Synthesis of gcle and gclh, intermediates of cephalosporins

Preface of Yang Yihong, Zhang Heng, Yang Jianshe (Wuhan Institute of chemical technology, Wuhan 430073, Hubei) Gcle and gclh are new intermediate materials for the synthesis of cephalosporins Their chemical names are p-methoxybenzoy-7-phenylacet-amido-3-chloromethylyl-3-cephem-4-carboxylate (gcle) and 7-phenylacetam-3-chloromethylcephalosporin-1-7-phen Y1acet amido-3-ch1ormethy1-3-cephem-4-carboxylate (gclh) is another kind of new cephalosporin mother nuclear intermediate material, which is used to synthesize cephalosporin drugs after 7-ACA, 7-ADCA, 7-amino-3-deacetoxycephalosporin and cephalosporin C its structural formula is shown in Figure 1 Due to the existence of 3-chloromethyl active groups in gcle and gclh molecules, it provides a cheaper raw material and a simpler synthesis method for the synthesis of 3-cephalosporins with different group substitutions Gcle and gclh were first industrialized produced by Otsuka pharmaceutical company in Japan and put into the market At present, there are a few domestic manufacturers producing gcle in small quantities, but there are still problems in production process, high production cost and poor product quality Currently, gcle and gclh raw materials used in China are mainly imported Therefore, it is urgent to study the synthesis method and process of gcle, improve its quality, reduce its cost and make it self-sufficient Gcle and gclh were synthesized from penicillin by two methods: (1) halogenation after ring expansion; (2) pre halogenation before ring expansion There are many reports on (1) method in domestic and foreign literature, while (2) method is mainly reported in Japanese literature Since (2) method is used to produce gcle and gclh, the production capacity of Japan has reached about 300t / A 1 The synthesis of gcle and gclh by halogenation method after ring expansion is mainly made from penicillin potassium salt through esterification, oxidation, ring expansion, reduction and chlorination See Figure 2 for the synthesis route 1.1 in the esterification reaction, penicillin p-methoxybenzyl chloride was prepared by reacting penicillin potassium salt with p-methoxychlorobenzyl chloride, et3n and bu4nbr, using N, N-dimethylformamide (DMF) and dichloromethane as solvent, heating and refluxing for 6h Penicillin G p-methoxybenzyl ester can also be prepared by mixing penicillin potassium salt with p-methoxychlorobenzyl in a dry DMF solvent and catalyzed by potassium iodide for 3 hours at 50-55 ℃ Diphenylchloromethane and et3n can also be added into acetonitrile solution of penicillin and reacted at 50 ℃ for 8 hours to obtain penicillin diphenyl methyl ester in 90% yield And the product can be directly used for the next reaction without refining 1.2 oxidation reaction penicillin can be oxidized to sulfoxide by many methods, such as penicillin carboxylate can be oxidized in seoti (no) · 2H Under the action of 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 was used 0 As oxidant It can also be oxidized by inorganic oxidants and organic peroxides, such as manganese dioxide, sodium periodate, peracetic acid, m-chloroperoxybenzoic acid, etc at low temperature to prepare the corresponding penicillin sulfoxide carboxylate with a yield of more than 90% If penicillin G potassium salt is oxidized with 20% cheap hydrogen peroxide in acetic anhydride, keeping the pH in the range of 4-5 and the temperature in 0-5 ℃ for 2-3 h, high yield of penicillin sulfoxide can be obtained In the preparation of penicillin sulfoxide ester from penicillin potassium salt, different reaction sequences can be used for esterification and oxidation reactions Because the stability of penicillin ester is stronger than that of penicillin acid, it is better to esterification first and then oxidation The two-step reaction can be carried out continuously, and the total yield can reach more than 80% The yield of penicillin diphenyl methyl ester was 90% And the product can be directly used for the next reaction without refining 1.2 oxidation reaction penicillin can be oxidized to sulfoxide by many methods, such as penicillin carboxylate can be oxidized in seoti (no) · 2H Under the action of 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 was used 0 As oxidant, it can also be oxidized by inorganic oxidants, such as manganese dioxide, sodium periodate, peracetic acid, m-chloroperoxybenzoic acid, etc at low temperature to prepare the corresponding penicillin sulfoxide carboxylate, with a yield of more than 90% If penicillin G potassium salt is oxidized with 20% cheap hydrogen peroxide in acetic anhydride, keeping the pH in the range of 4 "5, and the temperature in 0-5 ℃ for 2-3 hours, high yield of penicillin sulfoxide can be obtained In the preparation of penicillin sulfoxide ester from penicillin potassium salt, different reaction sequences can be used for esterification and oxidation reactions Because