Preparation method of cefditoren pivoxil intermediate

Abstract

The present invention discloses a preparation method of cefditoren pivoxil intermediate, which is obtained by reacting carboxyl-protected 7-ADCA as the starting material with 4-methylthiazole-5-carbaldehyde activated by a nitrogen-containing reagent. As the most core intermediate of cefditoren pivoxil, 7-ATCA requires the use of expensive iodine compounds as catalysts and the participation of phosphorus reagents with relatively large pollution and complex post-treatment in the traditional synthesis process. In the present invention, an active intermediate reagent is obtained by treating 4-methylthiazole-5-carbaldehyde with an amine reagent. After reacting with the substrate, the construction of the olefin bond is effectively completed, and the target product is prepared. Through this technology, problems such as high cost, complex post-treatment, and large pollution in the traditional process can be avoided; by selecting different carboxyl-protected substrates, target products with a lower content of trans isomers can be prepared, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of a cefditoren pivoxil intermediate. Background Art

[0002] Cefditoren pivoxil is a third-generation cephalosporin antibacterial drug, which has a broad-spectrum antibacterial effect against Gram-positive bacteria and Gram-negative bacteria. In particular, it shows strong antibacterial activity against Staphylococcus spp., Streptococcus spp. including Streptococcus pneumoniae and other G+, Escherichia coli, Moraxella catarrhalis, Klebsiella spp., Proteus spp., Haemophilus influenzae and other G-, as well as anaerobic bacteria such as Peptostreptococcus spp., Propionibacterium acnes, Bacteroides spp. However, in the preparation process of the key intermediate 7-ATCA ((6, 7R)-7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid, also known as the cefditoren nucleus) of cefditoren, a large amount of iodine-containing reagents such as sodium iodide, potassium iodide, and trimethylsilyl iodide are used, resulting in high product costs. At the same time, phosphorus-containing reagents such as triphenylphosphine and triethyl phosphite are also used, causing problems such as complex post-treatment and large environmental pollution.

[0003] Chinese Patent CN201610082151.5 and US Patent US20060173175A1 use 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester as the starting material, replace it with sodium iodide, then produce a phosphonium salt with triphenylphosphine, and finally react with 4-methylthiazole-5-carboxaldehyde. Remove the phenylacetyl protecting group with phosphorus pentachloride / pyridine, and remove the carboxyl protecting group with phenol to obtain the 7-ATCA cefditoren nucleus. Chinese Patent CN201811388245.0 and Chinese Patent CN201711429569.X use 7-ACA as the starting material, protect the amino and carboxyl groups with hexamethyldisilazane, then replace and displace with trimethylsilyl iodide, form a 3-position phosphonium salt with a phosphate ester, and then react with 4-methylthiazole-5-carboxaldehyde to prepare the 7-ATCA cefditoren nucleus. Chinese Patent CN201811373495.7 uses D7-ACA as the starting material, oxidizes the 3-position hydroxyl group to an aldehyde with TEMPO, uses 4-methylthiazole-5-methanol as the side-chain starting material, iodinates it with sodium iodide, and then reacts with triphenylphosphine to generate a phosphonium salt and reacts with the aldehyde after oxidation at the 3-position to prepare the 7-ATCA cefditoren nucleus.

[0004] At present, the above several routes in the patent literature are mainly used to prepare 7-ATCA at home and abroad. A large amount of expensive iodine-containing reagents are used, resulting in high prices. At the same time, the use of organophosphorus compounds leads to complex post-treatment and serious environmental pollution.

