Preparation of 2-chloro-3-nitropyridine and its application background and overview in organic synthesis
2-Chloro-3-aminopyridine is a very useful pyridine derivative and an important pharmaceutical and pesticide intermediate. It can be used as a viscosity regulator, can synthesize anti-peptic ulcer drug pirenzepine, diazepine anti-AIDS drugs, leukotriene biosynthesis inhibitors, and can be used as a drug intermediate for pesticides. In addition, it and its derivatives can also be used as raw materials for food additives, ultra-efficient acylation catalysts and other substances, and can also be directly used as drugs and analytical detection reagents.
Preparation of 2-chloro-3-nitropyridine and its application in organic synthesis
At present, the preparation methods of 2-chloro-3-aminopyridine mainly include the following:
(1) Using 3-aminopyridine as raw material, a chlorination reaction occurs under the action of hydrogen peroxide and hydrochloric acid. After the reaction is completed, adjust the reaction solution to be alkaline to obtain the main product 2-chloro-3-aminopyridine And the by-product 2,5-dichloro-3-aminopyridine (Schich O.V., et al. Ber Dt Chem Ges, 1936, 69: 2593～2610). Patent CN101514185A discloses a production method of 2-chloro-3-aminopyridine. In this method, after obtaining the main product 2-chloro-3-aminopyridine, the by-product 2,5-dichloro-3-aminopyridine is Catalytic hydrogenation reduction to raw material 3-aminopyridine;
(2) Using 2-chloro-3-nitropyridine as raw material, prepare 2-chloro-3-aminopyridine by reduction of stannous chloride (Swinehart C.F., et al. US3837882, 1974);
(3) Use 2-chloronicotinamide as raw material to prepare 2-chloro-3-aminopyridine through Hofmann degradation reaction (Jose V.C., et al. ES548693, 1986);
(4) 2-chloro-3-aminopyridine is prepared by catalytic hydrogenation using 2-chloro-3-nitropyridine as raw material and Pd-Fe/TiO2 as catalyst (Li Jun. Chemistry World, 2010, 12 :748-751).
CN201110439864.X provides a method for preparing 2-chloropyridine compounds, which is easy to operate and low in cost. The chemical reaction formula of di-tert-butyl dicarbonate is:
Specific steps include the following:
①Preparation of N-alkyl-3-nitro-2-pyridone: first nitrate 2-pyridone to obtain 3-nitro-2-pyridone, and then perform N-alkylation reaction with alkyl iodide, Obtain N-alkyl-3-nitro-2-pyridone; the alkyl group is methyl or ethyl;
② Preparation of 2-chloro-3-nitropyridine: Slowly add chlorinating agent to N-alkyl-3-nitro-2-pyridine at 90℃~130℃ for chlorination reaction and dealkylation protection Reaction to obtain 2-chloro-3-nitropyridine;
③Preparation of 2-chloro-3-aminopyridine: 2-chloro-3-nitropyridine is reduced by reducing agent to obtain 2-chloro-3-aminopyridine.
Preparation of 2-chloro-3-nitropyridine and its application in organic synthesis [2-3]
Preparation of 2-chloro-3-nitropyridine and its application in organic synthesis 1. Used in the synthesis of 4-(3-iodo-2-pyridyl)piperazine compounds
4-(2-pyridyl)piperazine compounds are a new class of benzylpyridine antagonists for the study or/and synthesis of capsaicin receptor (Vanilloid receptor1, TRPVl or VR1). Key intermediates. Vanilloid receptor 1 (according to the literature (Neuropharmacology 2002, 42, 873)) is a member of the potential ion channel family of transient receptors and is an important receptor for the development of new analgesics. Research or synthesis of effective antagonists of Vanilloid receptor 1 using 4-(2-pyridyl)piperazine as the skeleton has attracted increasing attention. So far, there have been a variety of compounds based on 4-(2-pyridyl)piperazine. The active structure of the skeleton. CN200810043775.1 improves the synthetic route of 4-(3-iodo-2-pyridyl)piperazine compounds. The specific improved synthetic route is shown in the following reaction formula:
In the above route, 2-chloro-3-nitropyridine (9) is used as the starting material, and N-alkylation reaction is carried out with N-tert-butoxycarbonylpiperazine and a base in an organic solvent to obtain 1 -tert-butoxycarbonyl-4-(3-nitro-2-pyridyl) piperazine (11); under the action of a reducing agent, the nitro group in compound (11) is reduced to obtain 1-tert-butoxycarbonyl- 4-(3-Amino-2-pyridyl)piperazine (12); compound (12) undergoes diazotization and iodination reaction to obtain 1-tert-butoxycarbonyl-4-(3-iodo-2-pyridyl)piperazine Azine (8); Compound (8) is deprotected under acidic conditions to obtain 4-(3-iodo-2-pyridyl)piperazine (7). In the synthetic route of the present invention, the starting material 2-chloro-3-nitropyridine (9) has been industrially produced, is cheap, and has a wide range of sources. The yield of each step of the reaction is high, and the conditions are mild, avoiding high or low temperatures. reaction.
Preparation of 2-chloro-3-nitropyridine and its application in organic synthesis 2. Use in the preparation of 4-(5-bromo-3-fluoropyridin-2-yl)morpholine
Compounds containing pyridine rings and compounds containing morpholine rings are important raw materials in the chemical industry and are widely used in pharmaceutical intermediates, pharmaceutical products, pesticides, pesticide intermediates, feed and feed raw materials and other fields. The 4-(5-bromo-3-fluoropyridin-2-yl)morpholine molecule contains a pyridine ring and a morpholine ring, and also contains easily reactive halogen atoms, which can be added to the target molecule through chemical reactions such as coupling reactions. At the same time, pyridine ring and morpholine ring are introduced, so it is widely used in the synthesis of GPR40 receptor activators, LSD1 inhibitors, Syk inhibitors and other drugs.
CN201711140717.6 provides a new preparation process of 4-(5-bromo-3-fluoropyridin-2-yl)morpholine. It solves the problems of high raw material prices and high operating conditions requirements in the existing technology. Technical solution of the present invention: a preparation method of 4-(5-bromo-3-fluoropyridin-2-yl)morpholine, including:
(1) Using 2-chloro-3-nitropyridine as raw material, 4-(3-nitropyridin-2-yl)morpholine is generated through substitution reaction;
(2)4-(3-nitropyridin-2-yl)morpholine generates 2-morpholinopyridin-3-amine through reduction reaction;
(3) 2-morpholinopyridin-3-amine undergoes diazotization and substitution reaction to generate 4-(3-fluoropyridin-2-yl)morpholine;
(4) 4-(3-Fluoropyridin-2-yl)morpholine undergoes a substitution reaction to obtain the target compound 4-(5-bromo-3-fluoropyridin-2-yl)morpholine.
Beneficial effects of the present invention: The present invention uses 2-chloro-3-nitropyridine as the starting material and synthesizes the target compound through four-step reactions. The raw materials of this route are cheap and easy to obtain, the operating conditions are mild and easy to control, and the product is easier to purify, which is beneficial to practical application.