the stability of penicillin ester is stronger than that of penicillin acid, it is better to esterification first and then oxidation The two-step reaction can be carried out continuously, and the total yield can reach more than 80% The yield of ester is 56% - 73% The product can also be dissolved i n DMF solvent, deoxidized and reduced to 30 Mn at room temperature with acetyl chloride under the catalysis of potassium iodide, then extracted, washed, concentrated and crystallized by dichloromethane, with a yield of 91.6% 1.5 halogenation reaction The intermediate of 3-cyclo-exomethylenecephalosporanate was reacted with DBU (1,5-diazabicyc10 [5.4.0] undec-5-ene) and chlorinator tert-buty1hpochlorite at - 80 ℃ in tetrahydrofuran solvent After adding trimethyl phosphite and heating to 0 ℃, gcle was obtained by post-treatment The yield was about 60% It can also react with DBN (1,4-diazabicyclo [4.3.0] non-5-ene) and bromine in tetrahydrofuran solvent at - 78 ℃ for 10 minutes, and then the product of 3-bromomethyl can be obtained by the post-treatment The yield is up to 95% The product of 3-bromomethyl was obtained by the reaction of epicyclic methylene cephalosporane with DBU and bromine in tetrahydrofuran solvent for 30 min, then extracted and concentrated with dichloromethane The yield was 80.5% The key technology of gcle and gclh synthesis by this method is ring expanding and chlorination reaction, especially the chlorination reaction needs to be carried out at a lower temperature, and the source of chlorinating agent used is limited If the 3-position is changed to bromine, it is not only easy to prepare, but also the reaction activity is improved, which can solve this problem 2 Gcle and gclh were prepared by the ring opening, chlorination and closed-loop reaction of penicillin sulfoxide ester in the halogenation method before ring expansion See Fig 3 for the synthesis route In this method, penicillin sulfoxide and ammonium benzenesulphonate are added in organic solvent, inorganic salt and acid catalyst are added to carry out ring opening reaction first, and then the intermediate of azacyclobutanone thiosulfinate is formed Then, the ring opening product was dissolved in chloroform or dichloromethane and the saturated solution of sodium chloride added with sulfuric acid was added In the two-phase system, the reaction was carried out by electrolysis with platinum electrode at a temperature of 15-17 ℃ for 40 min the chlorination of allylic position outside the ring was carried out by using the active halogenants such as C12, hoc1, C120 and so on After separation, allylic chlorination product was obtained with an yield of 82% Up After Zui, gcle or gclh was obtained by ammonia water closed-loop However, it is difficult to control the reaction conditions If the reaction conditions are not properly controlled, the reaction is difficult to proceed smoothly, which will cause more side reactions and affect the yield There are few reaction steps and raw materials used in this method If these problems can be solved, it is a low-cost method The application of gcle and gclh is similar to that of 7-ACA and cephalosporin C they are mainly used for the synthesis of cephalosporins with 7 different side chains and 3 different substituents At present, the selling price of gcle and gclh is about $84 / T, while the selling price of 7-ACA is $102 / T using gcle and gclh to produce semi synthetic cephalosporins, such as cefazolin, cefepime, cefpirome, etc., has the advantages of high yield, simple process and low cost, so it has the potential to replace 7-ACA and cefepime C For example, cefazolin was synthesized with 7-ACA, tetrazolic acid and thiadiazole in two steps with a total yield of 68.6% The total yield of cefazolin synthesized by gcle instead of 7-ACA is 83.86%, with low cost and good quality Cefepime was prepared by the reaction of gclh with n-methyl-pyrrole and the introduction of 3-substituents, the removal of ester group and the reaction with side chain benzothiazole mercaptan active ester Conclusion: gcle and gclh are new mother nuclear intermediates for the synthesis of cephalosporins They are used to synthesize 7 different side chains and 3 different substituted methyl cephalosporins They have the advantages of high yield, low cost, good quality and so on The synthesis technology of gcle and gclh is very difficult Although there is some progress in the synthesis technology research in China, the cost is still high and the quality is still poor compared with the imported products Therefore, it is an urgent task to research and develop the synthesis technology which is simple, low cost, high quality and suitable for large-scale industrial production to replace imported products About the author: Yang Yihong (1 9 5 4 -), female, associate professor of pharmaceutical engineering, Wuhan Institute of chemical technology, engaged in the teaching and research of pharmaceutical engineering