[0005] Chinese Patent CN201811555437.6 uses 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid as the starting material. First, the carboxyl group is esterified, and then it is formylated with hexamethylenetetramine. The side chain is made into a Grignard reagent with 4-methyl-5-chloromethylthiazole and magnesium. After the reaction, an alcohol is formed, and then 7-ATCA, the cephalotolen nucleus, is obtained by dehydration. This patent provides a method that does not use iodine and phosphine, but uses hexamethylenetetramine, an easily explosive dangerous substance. At the same time, a high-temperature dehydration step is required, which causes certain damage to the β-lactam ring and leads to a decrease in the yield. Summary of the Invention

[0006] To solve the above problems, the present invention provides a method for preparing a cefditoren pivoxil intermediate, which avoids using iodine reagents and phosphine reagents, has low cost, is environmentally friendly, has little danger, is easy to industrialize, and the obtained product can remove the protecting group in phenol to obtain the cephalotolen nucleus 7-ATCA.

[0007] The present invention is achieved through the following technical solutions:

[0008] A method for preparing a cefditoren pivoxil intermediate, comprising the following steps:

[0009] (1) Activation of the side chain: Add 4-methylthiazole-5-carbaldehyde to an organic solvent, and then add an amine reagent for reflux reaction to obtain an imine intermediate (Compound 2). After the reaction ends, the solvent and the excess amine reagent can be distilled off and reserved for dissolution for the next reaction, or the reaction solution can be directly cooled for the next reaction.

[0010] The organic solvent is preferably toluene, xylene, dichloroethane or dichloromethane, and the dosage is 3 to 20 times the weight of 4-methylthiazole-5-carbaldehyde.

[0011] The amine reagent can be a primary amine, a secondary amine or an ammonium salt, preferably ethylamine, propylamine, methylamine chloride, diethylamine, benzylamine, cyclohexylamine, n-butylamine, and the dosage is 1.2 to 2.0 times the molar amount of the reactant 4-methylthiazole-5-carbaldehyde.

[0012] The temperature of the reflux reaction is 40 to 120 °C.

[0013] (2) Dissolve Compound 1 in an organic solvent, add pyridine and trimethylchlorosilane, heat to 25 to 40 °C, and react for 2 to 5 h to protect the amino group, and cool to -10 to 0 °C for standby.

[0014] Compound 1 has the following structure: In the formula, R is a carboxyl protecting group, preferably p-methoxybenzyl, benzhydryl, allyl, tert-butyldimethyl or tert-butyl, etc. Different protecting groups have different effects on the subsequent E and Z isomers. Compound 1 can be prepared by reacting 7-ADCA with diphenyldiazomethane or known carboxyl protecting agents such as p-methoxybenzyl chloride.

[0015] The organic solvent is preferably toluene, xylene, dichloroethane or dichloromethane.

[0016] The molar ratio of Compound 1, trimethylchlorosilane and pyridine is 1:(1.0 - 1.2):(1.1 - 1.5).

[0017] (3) Cool the imine intermediate to below 30°C, slowly add it to the reaction solution obtained in step (2), then add an organic base, and react at -10 to 30°C. After the reaction is completed, wash with hydrochloric acid, then wash with water, then concentrate the organic layer, add methanol for crystallization to obtain the intermediate of cefditoren pivoxil of the present invention, (6R, 7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

[0018] The molar ratio of Compound 1 to 4-methylthiazole-5-carbaldehyde used in this step is 1:(1.2 - 2.0).

[0019] The organic base is preferably one or a mixture of pyridine, triethylamine, diethylamine, quinoline, lithium methoxide and potassium carbonate, and the dosage is 0 - 4.0% of the molar amount of Compound 1. When directly using the imine intermediate solution in step (1) in step (3), the dosage of the organic base is very small or 0. At this time, the residual amine reagent in the imine intermediate solution can be used as a catalyst.

[0020] The synthetic route of the present invention is as follows: The washing aqueous layer can be further processed to recover the unreacted 4-methylthiazole-5-carbaldehyde. The recovery method is to add dichloromethane to the aqueous layer, adjust the pH to 12 - 13 with 20% sodium hydroxide aqueous solution cooled in temperature, separate the liquid, concentrate the organic layer to obtain 4-methylthiazole-5-carbaldehyde. The recovered 4-methylthiazole-5-carbaldehyde can be used for the synthesis of the imine intermediate after drying.

