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Market analysis of several important pharmaceutical intermediates
2019-03-27
来源：亚科官网
As an important industry in the field of fine chemicals, medicine has become the focus of development and competition in the past decade. With the advancement of science and technology, many medicines have been continuously developed for the benefit of mankind. Here are a few important pharmaceutical intermediates.
What is pharmaceutical intermediate?
Pharmaceutical intermediates are some chemical raw materials or chemical products used in the synthesis process of bulk pharmaceutical chemicals (BPC). They do not require the production license of BPC. They can be produced in ordinary chemical plants. As long as they reach some levels, they can be used for BPC synthesis. According to the degree of influence on the quality of the final drug substance, it can be divided into non-GMP intermediates and GMP intermediates. Non-GMP intermediates refer to pharmaceutical intermediates before the starting materials of BPC; GMP intermediates refer to pharmaceutical intermediates produced under the requirements of GMP (Good Manufacturing Practice), ie, a substance produced in the synthesis step that undergoes further molecular changes or purification before becoming a drug substance.
Several important pharmaceutical intermediates
1, 1-(6-methoxy-2-naphthyl)ethanol
The non-steroidal anti-inflammatory drug naproxen has a variety of synthetic methods, wherein the carbonylation synthesis route is highly selective and environmentally friendly, making the carbonylation synthesis non-steroidal anti-inflammatory drug superior to the conventional route. The key intermediate for the carbonylation synthesis of naproxen is 1-(6-methoxy-2-naphthyl)ethanol. Domestically, Hunan University uses 2-methoxynaphthalene as raw material and 1,3-dibromo-5,5-dimethylhydantoin hydrochloride as catalysis to catalyze bromoacetylation, acetylation, and palladium heterogeneous catalysis under normal pressure using. The product is finally obtained by hydrogenation reduction through an intermediate product such as 1-bromo-2-methoxynaphthalene or 5-bromo-6-methoxy-2-acetylnaphthalene.
2, 4-propylthio o-phenylenediamine
4-propylthio-o-phenylenediamine is a key intermediate for a broad-spectrum anthelmintic drug, albendazole, a new drug that was marketed in the late 1980s and is less toxic to humans and animals. Imidazole drugs are the most potent in Chinese medicine. Using o-nitroaniline as raw material, and sodium thiocyanate in the presence of methanol, thiocyanation and propyl bromide substitution to obtain 4-propylthio-2-nitroaniline, followed by reduction to obtain 4-propylthio-o-benzene diamine, since 4-propylthio-2-nitroaniline has a propylthio group structure, its reduction to 4-propylthio-o-phenylenediamine is the key. Foreign studies have used nickel or platinum-based metal catalytic hydrogenation. The technology is difficult to industrialize because the catalyst is easily poisoned or the propyl sulfide is easily destroyed; and the hydrazine hydrate is easy to be destroyed by reduction; therefore, it is most suitable for industrial production by sodium sulfide reduction method, although it will produce certain salty wastewater, but the technology is reliable. Another report on the reduction of carbon monoxide catalysts at home and abroad is reported, but there is still a distance from industrialization.
3, α-methylene cyclic ketone
α-methylene cyclic ketone is an active center of many anticancer active drugs, and its α,β-unsaturated ketone structure belongs to a concealed group of anticancer active groups, and is important for the synthesis of many important cyclic anticancer drugs intermediate. The literature reports that the synthetic route has three, 1) condensation of cycloketone and formaldehyde; 2) production of β-dialkylamine methylcycloketone by Mannich reaction, thermal decomposition of product amine or quaternary ammonium salt to produce α-methylene ring; 3) after condensation reaction of a cyclic ketone with diethyl oxalate and reacting with formaldehyde to obtain an α-methylene cyclic ketone. The Guangzhou Institute of Materia Medica of the Chinese Academy of Sciences developed the reaction of cyclopentanone, cyclohexanone and isophorone with diethyl oxalate, respectively, and the reaction product was reacted with formaldehyde to obtain the corresponding α-methylenecyclopentanone. α-methylenecyclohexanone and α-methylene isophorone and the like. The first step is to react in the presence of a solvent, and the solvent is generally selected from the group consisting of dimethyl sulfoxide and tetrahydrofuran.
4, 4,4'-dimethoxyacetoacetate methyl ester
4,4'-dimethoxyacetoacetate methyl ester is an important intermediate for the treatment of cardiovascular and cerebrovascular diseases, nilvadipine, which was developed by Fujisawa Pharmaceutical Co., Ltd., and the second generation of calcium antagonism in 1989. The agent is currently the leading drug for cardiovascular and cerebrovascular diseases in the international market, and there is no domestic production. Methyl dimethoxyacetate is synthesized from glyoxylic acid as raw material and trimethyl orthoformate in the presence of concentrated sulfuric acid. The latter is reacted with methyl acetate and sodium methoxide to obtain 4,4'-dimethoxyacetoacetate ester.
5. C3-Chlorocephalosporin
C3-chlorocephemic acid is an important cephalosporin cefaclor intermediate. Cefaclor is the second-generation high-efficiency oral cephalosporin developed by American Lilly Company. Due to its obvious curative effect and oral superiority, its sales reached more than 80 million in the United States in 2001, ranking second in antibiotics. There are two kinds of C3-chlorocephemate synthesis routes. 1) The penicillin G salt is synthesized by oxidation, esterification, ring expansion, reduction, oxidation, reduction, oxidation, deacetylation, hydrolysis, etc., and there are too many steps with low yield; 2) 7-aminocephalosporanic acid (7-ACA) as raw material, 7-ACA is highly active in the 7-position amino group and 4-position carboxyl group when undergoing 3-position nucleus reformation. First, protection is required. 4-carboxyl protection is commonly used to prepare tert-butyl ester, diphenylmethyl ester and p-nitrobenzyl ester; 7-amino protection can be phenoxymethyl, benzyl, and trimethyl, protected with a silylating agent such as chlorosilane. Then, a nucleophilic substitution and reduction reaction is carried out by first nucleophilicly replacing the ethoxy group with cephalosporanic acid by a sulphur-containing nucleophile such as ethyl xanthate, thiourea or thiol, and then hydrogenating with nickel as a catalyst. Reduction to form 3-ring exo-methylene cephalosporanic acid; then oxidation and reduction of the outer double bond, the oxidant is generally selected from ozone, the key to control the oxidation depth, commonly used reducing agents are bisulfite, dimethyl sulfide, sulfur dioxide and trimethyl phosphate; the third step is chlorination, deprotection and hydrolysis. The chlorinating agent can be selected from SOCl2, PCl3, POCl3, COCl3 or solid phosgene. It can be chlorinated, deacylated and hydrolyzed. The C3l chloroceporonic acid mother nucleus is obtained.
Related links: 3-acetyl-2,5-dimethylthiophene
Edited by Suzhou Yacoo Science Co., Ltd.
