows:

[0065] TMSI: Trimethyliodosilane

[0066] HMDS: Hexamethyldisilazane

[0067] BSA: N,O-bis(trimethylsilylacetamide)

[0068] 7-ACA: 3-Acetylcephalosporanic acid (Yili Chuaning Biotechnology Co., Ltd.)

[0069] 7-PA-ACA: 7-(2-Phenylacetamido)-3-(acetoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[0070] DMSO: Dimethyl sulfoxide

[0071] Enzyme: Immobilized penicillin acylase (Manufacturer: Zhejiang Yefeng Pharmaceutical Co., Ltd.)

[0072] Compound A: 7-(2-phenylacetamido)-3-((Z / E)-2-(2-methylcyclopenten-1,3-dienyl)vinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2-carboxylic acid

[0073] Compound B: 7-(2-phenylacetamido)-3-((1Z)-2-(2-methylcyclopenten-1,3-dienyl)vinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2-carboxycyclohexylamine salt

[0074] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0075] Example 1

[0076] 7-PA-ACA Preparation

[0077] 136.1 g (0.50 mol) of 7-ACA and 400 ml of dichloromethane were added to a clean reaction flask. At 20-25°C, 121.8 g (0.60 mol) of BSA was added with stirring until dissolved. The mixture was then cooled to 0-5°C, and 85 g (0.55 mol) of phenylacetyl chloride was added. The mixture was spotted by TLC (developing solvent: DMC:MeOH = 5:1). After the reaction was complete, the internal temperature was controlled at 20-25°C, and the dichloromethane was evaporated under reduced pressure. After the dichloromethane was evaporated to dryness, 100 ml of ethyl acetate and 500 ml of purified water were added. The mixture was stirred rapidly until a white solid was formed. Stirring continued for 30 minutes. The mixture was filtered, and the filter cake was washed with 100 ml * 2 ml of purified water, then soaked in 200 ml of anhydrous methanol. After filtration, the filter cake was dried under vacuum to obtain 191.5 g of a white solid, 7-PA-ACA, with a yield of 98.2%.

[0078] Example 2

[0079] In a reaction flask under nitrogen protection, 156.0 g (0.40 mol) of 7-PA-ACA, 116.2 g (0.44 mol) of triphenylphosphine, 780 g of dichloromethane, and 78 g of hexamethyldisiloxane were added. Then, 71.0 g (0.44 mol) of hexamethyldisilazane (HMDS) was added, and the mixture was refluxed at 38–43 °C for 7 h. The temperature was then lowered by 0–5 °C, and 131.3 g (0.88 mol) of N,N-diethylaniline and 88.0 g (0.44 mol) of trimethyliodosilane were added. The mixture was reacted at 0–14 °C until complete. The temperature was then lowered to -10 °C, and a mixture of 15.6 g of DMSO and 156 g of BSA was added. Finally, 58.1 g (0.88 mol) of anhydrous lithium acetate was added, and the temperature was lowered to -20 °C. At -25℃, 101.8 g (0.8 mol) of 4-methyl-5-formylthiazole was added. The reaction was maintained at this temperature for 48 h. HPLC showed that the reaction was complete. Dichloromethane was concentrated under reduced pressure at room temperature, and 936 g of ethanol was added dropwise while controlling the temperature at 20-30℃. A yellow solid (A) precipitated, which was filtered and washed with ethanol. 298.6 g of wet product A was obtained (pure product: 176.6 g, yield 91.0%, EA product / Z+E = 3.95%, Δ3-form-A product 0.83%).

[0080] Example 3

[0081] The above product A was added to 500g of 2-pentanone and stirred at 20~25℃ to dissolve. After filtering to remove insoluble matter, 41.4g (0.41mol) of cyclohexylamine was added and the temperature was lowered to 5~10℃. A bright yellow solid precipitated. After filtration, 282.7g of wet product B was obtained (pure product: 177.5g, yield 94.0%, E ratio (E+Z) 0.07%; Δ3-form-B product 0.03%).

[0082] Example 4

[0083] Preparation of Z-type 7-ATCA

[0084] The 282.7g of product B obtained above was dissolved in 800ml of water. After dissolution, 2g of activated carbon was added for decolorization, and the mixture was filtered. 10g of immobilized penicillin acylase was added to the filtrate. The reaction was carried out at 25-30℃, with 3% sodium bicarbonate aqueous solution added dropwise to control the pH at 7.0-8.5. After the reaction was complete, the mixture was filtered, and the pH was adjusted to 1.0-1.2 with dilute hydrochloric acid. Then, ammonia was used to adjust the pH to 3.0-3.4. After drying, 90.4g of pale yellow powder Z-type 7-ATCA product was obtained. (Purity = 99.55%, E-7-ATCA = 0.08%, Δ3-isomer 7-ATCA = 0.03%; 7-ADCA = 0.02%; phenylacetic acid = 0.07%; cyclohexylamine residue = 0.07%, water = 0.5%; yield 90.1%). The HPLC chromatogram is shown below. Figure 1.

