Preparation method of tebipenem pivoxil and intermediate thereof

Abstract

The invention provides a preparation method of tebipenem pivoxil. A three-step method synthesis route taking MAP (compound 2) and TAT (compound 3) as starting raw materials is adopted. The preparation method is characterized in that in the first step, the temperature of reaction for preparing an intermediate compound 4 of the tebipenem pivoxil from the MPA and the TAT is -4 to 5 DEG C. Compared with the preparation method using the three-step method synthesis route in the prior art, the preparation method has the following advantages: the step avoids ultralow reaction temperature, so that the method is mild in reaction condition, easy to implement and suitable for industrialized production; furthermore, the reaction yield in each step is increased and the purify of reactants is improved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of tipipenem axetil. Background technique [0002] As a new member of carbapenem antibiotics, Tebipenem (Tebipenemivoxil, or translated as Tibipenem) has strong antibacterial activity against Gram-positive and Gram-negative bacteria, and is effective against Staphylococcus aureus, Pneumococcus, Streptococcus and Moraxella catarrhalis (Branhamella genus) are sensitive, and the curative effect is better for penicillin-sensitive drug-resistant Streptococcus pneumoniae and Haemophilus influenzae. Tipipenem granules are the first carbapenem antibiotics administered orally in the world. They have strong clinical compliance, low antibacterial concentration, are not easy to lead to the emergence of bacterial resistance, and have few side effects. With the advantages of high drug safety, it can be used for the treatment of ear, nose, throat and upper respirato...

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Problems solved by technology

For example, Takeshi Isoda et al (Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084) and pharmacokinetic studies), Japanese Journal of Antibiotics J.Antibiot.59 (4): 241-247, 2006) in the synthesis method of tipipenem ester reported, the reaction temperature is -20 ℃ during the condensation reaction, and the conditions are harsh ; The esterification reaction is extracted by ethyl acetate, dehydrated by anhydrous magnesium sulfate and put on a silica gel column. The amount of solvent is large and the cost is high, so it is not suitable for industrial production

[0007] In the synthesis method of tipipenem reported by Peng Dongming et al. (Research on the synthesis of tibipenem ester, Chinese Journal of Antibiotics, 2013, 38(1): 41-43), the reaction temperature for the condensation reaction is -30°C~ -20°C, the conditions are harsh; the hydrogenation reaction uses tetrahydrofuran and water system. In this system, palladium carbon and acid complexation phenomenon is serious, and the resulting product is black in color and low in purity; the esterification reaction is extracted with ethyl acetate and anhydrous magnesium sulfate Dehydration, crystallization of acetone and isopropyl ether, the two single impurities of the obtained product are 0.2% and 0.3%, which cannot reach the quality standard of less than 0.1%.

[0008] Chinese patent application CN106083858A reports a preparation method of tipipenem, wherein the reaction temperature is -20--25°C during the condensation reaction, and the conditions are harsh; the intermediate compound 4 is washed with ethyl acetate and water, because the intermediate compound 4 Soluble in ethyl acetate, so the yield is very low; when preparing the intermediate compound 5, the reaction with 0.5% palladium carbon is not complete, it is not easy to crystallize, and the yield is low; Tipipenem ester hydrochloride, deacidification with 2% sodium bicarbonate, acetone, isopropyl ether crystallization to obtain tipipenem ester, complex operation, intermediate tipipenem ester is difficult to salt with hydrochloric acid, can not be carried out Industrial production

[0009] In particular, in the above-mentioned prior art, the reaction temperatures of the condensation reactions of compounds 2 and 3 are all below -20°C, and the conditions are harsh.

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