[0021] The present invention has the following positive and beneficial effects:

[0022] The present invention prepares the key intermediate of the present invention by synthesizing an active nitrogen-containing intermediate and further reacting with the allylic position connected to the carboxyl group, and the cephalotolen nucleus 7-ATCA can be obtained by removing the protecting group in phenol.

[0023] (1) The present invention avoids the use of iodinating agents and phosphine reagents, reduces costs, simplifies the post-treatment, and causes less pollution.

[0024] (2) By selecting different carboxyl-protected substrates, the present invention can prepare a target product with a lower content of the trans isomer, which is suitable for industrial production. Specific embodiments

[0025] The present invention will be described in detail below in conjunction with the embodiments, but the scope of protection required by the present invention is not limited to the scope described in the embodiments.

[0026] Example 1: (1) Add 100 mL of toluene to a reaction flask, add 10.0 g of 4-methylthiazole-5-carbaldehyde, add 6.4 g (1.2 eq) of methylammonium chloride, heat up (temperature 110 °C) and reflux to separate water for 5 h to prepare an imine intermediate solution, cool down under nitrogen protection, and cool down to 0 °C for use;

[0027] (2) Add 100 mL of toluene to another reaction flask, add 20.0 g of diphenylmethyl 7-amino-3-methylcephalosporanic acid, add 5.0 g (1.2 eq) of pyridine, 6.3 g (1.1 eq) of trimethylchlorosilane, heat up to 35-40 °C and keep the temperature for reaction for 2 h, and cool down to 0 °C;

[0028] (3) Add the prepared imine intermediate solution to the reaction solution in step (2), keep the temperature at 0-10 °C and react for 8 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2-3 with a 5% hydrochloric acid solution, keep the temperature and stir for 0.5 h, separate the layers, keep the water layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under reduced pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, and dry at 50 °C under a negative pressure of 0.092 MPa to obtain 21.2 g of yellow crystalline powder of diphenylmethyl (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, with a yield of 82.3% and an HPLC purity of 99.3%, and no E isomer.

[0029] Example 2: (1) Add 100 mL of toluene to a reaction flask, add 10.0 g of 4-methylthiazole-5-carbaldehyde, add 12.6 g of benzylamine, heat up (110 °C) and reflux to separate water for 3 h to prepare an imine intermediate solution, cool down under nitrogen protection, and cool down to 0 °C for use;

[0030] (2) Add 100 mL of toluene to another reaction flask, add 20.0 g of diphenylmethyl 7-amino-3-methylcephalosporanate, add 5.0 g of pyridine and 6.3 g of trimethylchlorosilane, heat up to 35 - 40 °C and keep the reaction for 2 h, then cool down to 0 °C;

[0031] (3) Add the imine intermediate solution prepared above to the reaction solution in step (2), keep the reaction at 0 - 10 °C for 8 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2 - 3 with 5% hydrochloric acid solution, keep stirring for 0.5 h, separate the layers, keep the aqueous layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under negative pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, dry at 50 °C under a negative pressure of 0.092 MPa to obtain 21.9 g of yellow crystalline powder of diphenylmethyl (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, with a yield of 85.0% and an HPLC purity of 99.4%, and no E isomer.

[0032] Example 3: (1) Add 100 mL of toluene to a reaction flask, add 10.0 g of 4-methylthiazole-5-carbaldehyde, add 11.7 g of cyclohexylamine, heat up (110 °C) to reflux and separate water for 5 h to prepare an imine intermediate solution, cool down to 0 °C under nitrogen protection for standby;

[0033] (2) Add 100 mL of toluene to another reaction flask, add 20.0 g of p-methoxybenzyl 7-amino-3-methylcephalosporanate, add 5.6 g of pyridine and 7.5 g of trimethylchlorosilane, heat up to 35 - 40 °C and keep the reaction for 2 h, then cool down to 0 °C;

[0034] (3) Add the imine intermediate solution prepared above to the reaction solution in step (2), keep the reaction at 0 - 10 °C for 8 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2 - 3 with 5% hydrochloric acid solution, keep stirring for 0.5 h, separate the layers, keep the aqueous layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under negative pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, dry at 50 °C under a negative pressure of 0.092 MPa to obtain 21.5 g of yellow crystalline powder of p-methoxybenzyl (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, with a yield of 83.5% and an HPLC purity of 99.3%, and no E isomer.

