Research status of H 2 receptor antagonist lafutidine

There are two main methods for the synthesis of lafutidine: using 2-amino-4-methylpyridine as the starting material, first halogenating, amino being replaced by halogen, then oxidizing, methyl being oxidized to carboxyl, carboxyl being reduced to aldehyde, and then 2-butene-1, After the etherification of 4-diol, it was chlorinated, condensed with o-phthalimide potassium salt, hydrazine hydrolyzed, and finally hydrolyzed with 2-furylmethylthio-s-oxoacetic acid p-nitrophenol ester amine to obtain lafutidine, or etherified with 2-butene-1,4-diol from 2-halo-4 - (piperidinymethyl) pyridine, After condensation with 2-furomethyl-s-oxoacetic acid p-nitrophenol ester, lafutidine was obtained Hirakawan et al Took 2-amino-4-methylpyridine as the starting material, the amino group was brominated, oxidized to acid, then reduced, aldehyde, acetaldehyde, etherified and deprotected with the single protection product of 2-butene-1,4-diol, then reacted with Gabriel, hydrazide, amidation, acetal hydrolysis, and finally condensed with piperidine to obtain lafutidine with a total yield of 3% This reaction route is long In addition to the two steps of protection and deprotection, it also goes through two steps of oxidation and reduction The steps are complicated and the reaction yield is relatively low The reaction route is shown in Figure 1: Tao Feng et al Used toluene instead of benzene, which was less toxic, as the acetalation solvent, and directly reacted with 4 - (tetrahydropyran-2-oxy) - (2Z) - butene-1-ol without separation, with a yield of 80.9% Three steps of deprotection, Gabriel reaction and hydrazinolysis were reversely applied to complete the "one pot method", and DMF was used as the solvent to simplify the process, with the yield increased from 41.2% to 69.9% The total yield after improvement is 6.8%, but in addition to the two steps of protection and deprotection, the reaction steps of oxidation and reduction also need to be carried out, and the by-products will be generated in the oxidation-reduction step, which will affect the yield of the next step The roadmap is shown in Figure 2: Yang Xuhua et al Brominated, oxidized and reduced with 2-amino-4-methylpyridine, Then 2-bromo-4 - (piperidinyl) pyridine was synthesized by reacting with p-toluenesulfonyl chloride, ester and piperidine, and then 2 - [4 - (2-oxtetrahydropyranyl) - cis-2-butene-1-oxy] - 4 - (1-piperidinyl) pyridine was obtained by etherification with 4 - (2-oxtetrahydropyranyl) - cis-2-butene-1-oxy] - 4 - (1-piperidinyl) pyridine The total yield was 13% Although this reaction route has greatly improved the reaction yield, it still includes two reaction steps: oxidation and reduction, which can not effectively avoid the generation of by-products, and the process can still be improved The reaction route is shown in Figure 3 Huang Xianfeng et al Prepared 2-Chloro-4 - (chloromethyl) pyridine from 2-amino-4-methylpyridine through two-step chlorination and reaction with sulfonyl chloride under the action of AIBN, then condensed with piperidine in DMF to obtain 2-Chloro-4 - (piperidine-1-ylmethyl) pyridine, the key intermediate of lafutidine, and then with 2-butene-1, Etherification, THP removal, Gabriel reaction, hydrazinolysis of the single protective product of 4-diol, followed by acylation to produce H 2 This reaction route can effectively avoid the occurrence of the by-products of the reaction, and the subsequent reaction can be carried out smoothly without complicated separation and purification steps Moreover, the reaction steps are reduced, the total yield of the reaction is effectively increased to 23.2%, and the synthesis cost is reduced The route is shown in Figure 4 References: [1] Fukushima y, Otsuka h, is hikawa m, et al Potent and long-lasting action of lafutidine on the human hist amine H 2 - receiver [J] Digest, 2001, 64 (3): 155-160 [2] Ishiia, Nishimura y, Kondo h, Et al Preparationof n - [(pyridyloxy) alkyl] - or N - [(pyridyloxy) alkenyl] - 2 - (furfurfurylselfinyl) acetamidesas histamine H 2 receptor antagonists [P] JP: 5059045, 1993-03-09 (CA 1993, 119:139114) [3] Wen Ren Pharmaceutical synthetic chemistry [M] Beijing: Chemical Industry Press, 1988, 74-77 [4] Ishii a, Nishimura y, Kondo h, et al Phthalimide compounds andmethods of producing same[P] US: 5382589 [5].Hirskawa N, Kashiwaba N Intermediates for pyridyloxy compoundshaving ulitity as anti- pepticulcer agents[P] US: 4977267, 1990-12-11 [6].Hirskawa N, Kashiwaba N 4-Aminomethyl-pyridyl-2-oxyderivatives having antiulcer activity [P] US: 4912101, 1990-03-27 [7] Ikswa h, Matsumoto h methods of producing aminobetanederivatives [P] Us: 5616711, 1997-04-01 [8] Preparation of Nishimura Taixin, Xiangchuan Guanghao, furan methyl sulphonyl acetic acid (p-nitro) phenol ester [P] JP: 7010862, 1995-01-13 [9] Kokubunji n h, KAW as AKI N K, Hino h m, etal.4-Aminomethylpyridyl-2-oxyderivatives having antiulceractivity[P] US: 4912101, 1990-03-27 [10].Hirakawa N, Kashiwaka H, Mats umoto H, et al Preparation ofN-[pyridyloxy-butenyl]- (furfurylthio) acet amides and analogs as ulcerinhibi-tors[P] EP: 282077, 1988-09-14 [11].Ikawa H, Matsumoto H, Matsumoto M, etal Method of producingamino butene derivatives[P].  EP: 582304, 1993-08-05 [12].Hirakawa N, Matsumoto H, Hosoda A, et al A novel hista-mine (H 2 ) receptor antagonist withgastroprotective activityⅡ.Synthesis and pharmacological evaluation of2-furfurylthio and 2-furfurylsulfinyl acetamide derivatives with heteroaromaticrings[J] ChemPharm Bull, 1998, 46 (4): 616-622 [13] Tao Feng Synthesis of lafutidine [J] Chinese Journal of pharmaceutical industry, 2004, 35 (7): 393-395 [14] Yang Xuhua, Zhang Xiaofeng, AI Haima Improvement of the synthesis process of lafutidine [J] Journal of Jiangxi Normal University, 2007, 31 (5): 538-540 [15] Huang Xianfeng, song Guoqiang, he Qilong, etc synthesis process of cis-1,4-butenediol pyranosyl monoprotective product: China, Cn201110333367.1 [P] 2012-7-11 [16] Huang Xianfeng, song Guoqiang, he Qilong, etc synthesis method of 2-Chloro-4 - (piperidinymethyl) pyridine: China, cn201110297032.9 [P] 2012-1-4