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Foreword GCLE and GCLH are novel intermediates for the synthesis of cephalosporin antibiotics. The chemical name is 7-phenylacetylamino-3-chloromethylcephem aceto-p-methoxybenzyl ester (p-methoxybenzy) 7-phenylacetate —amido-3-chloromethyl-3-cephem-4 carboxylate, abbreviated as GCLE) and 7-phenylacetamido-3-chloromethylcephalosporanic acid diphenylmethyl ester (dipheny1methy1-7-pheny1acet-amido-3_ch1oromethy1 -3 cephem-4-carboxylate, abbreviated as GCLH), which are followed by 7-ACA (7-aminocephalosporanoic acid), 7-ADCA, (7-amino-3-desacetoxyheadholdenoic acid) Another novel cephalosporin parent core intermediate material for the synthesis of cephalosporin drugs after cephalosporin C, the structural formula of which is shown in Figure 1.
Due to the presence of 3 chloromethyl reactive groups in GCLE and GCLH molecules, it provides a cheaper synthetic raw material and a simpler synthesis method for the synthesis of 3 cephalosporin antibiotics with different group substitutions. GCLE and GCLH are first industrialized production and put on the market by Japan's Otsuka Pharmaceutical Co., Ltd. At present, there are a few manufacturers in China that produce GCLE in small quantities, but the production process still has problems, the production cost is high, the product quality is poor, and the domestic application is currently applied. The GCLE and GCLH raw materials are mainly imported. Therefore, it is imperative to study the synthesis methods and processes of GCLE, improve the quality, reduce its cost, and make it self-sufficient. The synthesis of GCLE and GCLH is mainly based on penicillin and is synthesized by two methods: (1) halogenation after ring expansion; (2) chlorination before ring expansion. There are many reports on the (1) method in the domestic and foreign literatures, and (2) mainly in Japanese literature research reports. Japan uses the (2) method to produce GCLE and GCLH, and its production capacity has reached about 300t/a.
1 Halogenation after ring expansion The synthesis of GCLE and GCLH is mainly prepared by using penicillin potassium salt as raw material, esterification, oxidation, expansion, reduction and chlorination. The synthetic route is shown in Figure 2.
1.1 Esterification reaction Penicillin potassium salt and p-methoxybenzyl chloride, under the action of Et3N and other organic amines and Bu4NBr, with N, N-dimethylformamide (DMF) and dichloromethane as solvent After refluxing for 6 h, penicillin p-methoxybenzyl ester can be obtained by post-treatment. Penicillin potassium salt and p-methoxybenzyl chloride can also be catalyzed by potassium iodide in a dry DMF solvent, stirred at 50-55 ° C for 3 h, and then treated to obtain penicillin G p-methoxybenzyl ester. It is also possible to add diphenylchloromethane and Et3N to a solution of penicillin in acetonitrile and react at 50 ° C for 8 h to obtain penicillin diphenylmethyl ester in a yield of 90%? And the product can be directly used in the next reaction without refining.
1.2 Oxidation reaction The oxidation of penicillin to sulfoxide can be used in many oxidation methods, such as penicillin carboxylate in SeO Ti (NO )·2H. 0,Te (OH) ,Ce (NO3)3' 6H20,RuO4,H2SeO4 or K2Ti0(C204)2'2H20,Na2W04'2H20,Na2W04'2H2O/NaBO3'4H20,V20,Na MoO and other catalysts 30% "35% H. 0. Used as an oxidizing agent. It can also be oxidized with inorganic oxidants and organic peroxides, such as manganese dioxide, sodium periodate, peracetic acid, m-chloroperoxybenzoic acid, etc. The corresponding penicillin sulfoxide carboxylate is obtained in a yield of more than 90% _5I. If the penicillin G potassium salt is used in an acetic acid anhydride with an inexpensive 20% hydrogen peroxide, the pH is maintained at an acidic range of 4-5. The oxidation reaction is carried out at 0 to 5 ° C for 2 to 3 hours, and a high yield of penicillin sulfoxide can be obtained.
The penicillin sulfoxide ester can be prepared from the penicillin potassium salt. Different reaction sequences can be used for esterification and oxidation. Since the stability of penicillin ester is stronger than that of penicillin acid, it is better to oxidize after esterification. The two-step reaction can be carried out continuously. The total yield can reach more than 80%.
In the acetonitrile solution, the reaction was carried out at 50 ° C for 8 h to obtain penicillin diphenylmethyl ester in a yield of 90%? And the product can be directly used in the next reaction without refining.
1.2 Oxidation reaction The oxidation of penicillin to sulfoxide can be used in many oxidation methods, such as penicillin carboxylate in SeO Ti (NO )·2H. 0,Te (OH) ,Ce (NO3)3' 6H20,RuO4,H2SeO4 or K2Ti0(C204)2'2H20,Na2W04'2H20,Na2W04'2H2O/NaBO3'4H20,V20,Na MoO and other catalysts 30% "35% H. 0. Used as an oxidizing agent; can also be oxidized with an inorganic oxidizing agent, such as manganese dioxide, sodium periodate, peracetic acid, m-chloroperoxybenzoic acid, etc., at a low temperature to obtain a corresponding Penicillin sulfoxide carboxylate, the yield is more than 90%. If the penicillin G potassium salt is used in an inexpensive 20% hydrogen peroxide in acetic anhydride, keep the pH in the acidic range of 4"5, the temperature is 0 ~ 5 °C The oxidation reaction is carried out for 2- to 3 hours, and a high yield of penicillin sulfoxide can be obtained.