[0085] Example 5

[0086] Preparation of ceftoram sodium

[0087] Add 200 mL of acetone and 150 g of water to a clean reaction flask. Add 64.6 g of 7-ATCA (0.20 mol), cool to 10 °C, and add 70.0 g of AE (0.24 mol). The system becomes a suspension. Then, add 33 g of diisopropylethylamine dropwise. After reacting for 2 hours, take a sample and perform HPLC analysis to check the 7-ATCA residue: 0.1%. Add 500 mL of butyl acetate. Let stand, separate the layers, and add another 400 mL of butyl acetate to the lower aqueous phase. After separation, collect the lower aqueous phase, combine the butyl acetate layers, add 50 g of water for extraction, separate the layers again, combine the aqueous phases, add 56 g of sodium isooctanoate, stir to dissolve, and maintain the temperature at 10-20 °C. Add 1350 g of acetone dropwise. A solid precipitates. Filter and dry at 60℃ to obtain 108.4 g of off-white solid ceftorand sodium dihydrate (molar yield 96.0%, water 6.84%. HPLC=99.5%, E-isomer ceftorand sodium 0.05%, Δ3-isomer ceftorand sodium 0.02%, ATZ=0.2%, 7-ATCA 0.1%, cyclohexylamine residue not detected). NMR spectrum is shown below. Figure 2 .

[0088] IR: Instrument: Cary 630 FTIR KBr tablet press

[0089]

[0090] Example 6

[0091] Preparation of 7-PA-ACA

[0092] 136.1 g (0.50 mol) of 7-ACA and 500 ml of dichloromethane were added to a clean reaction flask. At 20-25°C, 101.5 g (0.50 mol) of BSA was added with stirring until dissolved. The temperature was lowered to 0-5°C, and 92.7 g (0.60 mol) of phenylacetyl chloride was added. The reaction was observed by TLC (developing solvent: DMC:MeOH = 5:1). After the reaction was complete, the internal temperature was controlled at 20-25°C, and dichloromethane was evaporated under reduced pressure. After the dichloromethane was evaporated to dryness, 100 ml of ethyl acetate and 500 ml of purified water were added. The mixture was stirred rapidly until a white solid was formed. Stirring continued for 30 minutes. The mixture was filtered, and the filter cake was washed with 100 ml * 2 ml of purified water, then soaked in 200 ml of anhydrous methanol. After filtration, the filter cake was dried under vacuum to obtain 192.0 g of a white solid, 7-PA-ACA, with a yield of 98.5%.

[0093] Example 7

[0094] In a reaction flask under nitrogen protection, 156.0 g (0.40 mol) of 7-PA-ACA, 116.2 g (0.44 mol) of triphenylphosphine, 936.0 g of dichloromethane, and 93.6 g of hexamethyldisiloxane were added. Then, 92.3 g (0.52 mol) of hexamethyldisilazane (HMDS) was added, and the mixture was refluxed at 38–43 °C for 9 h. The temperature was then lowered by 0–5 °C, and 119.3 g (0.80 mol) of N,N-diethylaniline and 88.0 g (0.44 mol) of trimethyliodosilane were added. The mixture was reacted at 0–14 °C until complete. The temperature was then lowered to -10 °C, and a mixture of 15.6 g of DMSO and 156.0 g of BSA was added. Then, 79.2 g (1.20 mol) of anhydrous lithium acetate was added. The temperature was lowered to -20 °C to -25 °C, and 81.4 g of... 0.12 mol of 4-methyl-5-formylthiazole was reacted at room temperature for 48 hours. The residue was ≤2.0%. Dichloromethane was concentrated under reduced pressure at room temperature. 624 g of ethanol was added dropwise while controlling the temperature at 20-30 °C. A yellow solid (A) precipitated. The solid was filtered and washed with ethanol to obtain 289.2 g of wet product A (pure product: 172.7 g, yield 89.0%, EA product / Z+E=3.88%; Δ3-form-A product 0.54%).

[0095] Example 8

[0096] The above 289.2g of product A was added to 500g of 2-pentanone and stirred at 20~25℃ to dissolve. After filtering to remove insoluble matter, 41.4g (0.41mol) of cyclohexylamine was added and the temperature was lowered to 5~10℃. A bright yellow solid precipitated. After filtration, 270.7g of wet product B was obtained (pure product yield was 172.1g, yield was 93.1%, (E+Z) ratio was 0.15%, and Δ3-form-B product was 0.02%).

