Research status of carbamazepine

At present, there are many kinds of antiepileptic drugs, including new drugs, classic drugs, etc Although new drugs are ideal in pharmacokinetics, long-term toxicity and side effects have not been determined The most important thing is that these drugs need to be imported, the price is expensive, and the economic burden of patients is large Carbamazepine was synthesized by Ciba Geiger company of Switzerland in the 1950s, and listed in the form of tablet by Novartis company in the late 1960s Since its listing, carbamazepine has been active in the market of antiepileptic drugs with its advantages of safety, broad spectrum, and definite curative effect In addition, according to the data analysis of the World Conference on APIs, it can be seen that at the beginning of the 21st century, carbamazepine will still have a large demand, with an output value of several hundred million yuan At the same time, carbamazepine is also the key raw material for the synthesis of the new antiepileptic drug oxcarbazepine, and the demand for oxcarbamazepine in the international market is steadily increasing, which will further promote the demand growth of carbamazepine API market There are many literatures and patent reports on the synthesis of carbamazepine and its intermediates There are two methods for the synthesis of carbamazepine in the national API process collection Method 1 using o-Nitrotoluene as the starting material, 2 was obtained by one-step condensation, 2 '- dinitrobenzene, in Fe HCl - CH 3 CH 2 oh and H 3 PO 4 - CH 3 CH 2 Diaminodibenzyl phosphate was obtained by reducing dinitro in Oh system and forming salt Then it was cyclized at 300 ℃ to obtain diaminodibenzyl Under the condition of 400-500 ℃ and Fe powder as catalyst, the key intermediate of carbamazepine was obtained by dehydrogenation Finally, carbamazepine was obtained by one pot acylation and ammoniation with the yield of 11.4% The disadvantages of this process include: (1) Fe powder as reducing agent can produce a large amount of iron mud, which is difficult to deal with; (2) cyclization is carried out at high temperature, which has explosion risk, low yield and high energy consumption; (3) the solvent of acylation reaction is benzene which should be avoided by the state, which has great harm to people and the environment The reaction route is shown in Figure 1 Method 2 The technical route and method of preparing Iminodibenzyl from o-Nitrotoluene are one by one It is based on Iminodibenzyl as the starting material, and under the action of CoCl2, 5-formylchloroiminodibenzyl is obtained, then 5-chloroformyliminodistilbene is obtained by bromination at the 10th position and HBr removal, and finally carbamazepine is obtained by ammonia gas in ethanol solvent with the yield of 14.9% Compared with the synthesis method in Fig 2, the synthesis method is improved and the yield is also improved The disadvantages are: (1) phosgene is a highly toxic compound, which is harmful to chloroformylation; (2) the steps are tedious and the yield is low; (3) benzoyl peroxide is very active and has potential safety risks; (4) bromine is introduced into the reaction, which will inevitably have more or less bromine and byproducts residues, affect the quality of the product and limit the scope of use of the product The reaction route is shown in Figure 2 In the literature reported by Wang Haibo, hydrazine hydrate was used as reducing agent instead of Fe powder, FeO (OH) as catalyst instead of HCl, dinitrobenzene was reduced in 85.4% yield, and aluminum trichloride Lewis acid was used to replace phosphoric acid as ring agent to prepare iminobenzene in 72.6% yield The total yield can reach 27.9%, but hydrazine hydrate is not stable and FeO (OH) should be self-made The reaction route is shown in Figure 3 Wang Jikang et al Reduced 2,2 '- dinitrobenzene instead of Fe powder or hydrazine hydrate by catalytic hydrogenation with active nickel, which improved the reduction yield, about 99.0%, and reduced the waste discharge, environmental protection and high efficiency The total yield of other compounds is 28.6% The reaction route is shown in Figure 4 Carbamazepine was obtained by four steps using Iminodibenzyl as starting material Among them, chlorobenzene is selected as the reaction solvent, which makes the solvent from four to two, that is to save cost, reduce pollution and protect the environment In chloroformylation, triphosgene, which is relatively cheap, safe and stable, is used to replace the toxic phosgene, so as to avoid the risk of phosgene leakage The intermediate of chloroformylation, bromination, de HBr and ammoniation is not separated, and the "one pot method" is completed, which can reduce the production cycle and equipment dosage, save the cost, and the total yield is 33.6% This research has made an important contribution