[0035] Example 4: (1) Add 100 mL of toluene into a three-necked flask, add 10.0 g of 4-methylthiazole-5-carbaldehyde, add 6.5 g of ethylamine, heat up (to 110 °C) and reflux to separate water for 7 h to prepare an imine intermediate solution, cool down under nitrogen protection, and cool down to 0 °C for standby;

[0036] (2) Add 100 mL of toluene into another reaction flask, add 20.0 g of 7-amino-3-methylcephalanic acid p-methoxybenzyl ester, add 5.6 g of pyridine, 7.5 g of trimethylchlorosilane, heat up to 35 - 40 °C and keep the temperature for reaction for 2 h, cool down to -10 °C for standby;

[0037] (3) Add the imine intermediate solution prepared above into the reaction solution of step (2), keep the temperature at 0 - 10 °C and react for 8 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2 - 3 with 5% hydrochloric acid solution, keep the temperature and stir for 0.5 h, separate the layers, keep the water layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under negative pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, dry at 50 °C under a negative pressure of 0.092 MPa to obtain 19.1 g of yellow crystalline powder of (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid p-methoxybenzyl ester, with a yield of 74.2% and an HPLC purity of 98.7%, and no E isomer.

[0038] Example 5: (1) Add 100 mL of 1, 2-dichloromethane into a reaction flask, add 9.2 g of 4-methylthiazole-5-carbaldehyde, add 7.7 g of n-butylamine, heat up (to 110 °C) and reflux to separate water for 15 h to prepare an imine intermediate solution, cool down under nitrogen protection, and cool down to 0 °C for standby;

[0039] (2) Add 100 mL of toluene into another reaction flask, add 20.0 g of 7-amino-3-methylcephalanic acid diphenylmethyl ester, add 5.0 g of pyridine, 6.3 g of trimethylchlorosilane, heat up to 35 - 40 °C and keep the temperature for reaction for 2 h, cool down to 0 °C;

[0040] (3) Add the imine intermediate solution prepared above to the reaction solution in step (2), keep the temperature at 0 - 10 °C and react for 8 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2 - 3 with 5% hydrochloric acid solution, keep the temperature and stir for 0.5 h, separate the layers, keep the aqueous layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under negative pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, dry at 50 °C under a negative pressure of 0.092 MPa to obtain 22.3 g of yellow crystalline powder of diphenylmethyl (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, with a yield of 86.6% and no E isomer.

[0041] Example 6: (1) Add 100 mL of 1,2-toluene to a reaction flask, add 11.9 g of 4-methylthiazole-5-carbaldehyde, add 7.5 g of n-butylamine, heat up to reflux (110 °C) and separate water for 5 h to prepare an imine intermediate solution, cool down under nitrogen protection to 0 °C for standby;

[0042] (2) Add 100 mL of toluene to another reaction flask, add 20.0 g of p-methoxybenzyl 7-amino-3-methylcephalosporanate, add 5.7 g of pyridine and 7.2 g of trimethylchlorosilane, heat up to 35 - 40 °C and keep the temperature for reaction for 2 h, then cool down to 0 °C;

[0043] (3) Add the imine intermediate solution prepared above to the reaction solution in step (2), keep the temperature at 0 - 10 °C and react for 5 h. After detecting that the raw materials have completely reacted, add 50 mL of water, adjust the pH to 2 - 3 with 5% hydrochloric acid solution, keep the temperature and stir for 0.5 h, separate the layers, keep the aqueous layer, wash the organic layer with 25 mL of water, separate the layers, distill the organic layer to dryness under negative pressure, add 30 mL of methanol, stir for 1 h, filter, wash with 10 mL of methanol, dry at 50 °C under a negative pressure of 0.092 MPa to obtain 23.9 g of yellow crystalline powder of p-methoxybenzyl (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, with a yield of 86.6% and HPLC purity: 98.6%, containing 0.5% E isomer.