[0097] Example 9:

[0098] Preparation of Z-type 7-ATCA

[0099] The obtained 270.0 g of substance B was dissolved in 800 ml of water. After dissolution, 3 g of activated carbon was added for decolorization, and the mixture was filtered. 10 g of immobilized penicillin acylase was added to the filtrate. The reaction was carried out at 25-30℃, with 3% sodium bicarbonate aqueous solution added dropwise to control the pH at 7.0-8.5. After the reaction was complete, the mixture was filtered, and the pH was adjusted to 1.0-1.2 with dilute hydrochloric acid, then adjusted back to 3.0-3.4 with ammonia water, yielding 88.4 g of a pale yellow Z-form 7-ATCA product with a purity of 99.5%, E-form 7-ATCA = 0.08%, Δ3-form 7-ATCA = 0.02%, 7-ADCA = 0.02%, phenylacetic acid = 0.07%, cyclohexylamine residue = 0.070%, and water content = 0.5%. The yield was 91.3%.

[0100] Example 10

[0101] Preparation of ceftoram sodium

[0102] Add 200 mL of acetone and 125 g of water to a clean reaction flask, then add 64.6 g of 7-ATCA (0.20 mol). Cool to 10 °C, then add 70.0 g of AE (0.24 mol). The system becomes a suspension, then add 24 g of triethylamine dropwise. After reacting for 2 hours, take a sample and perform HPLC analysis to check the 7-ATCA residue: 0.2%. Add 400 mL of butyl acetate. Let stand, separate the layers, and add another 400 mL of butyl acetate to the lower aqueous phase. Combine the oil phases, add 50 mL of water to extract the oil phase, separate the layers, and combine the aqueous phases (light brown liquid). Add 53 g of sodium isooctanoate to the aqueous phase, stir to dissolve, and maintain the temperature at 10–20 °C. Add 1300 g of acetone dropwise. A solid precipitates. The sample was filtered and dried at 60°C to obtain 108.6 g of a white solid ceftriaxone sodium dihydrate (molar yield 96.2%, water content 6.42%, HPLC purity 99.5%, E-isomer ceftriaxone sodium 0.04%, Δ3-isomer ceftriaxone sodium 0.02%; ATZ 0.12%, 7-ATCA 0.09%, cyclohexylamine residue not detected).

Claims

1. A method for preparing a Z-type cefotaxime core, characterized in that, The steps include the following: Step 1: 7-ACA reacts with phenylacetyl chloride in an organic solvent to generate 7-PA-ACA; ； Step 2: In a solvent containing silyl ether, 7-PA-ACA is first protected with hydroxyl groups, then forms a phosphorus ylide reagent with TMSI and PPh3, and then undergoes a wittig reaction with 4-methyl-5-formylthiazole. By controlling the wittig reaction temperature, Z-form A product, E-form A product and Δ3-form A product are generated. ； Step 3: The product from step 2 is reacted with an organic amine in an organic solvent to form a salt, generating product B; ； Step 4: The product B is subjected to a phenylacetic acid removal reaction. After the reaction is completed, the pH is adjusted to 3.3~4.5 to generate Z-type 7-ATCA, which is the Z-type cefotaxime core. ； The temperature of the second Wittig reaction is controlled below -10°C.

2. The preparation method according to claim 1, characterized in that: In the first step, the organic solvent is dichloromethane, and the reaction temperature is 20~35℃; BSA is also added to the reaction, and the molar ratio of 7-ACA to BSA is 1:1 to 1.2, and the molar ratio of 7-ACA to phenylacetyl chloride is 1:1.1 to 1.

3.

3. The preparation method according to claim 1, characterized in that: The solvent containing the silicone ether in the second step is a mixture of dichloromethane and hexamethyldisil ether.

4. The preparation method according to claim 3, characterized in that: In the mixed solvent of dichloromethane and hexamethyldisiloxane, the amount of dichloromethane is 5 to 6 times the weight of 7-PA-ACA, and the amount of hexamethyldisiloxane is 0.1 to 0.2 times the weight of dichloromethane.

5. The preparation method according to claim 1, characterized in that: The Wittig reaction temperature in the second step is -25 to -20°C; The second step of the Wittig reaction is carried out in a mixed system of BSA and DMSO under the action of an inorganic base; The inorganic base is preferably anhydrous lithium acetate, and the amount used is 2 to 3 times the molar amount of 7-PA-ACA. The amount of BSA used is 1 to 1.2 times the weight of 7-PA-ACA; the amount of DMSO used is 0.1 to 0.2 times the weight of BSA.

6. The preparation method according to claim 1, characterized in that: The organic amine used in the third step is selected from cyclohexylamine.

7. The preparation method according to claim 1, characterized in that: The organic solvent used in the third step is selected from alcohol solvents or ketone solvents, and is more preferably a ketone solvent.

8. The preparation method according to claim 7, characterized in that: The ketone solvent is selected from one or more of 2-butanone, acetone, and 2-pentanone, and is more preferably 2-pentanone.

9. The preparation method according to claim 1, characterized in that: The enzyme used in the fourth step of the dephenylacetic acid removal reaction is immobilized penicillin acylase; The reaction temperature is 20~30℃, and the reaction pH is 7.0~8.

5.

10. The preparation method according to claim 1, characterized in that: The fourth step, pH adjustment, is carried out in stages: first, acid is used to adjust it to 1.0~2.0, and then alkali is used to adjust it back to 3.3~4.5.

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