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Preparation method of cefditore

A technology of cefditoren pivoxil and cefditoren pivoxil, which is applied in the field of preparation of cefditoren pivoxil, can solve the problems of increasing the amount of iodomethyl pivalate, large amount of iodomethyl pivalate, and large impurities , to achieve the effect of reducing the possibility of acylation and alkylation reactions, ingenious route design, and good selectivity

Active Publication Date: 2015-12-23
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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Problems solved by technology

[0008] Document is for making cefditoren sodium reaction completely, has selected-20 ℃ as temperature of reaction and has increased the consumption of iodomethyl pivalate (ceftitoren sodium: iodomethyl pivalate mol ratio=1:2.1), The cefditoren sodium that participates in the reaction under this condition does not have residue substantially, but because the used reaction temperature is too high, the consumption of iodomethyl pivalate is too large, the impurity that causes generation such as hydroxymethyl cefditoren pivoxil, Δ- 3 Isomers, E isomers and α-pivaloyl cefditoren pivoxil, dimers, ring-opening dimers and other impurities are too large, which directly reduces the efficacy and quality of the product, and the obtained cefditoren pivoxil It is difficult for ester products to meet the requirements of the Pharmacopoeia

Method used

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  • Preparation method of cefditore
  • Preparation method of cefditore

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] At room temperature and protected from light, add 32.4g (0.10mol) of 7-ATCA and 37.6g (0.1075mol) of AE-active ester into 200ml of dichloromethane, add 1.0g of 4-dimethylaminopyridine, stir and cool down to 0°C ~5°C, slowly add 14.6g (0.145mol) triethylamine dropwise, after the addition, keep warm at 10°C~15°C for reaction, HPLC monitoring 7-ATCA1 HNMR (500MHz,D 2 O): 8.90 (1H, S), 6.75 (1H, S), 6.77 (1H, d, J = 11.8Hz), 6.32 (1H, d, J = 11.6Hz), 5.85 (dd, J 1 =4.8Hz,J 2 =8.0Hz,1H),5.26(d,J=4.8Hz,1H),3.83(3H,s),3.57(1H,d,J=18.6Hz),3.40(1H,d,J=18.6Hz), 2.34 (3H, s), 2.26–2.18 (m, 2H), 1.19 (d, J=6.4Hz, 12H, CH3).

[0028]Under room temperature dark conditions, add 60.8g (0.1mol) cefditoren acid diisopropylamine to 300ml N, N-dimethylformamide, then add 6.1g (10%) tetrabutylammonium bromide and sodium carbonate 5.3g (0.05mol), cooled to -15~-20°C, added 28.4g (0.1175) iodomethyl pivalate, and reacted at -15°C~-20°C, HPLC monitoring cefditoren sodium 3 The isomer conten...

Embodiment 2

[0030] Under the condition of avoiding light at room temperature, add 32.4g (0.10mol) of 7-ATCA and 38.0g (0.1085mol) of AE-active ester into 200ml of dichloromethane, add 1.0g of 4-dimethylaminopyridine, stir and cool down to 0°C ~5°C, slowly add 14.6g (0.145mol) triethylamine dropwise, after the addition, keep warm at 10°C~15°C for reaction, HPLC monitoring 7-ATCA<0.5% means the reaction is complete, after the reaction is completed, add 400ml to the reaction solution Pure water, stirred for 15 minutes, separated, collected the water phase, extracted once with dichloromethane, adjusted the pH to 3.5-4.4 with dilute hydrochloric acid, extracted three times with 1000ml ethyl acetate, washed once with water, and added to the ethyl acetate extract Add 3800mL of an aqueous solution containing 40g of diisopropylamine to the mixture, stir the reaction, and precipitate a solid at 5-10°C, filter and vacuum-dry to obtain 55.3g of a light yellow powdery solid, with a yield of 91.0%; the ...

Embodiment 3

[0033] Under the condition of avoiding light at room temperature, add 324g (1mol) 7-ATCA and 383g (1.095mol) AE-active ester into 2000ml dichloromethane, add 11g 4-dimethylaminopyridine, stir and cool down to 0℃~5℃, Slowly add 148g of triethylamine dropwise. After the addition, keep it warm at 10°C to 15°C for reaction. HPLC monitors that 7-ATCA<1.0% means the reaction is complete. After the reaction is complete, add 4000ml of pure water to the reaction solution, stir for 30min, and separate the liquid Collect the water phase, extract the water phase with dichloromethane once, adjust the pH to 3.5-4.4 with dilute hydrochloric acid, extract three times with 5L ethyl acetate, wash once with water, add an aqueous solution containing 350g diisopropylamine to the ethyl acetate extract 21 L, stirred and reacted, solid precipitated at 5-10°C, vacuum-dried by suction to obtain 560 g of light yellow powdery solid, yield 92.1; purity by HPLC was 99.24%, E isomer was not detected.

[003...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of cefditore. The method comprises the following steps that (1) under the photophobic condition, 7-ATCA and AE-active ester are added into methylene dichloride; catalysts are added; the temperature is lowered to 0 to 5 DEG C; triethylamine is added to obtain cefdiporen acid; a water solution of organic amine is added into organic solvents containing dissolved cefdiporen acid; crystal separation is carried out to obtain organic amine salts of the cefdiporen acid; (2) the organic amine salts of the cefdiporen acid take a reaction with iodomethyl pivalate under the existence of tetrabutylammonium bromide and sodium carbonate in N,N-dimethyl formamide to obtain the cefditore. The preparation method has the advantages that the organic amine salts of the cefdiporen acid are used; the defects of difficult storage and poor stability of the sodium salts of the cefdiporen acid are effectively avoided; E-shaped isomers are effectively removed; meanwhile, the esterification condition is optimized, so that the purity of final products is higher.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren pivoxil, chemical name: 2,2-dimethylpropionyloxymethyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2- Methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1- Azabicyclo[4.2.0]oct-2-ene-2-carboxylate, trade name: Meiact. Developed by Japan's Meiji Seika Co., Ltd. and launched in Japan in 1994, it is used to treat infections caused by Gram-positive and Gram-negative bacteria. [0003] Studies have shown that cefditoren axetil is effective in the treatment of community-acquired respiratory tract infections caused by five major pathogenic bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Moraxella catarrhalis. Compared with third-generation cephalosporins, quinolones, macrolides, and β-lactam antibiotics containing enz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/24C07D501/04
CPCC07D501/04C07D501/24
Inventor 谢娜刘英超刘桂军
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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