to the clean production of carbamazepine, and finally optimized the process to reduce the emissions of three wastes The reaction route is shown in Figure 5 Sinha a K et al Reported a relatively new method for the synthesis of carbamazepine Starting from diphenyl dicarboxylate, carbamazepine was obtained by chlorination in sulfoxide chloride, oxidation in PA, reduction in hydrazine hydrate, and finally carbamazepine was obtained by chloroformylation and ammoniation The yield was about 40.0% Because of the high price of raw and auxiliary materials, the process is not easy to obtain, and the intermediate needs to be purified by column chromatography At present, the synthesis of carbamazepine at home and abroad (including Novartis) is basically based on o-Nitrotoluene as the starting material, which is condensed to 2,2 '- dinitrobenzene in one step in three solvents, and then 2,2' - dinitrobenzene is obtained by Pd / C reduction, 2 '- diaminodibenzyl was synthesized as a salt in phosphoric acid to obtain phosphate, and then cyclized at 300 ℃ to obtain diaminodibenzene The diaminodibenzene was chloroformylated in (CoCl2) 3, and then 5-formylchloroaminostilbene was obtained by Bromination and HBr removal Finally, carbamazepine was obtained through seven steps of ammoniation At present, this process has been very mature, but we found that there are still many shortcomings in the existing process: (1) there are many kinds of raw and auxiliary materials with high cost; (2) the steps are complex and tedious; (3) there are many kinds of reaction solvents involved with heavy pollution; (4) there are potential safety hazards, explosion and other risk factors; (5) The introduction of bromine into the reaction will inevitably result in more or less residual bromine and byproducts, which will affect the quality of products and bring harm to patients' health Therefore, if we can develop a low-cost, low pollution, high stability and high-quality synthetic route of carbamazepine, it will have great social and economic benefits References [1] Ye Songlin, Duan Shidao, Wu Yingzheng, et al National API technology collection [M] Beijing: State Administration of medicine, 1980: 770-773 [2] Yin wanpo, Li Rong, Ke Lei, et al Catalytic dehydrogenation of Iminodibenzyl to iminodityl on iron oxide [J] Molecular catalysis, 2004, 18 (4): 248-251 [3] radhiam arugulati, Sanjay Singh, Asutosh Agawal, et al Catalyst and its preparation method and the application of the catalyst in the production of 5h dibenzo - (B, f) - aza [P] CN, 100453175, 2005-05-18 [4] Li Ruijiang, Zhu Zibin, Wu Yongqiang, et al Crystallization and separation method for the production of iminodistilbene by catalytic dehydrogenation of Iminodibenzyl [P] CN, 10243539, 2012-05-02 [5] Su Weike, Liang xianrui, Jiang Qilin, Et al A chemical synthesis method of iminodistilbene [P] CN, 101307021, 2008-11-19 [6] Zhou Jinping Synthesis process and quality control of Iminodibenzyl [D] Master's thesis, Hunan University, 2010 [7] Vyas KD, jafri WS, kularni a k.process for preparing carbamazepine from minostilbene [P] Us, 6245908, 2001-06-12 [8] Zoltan C, Zoltan s, ferrenc Bartha, Et al Process for the preparation of 5 - (carbamoyl) - 5 h-dibenz [b, F] Azepines [P] EP, 0423679, 1991-04-24 [9] Pu Yihua, sun Guojian, Yu Feng A carbamazepine drug and its preparation method [P] CN, 1616433, 2005-05-18 [10] Chen Hong, Wang Yingli, Liu Tongbin, et al A synthesis method of iminostachlor [P] CN, 103086969, 2013-05-08 [11] Dai Liyan, Hu Weiya Study on the synthesis of iminodistilbene participated by BTC [D] Master's thesis, Zhejiang University, 2008-06-10 [12] Wang Haibo Improvement on the synthesis method of 10,11-dihydro-5h-dibenzo [b, F] azadiazepine [J] Chinese Journal of pharmaceutical industry, 2001, 32 (1): 35-36 [13] bergmanj, sand P synthesis of indoles via ring closure of 2-alkylnitroaniline derivative [J] Tetrahedron, 1990, 46 (17) : 6085-6112 [14] Kitamura R, Kitamura e, Kitamura T, et al 2,2 '- iminobibenzyl [P] De, 210845 5, 1971-09-16 [15] H Γ kluchnikov Inorganic synthesis [M] Shanghai: Shanghai Science and Technology Literature Press, 1989, 252 [16] Wang Jikang, Wang Guilin, Yan Wei, et al Synthesis of 10,11-dihydro-5h-dibenzo [b, F] azatrex [J] Chinese Journal of pharmaceutical industry, 2002, 33(11): 525-526 [17] Caraculacu A , Bestiuc L , Popescu V , et al Process for preparingdibenzyl diamines[P] RO: 863 97 , 1985-03-15 [18] Sinha A K, Agarwal P K A new synthesis of carbamazepine [J] India J Chem, 1982, 21: 237-238 [19] Patel P M, Bhatt P V, Wadia D N, et al Rearrangement of phenyloxindoleto 5H-dibenzo[b, f] AZ pine [J] Asian J Chem, 2006, 18 (2): 1578-1580 [20] Dai Liyan, Hu Weiya, Wang Xiaozhong, et al New process for synthesis of iminodistilbene and removal of chloroformyl protecting group [J] Journal of chemical industry, 2008, 59 (9): 2419-2423