[0044] Example 7: Recovery of 4-methylthiazole-5-carbaldehyde in the aqueous layer:

[0045] Take the washing water layer of Example 3, add 50 mL of dichloromethane, adjust the pH to 12 - 13 with 20% sodium hydroxide aqueous solution, stir for 10 min, let stand for 30 min and separate the layers. Extract the water layer with 20 mL of dichloromethane. Combine the two dichloromethane layers, concentrate the solvent under negative pressure to obtain 5.1 g of yellow solid with an HPLC purity of 98%, which can be directly used in the preparation of imine intermediates.

[0046] Example 8: Preparation of 7 - ATCA:

[0047] 10.0 g of diphenylmethyl (6R, 7R)-7 - amino - 3 - [(1Z)-2-(4 - methyl - 5 - thiazolyl)vinyl]-8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylate prepared in Example 1 was added to a reaction flask, 30.0 mL of phenol was added, and the temperature was raised to 40 - 45 °C for reaction for 10 h. The raw materials were detected to have completely reacted. The temperature was lowered to 10 °C, 60 mL of ethyl acetate was added, 100 mL of 5% sodium bicarbonate solution was added, stirred for 1 h, let stand and separate the layers. The water layer was added with 30 mL of ethyl acetate, stirred for 20 min, let stand and separate the layers. The organic layer was recycled the solvent. The water layer was adjusted to pH = 5.5 - 6.0 with 1 mol / L hydrochloric acid solution, stirred for 1 h until a large amount of materials precipitated, then adjusted to pH = 5.0 ± 0.1 with 1 mol / L hydrochloric acid solution, stirred for 1 h and filtered, washed with 50 mL of purified water, and then dried under vacuum at 0.09 MPa and 45 °C to obtain 5.9 g of yellow powder with a yield of 89.5% and an HPLC purity of 99.6%, without E - isomer.

[0048] 'H - NMR (DMSO - d 6 ): 2.36 (s, 3H); 3.1 - 3.5 (m, 2H merged with DMSO - peak); 4.81 - 4.83 (d, 1H); 5.05 - 5.07 (d, 1H); 6.31 - 6.35 (d, 1H); 6.65 - 6.69 (d, 1H); 8.91 (s,1H).

[0049] Comparative Example 1: When using 7 - amino - 3 - tert - butyl cephalosporanic acid as the substrate, the preparation method was the same as that in Example 1, and (6R,7R)-7 - amino - 3 - [(1Z)-2-(4 - methyl - 5 - thiazolyl)vinyl]-8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid tert - butyl ester was obtained with a yield of 91.5%, a purity of 97.6%, and 0.8% of E - isomer.

[0050] Comparative Example 2: Using the method of Example 1, when 4-methylthiazole-5-carbaldehyde was adjusted to 3 equivalents, (6R,7R)-7-amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester was prepared with a yield of 85.3%, HPLC purity of 99.1%, and no E isomer.

[0051] Example 9: Synthesis of cefditoren sodium (which can be prepared according to the publicly disclosed method):