The penicillin sulfoxide ester can be prepared from the penicillin potassium salt. Different reaction sequences can be used for esterification and oxidation. Since the stability of penicillin ester is stronger than that of penicillin acid, it is better to oxidize after esterification. The two-step reaction can be carried out continuously. The total yield can reach more than 80%. The ester has a yield of 56% to 73%. The obtained extracyclic methylene cephalosporan sulfoxide can also be dissolved in DMF solvent, deoxygenated with acetyl chloride under potassium cation catalysis for 30 min at room temperature, extracted with dichloromethane, washed with water, concentrated, Crystallization gave an extramethylene methylene cephalosporate with a yield of 91.6%.
1.5 Halogenation reaction The obtained 3-monomethylene methanecephalosporate intermediate in tetrahydrofuran solvent with DBU (1,5-diazabiCyC10[5.4.0]undec-5-ene) and chlorine The tert-buty1hypochlorite was reacted at -80 ° C for 10 min, then trimethyl phosphite was added to the temperature to 0 ° C, and then treated to obtain GCLE, the yield was about 60%. The extramethylene methylene cephalosporate can also be reacted with DBN (1,4-diazabicyclo [4.3.0] non-5-ene) and bromine at -78 ° C for 10 min in tetrahydrofuran solvent, and then heated. The reaction was carried out at 0 ° C for 10 min, and then post-treated to obtain a 3-bromomethyl product in a yield of up to 95%. The extra-methylene cephalosporanate is reacted with DBU and bromine in a solvent of tetrahydrofuran at 20 to 15 ° C for 30 min, extracted with dichloromethane, concentrated, and separated to obtain a 3-bromomethyl product. The yield was 80.5%.
The key techniques for the synthesis of GCLE and GCLH by this method are ring expansion and chlorination. In particular, the chlorination reaction needs to be carried out at a lower temperature. The source of the chlorinating agent used is limited. If the 3-position is changed to brominated Not only is it easier to prepare, but also the reactivity is improved, which can solve this problem.
2 Halogenation before ring expansion The ring opening, chlorination and ring closure reactions of penicillin sulfoxide are used to prepare GCLE and GCLH. The synthetic route is shown in Fig. 3.
In this method, penicillin sulfoxide and ammonium benzenesulfinate are added to an organic solvent, and an inorganic salt and an acid catalyst are added to carry out a ring-opening reaction to form an azetidinone thiosulfinate intermediate. Then, the ring-opening product is dissolved in an organic solvent such as chloroform or dichloromethane, and a saturated solution of sodium chloride added with sulfuric acid is added, and the reaction is carried out by a platinum electrode in a two-phase system, and the temperature is controlled at 15 to 17 ° C for 40 minutes, using electrolysis. The produced active halogenating agent such as C12, HOC1, c120 and the like are subjected to chlorination reaction of the exocyclic ally position, and after separation, the allylic chlorinated product is obtained, and the yield is over 82%. After zui, the GCLE or GCLH is closed with ammonia water. However, this method is technically difficult and the reaction conditions are difficult to control. If the reaction conditions are not properly controlled, the reaction is difficult to proceed smoothly, which may cause more side reactions and affect the yield. The reaction step of the method and the variety of raw materials used are small, and if these problems can be solved, it is a relatively low cost method.
The application of GCLE and GCLH is similar to that of 7-ACA and cephalosporin C. It is mainly used in the synthesis of cephalosporin drugs with 7 different side chains and 3 different methyl groups. At present, GCLE and GCLH are priced at about US$84/t, while 7-ACA is priced at US$1,022/t. Semi-synthetic cephalosporins are produced by GCLE and GCLH, for example: cefazolin, head-bearing Mengduo It has the advantages of high yield, simple process and low cost, so it has a great potential to replace 7-ACA and cephalosporin C. For example, cefazolin was synthesized in two steps using 7-ACA with tetrazolium acetate and thiadiazole, and the total yield was 68.6%. The total yield of cefazolin synthesized by GCLE instead of 7-ACA is 83.86%, and the cost is low and the quality is good. GCLH is firstly reacted with N-methylpyrrole to introduce a 3-position substituent, which is reacted with a side chain benzothiazole thiol active ester after removal of the ester group, and then treated to obtain cefepime.
3 Conclusions GCLE and GCLH are novel parent core intermediates for the synthesis of cephalosporins, which are used to synthesize 7 different side chains, 3 different cephalosporin drugs with different substitutions, with high yield and low yield. Cost, good quality and other advantages, its application is increasingly widespread. The synthesis technology of GCLE and GCLH is difficult. Although there are some progress in the research of synthetic technology in China, the cost is still high, and the quality is still poor compared with imported products. Therefore, it is a top priority to research and develop synthetic processes that are simple, low-cost, high-quality, and suitable for large-scale industrial production.
About the author: Yang Yihong (1 9 5 4-), female, associate professor of pharmaceutical engineering at Wuhan Institute of Chemical Technology, engaged in pharmaceutical engineering teaching and drug research.
The advantages of food additives are these followed:
1. Improve the appearance of food.
2. Keep and enhance the nutrition value of food.
3. Increase the variety and conveniences of food.
4. Miantain freshness and prolong shelf life.
5. Provide leavening or control acidity and alkalinity.
Yang Yihong, Zhang Wei, Yang Jianshe (Wuhan Institute of Chemical Technology, Wuhan 430073, China)