[0052] Under the conditions of room temperature and avoiding light, 5.0 g (0.0154 mol) of 7-ATCA and 5.8 g (0.0167 mol) of AE-active ester were added to 30 mL of dichloromethane, 0.15 g of 4-dimethylaminopyridine was added, the mixture was stirred and cooled to 0 °C - 5 °C, 2.25 g (0.0224 mol) of triethylamine was slowly added dropwise, and after addition, the reaction was carried out at 10 °C - 15 °C with HPLC monitoring until the content of 7-ATCA was <0.5% indicating the reaction was complete. After the reaction was completed, 15 mL of pure water was added to the reaction solution, stirred for 15 min, separated, and the aqueous phase was collected. The aqueous phase was extracted once with dichloromethane and then the pH was adjusted to 3.5 - 4.4 with dilute hydrochloric acid, and extracted three times with 150 mL of ethyl acetate, washed once with water. An aqueous solution containing 6.0 g of diisopropylamine was added to the ethyl acetate extract, stirred and reacted, and a solid precipitated at 5 - 10 °C. The solid was filtered and dried under vacuum to obtain 8.5 g of a slightly yellow powdery solid with a yield of 91.0%; the purity detected by HPLC was 99.06%, and no E isomer was detected. Under the conditions of room temperature and avoiding light, 8.5 g (0.1 mol) of cefditoren acid diisopropylamine was added to 42 mL of N,N-dimethylformamide, 0.8 g (10%) of tetrabutylammonium bromide and 0.7 g (0.0070 mol) of sodium carbonate were added, cooled to -15 °C - 20 °C, 4.0 g (0.0168 mol) of iodomethyl pivalate was added, and the reaction was carried out at -15 °C - 20 °C with HPLC monitoring until the content of cefditoren sodium was <3% indicating the reaction was complete. The reaction was stopped, 20 mL of 2% sodium thiosulfate aqueous solution and 70 mL of ethyl acetate were added dropwise to the reaction solution and stirred, the pH was adjusted to 6.0 with dilute hydrochloric acid, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with 1% sodium thiosulfate aqueous solution and then with 2% sodium carbonate solution, washed with water, decolorized with activated carbon, the filtrate was evaporated to dryness under reduced pressure at 20 °C, anhydrous ethanol was added, and crystallized by freezing at about -10 °C for 4 h, filtered, and the filter cake was dried under reduced pressure below 40 °C to obtain 8.3 g of a light yellow solid with a yield of 95.8% and HPLC content of 99.15%.

[0053] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Preparation method of cefditoren pivoxil intermediate (6,7R)-7-amino-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid It is characterized in that it comprises the following steps (1) React 4-methylthiazole-5-carbaldehyde with an amine reagent to prepare an imine intermediate The amine reagent is ethylamine, propylamine, methylamine chloride, benzylamine, cyclohexylamine or n-butylamine (2) React compound I, pyridine and trimethylchlorosilane to protect the amino group Compound I has the following structure: ; In the formula, R is a carboxyl protecting group, which is p-methoxybenzyl, diphenylmethyl, allyl or tert-butyl (3) Add the imine intermediate obtained in step (1) into the reaction solution of step (2) to carry out a base-catalyzed reaction to obtain the target product The catalyst used is an organic base, which is one or a mixture of pyridine, triethylamine, diethylamine and quinoline, and the dosage is 0-4.0% of the molar amount of compound 1 2. The preparation method according to claim 1 It is characterized in that In step (1), the dosage of the amine reagent in the reaction is 1.2-2.0 times the molar amount of the reactant of 4-methylthiazole-5-carbaldehyde 3. The preparation method according to claim 1 It is characterized in that The reaction conditions of step (1) are heating under reflux for 3-15 h; the reaction solution is directly used for the next step reaction, or separated and then dissolved for the next step reaction 4. The preparation method according to claim 1 It is characterized in that The reaction temperature of step (2) is 25-40 °C and the time is 2-5 h 5. The preparation method according to claim 1 It is characterized in that In step (2), the molar ratio of compound I, trimethylchlorosilane and pyridine is 1:(1.0-1.2):(1.1-1.5) 6. The preparation method according to claim 1 It is characterized in that The organic solvent used in the reaction is toluene, xylene, dichloroethane or dichloromethane 7. The preparation method according to claim 1 It is characterized in that The reaction temperature of step (3) is -10-30 °C for reaction; the separation process after the reaction is: first add hydrochloric acid for washing, then add water for washing, then concentrate the organic layer, add methanol for crystallization to obtain the target product 8. The preparation method according to claim 1 It is characterized in that The molar ratio of compound I to 4-methylthiazole-5-carbaldehyde is 1:(1.2-2.0)

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